CANCER AND IMPORTANT MEDICAL NEWS

CHEMOTHERAPY IS AN IMPORTANT COMPONENT OF HEAD AND NECK CANCER TREATMENT

2012-01-29T20:00:00.000+02:00

Lancet Oncol. 2012 Jan 17. [Epub ahead of print]

Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial.

Bourhis J, Sire C, Graff P, Grégoire V, Maingon P, Calais G, Gery B, Martin L, Alfonsi M, Desprez P, Pignon T, Bardet E, Rives M, Geoffrois L, Daly-Schveitzer N, Sen S, Tuchais C, Dupuis O, Guerif S, Lapeyre M, Favrel V, Hamoir M, Lusinchi A, Temam S, Pinna A, Tao YG, Blanchard P, Aupérin A.

Source

Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France.

Abstract

BACKGROUND:

Concomitant chemoradiotherapy and accelerated radiotherapy independently improve outcomes for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC). We aimed to assess the efficacy and safety of a combination of these approaches.

METHODS:

In our open-label phase 3 randomised trial, we enrolled patients with locally advanced, stage III and IV (non-metastatic) HNSCC and an Eastern Cooperative Oncology Group performance status of 0-2. We randomly allocated patients centrally with a computer program (with centre, T stage, N stage, and localisation as minimisation factors) in a 1:1:1 ratio to receive conventional chemoradiotherapy (70 Gy in 7 weeks plus three cycles of 4 days' concomitant carboplatin-fluorouracil), accelerated radiotherapy-chemotherapy (70 Gy in 6 weeks plus two cycles of 5 days' concomitant carboplatin-fluorouracil), or very accelerated radiotherapy alone (64·8 Gy [1·8 Gy twice daily] in 3·5 weeks). The primary endpoint, progression-free survival (PFS), was assessed in all enrolled patients. This trial is completed. The trial is registered with ClinicalTrials.gov, number NCT00828386.

FINDINGS:

Between Feb 29, 2000, and May 9, 2007, we randomly allocated 279 patients to receive conventional chemoradiotherapy, 280 to accelerated radiotherapy-chemotherapy, and 281 to very accelerated radiotherapy. Median follow-up was 5·2 years (IQR 4·9-6·2); rates of chemotherapy and radiotherapy compliance were good in all groups. Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy (HR 1·02, 95% CI 0·84-1·23; p=0·88) or very accelerated radiotherapy (0·83, 0·69-1·01; p=0·060); conventional chemoradiotherapy improved PFS compared with very accelerated radiotherapy (0·82, 0·67-0·99; p=0·041). 3-year PFS was 37·6% (95% CI 32·1-43·4) after conventional chemoradiotherapy, 34·1% (28·7-39·8) after accelerated radiotherapy-chemotherapy, and 32·2% (27·0-37·9) after very accelerated radiotherapy. More patients in the very accelerated radiotherapy group had RTOG grade 3-4 acute mucosal toxicity (226 [84%] of 268 patients) compared with accelerated radiotherapy-chemotherapy (205 [76%] of 271 patients) or conventional chemoradiotherapy (180 [69%] of 262; p=0·0001). 158 (60%) of 265 patients in the conventional chemoradiotherapy group, 176 (64%) of 276 patients in the accelerated radiotherapy-chemotherapy group, and 190 (70%) of 272 patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment (p=0·045).

INTERPRETATION:

Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy cannot compensate for the absence of chemotherapy. We noted the most favourable outcomes for conventional chemoradiotherapy, suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules.

DRUG LEVEL MONITORING OF IMATINIB MAY BE BENEFICIAL

2012-01-29T19:59:00.000+02:00

Ther Drug Monit. 2012 Feb;34(1):85-97.

The role of therapeutic drug monitoring of imatinib in patients with chronic myeloid leukemia and metastatic or unresectable gastrointestinal stromal tumors.

Teng JF, Mabasa VH, Ensom MH.

Source

From the *Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver; †Department of Pharmacy, Burnaby General Hospital, Burnaby; and ‡Department of Pharmacy, Children's and Women's Health Centre of British Columbia, Vancouver, Canada.

Abstract

Imatinib mesylate is a tyrosine kinase inhibitor used as first-line treatment in Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) and metastatic or unresectable gastrointestinal stromal tumors (GIST). Therapeutic drug monitoring (TDM) for imatinib has been suggested to improve efficacy, assess compliance, and evaluate drug-drug interactions. Imatinib has proven efficacy in improving treatment response and survival in patients with Ph+ CML and GIST. Several analytical methods are available to quantify total plasma imatinib concentrations. A good relationship exists between total imatinib plasma concentrations and pharmacologic response. Clinical evaluation of pharmacologic response to imatinib alone may be insufficient given the long duration of therapy before clinical response in patients with Ph+ CML and GIST. Thus, the authors have used a previously published 9-step decision-making algorithm to evaluate the utility of TDM for imatinib. The suggested trough concentrations for improved complete cytogenetic or major molecular response in patients with Ph+ CML and improved time to progression for patients with GIST are >1000 and >1100 ng/mL, respectively. Imatinib exhibits interindividual pharmacokinetic variability. Increased apparent clearance of imatinib has been observed in chronic phase chronic myeloid leukemia and increased body weight. Decreased apparent clearance has been observed in renal impairment and patients on concomitant medications with potent inhibition of cytochrome P450 3A4. Duration of therapy in patients with Ph+ CML and GIST is lifelong. Based on the available evidence, TDM for imatinib may provide additional information on efficacy, compliance, and safety than clinical evaluation alone. Patients with suboptimal response to treatment, treatment failure, rare adverse events, drug interactions, or suspected nonadherence will attain the greatest benefit from TDM.

WOMEN WITH NSCLC LIVE LONGER THAN MEN

2012-01-29T19:58:00.002+02:00

Lung Cancer. 2012 Jan 20. [Epub ahead of print]

Differential effect of age on survival in advanced NSCLC in women versus men: Analysis of recent Eastern Cooperative Oncology Group (ECOG) studies, with and without bevacizumab.

Wakelee HA, Dahlberg SE, Brahmer JR, Schiller JH, Perry MC, Langer CJ, Sandler AB, Belani CP, Johnson DH; Eastern Cooperative Oncology Group.

Source

Department of Medicine/Division of Oncology, Stanford University, Stanford, CA, United States.

Abstract

BACKGROUND:

The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex.

PATIENTS AND METHODS:

Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel±bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of <60 or ≥60 years old. Eligible E4599 patients (N=850) were similarly separated by age and sex and by treatment (±bevacizumab). Survival was calculated separately for each cohort.

RESULTS:

The median survival time (MST) for women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women <60 (p=0.03). MST was 7.4 and 8.3 months for men ≥60 and <60 years old respectively (NS). In E4599 the age <60 by bevacizumab treatment interaction was statistically significant (p=0.03) for women (younger had greater benefit), with no age effect in men.

CONCLUSIONS:

In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599.

AN ANTICIPATED CHEMOTHERAPY INTENSIFICATION FAILURE IN TESTICULAR CANCER

2012-01-29T19:57:00.002+02:00

J Clin Oncol. 2012 Jan 23. [Epub ahead of print]

Randomized Phase III Study Comparing Paclitaxel-Bleomycin, Etoposide, and Cisplatin (BEP) to Standard BEP in Intermediate-Prognosis Germ-Cell Cancer: Intergroup Study EORTC 30983.

de Wit R, Skoneczna I, Daugaard G, De Santis M, Garin A, Aass N, Witjes AJ, Albers P, White JD, Germa-Lluch JR, Marreaud S, Collette L.

Source

Ronald de Wit, Erasmus University Medical Center and Daniel den Hoed Cancer Center, Rotterdam; Alfred J. Witjes, Radboud University Hospital, Nijmegen, the Netherlands; Iwona Skoneczna, Marie Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland; Gedske Daugaard, Rigshospital, Copenhagen, Denmark; Maria De Santis, Ludwig Boltzmann-Institute for Applied Cancer Research Vienna and Applied Cancer Research-Institution for Translational Research Vienna/Kaiser Franz Josef-Spital, Vienna, Austria; August Garin, Cancer Research Center, Moscow, Russia; Nina Aass, Oslo University Hospital and University of Oslo, Oslo, Norway; Peter Albers, Heinrich-Heine-University, Dusseldorf, Germany; Jeffery D. White, Glasgow-Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; José R. Germa-Lluch, Bellvitge Institute for Biomedical Research, Institut Catala d'Oncologia, Barcelona, Spain; and Sandrine Marreaud and Laurence Collette, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.

Abstract

PURPOSETo compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC). PATIENTS AND METHODSPatients were randomly assigned to receive either T-BEP or standard BEP. Patients assigned to the T-BEP group received paclitaxel 175 mg/m(2) in a 3-hour infusion. Patients who were administered T-BEP received primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. The study was designed as a randomized open-label phase II/III study. To show a 10% improvement in 3-year progression-free survival (PFS), the study aimed to recruit 498 patients but closed with 337 patients as a result of slow accrual. RESULTS: 0.37 to 0.97) and was statistically significant (P = 0.03). Overall survival was not statistically different. CONCLUSIONT-BEP administered with G-CSF seems to be a safe and effective treatment regimen for patients with intermediate-prognosis GCC. However, the study recruited a smaller-than-planned number of patients and included 7.7% ineligible patients. The primary analysis of the trial could not demonstrate statistical superiority of T-BEP for PFS. When ineligible patients were excluded, the analysis of all eligible patients demonstrated a 12% superior 3-year PFS with T-BEP, which was statistically significant.

MELANOMA PATIENTS LUNG LESIONS NOT ALWAYS MELANOMA

2012-01-29T19:56:00.002+02:00

January 25, 2012 — Melanoma frequently metastasizes to the lungs. However, a study that investigated suspicious lung nodules in patients with metastatic melanoma found that nearly one third had nonmelanoma pathology.
The findings, from 229 patients with metastatic melanoma treated at the Memorial Sloan-Kettering Cancer Center in New York City, were published online last year in the Annals of Oncology.
The "initially surprising high incidence of nonmelanoma pathology at biopsy" reported in this study reinforces an important message, write Mark Middleton, MD, and colleagues from the Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom, in an editorial published online December 26, 2011, in the same journal.
"It tells us that it is not safe to assume that lung lesions found at presentation or during follow-up for melanoma represent disease relapse," they write. "The message has to be: if in doubt — biopsy."
Standard of Care
The biopsy allows pathologists to differentiate lung cancers that represent a metastasis and those that are primary.
"Histological confirmation of metastases is the standard of care at our institution," write the researchers from Memorial Sloan-Kettering Cancer Center. They note that the National Comprehensive Cancer Network guidelines recommend that initial clinical recurrence should be confirmed pathologically by biopsy wherever possible.
In their study, 229 patients with metastatic melanoma had a biopsy of a suspicious new lung lesion from 1996 to 2006. In this group, 12% of the lesions were benign on biopsy, and although the majority (88%) of lesions were malignant, only 69% were melanoma.
Among those found to have nonmelanoma pathology were 14% of patients who had a new potentially curable primary lung cancer, underscoring the need to make an accurate diagnosis, they write.
"In clinical situations in which one would expect a diagnosis of melanoma, another diagnosis was made in 31% of cases," the authors note.
"It is not only crucial to distinguish between benign and malignant disease, but also necessary to establish a definitive histological diagnosis before initiation of therapy," they add.
Problem for Oncologists
"The management of pulmonary nodules detected in patients followed-up after a diagnosis of melanoma presents a particular problem for oncologists," the editorialists note.
It can make a big difference to patient survival. They note that patients who have a complete resection of pulmonary metastases achieve a 5-year survival rate of 21% to 22%, but this falls to 0% to 13% in patients who have an incomplete resection, and to less than 10% in patients who receive medical therapy.
In addition, the authors note that 5-year survival as high as 39% has been reported in patients with solitary pulmonary lesions who underwent pulmonary metastasectomy.
"Our study highlights the importance of tissue diagnosis before decision making regarding treatment for these patients," the authors conclude.
The authors have disclosed no relevant financial relationships.
Ann Oncol. Published online August 4, 2011, and December 26, 2011. Abstract, Editorial

ONCOTYPE FOR STAGE I NSCLC?

2012-01-29T19:56:00.000+02:00

January 27, 2012 — A new assay that tests 14 genes can clarify the prognosis of patients who are diagnosed with early-stage nonsmall-cell lung cancer (NSCLC), and is more accurate than relying on clinical criteria, researchers report in a paper published online today in the Lancet.
The assay identifies patients with early-stage NSCLC who are at low, intermediate, and high risk for death within 5 years. This information can be used to decide on additional treatment, according to the researchers, headed by Michael Mann, MD, and David Jablons, MD, from the thoracic surgery division at the University of California, San Francisco (UCSF). The test is already available commercially as the Pinpoint Dx Lung Assay (Pinpoint Genomics Inc).
Although there have been studies of several different assays of this type in the past, they were all small. This one stands "head and shoulders above everything else" and is ready for "prime time" clinical use, according to John Minna, MD, professor of molecular pulmonology oncology at the University of Texas (UT) Southwestern Medical Center in Dallas.
In an editorial that will appear in a future print issue of the Lancet, Dr. Minna and Yang Xie, PhD, who is assistant professor of clinical sciences at the UT Southwestern Medical Center, write that this assay is "ready for widespread clinical testing."
Assay is Prognostic
This assay is prognostic; it can help clinicians clarify the prognosis of patients with early-stage NSCLC, Dr. Minna explained in an interview. The initial validation study was conducted in patients with stage I NSCLC; further validation studies were conducted in patients with stage I, II, or III NSCLC.
Many of these patients with early-stage NSCLC are treated with surgery alone, he said. For stage I NSCLC, the use of chemotherapy after surgery remains controversial; studies have not shown a clear benefit and the treatment is associated with adverse effects and an increase in cost.
With many solid tumors, the expectation is that if you catch it early, resection should be curative, Dr. Minna explained. But in the case of lung cancer, unlike many other cancers, survival is rather poor — only about 50% to 60%, he noted.
"This happens because even if the resected tumor is small, in many cases the cells have already metastasized to other sites," he continued. There is no way to identify when this happened, he pointed out. "If you look under the microscope, you won't see anything."
In such situations, the assay can be helpful. By identifying gene-expression patterns associated with a low, medium, and high risk for death, the assay can identify patients whose early-stage lung cancer has already likely metastasized and who can benefit from additional therapy such as chemotherapy, he explained.
The theory underlying this research, Dr. Minna said, is that tumors that are more aggressive and are likely to have already metastasized will have a different gene-expression pattern than tumors that are localized. This is why the study showed that certain gene-expression patterns were highly correlated with different degrees of risk for death. However, whether the 14 genes in this assay are actually involved in driving the tumor is unclear, he added.
The research on driver-gene mutations in lung cancer, which has resulted in specific tests for gene mutations that are predictive assays — such as the test for EGFR mutations that predicts response to erlotinib and that for the ALK fusion that predicts response to crizotinib — does not apply in this situation. Those are predictive assays, whereas the new assay is prognostic, he explained.
In the real word, he can envision the 2 types of assays being used alongside one another. The 2 tests could be conducted on the same piece of lung tissue removed at the time of surgery. In fact, this is one of the advantages of the new assay, Dr. Minna noted: It is carried out on paraffin-embedded specimens, whereas previous prognostic assays have needed frozen tissue samples, which can cause practical problems.
Testing the New Assay
The assay was developed by UCSF researchers, and then licensed to and developed further at Pinpoint Genomics (based in Mountain View, California). It tests for 11 cancer-related target genes (BAG1, BRCA1, CDC6, CDK2API, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR, WNT3A) and 3 reference genes (ESD, TBP, YAP1).
The initial test was conducted at UCSF in 361 patients with nonsquamous NSCLC. In the cohort, 66% had stage I disease, 12% had stage II disease, 17% had stage III disease, and 3% had stage IV disease. For 2%, disease stage was undetermined.
The first validation study was conducted independently on a masked cohort of 433 patients, all with stage I NSCLC, at several community Kaiser Permanente Northern California hospitals. The assay predicted that 5-year overall survival would be achieved by 71% of patients identified as being at low risk, 58% identified as being at intermediate risk, and 49% identified as being at high risk.
The second validation study was conducted at several leading Chinese cancer centers that are part of the China Clinical Trials Consortium. Of the 1006 patients with NSCLC, 47% had stage I disease, 22% had stage II disease, and 26% had stage III disease; disease stage was undetermined in only 1%. The assay predicted that 5-year overall survival would be achieved by 74% identified as being at low risk, 57% identified as being at intermediate risk, and 45% identified as being at high risk. These figures are nearly identical to those obtained in the first validation study.
The assay performed better than standard criteria, such as sex, age, tumor size, and even disease stage, the researchers note. It even outperformed National Comprehensive Cancer Network guidelines to identify high-risk patients with stage I disease, they add.
"This assay provides prognostic differentiation of patients with early-stage disease and might be helpful in the identification of the most appropriate application of treatment guidelines to improve clinical outcomes," the authors conclude.
Next Step: Clinical Trial
The next step the researchers are planning is a prospective clinical trial in patients identified as being at high risk; they will be randomized to either observation or chemotherapy. This trial will "directly test the effectiveness of the application of guidelines for adjuvant treatment on the basis of this molecular enhancement of risk stratification in patients with stage I disease," they explain.
However, the results will not be available for some time — the accrual alone for this trial will take 5 to 7 years and there will be additional years for follow-up, they note.
In the meantime, the authors suggest that this new assay "might provide additional, validated prognostic information to clinicians as they consider therapeutic choices that may improve outcomes for their patients."
Several of the authors report a consulting relationship with Pinpoint Genomics Inc. Both editorialists report being involved in a patent application for a lung cancer prognosis signature based on nuclear hormone receptors.
Lancet. Published online January 27, 2012. Abstract

MEDICAL TESTING WITH SMARTPHONES?

2012-01-29T19:55:00.001+02:00

SEOUL (Reuters) Jan 23 - If Korean researchers have their way, smartphones of the future might be able to perform medical tests -- and perhaps even diagnose cancer.
A team of scientists at Korea Advanced Institute of Science of Technology (KAIST) said in a paper published January 6 in Angewandte Chemie, a German science journal, that touch screen technology can be used to detect biomolecular matter, much as is done in medical tests.
"It began from the idea that touch screens work by recognizing the electronic signs from the touch of the finger, and so the presence of specific proteins and DNA should be recognizable as well," said Professor Hyun-gyu Park, who led the study together with Dr. Byong-yeon Won.
The touch screens on smartphones, PDAs or other electronic devices work by sensing the electronic charges from the user's body on the screen. Biochemicals such as proteins and DNA molecules also carry specific electronic charges.
According to data from KAIST, touch screens can recognize the existence and the concentration of DNA molecules placed on them, a first step toward one day being able to use the screens to carry out medical tests.
"We have confirmed that (touch screens) are able to recognize DNA molecules with nearly 100% accuracy just as large, conventional medical equipment can and we believe equal results are possible for proteins," Prof. Park told Reuters TV.
"There are proteins known in the medical world like the ones used to diagnose liver cancer, and we would be able to see the liver condition of the patient."
The research team added that it is currently developing a type of film with reactive materials that can identify specific biochemicals, hoping this will allow the touch screens to also recognize different biomolecular materials.
But confirming that the touch screen can recognize the biomolecular materials, though key, is only the first step.
Since nobody would put blood or urine on a touch screen, the sample would be placed on a strip, which would then be fed into the phone or a module attached to the phone through what Prof. Park called an "entrance point."
"The location and concentration of the sample would be recognized the same way the touch of the finger is recognized," he added.
There are no details yet on a prospective timetable for making the phone a diagnostic tool, however.
SOURCE: http://bit.ly/tuxZ6V
Angewandte Chemie 2012.

OXALIPLATIN REAL-WORLD RESULTS

2012-01-29T19:54:00.002+02:00

January 25, 2012 — The addition of oxaliplatin to adjuvant 5-fluorouracil in patients with stage III colon cancer is just as effective at improving survival in real-world community settings as it is in randomized clinical trials (RCTs), according to the results of a study published online January 20 in the Journal of the National Cancer Institute.
"This is confirmation that the drug is really of benefit," Hanna K. Sanoff, MD, from the University of Virginia, Charlottesville, and the study's lead author, told Medscape Medical News.
"It's good news," she continued. "Even if things aren't done perfectly, like they are in clinical trials, we seem to still be helping patients in the real world get cured of their colon cancer. That's the good message to take from this study."
The effectiveness of oxaliplatin has been proven in RCTs, but the patients in such trials are younger, healthier, and less racially diverse than in the general cancer population. Overall, less than 2% of patients with stage III colon cancer are enrolled in RCTs.
To assess outcomes in the general population, Dr. Sanoff and her colleagues gathered data from 5 observational data sources: the Surveillance, Epidemiology, and End Results registry linked to Medicare claims (SEER–Medicare); the New York State Cancer Registry (NYSCR) linked to Medicaid claims; the NYSCR linked to Medicare claims; the National Comprehensive Cancer Network (NCCN) Outcomes Database; and the Cancer Care Outcomes Research & Surveillance Consortium (CanCORS).
All patients had stage III colon cancer, received chemotherapy within 120 days of surgery, and were 75 years or younger.
"There are a few different ways to look at real-world outcomes, and one is not necessarily better than another. In fact, there's no good way in the United States to do a global, whole-country assessment. One of the reasons we did it like this, with all these different groups, was to try to get a better sense of how these diverse groups might have differed," she said.
"If you look at Medicaid patients, who are probably different than Medicare patients, and patients treated at great cancer centers, which is what the NCCN is, and you look at people in CanCORS, which has VA patients and a couple of HMOs, [it makes] a pretty diverse group. We wanted to try to get as broad a look as we could," Dr. Sanoff explained.
Next, the researchers compared overall survival between patients treated with oxaliplatin and those treated with nonoxaliplatin adjuvant chemotherapy in the community databases and in 5 RCTs in the Adjuvant Colon Cancer Endpoints (ACCENT) group.
"We used the data from 5 different trials — X-ACT, PETACC-3, MOSAIC, C-07, and C89803 — and used that as our gold standard," Dr. Sanoff explained.
The 3-year overall survival among the 1273 patients in the pooled RCTs was 86%. There was a 4% absolute and a 20% relative improvement in survival, compared with nonoxaliplatin-treated patients (adjusted hazard ratio of death, 0.80; 95% confidence interval, 0.70 to 0.92; P = .002).
Survival was "remarkably" similar in community-treated patients.
In the patients in the SEER–Medicare group (n = 1152), 3-year overall survival was 80%; in the CanCORS group (n = 129), it was 88%; in the NYSCR–Medicaid group (n = 54), it was 82%; in the NYSCR–Medicare group (n = 180), it was 79%; and in the NCCN group (n = 438), it was 86%.
The survival advantage was maintained in older, sicker, and minority patients.
Study Allays Concerns
Commenting on this study for Medscape Medical News, Alok A. Khorana, MBBS, from the University of Rochester School of Medicine and Dentistry in New York, affirmed the study's conclusion.
"Oxaliplatin-based combination therapy is generally accepted to be the standard of care for adjuvant treatment in the stage III setting, based on large multiple RCTs; however concerns have been raised that the real-world population differs substantially from patients enrolled in clinical trials. In particular, patients with comorbidities, older patients, and minorities are often underrepresented," he said.
This study of real-world outcomes demonstrates that oxaliplatin is associated with better outcomes in the community setting, "and thus does much to allay these concerns," he said.
Dr. Khorana pointed out that although this was an outcomes study, the patients were not randomly assigned to oxaliplatin; therefore, the study does not have the same level of evidence as an RCT. "But it is indeed consistent with the data from RCTs," he said.
Dr. Sanoff has disclosed no relevant financial relationships. Dr. Khorana reports receiving honoraria/consulting fees from sanofi-aventis, the maker of oxaliplatin.
J Natl Cancer Inst. Published online January 20, 2012. Abstract

S.C DOSING OF VELCADE APPROVED

2012-01-29T19:53:00.003+02:00

(Reuters) Jan 23 - Takeda said U.S. health regulators gave approval to market subcutaneous shots of its cancer drug Velcade (bortezomib).
Velcade, which is already approved as a treatment for multiple myeloma and mantle cell lymphoma, has so far been approved to be given as intravenous shots.
The new approval was based on results from a randomized phase 3 non-inferiority trial conducted in 222 bortezomib-naive patients with relapsed multiple myeloma.
In a press release issued by Takeda, Dr. Noopur Raje, director of the Center for Multiple Myeloma at Massachusetts General Hospital Cancer Center, said
"Considering this new subcutaneous route of administration for VELCADE is important for our patients, including those with poor vein access and those with pre-existing peripheral neuropathy or a high risk of developing peripheral neuropathy."
The updated label also includes a contraindication for intrathecal administration as fatal events have occurred with the inadvertent intrathecal administration of Velcade.

CONTAMINATED MEDICINES IN PACISTAN-WHAT ABOUT GREECE?

2012-01-29T19:53:00.000+02:00

LAHORE, Pakistan (Reuters) Jan 24 - The government in Pakistan's Punjab province is scrambling to recall contaminated drugs that have killed at least 27 people over the last month, provincial health officials said on Tuesday.
Thousands of doses of the faulty medicines were freely provided to patients with heart problems at the government-run Punjab Institute of Cardiology in the eastern city of Lahore.
"We are trying to retrieve all the medicines given out at this hospital," said Jehanzeb Khan, the Punjab health secretary. Thousands of prescriptions were handed out at the facility in the last month, hospital officials said.
Investigators suspect bits of metal in the pills are responsible for the symptoms, which include heavy bleeding.
Over 100 people have been admitted to hospitals in Lahore because of symptoms caused by the faulty medicines.
Sources at the Punjab health department told Reuters that the death toll from the medicines is much higher than the official count.
The government has banned five drugs believed to be contaminated, and police have arrested three people in connection with the deaths.
At least one pharmaceutical factory, not named by police, has been sealed.
The provincial government formed a committee to probe the deaths. Faisal Masood, a member of the committee, said the deaths began last month.
"Patients were coming in with symptoms similar to dengue fever. But then we realized it wasn't that," he said.
"The one thing common in all patients was heart disease, and that they were getting medicines from the Punjab Institute of Cardiology."
Pakistan's cash-strapped government, accused of ineptitude and corruption, spends little on health and many Pakistanis have little faith in state-run medical centers.

NEOADJUVANT BEVACIZUMAB IN BREAST CANCER IMPROVES pCR BY THE UNIMPRESSIVE RATE OF 4%

2012-01-29T19:52:00.000+02:00

January 25, 2012 — Just months after the US Food and Drug Administration (FDA) revoked the metastatic breast cancer indication for bevacizumab (Avastin, Roche/Genentech), new data show a benefit from this drug in nonmetastatic disease in a neoadjuvant setting.
Two large studies, published in the January 25 issue of the New England Journal of Medicine, demonstrate that the addition of bevacizumab to docetaxel-based chemotherapy regimens significantly improves the rate of pathological complete response before surgery in women with nonmetastatic HER2-negative breast cancer.
In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial, conducted in the United States, the neoadjuvant addition of bevacizumab to a variety of chemotherapy regimens significantly increased the rate of pathological complete response, compared with no bevacizumab (34.5% vs 28.2%; P = .02); patients received the targeted therapy for the first 6 cycles of chemotherapy.
In the GeparQuinto (GBG44) trial, conducted in Germany, the rates of pathological complete response were also better with than without bevacizumab in patients undergoing 2 different chemotherapy regimens (18.4% vs 14.9%; odds ratio with bevacizumab, 1.29; 95% confidence interval, 1.02 to 1.65; P = .04); all patients received 8 cycles of bevacizumab.
The primary end point in both studies was pathological complete response. However, the GBG44 trial used a more stringent definition and had more patients with more advanced disease, which resulted in fewer patients achieving the end point.trials do not resolve existing controversies.
These results stir up old concerns, suggests an editorial accompanying the study. "These 2 well-performed trials do not resolve existing controversies surrounding bevacizumab therapy," write Alberto J. Montero, MD, and Charles Vogel, MD, from the division of hematology/oncology at the University of Miami Sylvester Comprehensive Cancer Center in Florida.
In brief, those controversies are about the "ever-increasing cost" of new cancer treatments and the predictive value of surrogate markers. What remains unclear is whether bevacizumab will ever ultimately be shown to improve survival in breast cancer.
In the metastatic setting, the improvement in progression-free survival with the use of bevacizumab never panned out in terms of overall survival, which precipitated the recent FDA decision.
Now, in the neoadjuvant setting, the surrogate marker in question is an even earlier measure than progression-free survival — pathological complete response.
But the German investigators are quite hopeful that the results from their 1948-patient study will eventually translate into a survival benefit.
"Given that pathological complete response has been shown to be highly correlated with outcome, particularly in patients with triple-negative disease, we speculate that the beneficial effect will be sustained," write the authors, led by Gunter von Minckwitz, MD, from the German Breast Group in Neu-Isenburg. They were referring to their finding that the rates of pathological complete response were 27.9% without bevacizumab and 39.3% with bevacizumab in a subset of 663 patients with triple-negative tumors (P = .003).
The Americans are more sanguine about any would-be survival benefit in their 1206-patient trial.
"The effect of adding bevacizumab in the NSABP B-40 trial was less dramatic than was the effect of adding docetaxel in the NSABP B-27 trial, so it is not clear whether the neoadjuvant effect of bevacizumab would translate into a substantial benefit to patients," write the authors, led by Harry Bear, MD, from Virginia Commonwealth University in Richmond. Notably, unlike the GBG44 trial, the NSABP B-40 trial did not find that patients with triple-negative disease received a significant benefit from the addition of bevacizumab; however, there was a trend, Dr. Bear and colleagues report.
Even if a survival benefit is eventually found in these trials, Drs. Montero and Vogel express concern in their editorial that the whole enterprise of targeted therapies for cancer is too costly.
"In the context of unsustainable expenditures for cancer care in the United States, any survival benefit of bevacizumab, or other molecularly targeted drugs, will be balanced against the considerable development costs of modern molecularly targeted oncology drugs," they write.
The addition of bevacizumab also increased the rates of a variety of adverse events in both trials. In the NSABP B-40 trial, those events included hypertension, left ventricular systolic dysfunction, the hand–foot syndrome, and mucositis.
Definition of Response Is Critical
It is important to examine and understand the different end points used in the 2 trials, explain Drs. Montero and Vogel in their editorial.
In the German GBG44 trial, pathological complete response was defined as the absence of residual tumor in the breast and nodes. In the American NSABP B-40 trial, the less stringent definition of the absence of residual tumor in the breast was used.
In the GBG44 study, the overall rate of pathological complete response with the addition of bevacizumab was 3.5 percentage points higher than the rate without bevacizumab.
In the NSABP B-40 study, the rate with bevacizumab was 6.3 percentage points higher than the rate without bevacizumab. But, if the GBG44 definition of pathological complete response is applied to the NSABP B-40 results, the affect largely disappears, note the editorialists.
"When the more stringent definition of pathological complete response was used, the differences noted in the NSABP B-40 were no longer significant," they explain.
Study Details
These 2 trials are among a number of new trials examining the use of bevacizumab in combination with chemotherapy in the neoadjuvant setting that were hatched by investigators after the FDA granted bevacizumab accelerated approval in 2008 for the first-line treatment of HER2-negative metastatic breast cancer.
In NSABP B-40, patients were randomized to receive neoadjuvant therapy consisting of docetaxel, docetaxel plus capecitabine, or docetaxel plus gemcitabine for 4 cycles, with all regimens followed by treatment with doxorubicin–cyclophosphamide for 4 cycles.
Patients were also randomly assigned to receive or not to receive bevacizumab for the first 6 cycles of chemotherapy.
Patients in NSABP B-40 were required to have a primary tumor 20 mm or larger and tumor stage T1c to T3, nodal stage N0 to N2a, and no distant metastases.
In GBG44, patients were randomized to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients with untreated HER2-negative breast cancer were eligible if they had large tumors (median, 40 mm), hormone-receptor-negative disease, or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy, and no increased cardiovascular or bleeding risk.
NSABP B-40 was funded by the National Cancer Institute, F. Hoffmann-La Roche, Genentech USA, and Eli Lilly. The NSABP B-40 authors have disclosed no relevant financial relationships. GBG44 was funded by sanofi-aventis and Roche, Germany. Some of the GBG44 authors report financial relationships with sanofi-aventis, Roche, and other companies.
N Engl J Med. 2012; 366:299-309, 310-320, 374-375. GBG44 Abstract, NSABP B-40 Abstract, Editorial

10% RATE OF ORAL HPV INFECTION

2012-01-29T19:50:00.003+02:00

January 27, 2012 — A major study of oral infection with human papillomavirus (HPV) — now known to cause of a subset of oropharyngeal cancer — has found a much higher incidence in men than in women and has established sexual transmission as the main way it spreads. It also raises questions about whether existing HPV vaccines offer protection.
There is a rising incidence in oral HPV infection and in HPV-positive oropharyngeal cancer in the United States. "The curves are a little bit frightening," said lead author Maura Gillison, MD, PhD, from Ohio State University in Columbus. But she pointed out that vaccines against HPV are already marketed, so "we have the means to prevent this already sitting on our pharmacy shelves."
The HPV vaccines (Gardasil and Cervarix) were developed to offer protection against cervical cancer after the link between cervical HPV infection and cervical cancer was firmly established, and are targeted mainly to girls.
The link between oral HPV infection and oral HPV cancer was established more recently; Dr. Gillison reported that the research is about 20 years behind that for cervical cancer. There is speculation — although no hard data — that the same vaccines could offer protection against HPV-associated oral cancer. Because this is more prevalent in men, it would make sense to vaccinate boys as well as girls.
"We need to have thorough and accurate discussions about HPV vaccination," Dr. Gillison said. "We have identified a new cancer...and we have identified its Achilles heel," she added.
Dr. Gillison spoke at a presscast at the 2012 Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Therapeutic and Radiation Oncology and held in Phoenix, Arizona. The study was published online January 26 in JAMA: The Journal of the American Medical Association to coincide with its presentation.
Sexual Transmission
This the first major prevalence study of oral HPV infection in the United States, according to an accompanying editorial, subtitled "Hazard of Intimacy."
Editorialist Hans Schlecht, MD, MMSc, from Drexel University College of Medicine in Philadelphia, Pennsylvania, writes that the "results are remarkable for a number of reasons," including the fact that they allow estimation of oral HPV prevalence based on sexual experience, smoking status, and immune suppression.
One of the main findings from this study is that the main method of transmission is sexual, and that the prevalence of oral HPV infection increases with the number of sexual partners reported.
Another finding is "a striking bimodal pattern with age" in men, with peaks in men 30 to 34 and 60 to 64 years of age.
During the presscast, Dr. Gillison speculated that these peaks in oral HPV infection might be partially explained by a "birth cohort" effect. The peak in older men could be related to the fact that they would have been making their sexual debut during the sexual revolution of the 1960s; the dip in middle-aged men could be the result of the dampening impact that the HIV epidemic had on sexual behavior. The peak in younger men could be related to one result of that epidemic — the perception that oral sex is "safe sex."
The new data showing a rising incidence of HPV oropharyngeal cancer raise questions about exactly how safe oral sex is.
In his editorial, Dr. Schlecht suggests that "clinicians should encourage their patients who engage in oral sex to use barrier protection."
First Major Prevalence Study
This study used 2009/10 data from the National Health and Nutrition Examination Survey (NHANES), and analyzed tissue collected from an oral rinse and gargle collected from 5579 people 14 to 69 years of age.
The overall prevalence of HPV oral infection was 6.9%; the particular strain associated with oropharyngeal cancer, HPV16, was found in 1%. "Although this 1% may sound small, this means that around 2.1 million individuals in the United States are infected," Dr. Gillison explained.
However, the incidence in men is significantly higher than it is in women (10.0% vs 3.6%; P < .001).
In addition, the bimodal distribution, with peaks in younger and older individuals, was seen only in men. Why the incidence of oral HPV infection in men is so much higher is not clear, Dr. Gillison said.
Men did report having more sexual partners than women, but this difference in sexual behavior explains only about 16% of the difference in prevalence, the authors note. Another explanation could be higher rate of transmission to men performing oral sex on woman than to women performing oral sex on men; there is some evidence for this in the data. But there are also many other factors, including the fact that women who have already been exposed to cervical HPV infection have greater protection against subsequent oral HPV infection.
The bimodal distribution of oral HPV infection in men is different than that of cervical HPV infection, which peaks in women in their 20s and then generally drops off, although a later peak in older women is seen in some populations.
"It is clear that the natural history of HPV is different in the 2 genders," Dr. Gillison reported.
There was a higher prevalence of oral HPV infection in black than in white people, although this did not reach statistical significance (10.5% vs 6.5%; P = .06). There was also a higher prevalence in current smokers and heavy consumers of alcohol (which increased with intensity of use for both), as well as in current and former marijuana users.
There was little HPV oral infection in individuals who had no history of any sexual contact. Compared with this group, the prevalence was 8 times higher in sexually experienced individuals, and increased significantly with the number of sexual partners. For instance, the prevalence was 20% in people who reported having more than 20 sexual partners.
"These data indicate that transmission by casual, nonsexual contact is likely to be unusual," the authors write.
They note that previous studies have suggested a link between oral sexual behavior and an increased risk for HPV-positive oropharyngeal cancer, but the way the data were collected in the current study precluded association with any particular behavior. However, the data did show that oral HPV infection is more common in sexually experienced people who do not report performing oral sex than in those who were not sexually experienced, which suggests that transmission occurs through other sexually associated contact, such as deep kissing.
This adds weight to the notion that HPV vaccination should be targeted at individuals who are 9 to 13 years of age, in an effort to reach them before any sexual behavior, including deep kissing, begins. This suggestion has been made previously by Dr. Gillison, although she emphasized that protection against oral HPV infection with the existing HPV vaccines has not been proven. She has been trying to conduct such a study for the past 5 years, but has run into funding problems; she hopes to hear soon about funding from the National Cancer Institute, she told journalists in the audience.
Extending HPV vaccination to offer protection against oropharyngeal cancer was discussed by several experts, in addition to Dr. Gillison, last year when it was highlighted by the American Society for Clinical Oncology.
The study was supported by an unrestricted grant from Merck, and was also funded by Ohio University and the Intramural Research Program of the National Cancer Institute. Dr. Gillison reports acting as a consultant to Merck and GlaxoSmithKline, both manufacturers of HPV vaccines. Dr. Schlecht has disclosed no relevant financial relationships.
JAMA. Published online January 26, 2012. Abstract, Editorial
2012 Multidisciplinary Head and Neck Cancer Symposium (MHNCS): Abstract LBPL1. Presented January 26, 2012.

IMPROVED SURVIVAL IN BRCA+ PATIENTS WITH OVARIAN CANCER

2012-01-29T19:50:00.000+02:00

January 24, 2012 — Mutations in BRCA1 and BRCA2 genes are currently the strongest known genetic risk factors for developing both breast and epithelial ovarian cancer, but in the case of ovarian cancer, they are also associated with improved survival.
According to a study published in the January 25 issue of the JAMA: The Journal of the American Medical Association, having a germline mutation in BRCA1 or BRCA2 is associated with improved 5-year overall survival from ovarian cancer, with BRCA2 carriers having the best prognosis.
The 5-year overall survival was 36% (95% confidence interval [CI], 34% to 38%) for noncarriers of the mutation, compared with 44% (95% CI, 40% to 48%) for BRCA1 carriers and 52% (95% CI, 46% to 58%) for BRCA2 carriers.
The authors note that these differences in survival remained even after adjustment for confounders such as stage, grade, histology, and age at diagnosis (hazard ratio [HR] for BRCA1, 0.73; P < .001; HR for BRCA2, 0.49; P < .001).
However, the implications of these results could still be limited in the clinical setting, explained study author Paul Pharoah, BM, BCh, PhD, reader in cancer epidemiology at the University of Cambridge, United Kingdom. "Knowing BRCA1/2 status would allow the clinician to say something about likely prognosis but, until we know more about the interaction with specific treatments, one would not have sufficient evidence to treat the different cancers differently," he told Medscape Medical News.
"However, we believe that in the context of randomized controlled trials, it will be important to include BRCA testing in the protocol so that we can learn whether BRCA carriers respond differently than noncarriers, so that, in due course, it will be possible to provide targeted therapies," he said.
Dr. Pharoah pointed out that PARP inhibitors target the molecular pathways affected by BRCA mutations. "One can envision the testing of patients and the use of such targeted therapy in the near future," he added.
Implications for Research
In an accompanying editorial, David M. Hyman, MD, from the Memorial Sloan-Kettering Cancer Center, and David R. Spriggs, MD, from the Weill Cornell Medical College, both in New York City, agree that these data have implications for future research.
They note that phase 3 studies that do not "stratify by BRCA mutation status or account for this factor in a preplanned statistical analysis risk possible confounding," because about 15% of unselected patients with serous ovarian cancer carry these mutations.
Other studies have also found differences in chemotherapy response and progression-free survival between sporadic BRCA1- and BRCA2-associated ovarian cancers, the editorialists continue. "Germline BRCA testing needs to be consistently incorporated into both the routine management and future phase 3 trials of ovarian cancer."
Of perhaps equal importance, these results "provide impetus for rethinking the current approach to the development of targeted agents in molecularly defined subsets of ovarian cancer," they add.
Tumor Differences, Better Survival
In their study, Dr. Pharoah and colleagues investigated 1213 ovarian cancer patients with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and 2666 noncarriers drawn from 26 observational studies on the survival of women with ovarian cancer.
The women were followed-up at variable intervals from 1987 to 2010; during the 5 years after diagnosis, 1766 deaths occurred.
There were a number of significant differences between the clinical features of BRCA1 and BRCA2 carriers and those of noncarriers. Tumors in women with the BRCA1/2 mutations were more likely to be of serous histology and less likely to be mucinous than those in noncarriers. BRCA1 and BRCA2 carriers were also more likely to have stage III/IV tumors and poorly differentiated or undifferentiated tumors.
When the data were adjusted for only study site and year of diagnosis, BRCA1 carriers had better survival than noncarriers (HR, 0.78; P < .001). When adjusted for other factors, such as stage and age at diagnosis, survival improved slightly (HR, 0.73; P < .001).
Patients with BRCA2 mutations had a greater survival advantage than noncarriers (HR, 0.61; P < .001); this improved after adjustment for other factors (HR, 0.49; P < .001).
In a subset of 1129 patients who had residual disease after primary surgery, the authors found that optimal debulking had taken place in 85% of noncarriers, 87% of BRCA1 carriers, and 91% of BRCA2 carriers. After adjustment for year of diagnosis and study site, they found no significant difference in the likelihood of optimal debulking between noncarriers and BRCA1 (P = .74) or BRCA2 (P = .46) carriers. After adjustment for residual disease, the HR estimates did not substantially change for relative survival.
Routine testing of women with high-grade serous epithelial ovarian cancer might be warranted, write the authors, given the prognostic information provided by BRCA1 and BRCA2 status and the potential for personalized treatment in mutation carriers.
"Our results also show that more research is needed into the cellular differences between tumors in BRCA carriers and noncarriers so that we might begin to understand why the latter do less well and perhaps help identify targeted therapies for them," said Dr. Pharoah.
The study was funded from multiple sources, as noted in the paper. Dr. Pharoah, Dr. Hyman, and Dr. Spriggs have disclosed no relevant financial relationships. Several of the study coauthors report financial relationships, as noted in the paper.
JAMA. 2012;307:382-390, 408-410. Abstract, Editorial

OXALIPLATIN BENEFIT IN ADJUVANT TREATMENT OF COLORECTAL CANCER

2012-01-29T19:48:00.003+02:00

January 27, 2012 (San Francisco, California) — Adjuvant therapy with capecitabine plus oxaliplatin (XELOX) significantly improves overall survival, compared with bolus 5-fluorouracil/leucovorin (5-FU/LV), in patients with resected stage III colon cancer, even 6 to 7 years after the completion of treatment, according to researchers here at the 2012 Gastrointestinal Cancers Symposium.
Oxaliplatin "should now be considered standard treatment for stage III colon cancer," said presenting author Hans-Joachim Schmoll, MD, from the University Clinic Halle (Saale) in Germany.
In this phase 3 randomized trial, 1806 patients with stage III colon cancer underwent adjuvant therapy with either bolus 5-FU/LV or capecitabine plus oxaliplatin.
At a follow-up of 4.75 years, there was a disease-free survival advantage for oxaliplatin over 5-FU/LV (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.69 to 0.93; P = .0045), but the difference in overall survival was not significant.
The latest long-term survival results, with a median follow-up of 6 years, show that the oxaliplatin regimen provided more overall survival benefits than the 5-FU/LV regimen (73% vs 67%; HR, 0.83; P = .0367).
In addition, disease-free survival, the primary end point of the study, was significantly better with oxaliplatin than with 5-FU/LV after a median follow-up of 7 years (63% vs 56%; HR, 0.80; P = .0038).
"Even when we adjusted for prognostic factors such as lymph node status, time from surgery to treatment, and sex and age, the positive treatment effect of [oxaliplatin] remained," Dr. Schmoll announced.
Patients who were older than 70 years benefited less from the oxaliplatin regimen than younger patients, he noted. The trial included a large proportion of patients in this age group — 22% of all enrolled patients, he said.
In fact, in a long-term survival analysis, patients older than 70 years who received oxaliplatin had a hazard ratio of 1. "Although MOSAIC showed that older patients had some improvement with oxaliplatin plus 5-FU/LV, our results in older patients were not clinically significant," Dr. Schmoll said. The MOSAIC trial showed that oxaliplatin plus 5-FU/LV (FOLFOX4) improved 3-year disease-free survival, compared with intravenous and bolus 5-FU/LV as adjuvant therapy in patients with stage II/III colon cancer.
With a median follow-up of 7 years, deaths from colon cancer were 26% in the 5-FU/LV group, compared with 20% in the oxaliplatin group. Oxaliplatin "clearly provides better overall survival and relapse-free survival," Dr. Schmoll said.
"This trial had an acceptable design, but the fact that it included just stage III patients shows us that it's best to be careful about the inclusion of patients with similar stage and molecular subtypes in clinical trials," said Gail Eckhardt, MD, from the University of Colorado at Denver. "This study showed extensive analysis of treatment effects, but toxicity — especially diarrhea and hand–foot syndrome — will be the prime question going forward as we begin to add new agents to this regimen," she noted.
Dr. Eckhardt said researchers need to come up with a better way to measure predictive biomarkers of oxaliplatin response, as well as more data on the optimal duration of therapy. Whether or not 6 months of treatment with oxaliplatin is necessary in colon cancer is being addressed by an ongoing Southwest Oncology Group (SWOG) trial. "The results of that trial should provide us with some answers," she said.
Dr. Schmoll reports being a consultant or advisor to Merck and Roche. Dr. Eckhardt reports being a consultant or advisor to Genentech, Millennium, Onconova, Oncothyreon, and sanofi-aventis.
2012 Gastrointestinal Cancers Symposium (GICS): Abstract 388. Presented January 21, 2012.

PATIENTS TAKING VEMURAFENIB MUST BE TESTED FOR H-RAS MUTATION

2012-01-29T19:48:00.000+02:00

January 20, 2012 — Patients with advanced melanoma who are treated with vemurafenib (Zelboraf, Plexxikon/Roche) should be tested for RAS mutations, according to an editorial published in the January 19 issue of the New England Journal of Medicine.
A study that accompanies the editorial reports that RAS mutations frequently occur in secondary skin tumors that develop in vemurafenib-treated patients.
The testing is necessary because there is "potential for secondary tumor development" that arises from treatment with vemurafenib and other BRAF inhibitors, writes Ashani T. Weeraratna, PhD, from the molecular and cellular oncogenesis program at The Wistar Institute in Philadelphia, Pennsylvania, in her editorial.
These secondary skin tumors — namely, cutaneous squamous cell carcinomas and keratoacanthomas — are relatively benign, compared with melanoma, and are no reason to discontinue vemurafenib, said Dr. Weeraratna. However, testing will alert clinicians to which patients have RAS-driven secondary tumors.
The testing is important because patients with RAS mutations could also develop secondary cancers in organs beyond the skin, advised Dr. Weeraratna.
"If patients have RAS mutations they should be monitored closely for any development of cutaneous squamous cell carcinomas in all organs," she told Medscape Medical News.
"Although cutaneous squamous cell carcinomas are not deadly, these lesions can be life-threatening when they occur in other organs," Dr. Weeraratna writes in her editorial.
She discussed other potentially affected organs.
"Squamous cell carcinomas can potentially arise in any organ with a squamous epithelium, essentially a layer of flattened epithelial cells that line the basement membranes of organs. A squamous epithelium is found most often in organs where rapid filtration and diffusion is necessary, such as the alveolar lining of the lungs and the glomerulus (kidney). Thus, squamous cell carcinomas can be found in organs such as the lungs, cervix, and esophagus, and also account for a large proportion of head and neck cancers," Dr. Weeraratna explained.
Importantly, there is no evidence that vemurafenib triggers tumors in other organs. "It is as yet unclear whether the generation of squamous cell carcinomas in these organs, upon BRAF inhibitor therapy, occurs, but these data certainly alert us to that potential risk," she said.
MEK Inhibitors May Help
In this study of melanoma patients, the investigators sought to characterize the molecular mechanism behind the development of secondary skin cancers in patients treated with vemurafenib.
They admit that a skin cancer drug that causes other skin cancers is unexpected.
The development of cutaneous squamous cell carcinomas and keratoacanthomas "is the opposite of what would be expected from a targeted oncogene inhibitor," write the study authors, led by Fei Su, PhD, from Hoffman-La Roche Pharmaceuticals in Nutley, New Jersey.
In their search to understand this toxicity, the investigators analyzed the DNA of a sampling of these tumors and found a high rate of RAS mutations (21 of 35 tumors; 60%).
"Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib," write the authors.
"This study points out that BRAF inhibitors should only be used in patients who have cancers driven by BRAF mutations, and it raises the concern that cancers driven by RAS mutations (KRAS, HRAS, or NRAS) can be paradoxically activated instead of inhibited with this class of drugs," said coauthor Antoni Ribas, MD, PhD, in email correspondence with Medscape Medical News. He is from the division of hematology–oncology at the UCLA Medical Center in Los Angeles, California.
Why patients treated with vemurafenib have such a high rate of RAS mutations in these secondary cancers is not known.
However, the investigators performed animal-model studies that suggest that the development of RAS-mutation-driven secondary tumors might be prevented with a MEK inhibitor, another class of drugs. There might be "usefulness of combining a BRAF inhibitor with a MEK inhibitor to prevent this toxic effect" of secondary cancers, write the authors.
There has already been clinical investigation of this concept — a phase 2 study of the combination of the MEK inhibitor GSK1120212 and the RAF inhibitor GSK2118436 in metastatic melanoma.
That study, which was presented at the 2011 annual meeting of the American Society of Clinical Oncology, and reported at that time by Medscape Medical News, showed that the toxicity of the combination seemed to be lower than that of either agent used alone.
N Engl J Med. 2012;366: 207-215, 271-273. Abstract, Editorial

1,7% CR WITH TKIs IN METASTATIC RENAL CANCER-NOT SO IMPRESSIVE

2012-01-29T19:47:00.002+02:00

NEW YORK (Reuters Health) Jan 17 - In a small minority of patients with metastatic renal cell carcinoma, the tyrosine kinase inhibitors (TKIs) sunitinib or sorafenib prompt complete remission, European researchers report.
And some of those patients remain in remission after therapy stops.
"Complete remissions rarely occur with TKIs, but they sometimes do (1-2%). One important question is whether treatment should be continued or not when this phenomenon occurs," said Dr. Laurence Albiges, lead author of the report, in an email to Reuters Health.
Dr. Albiges of Institut Gustave Roussy, Villejuif, France and colleagues studied 64 patients who had a complete response to sunitinib or sorafenib, either alone or in combination with surgery, radiation, or radiofrequency ablation.
This group accounts for about 1.7% of patients treated for metastatic RCC with these agents at 14 centers in France and one in Switzerland, according to estimates by the authors.
Fifty-nine patients received sunitinib; the other five received sorafenib. Sixty had clear cell histology.
The protocol for sunitinib was 50 mg daily for four weeks, followed by two weeks off treatment. Patients on sorafenib took 800 mg daily, given continuously in four-week cycles. Both drugs could be given either as part of a trial, or in an approved setting.
Everyone had undergone nephrectomy. Most were of favorable or intermediate risk, but three of the patients had been considered high-risk, the authors noted in a January 9th online paper in the Journal of Clinical Oncology.
Thirty-six patients achieved remission with a TKI alone (i.e. without local treatment), after a median 12.6 months of therapy. Eight of those continued to take a TKI. Of the 28 who stopped, 17 (61%) are still in complete remission after a median follow-up of 255 days, according to the report.
Of the 28 patients who also received local treatment, 25 stopped taking their TKI - including 12 (48%) who remain in complete remission at a median follow-up of 322 days.
"Our study supports the possibility (of stopping) treatment with careful follow up," Dr. Albiges said. "With this strategy, relapse will occur in only half of the patients, and importantly, most of these patients will remain responsive to further rechallenge."
Because of the small number of patients in each group, say the investigators, "it was not possible to draw any conclusions about differences in relapse rates between patients who continued or stopped therapy."
They conclude that "stopping treatment with a TKI after complete remission may be an acceptable option" but "further research is also needed to identify factors to aid selection of patients who would be at less risk of recurrence after discontinuation."
SOURCE: http://bit.ly/yoM8u9
J Clin Oncol 2012.

DUAL BLOCKADE OF HER2 IS BENEFICIAL

2012-01-29T19:46:00.001+02:00

January 20, 2011 — Lapatinib is less effective than trastuzumab for HER2-positive breast cancer, but the combination, known as dual blockade, is nearly twice as effective as monotherapy with either, according to the results of 2 studies published online January 17, one in the Lancet Oncology and the other in the Lancet.
Positive results using dual blockade (pertuzumab plus trastuzumab) were reported last month at the San Antonio Breast Cancer Symposium, and reported at that time by Medscape Medical News.
Editorials accompanying the 2 studies note that perhaps as important as the actual results is how the studies were conducted. Both studies show the value of academic collaborations in such defining trials, and that such trials should not be conducted by pharmaceutical companies alone.
In the first study — a randomized phase 3 trial known as GeparQuinto — eligible patients had untreated HER2-positive operable or locally advanced breast cancer.
In all, 620 eligible women were randomized in a 1:1 ratio to receive neoadjuvant treatment with 4 cycles of intravenous epirubicin 90 mg/m² plus intravenous cyclophosphamide 600 mg/m² every 3 weeks. This was followed by 4 cycles of intravenous docetaxel 100 mg/m² every 3 weeks with either intravenous trastuzumab 6 mg/kg (with a loading dose of 8 mg/kg) for 8 cycles every 3 weeks or oral lapatinib (1000 to 1250 mg/day) throughout all cycles before surgery.
The investigators report that 30.3% of patients in the trastuzumab group and 22.7% of patients in the lapatinib group had a pathological complete response (odds ratio, 0.68; 95% confidence interval [CI], 0.47 to 0.97; P = .04).
Chemotherapy with trastuzumab was associated with more edema (39.1% vs 28.7%) and dyspnea (29.6% vs 21.4%), and with lapatinib was associated with more diarrhea (75.0% vs 47.4%) and skin rash (54.9% vs 31.9%).
Treatment was discontinued in 14% of the trastuzumab group and 33.1% of the lapatinib group. There were 70 serious adverse events in the trastuzumab group and 87 in the lapatinib group.
Because lapatinib was associated with such a high rate of significant adverse effects, lead investigator Michael Untch, MD, from the Helios Klinikum, Berlin-Buch, in Germany, and colleagues advise that "unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy."
"This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab," the investigators conclude.
Stephen K. Chia, MD, from the division of medical oncology at the British Columbia Cancer Agency in Vancouver, commends the study design in an accompanying editorial, and notes that "the rapid accrual in GeparQuinto is essential to minimize overall timelines for drug development."
Dr. Chia writes that "no adjuvant trials should be done without an adequate signal from preoperative trials showing safety, efficacy, target modulation, and, ideally, the identification of predictive biomarkers such that we no longer pick a loser to study in larger and more resource-intensive adjuvant trials."
Dual Blockade Is Better
In the second study, José Baselga, MD, from the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, and colleagues randomized women from 23 countries with HER2-positive primary breast cancer with tumors more than 2 cm in diameter to oral lapatinib 1500 mg, intravenous trastuzumab (a loading dose of 4 mg/m² and subsequent doses of 2 mg/kg), or lapatinib 1000 mg plus trastuzumab.
The study design called for women to receive anti-HER2 therapy alone for the first 6 weeks; weekly paclitaxel (80 mg/m²) was then added to the regimen for 12 weeks before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary end point was the rate of pathological complete response.
In all, 154 patients received lapatinib, 149 received trastuzumab, and 152 women received both.
Pathological complete response rate was significantly higher in women receiving dual therapy (51.3%; 95% CI, 43.1 to 59.5) than in those receiving trastuzumab alone (29.5%; 95% CI, 22.4 to 37.5), for a difference of 21.1% (95% CI, 9.1 to 34.2; P = .0001).
Dr. Baselga's team found no significant difference in pathological complete response rates between the lapatinib (24.7%; 95% CI, 18.1 to 32.3) and trastuzumab (–4.8%; 95% CI, –17.6 to 8.2; P = .34) groups.
There were no cases of major cardiac dysfunction. Grade 3 diarrhea was more frequent with lapatinib (23.4%) and lapatinib plus trastuzumab (21.1%) than with trastuzumab (2.0%). Grade 3 liver-enzyme alterations were more frequent with lapatinib (17.5%) and lapatinib plus trastuzumab (9.9%) than with trastuzumab (7.4%).
"The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumor activity in models of HER2-overexpressing breast cancer," Dr. Baselga and colleagues write.
They conclude that "dual inhibition of HER2 with lapatinib and trastuzumab in combination with paclitaxel is better than single-agent HER2 targeting. Our study also supports investigation of novel targeted agents for breast cancer in the neoadjuvant setting, when tumors have not yet acquired resistance to therapy and when chances of clinical benefit are highest.
Michael Gnant, MD, from the Department of Surgery, and Guenther G. Steger, MD, from the Department of Medical Oncology, both at the Medical University of Vienna, Austria, caution in an accompanying editorial that findings from neoadjuvant and adjuvant treatment trials such as the 2 described here need to be viewed "from a scientific and a regulatory perspective."
"Trials in the neoadjuvant setting based on research-based hypotheses (after establishment of drug safety) could lead to a saving of enormous sums in drug development costs, and promising new drugs for treatment of early breast cancer could become available much more quickly than at present," Drs. Gnant and Steger believe.
Echoing the point that Dr. Chia made in his editorial, the Austrian editorialists note that "questions about duration of treatment and possible differential efficacy in biomarker-selected patient subcohorts need to be incorporated into clinical trials of targeted therapies."
Drs. Gnant and Steger assert that "standard defining trials should not be left to drug manufacturers, with their economic incentive towards protracted treatment durations, alone; such trials are best governed by collaborative academic groups and should be accompanied by translational research enterprises."
Both trials were supported by GlaxoSmithKline, the manufacturer of lapatinib. GeparQuinto also received support from Roche, the manufacturer of trastuzumab and pertuzumab, and sanofi-aventis. Dr. Untch has disclosed no relevant financial relationships. Dr. Chia reports receiving an honorarium from GlaxoSmithKline and an unrestricted research grant from Hoffmann-La Roche. Dr. Baselga reports receiving honoraria from Roche. Dr. Gnant reports serving on advisory boards for and received consulting fees from AstraZeneca and Novartis; and receiving lecture fees or research support from Roche, Schering, Pfizer, Novartis, AstraZeneca, sanofi-aventis, GlaxoSmithKline, and Amgen. Dr. Steger reports serving on advisory boards for and/or receiving consulting fees or support from AstraZeneca, Roche, Amgen, Novartis, and GlaxoSmithKline.
Lancet Oncol. Published online January 17, 2012. Abstract, Editorial
Lancet. Published online January 17, 2012. Abstract, Editorial

A PROMISING BIOMARKER FOR EARLY DIAGNOSIS OF PANCREATIC ADENOCARCINOMA

2012-01-22T23:28:00.002+02:00

January 18, 2012 (San Francisco, California) — A new immunoassay can detect early pancreatic cancer with fairly high specificity and sensitivity, according to researchers. However, this conclusion comes from a study with only 28 patients.
The new immunoassay is based on the antibody PAM4 and detects pancreatic ductal adenocarcinoma (PDAC). It correctly detected stage 1 PDAC in 18 of 28 patients (64%) previously diagnosed with the disease at that early stage.
These patients were a subset of a larger group of confirmed PDAC patients with all stages of disease. The PAM4 immunoassay was able to correctly detect 76% of this larger group of PDAC patients (225 of 298).
The study tested patients with other cancers (n = 99), patients with benign disease of the pancreas (n = 126), and healthy adults (n = 79). To assess how common the marker is, PAM4 antigen levels were evaluated in 602 individuals with the enzyme immunoassay.
But the researchers are focused on finding a biomarker for early-stage pancreatic cancer.
Early detection can improve survival, said lead author David V. Gold, PhD, director of laboratory administration and a senior member of the Garden State Cancer Center in Morris Plains, New Jersey.
He spoke at a press conference hosted by the 2012 Gastrointestinal Cancers Symposium, which begins this week.
The 5-year survival rate for patients with stage 1 disease is 20%, said Dr. Gold. This is considerably better than the 5-year survival rate of 2% to 3% seen in all of PDAC. "Early detection and improved therapy go hand in hand," he said.
"Pancreatic cancer symptoms are vague; the disease tends to develop and grow silently. By the time it is detected, it has often spread to other parts of the body, making it nearly impossible to cure. These study results are extremely encouraging and may eventually lead to improved detection of the disease in high-risk individuals," Dr. Gold said in a press statement.
Dr. Gold and his team combined the PAM4 immunoassay with the CA19-9 immunoassay, which is commonly used to monitor the course of the disease. Together, the 2 immunoassays were able to detect 85% of patients with PDAC. "We combined the results of the 2 assays and discovered a significant improvement in the detection of PDAC while maintaining a high level of specificity," said Dr. Gold. Unfortunately, there was no improvement with the combination in the rate of detection of early-stage patients.
The study results inspired praise from one expert not involved with the study. The test "shows tremendous promise," said Morton Kahlenberg, MD, from the University of Texas Health Science Center at San Antonio, who moderated the press conference.
Dr. Gold noted that the CA19-9 test is approved by the US Food and Drug Administration for monitoring pancreatic cancer progression, but that no test is approved for the detection and diagnosis of pancreatic cancer.
PAM4 Antibody Appears Mostly Restricted to PDAC
The study is a collaboration of researchers from the Garden State Cancer Center; the University of Göttingen in Germany; Johns Hopkins Medical Institutions in Baltimore, Maryland; and the New York University Medical Center in New York City.
Some of the patients in the study had cancer of the organs surrounding the pancreas. The investigators found that about half of patients with extrahepatic biliary (50%) and periampullary (48%) adenocarcinomas tested positive for the PAM4 protein. In the press statement, Dr. Gold said that this finding was not unexpected because these cancers originated in closely related organs.
The researchers also used the immunoassay to get a sense of how common the PAM4 protein is in other pancreatic disorders (n = 126). Nineteen percent of patients with benign pancreatic disease and 23% of those with chronic pancreatitis tested positive for the PAM4 protein.
"These results demonstrate that the reactivity of the PAM4 antibody is highly restricted to PDAC," said Dr. Gold.
"To the best of our knowledge, there are no biomarkers or target antigens that are expressed at a similarly high frequency and concentration in PDAC, and that show such specificity," he said.
According to press materials, the researchers are planning to use the PAM4 biomarker to screen patients who are considered to be at high risk for pancreatic cancer for the presence of PDAC at an early stage of tumor growth. The subjects include those with chronic pancreatitis, those with sudden-onset diabetes, and those with a family history of PDAC.
The study was supported in part by grants from the National Institutes of Health and the Turpin Foundation. Coauthor David M. Goldenberg, ScD, MD, is an employee of Immunomedics and owns stock in the company.
2012 Gastrointestinal Cancers Symposium (GICS). Abstract 151. To be presented January 20, 2012.

AN INTERESTING COMBINATION FOR PROSTATE BIOCHEMICAL FAILURE

2012-01-22T23:27:00.003+02:00

NEW YORK (Reuters Health) Jan 12 - Finasteride and flutamide in combination produce significant declines in prostate specific antigen (PSA) in men with biochemical failure after local therapy, researchers report.
Dr. Paul J. Monk of Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus, Ohio and colleagues note that about a third of men treated for localized prostate cancer will have serological progression.
As an alternative to androgen deprivation therapy - which has a high response rate but a myriad of side effects - the researchers propose peripheral androgen blockade with a 5-alpha reductase inhibitor (finasteride) and an antiandrogen (flutamide).
"Because patients with PSA-only recurrences after definitive local therapy are not necessarily destined to die of their disease, they are excellent candidates for therapy that may have lower toxicity, while retaining the potential to control their disease," the investigators said in their report, published online December 16 in Cancer.
They tested the effect of daily therapy with finasteride 5 mg and flutamide 750 mg in 99 men who'd each had a PSA increase of at least 1 ng/mL.
The PSA level fell by at least 80% in 96% of subjects, and it became undetectable (<0.2 ng/mL) in 73%. The median time to a nadir value was 3.2 months.
The median time to PSA progression was 85 months. The five-year overall survival rate was 87%. And with a median follow-up of 10 years, the median survival time has not been reached.
Currently 22 patients remain on therapy. Of the 77 patients off protocol treatment, 43 have died, including 13 who died of progressive prostate cancer.
Eighteen men stopped therapy for side effects, mainly diarrhea, liver enzyme elevations, and gynecomastia. Another 21 came off the protocol because of disease progression. Nine withdrew their consent.
The researchers say their five-year metastasis-free rate of 97% compares favorably with the 67% rate reported in a recently updated retrospective study of 450 men who did not receive any additional therapies after surgery.
Summing up, Dr. Monk pointed out, "The combination of finasteride and flutamide was well tolerated, durable and active making it a good option to incorporate in a controlled study in this important population of men."
SOURCE: http://bit.ly/y8AWYQ
Cancer 2011.

MOST TIMES UNNECESSARY IPSILATERAL ADRENALECTOMY FOR RENAL CANCER

2012-01-22T23:27:00.000+02:00

NEW YORK (Reuters Health) Jan 16 - Despite evidence supporting adrenal-sparing surgery, ipsilateral adrenalectomy remains common during radical nephrectomy for cancer, researchers from Canada report.
"Although adrenal sparing surgery has been stated in urologic guidelines, we know that guidelines are not necessarily the most effective means of encouraging change," Dr. Antonio Finelli from the University of Toronto told Reuters Health by email.
"Therefore, alternate strategies such as audit and feedback, although untested in this field, may be required to expedite uptake in the rapidly changing landscape of surgery for renal cancer," he added.
Dr. Finelli and colleagues, whose findings were published online December 15 in The Journal of Urology, reviewed pathology reports for more than 5,000 patients in the Ontario Cancer Registry who had undergone radical nephrectomy for renal cell carcinoma.
Although only 74 cases (1.4%) had adrenal involvement, the overall adrenalectomy rate was 40.1%. This rate decreased only slightly after studies appeared in support of adrenal-sparing surgery, from 40.6% in 1995 to 34.8% in 2004.
Adrenalectomy was performed in 51% of cases with tumors larger than 7 cm versus 30% of cases with tumors smaller than 4 cm. The adrenal gland was involved in just 3.2% of the larger tumors and 0.6% of the smaller tumors. Just under 1% of intermediate-sized tumors (4 to 7 cm) had adrenal involvement.
Besides increased tumor size, adrenal involvement was significantly higher when there was fat invasion of the tumor.
One-year and five-year survival rates were significantly lower with adrenal involvement (60.6% and 21.6%, respectively) than without adrenal involvement (91.5% and 77.9%, respectively).
"Ipsilateral adrenalectomy at the time (of) nephrectomy continues to be performed regardless of evidence to suggest that adrenal involvement is rare in most instances," Dr. Finelli concluded.
"Although there is no data to suggest that loss of an adrenal gland has significant physiologic consequences, in the setting of kidney cancer, contralateral adrenal involvement may occur at a later date necessitating surgery and lifelong steroid replacement," he added. "We are in the process of investigating the physiologic impact if any of adrenalectomy in patients with renal cancer."
SOURCE: http://bit.ly/y3S60q
J Urol 2012;187:398-404.

45 DAY INCREASE IN SURVIVAL-AT WHAT COST?

2012-01-22T23:25:00.000+02:00

January 18, 2012 (San Francisco, California) — The experimental agent regorafenib appears to significantly improve survival and delay disease progression in patients with metastatic colorectal cancer, according to data that will be presented at the 2012 Gastrointestinal Cancers Symposium.
In a phase 3 randomized trial, patients treated with regorafenib had a median overall survival of 6.4 months, compared with 5.0 months for placebo — a 29% increase in survival.
Regorafenib is under development by Bayer, and the company says it intends to file for approval for metastatic colorectal cancer sometime this year.
The drug is a novel oral multkinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases, explained lead author Axel Grothey, MD, professor of oncology at the Mayo Clinic in Rochester, Minnesota. "It can inhibit a variety of different kinases; this is really the main characteristic of the drug."
"In early clinical testing, regorafenib has shown an acceptable side-effects profile and preliminary antitumor effects," he said during a presscast that was held ahead of the meeting.
The CORRECT trial was conducted to evaluate the efficacy and safety of regorafenib in patients with metastatic disease who had progressed after receiving all approved standard therapies. "This highlights a patient population that has an unmet need and for which placebo randomization is ethically sound," said Dr. Grothey.
Superior Overall and Progression-Free Survival
The study cohort consisted of 760 patients with documented metastatic colorectal cancer who had progressed during standard therapy or within 3 months of receiving it. In the cohort, 505 patients were randomly assigned to oral regorafenib 160 mg (3 weeks on and 1 week off) plus best standard care, and 255 were assigned to placebo plus best standard care.
Patients were to continue with the treatment until disease progression, death, or unacceptable toxicity. The primary end point was overall survival. Secondary end points included progression-free survival, overall response rate, disease control rate, safety, and quality of life.
At a preplanned second interim analysis, there was a statistically significant survival benefit for regorafenib. The estimated hazard ratio for overall survival was 0.773 (95% confidence interval [CI], 0.635 to 0.941; 1-sided P = .0051).
In addition to improved overall survival, progression-free survival was superior; median progression-free survival was 1.9 months (95% CI, 1.88 to 2.17) for regorafenib and 1.7 months (95% CI, 1.68 to 1.74) for placebo. The estimated hazard ratio for progression-free survival was 0.493 (95% CI, 0.418 to 0.581; 1-sided P < .000001).
The authors found a substantial difference in disease control rate in the regorafenib and placebo groups (44% vs 15%; P <.000001). Because the prespecified overall survival efficacy boundary was crossed (1-sided nominal α = 0.0093), the Data Monitoring Committee recommended that the study be unblinded to allow patients in the placebo group to cross over.
Adverse events were consistent with observations from previous clinical trials, said Dr. Grothey. Dose adjustment was helpful in managing adverse effects; "most patients could continue on the drug in a dose-reduced manner," he explained.
The most frequent grade 3+ adverse events in the regorafenib group were hand–foot skin reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension (7%).
Dr. Grothey noted that regorafenib appears to be more effective in stabilizing disease and delaying progression than in shrinking tumors. He added that a subset of patients has responded particularly well to regorafenib and continue to have stable disease. He said that he is personally treating a patient who has been on the drug for 12 months whose disease has stabilized and who has not experienced any adverse effects.
"This is the first small-molecule kinase inhibitor with proof of efficacy in metastatic colorectal cancer," he said, adding that this is a potential new standard of care in this patient population.
There are plans to study regorafenib in patients with earlier-stage disease.
This is a very noteworthy study, said Morton Kahlenberg, MD, from the University of Texas Health Science Center at San Antonio, who moderated the presscast. He added that these are positive findings in people with disease that has already progressed and who have failed other therapies.
"This really lays the groundwork for further work," he added.
Dr. Grothey and several coauthors report multiple relationships, including relationships with Bayer.
2012 Gastrointestinal Cancers Symposium (GICS): Abstract LBA385. To be presented January 21, 2012.

VEMURAFENIB-RAS MUTATIONS-SKIN CANCER RISK AND MEK INHIBITORS

2012-01-22T23:24:00.000+02:00

AROMATASE INHIBITORS INCREASE CARDIOVASCULAR MORBIDITY

2012-01-22T23:23:00.002+02:00

Amir E, Seruga B, Niraula S, Carlsson L, Ocaña A
J Natl Cancer Inst. 2011 Sep 7; 103(17):1299-309
Changes clinical practice: The risks and benefits of adjuvant aromatase inhibitors (AIs) should be weighed carefully, especially in postmenopausal women with early-stage, hormone-receptor positive breast cancer who also have coronary artery disease. Use of tamoxifen or changing to tamoxifen after 2-3 years of an AI may be preferable to 5 years of adjuvant therapy with an AI.
This meta-analysis confirms that an aromatase inhibitor (AI) is not the best therapy for all postmenopausal women with hormone-receptor positive, early-stage, breast cancer. ^[1] This potentially practice-changing article provides new evidence for AI toxicities, which practitioners should consider when choosing between adjuvant endocrine therapies for postmenopausal breast cancer patients. The authors conducted the study to clarify why AIs, when compared with tamoxifen, increased disease-free survival but not overall survival. AI toxicities were suspected to counteract decreased recurrence rates. The authors thus conducted a literature-based meta-analysis of randomized controlled trials to compare relative toxicities of AIs versus tamoxifen as primary adjuvant endocrine therapy in postmenopausal women with early-stage breast cancer.
Included studies were randomized phase III clinical trials comparing AIs with tamoxifen as initial adjuvant therapy and total treatment durations of 5 years. Data was included from all randomly assigned patients regardless of hormone receptor status, with an intention-to-treat analysis. The authors prespecified six adverse events: cardiovascular disease, cerebrovascular disease, venous thrombosis (DVT), bone fracture, endometrial cancer, and other secondary cancers. They also assessed hypercholesterolemia. All grades of these adverse events were recorded. Three treatment cohorts were defined for the meta-analysis: 1) 5 years of AI versus 5 years of tamoxifen (upfront AI versus tamoxifen), 2) 2-3 years of tamoxifen followed by 2-3 years of AI versus 5 years tamoxifen (switching versus tamoxifen), 3) 2-3 years of tamoxifen followed by 2-3 years of AI versus 5 years AI (switching versus AI). Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare the relative frequency of an individual adverse event. Difference in absolute risk between groups was also calculated by the number needed to harm.
Seven trials with 30,023 patients were included in the analysis. The authors found that a longer duration of AI use was associated with an increased risk of cardiovascular disease (OR 1.26, 95% CI 1.10 to 1.43, p<0.001, number needed to harm (NNH)=132) and bone fracture (OR 1.47, 95% CI 1.34 to 1.61, p<0.001, NNH=46). Longer AI exposure was also associated with decreased risk of venous thrombosis (OR 0.55, 95% CI 0.46 to 0.64, p<0.001, NNH=79) and endometrial carcinoma (OR 0.34, 95% CI 0.22 to 0.53, p<0.001, NNH=258). Five years of AI use was associated with an increased risk of death without recurrence, which was not statistically significant compared to 5 years of tamoxifen use or tamoxifen for 2-3 years followed by AI for 2-3 years (OR 1.11, 95% CI 0.98 to 1.26, p=0.9). There was no statistically significant difference in odds of cerebrovascular disease or secondary malignancies.
With regards to the cardiovascular disease risk, 4.2% of the patients in the AI group and 3.4% of patients in the tamoxifen group suffered a cardiovascular event (difference in absolute risk 0.8%, NNH=132). All treatment cohorts demonstrated increased odds of cardiovascular events in the AI group (of any AI exposure duration) versus the tamoxifen group, although the magnitude was lower for the switching cohort than for the 5 year AI cohort.
Four of the included studies formally assessed hypercholesterolemia, though they were not graded consistently. Pooled data analysis showed that a longer duration of AI use was associated with a statistically significant increase in odds of hypercholesterolemia compared with tamoxifen (OR 2.36, 95% CI 2.15 to 2.60, p<0.001). The difference was less pronounced for the switching cohort than for the upfront AI cohort.
The authors discussed the distinct toxicity profiles of AIs and tamoxifen, including relatively rare adverse events which were not detected in the analyses of individual trials, and cautioned that absolute risk (rather than relative risk) should direct clinical decision making. While the effect size was small for the increase in absolute risk of cardiovascular disease in the entire studied population, certain subpopulations may suffer higher risk. Previously the Food and Drug Administration (FDA) warned of an increased incidence of cardiovascular events for women with pre-existing heart disease for anastrozole (17%) compared with tamoxifen (10%). The data in the meta-analysis suggests that this increased cardiovascular risk may extend to all AIs. Trials of tamoxifen versus placebo also show that tamoxifen is associated with a reduction in cardiovascular events. Tamoxifen may thus have a protective effect against cardiovascular disease. Oncologists should weigh carefully the risk and benefits of AI use in patients with pre-existing heart disease, or other risk factors for heart disease. Data suggests that upfront AI use is associated with increased odds of death without breast cancer recurrence compared with the use of tamoxifen alone or switching from tamoxifen to AI. Data also suggests that switching after 2-3 years tamoxifen to an AI is associated with a reduced number of deaths compared with AI alone or tamoxifen alone. Switching may lead to a reduction in risk of cumulative toxicities.
Multiple factors should be considered when choosing endocrine therapy for postmenopausal women with early-stage breast cancer in light of this data. If the patient has history of ischemic heart disease and lower risk of breast cancer recurrence, she should not be treated with an AI. If the patient has a higher risk of breast cancer recurrence, the practitioner should consider switching to an AI only after 2-3 years tamoxifen. Alternatively, a patient with high risk of DVT should probably avoid tamoxifen. Tobacco-using patients may have increased risk of cardiovascular disease with AIs and DVTs with tamoxifen, which complicates the decision-making process.
The authors acknowledge the limitations of the study such as the data analysis of literature rather than individual patient data and combining data from trials of different follow-up durations. There is also inevitably variable quality of data and reporting of adverse events by investigators. Adverse events are typically only collected until the endpoints are reached (primary endpoint was breast cancer recurrence in these trials), though the incidence of adverse events after breast cancer recurrence still has clinical relevance given the long lifespan of many women with both locally recurrent and metastatic breast cancer. The data unfortunately did not allow for consideration of potentially confounding host factors or use of concurrent medications. The risk of cardiovascular disease may also increase with longer follow-up, particularly given the large increase in hypercholesterolemia with AI use.
The current National Comprehensive Cancer Network (NCCN) guidelines for endocrine therapy for postmenopausal women with early-stage breast cancer recommend equally the options of AI for 5 years, tamoxifen for 2-3 years followed by AI to complete 5 years, and tamoxifen for 4.5 to 6 years followed by AI for 5 years.^[2] They also offer the option of tamoxifen for 5 years if there is a contraindication for or intolerance of AIs. However, the guidelines do not mention the consideration of prior cardiovascular disease history, cardiovascular disease risk, or recurrence risk when choosing between these different therapeutic options. In their discussion of adjuvant endocrine therapy, they mention that AIs are associated with "musculoskeletal symptoms, osteoporosis, and increased risk of bone fracture, while tamoxifen is associated with an increased risk of uterine cancer and deep venous thrombosis". The current version of the breast-cancer treatment guidelines recommend that "postmenopausal women with early breast cancer receive an AI as initial adjuvant therapy, sequential with tamoxifen, or as extended therapy in those situations where endocrine therapy is to be utilized… in postmenopausal women, the use of tamoxifen alone for five years is limited to those who decline or who have a contraindication to AIs".
The meta-analysis included all grades of cardiac toxicity, but there is also concern that AIs increase high-grade adverse cardiac events compared to tamoxifen. In the Breast International Group (BIG) 1-98 trial, the overall incidence of cardiac events was similar (letrozole 4.8% versus tamoxifen 4.7%) but the incidence of grade 3 to 5 cardiac adverse events was significantly higher in the letrozole arm.^[3] Recently published updated results for the BIG 1-98 treatment cohorts, with a follow-up of 12 years since randomization, now reveals a statistically significant difference in overall survival for the letrozole monotherapy arm compared with the tamoxifen monotherapy arm (hazard ratio [HR] 0.87, 95% CI 0.777 to 0.999, p=0.048) in the intention to treat analysis.^[4] In their analysis by inverse probability of censoring weighted (IPCW) Cox models (to create a scenario of informative missing data), the node negative patients had a HR of 0.82 (95% CI 0.65 to 1.02), and node positive patients had a HR of 0.74 (0.63 to 0.88). There was no significant difference in disease-free survival or overall survival for switching cohorts (tamoxifen followed by letrozole, or letrozole followed by tamoxifen) compared to letrozole alone.
Another important consideration when choosing between endocrine therapies is the age of the patient. A retrospective cohort study of women age 66 and older at the time of breast-cancer diagnosis found that more patients died of cardiovascular disease than of breast cancer (cardiovascular disease deaths 15.9% [95% CI 15.6 to 16.2] followed by breast cancer deaths 15.1% [95% CI 14.8 to 15.4]). The fully adjusted relative hazard of cardiovascular disease in this group of breast cancer patients was 1.24 (95% confidence interval [95% CI] 1.13 to 1.26).^[5]
In light of the meta-analysis results, the guidelines should also include cardiovascular risk factor screening and consider alternatives to AIs for women with a cardiovascular disease history, who are at high risk for developing cardiovascular disease, while also having a low risk of recurrence. For patients at higher risk of recurrence who may benefit more from AI therapy, a switching strategy combining tamoxifen and an AI would likely be the best choice. Patients at risk for coronary artery disease events should undergo risk-factor modification, particularly of hypercholesterolemia in the setting of AI use.^[6]

DUAL BLOCADE OF HER2+ BREAST CANCER MORE EFFECTIVE

2012-01-22T23:22:00.002+02:00

4 DRUG THERAPY OF HCV

2012-01-22T23:21:00.001+02:00

NEW YORK (Reuters Health) Jan 18 - Combining the experimental oral drugs asunaprevir and daclatasvir with the established treatment of peginterferon alfa-2a and ribavirin eliminated all traces of hepatitis C virus (HCV) in the blood of every volunteer, even after ribavirin-peginterferon alfa-2a treatment had already failed, in small phase II study released online today by the New England Journal of Medicine.
The ten patients treated with all four drugs all had undetectable viral levels 12 weeks after treatment stopped, and nine still had undetectable levels after 24 and 48 weeks.
Another 11 patients received only asunaprevir and daclatasvir, and four of them had a sustained virologic response at 12 and 24 weeks after treatment.
"This is a watershed moment in the annals of HCV therapy because it shows that a sustained virologic response can be achieved without interferon," Dr. Raymond T. Chung of Massachusetts General Hospital wrote in an editorial in the January 19 issue.
Dr. Anna Lok of the University of Michigan and chief author of the study told Reuters Health that the cure rate for the peginterferon/ribavirin regime is low. "It's only 36%. But considering that these are difficult patients to treat, 36% is not too bad," she said.
All 21 patients in the current study had genotype 1 HCV, the most common in the U.S., and all had failed to respond to peginterferon plus ribavirin (i.e., they had not had at least a 2 log10 decline in HCV RNA after at least 12 weeks of treatment).
The response was far better when the four drugs were used. By the end of treatment, at week 24, all 10 patients in that group had undetectable levels of HVC RNA. Forty-eight weeks after the end of therapy, only one had any trace of the virus, and the amount was too small to quantify, according to the researchers.
About 4.1 million people in the United States and 180 million worldwide are infected by hepatitis C, with its associated risk of cirrhosis and liver cancer.
In the randomized phase II study, where patients knew what treatment they were getting, everyone received 600 mg of asunaprevir twice daily and 60 mg of daclatasvir once daily for 24 weeks. Both are made by Bristol-Myers Squibb, which paid for the trial.
Ten of the 21 also got 180 mcg of Pegasys brand peginterferon alfa-2a each week and Copegus brand ribavirin, where the daily dose was 1,000 mg for those weighing less than 75kg and 1,200 mg for those weighing more. Both are Roche products.
After 24 weeks of therapy, all 10 patients getting the four-drug regimen and five of the 11 patients receiving the non-interferon regimen had no trace of virus in their blood.
The six patients in the non-interferon group who had viral breakthrough during the treatment period all had HCV genotype 1a. Another patient in that group had viral recurrence after treatment ended.
By 24 weeks after treatment ended, the virus had returned in one of the 10 getting all four drugs. But that one person was retested 13 days after recurrence and levels of HCV RNA were undetectable, a phenomenon that was seen in other patients, said Dr. Lok. "Because it was not persistent, we believe 100% actually maintained virus clearance all the way to week 48."
"To be able to get to 90% or 100% is very remarkable," she said. "On the other hand, we all know that a lot of patients can't handle interferon and ribavirin because of the side effects. What we hear from the patients is that they hate interferon. They prefer not to get treatment. Everyone is looking for when can we have an interferon-free regimen."
In the new study, the side effects were similar in the two experimental groups. The three most common were diarrhea, fatigue and headache, reported by 45% to 73% of patients. Six patients had transient elevations of alanine aminotransferase to more than 3 times the upper limit of normal. Side effect rates were complicated by the fact six of the 11 volunteers randomized to receive only daclatasvir and asunaprevir received rescue therapy with interferon and ribavirin after a viral breakthrough.
None of the 21 dropped out because of the side effects.
Dr. Lok said 48 weeks of peginterferon and ribavirin usually costs about $40,000. Adding a protease inhibitor as a third drug costs another $50,000, and new biologicals often go for a comparable amount.
The eventual price of the experimental drugs is not known, assuming they are approved.
Thus, a four-drug regimen would add to the cost, Dr. Lok said, but "if this pans out, it's only 24 weeks of treatment. And if you get a cure once and for all, you don't have to worry about managing the complications of cirrhosis, liver transplant, liver cancer down the road."

RADIANT-2 MULTIFACTORIAL ANALYSIS-REFINING USE OF EVEROLIMUS IN NEUROENDOCRINE TUMORS

2012-01-22T23:19:00.002+02:00

January 17, 2012 (San Francisco, California) — In patients with advanced neuroendocrine tumors that originate outside the pancreas, a new set of prognostic factors can help identify which patients are at greatest risk for progression and are more likely to need therapy sooner, say researchers.
The prognostic factors were identified in a reanalysis of the phase 3 multinational study known as RADIANT-2 (RAD001 in Advanced Neuroendocrine Tumors), said lead author James Yao, MD, assistant professor and deputy chair of gastrointestinal oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
He spoke at a press conference hosted by the 2012 Gastrointestinal Cancers Symposium, which begins this week.
The significant prognostic factors include elevated levels of the blood biomarker chromogranin A (CgA), neuroendocrine tumors that originate in the lung, bone metastases, and a World Health Organization (WHO) performance status of 1 or more.
There have not been any "great" studies of this rare form of neuroendocrine tumors that have identified prognostic factors, said Dr. Yao. The RADIANT-2 data revealed that the patient population is "quite heterogenous," he said. The newly defined prognostic factors help identify who is "likely to progress in a short time" and "who actually needs treatment."
Dr. Yao said that the reanalysis had another potentially important finding — that everolimus might be more effective in the treatment of these tumors than originally reported.
In RADIANT-2, Dr. Yao and colleagues originally showed that progression-free survival was a median of 5.1 months longer with the combination of everolimus (Afinitor, Novartis) plus the carcinoid syndrome drug octreotide (Sandostatin, Novartis) than with octreotide alone (16.4 vs 11.3 months); the study results were reported last year by Medscape Medical News.
But the phase 3 study was found to have imbalances in its patient randomization, which put more patients with a poor prognosis in the everolimus group.
After adjusting for randomization imbalances, the researchers found in an exploratory analysis that the reduction in the risk for progression in patients treated with everolimus plus octreotide was 38% (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.51 to 0.87; P = .003). This is an improvement from the 23% risk reduction seen in the first analysis. Everolimus is likely "a little more active than previously thought," said Dr. Yao. A larger study to confirm these results is planned.
It is likely that the original study had randomization imbalances because the prognostic factors needed to stratify patients were not well defined at the start of the study, said Dr. Yao in a press statement.
In short, the researchers are learning as they go.
The subset of patients most likely in need of drug therapy is "all the more meaningful" because of the "limited treatment options" with this disease, said Morton Kahlenberg, MD, from the University of Texas Health Science Center at San Antonio, who moderated the press conference.
Everolimus was approved last year by the US Food and Drug Administration for the treatment of advanced pancreatic neuroendocrine tumors. The targeted therapy sunitinib (Sutent, Pfizer and Merck) was also approved for these tumors last year.
However, it is not known whether everolimus is effective in treating neuroendocrine tumors that do not originate in the pancreas. Currently, there are no approved therapies for the oncologic control of these types of neuroendocrine tumor, said Dr. Yao.
Study Details
In RADIANT-2, Dr. Yao and colleagues sought to assess the effectiveness of the combination of everolimus plus octreotide in patients with low- or intermediate-grade neuroendocrine tumors associated with carcinoid syndrome.
In the study, 429 patients with unresectable locally advanced or distant metastatic neuroendocrine tumors were randomized to receive either oral everolimus 10 mg daily (n = 216) or placebo (n = 213), both in conjunction with intramuscular octreotide LAR (long-acting repeatable) 30 mg every 28 days. Treatment was continued until disease progression, withdrawal from treatment because of adverse effects, or withdrawal of consent.
Of these patients, 357 discontinued study treatment and 1 was lost to follow-up.
The initial analysis of the study found that median progression-free survival was 16.4 months (95% CI, 13.7 to 21.2) in the combination group and 11.3 months (95% CI, 8.4 to 14.6) in the monotherapy group (HR, 0.77; 95% CI, 0.59 to 1.00; P = .026).
In the reanalysis, the investigators identified prognostic factors that predicted both good and poor outcomes in the trial.
They now report that median progression-free survival was significantly longer for patients with nonelevated CgA (27 vs 11 months; P < .001) and nonelevated 5-HIAA (17 vs 11 months; P < .001). The analyses also indicated the prognostic potential of age (14 vs 12 years; P = .01), WHO performance status of 0 vs 1 or more (17 vs 11; P = .004), liver involvement (14 vs not reached; P = .02), bone metastases (8 vs 15; P < .001), and lung as the primary site (11 vs 14; P = .06).
A multivariate analysis found that some factors were significantly associated with a greater likelihood of neuroendocrine tumor progression.
This analysis indicated that bone involvement (HR, 1.52; 95% CI, 1.06 to 2.18; P = .02) and lung as the primary site (HR, 1.55; 95% CI, 1.01 to 2.36; P = .04) were especially strong prognostic factors for progression-free survival, and that baseline CgA (HR, 0.47; 95% CI, 0.34 to 0.65; P < .001) and WHO performance status (HR, 0.69; 95% CI, 0.52 to 0.90; P = .006) were also significant.
Randomization in the trial also resulted patient group imbalances, especially in baseline CgA (median, 251 ng/mL for everolimus plus octreotide vs 137 ng/mL for octreotide alone), Dr. Yao reported.
Other randomization imbalances also favored the octreotide group, which had more patients with a WHO performance status of 1 or more and more with lung as the primary tumor site.
Dr. Yao reports receiving research funding and honoraria from Novartis, which sponsored the trial. Other authors report receiving research funding and honoraria or being employees of and owning stock in Novartis.
2012 Gastrointestinal Cancers Symposium (GICS): Abstract 157. To be presented January 20, 2012.

INCREASED TOXICITY OF PAZOPANIB IN COMBINATION WITH CHEMOTHERAPY

2012-01-22T23:17:00.002+02:00

Br J Cancer. 2012 Jan 12. doi: 10.1038/bjc.2011.608. [Epub ahead of print]

Open-label feasibility study of pazopanib, carboplatin, and paclitaxel in women with newly diagnosed, untreated, gynaecologic tumours: a phase I/II trial of the AGO study group.

du Bois A, Vergote I, Wimberger P, Ray-Coquard I, Harter P, Curtis LB, Mitrica I.

Source

Departments of Gynecology and Gynecologic Oncology, Kliniken Essen Mitte, Henricistrasse 92, 45136 Essen, Germany.

Abstract

Introduction:Although most patients with advanced gynaecologic malignancies respond to first-line treatment with platinum-taxane doublets, a significant proportion of patients relapse. Combining targeted agents that have non-overlapping mechanisms of action with chemotherapy may potentially increase the disease-free interval. Accordingly, this study evaluated the feasibility of combining pazopanib, an oral angiogenesis inhibitor, with paclitaxel and carboplatin.Methods:This open-label, phase I/II study planned to evaluate the safety and efficacy of paclitaxel 175 mg m(-2) plus carboplatin (AUC5 (Arm A) or AUC6 (Arm B)) once in every 3 weeks for up to six cycles with either 800 or 400 mg per day pazopanib.Results:Dose-limiting toxicities (DLTs) were observed in two of the first six patients enrolled at pazopanib 800 mg plus paclitaxel 175 mg m(-2) plus carboplatin AUC5. Of the six patients enrolled in the next and lowest dosing level planned in the study, pazopanib 400 mg plus paclitaxel 175 mg m(-2) plus carboplatin AUC5, two patients also experienced DLTs and the study was terminated. Two of the 4 DLTs observed overall were gastrointestinal perforations. Severe myelotoxicity was reported in 6 of 12 patients.Conclusion:Combining either 800 or 400 mg per day pazopanib with standard carboplatin/paclitaxel chemotherapy is not a feasible treatment option

A GREEK STUDY

2012-01-22T23:16:00.002+02:00

Br J Cancer. 2012 Jan 12. doi: 10.1038/bjc.2011.594. [Epub ahead of print]

Randomised phase-II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first-line treatment of patients with unresectable/metastatic colorectal cancer (mCRC).

Souglakos J, Ziras N, Kakolyris S, Boukovinas I, Kentepozidis N, Makrantonakis P, Xynogalos S, Christophyllakis C, Kouroussis C, Vamvakas L, Georgoulias V, Polyzos A.

Source

Hellenic Oncology Research Group (HORG), 55 Lomvardou str., Athens 11470, Greece.

Abstract

Background:To compare the efficacy and safety of CAPIRI+bevacizumab (Bev) in comparison with FOLFIRI+Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC).Methods:Patients were randomised to receive either FOLFIRI plus Bev 5 mg kg(-1) every 2 weeks (Arm-A) or CAPIRI plus Bev 7.5 mg kg(-1) every 3 weeks (Arm-B).Results:Three hundred thirty-three patients (Arm-A=167; Arm-B=166) were enrolled into the study. No difference was observed in median progression-free survival (PFS) (10.0 and 8.9 months; P=0.64), overall survival (25.7 and 27.5 months; P=0.55) or response rates (45.5 and 39.8.7%; P=0.32) for FOLFIRI-Bev and CAPIRI-Bev, respectively. Patients treated with CAPIRI-Bev presented significantly higher incidence of diarrhoea (P=0.005), febrile neutropenia (P=0.003) and hand-foot skin reactions (P=0.02) compared with patients treated with FOLFIRI-Bev. Treatment delays (P=0.05), dose reduction (P<0.001) and treatment discontinuation owing to toxicity (P=0.01) occurred more frequently in the CAPIRI-Bev arm.Conclusion:The PFS of FOLFIRI-BEV is not superior to that observed with the CAPIRI-Bev regimen. CAPIRI-Bev has a less favourable toxicity profile, requiring dose reductions, in order to be considered as an option in first-line treatment of patients with mCRC.

MYC PROGNOSTIC SIGNIFICANCE IN DLBCL

2012-01-22T23:15:00.003+02:00

Cancer. 2011 Dec 27. doi: 10.1002/cncr.27396. [Epub ahead of print]

Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab.

Akyurek N, Uner A, Benekli M, Barista I.

Source

Department of Pathology, Medical Faculty, Gazi University, Ankara, Turkey. akyurek@gazi.edu.tr.

Abstract

BACKGROUND:

Diffuse large B-cell lymphomas (DLBCLs) are a biologically heterogeneous group in which various gene alterations have been reported. The aim of this study was to investigate the frequency and prognostic impact of BCL2, BCL6, and MYC rearrangements in cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP)-treated DLBCL cases.

METHODS:

Tissue microarrays were constructed from 239 cases of DLBCL, and the expressions of CD10, BCL6, MUM1/IRF4, and BCL2 were evaluated by immunohistochemistry. MYC, BCL2, and BCL6 rearrangements were investigated by interphase fluorescence in situ hybridization on tissue microarrays. Survival analysis was constructed from 145 R-CHOP-treated patients.

RESULTS:

MYC, BCL2, and BCL6 rearrangements were detected in 14 (6%), 36 (15%), and 69 (29%) of 239 DLBCL patients. Double or triple rearrangements were detected in 7 (3%) of 239 DLBCL cases. Of these, 4 had BCL2 and MYC, 2 had BCL6 and MYC, and 1 had BCL2, BCL6, and MYC rearrangements. The prognosis of these cases was extremely poor, with a median survival of 9 months. MYC rearrangement was associated with significantly worse overall survival (P = .01), especially for the cases with GC phenotype (P = .009). BCL6 rearrangement also predicted significantly shorter overall survival (P = .04), especially for the non-GC phenotype (P = .03). BCL2 rearrangement had no prognostic impact on outcome. International Prognostic Index (P = .004) and MYC rearrangement (P = .009) were independent poor prognostic factors.

CONCLUSIONS:

Analysis of MYC gene rearrangement along with BCL2 and BCL6 is critical in identifying high-risk patients with poor prognosis.

ALERT FOR BRENTUXIMAB-PML CASES REPORTED

2012-01-22T23:15:00.000+02:00

January 13, 2012 — The US Food and Drug Administration (FDA) has issued a warning to healthcare professionals about the lymphoma drug brentuximab (Adcetris, Seattle Genetics).
Two new cases of progressive multifocal leukoencephalopathy (PML), which is a rare but serious brain infection, have been reported. Because of the seriousness of PML, which can result in death, a new boxed warning highlighting this risk has been added to the drug label, according to the FDA.
In addition, a contraindication was added, warning against the use of brentuximab with the cancer drug bleomycin because of the increased risk for pulmonary toxicity.
Brentuximab was approved by the FDA in August 2011 for the treatment of Hodgkin's lymphoma and systemic anaplastic large cell lymphoma. At the time of approval, 1 case of PML was described in the warnings and precautions section of the label. So there are now 3 cases associated with the drug.
The signs and symptoms of PML can develop over the course of several weeks or months. They can include changes in mood or usual behavior; confusion; thinking problems; loss of memory; changes in vision, speech, or walking; and decreased strength or weakness on one side of the body, the FDA says.
Healthcare professionals should suspend brentuximab dosing if PML is suspected, and discontinue the drug therapy if a diagnosis of PML is confirmed, according to the FDA.
Brentuximab generated much excitement among experts when study results were presented at the American Society of Hematology annual meeting in 2010. Some of the responses seen in refractory lymphoma were described as "amazing." The new drug is the first to be approved by the FDA for Hodgkin's lymphoma in more than 30 years, the company said.
More information about today's FDA announcement is available on the agency's Web site.
To report adverse events related to brentuximab, contact MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at www.fda.gov/medwatch, or by mail to MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

ASPIRIN IN PRIMARY CVD PREVENTION-BENEFITS AND RISKS

2012-01-14T13:51:00.002+02:00

January 10, 2012 (London, United Kingdom) — A new meta-analysis said to provide "the largest evidence to date regarding the wider effects of aspirin treatment in primary prevention" has shown that cardiovascular benefits are offset by an elevated risk of bleeding [1].
Senior author Dr Kausik Ray (St George's University of London, UK) commented to heartwire : "On a routine basis I would not recommend aspirin use in primary prevention. And it certainly should not be put in a polypill for mass use."
The current study did not find a significant reduction in cancer mortality. However, the lead author of a previous meta-analysis that did show a reduction in cancer death with aspirin says follow-up in the current study was not long enough to show such an effect.
The new analysis, published online January 9, 2012 in the Archives of Internal Medicine, included nine randomized placebo-controlled trials with a total of 100 000 participants. Results showed that during a mean follow-up of six years, aspirin treatment reduced total cardiovascular events by 10%, driven primarily by a reduction in nonfatal MI, but there was a 30% increased risk of nontrivial bleeding events. The number needed to treat to prevent one cardiovascular event was 120, compared with 73 for causing a nontrivial bleed.
Effect of Aspirin on Vascular and Nonvascular Outcomes or Death

Event	Odds ratio (95% CI)
Cardiovascular events	0.90 (0.85–0.96)
Nonfatal MI	0.80 (0.67–0.96)
Cardiovascular death	0.99 (0.85–1.15)
Cancer mortality	0.93 (0.84–1.03)
Nontrivial bleed	1.31 (1.14–1.50)

Possible Benefit in Those at High Risk
The authors conclude that the "rather modest benefits" and the significant increase in risk of bleeding do not justify routine use of aspirin in the primary-prevention population. They say that further study is needed to identify subsets that may have a favorable risk/benefit ratio. They note that their results suggest an increased risk of nontrivial bleeding in individuals receiving daily (vs alternate-day) aspirin treatment and a particularly unfavorable risk/benefit ratio for individuals at lower baseline cardiovascular risk.
An editorial accompanying the paper suggests that aspirin may be considered in patients with a CHD risk of more than 1% per year [2], but Ray said he thought that was an "oversimplification" of the results.
"There may be a benefit in higher-risk individuals, and there is a case for personalized medicine here. But we showed that as the event rate increased in the placebo group, the reduction in MI with aspirin also increased, but so too did the bleeding risk. The bleeding risk is always greater than the MIs prevented, but it depends on whether you think a nonfatal MI is worse than a significant bleed. So we could do better if we knew who would bleed and who would have an event. I think we need a dual risk score as is done for warfarin."
The cardiovascular results from this latest analysis are in line with those from the 2009 Antithrombotic Trialists' (ATT) Collaboration, and there seems to be agreement on the conclusions regarding heart disease. But there is less agreement on the use of aspirin for the prevention of cancer.
Disagreement Over Cancer Data
Lead author of last year's analysis showing a reduction in cancer mortality with aspirin, Dr Peter Rothwell (University of Oxford, UK) commented to heartwire : "This new meta-analysis just looks at the overall study results, and most of the studies only had three to four years of follow-up. That is not long enough to see a major effect on cancer mortality. In contrast, in our meta-analysis published last year we obtained individual patient data and followed patients long-term after the trials had finished, and in this way we were able to show a significant and impressive effect on cancer mortality."
Rothwell estimates that it takes at least five years to show an effect on cancer deaths, "but after this point you see quite an impressive effect." He noted that the new study also included both alternate and daily aspirin trials, but "all previous work has suggested that aspirin needs to be given every day to prevent cancer."
He added: "Their results are completely compatible with our results. They did show a trend toward a reduction in cancer mortality, which we believe would have become significant if they had longer-term data or if they looked at individual patient data."
The UK newspapers were today full of reports saying there is no benefit of aspirin in cancer prevention, exactly the reverse of the headlines after Rothwell's study came out last year. Rothwell says he is concerned about this. "The message today that aspirin does not prevent cancer is premature. The current study should not change advice on taking aspirin as a healthy person. It does not offer any additional information that we don't already know. We need to think about both risk of heart disease and cancer, and in general heart disease risk is coming down while cancer risk is increasing. There does appear to be a cancer benefit with long-term use, so if there is a family history of cancer I would think about taking aspirin. We have more studies with individual patient data coming out soon that will shed more light on the issue."
More Data Coming Soon
Rothwell says official guidance on primary prevention varies from country to country. "At the moment, the guidelines on primary prevention are just focused on heart disease. They have not looked at the cancer data. There are some new guidelines due to come out over the next year, and these should start to discuss the cancer findings. "
Ray, however, is not so convinced by the cancer data. "Our meta-analysis is much larger than Rothwell's. They had 25 000 individuals whereas we have more than 100 000 patients. As usual, in this situation, when you see the bigger picture, you see 'regression to the truth.' "
Ray commented to heartwire that assuming the trend toward fewer cancer deaths in the current analysis was real, the use of aspirin would produce three and half extra nontrivial bleeds for one cancer death prevented. But he suggested that the cancer data may be biased. "Cancer often shows up as bleeding, and if you are taking aspirin, you are more likely to bleed so are more likely to be investigated, which could affect survival." He also points out that Rothwell's study mixed primary- and secondary-prevention populations, while his study looked at only healthy individuals.
He added: "The cancer data are far from certain. The major reason to give aspirin is to prevent heart attacks and strokes, and in healthy people this benefit is outweighed by the risk of bleeding. Aspirin is not the same as statins, which are known to reduce mortality in primary prevention. Aspirin doesn't affect atherosclerosis; it modifies plaque rupture, which is the final step. That is why it works better in patients with established heart disease. Primary-prevention efforts are much better directed at the basics of diet, exercise, and smoking and reducing cholesterol and blood pressure."

GENOMICS OF CHOLANGIOCARCINOMA

2012-01-14T13:49:00.000+02:00

Gastroenterology. 2011 Dec 13. [Epub ahead of print]

Genomic and Genetic Characterization of Cholangiocarcinoma Identifies Therapeutic Targets for Tyrosine Kinase Inhibitors.

Andersen JB, Spee B, Blechacz BR, Avital I, Komuta M, Barbour A, Conner EA, Roskams T, Roberts LR, Factor VM, Thorgeirsson SS.

Source

Laboratory of Experimental Carcinogenesis, NIH, Bethesda, United States.

Abstract

BACKGROUND & AIMS:

Cholangiocarcinoma is a heterogeneous disease with poor outcome that accounts for 5%-10% of primary liver cancers. We characterized its genomic and genetic features and associated these with patient outcomes response to therapy.

METHODS:

We profiled the transcriptomes from 104 surgically resected cholangiocarcinoma samples collected from patients in Australia, Europe, and USA; epithelial and stromal compartments from 23 tumors were laser-capture microdissected. We analyzed mutations in KRAS, epidermal growth factor receptor (EGFR), and BRAF in samples from 69 tumors. Changes in gene expression were validated by immunoblotting and immunohistochemistry; integrative genomics combined data from the patients with data from 7 human cholangiocarcinoma cell lines, which were then exposed to trastuzumab and lapatinib.

RESULTS:

Patients were classified into 2 subclasses, based on 5-year survival rate (72% vs 30%, ((2)=11.61; P<.0007), time to recurrence (13.7 vs 22.7 months, P<.001), and the absence or presence of KRAS mutations (24.6%), respectively. Class comparison identified 4 survival subgroups (SG I-IV; ((2)=8.34; P<.03); SGIII was characterized by genes associated with proteasomal activity and the worst prognosis. The tumor epithelium was defined by deregulation of the HER2 network and frequent overexpression of EGFR, the hepatocyte growth factor receptor (MET), pRPS6, and Ki67, whereas stroma was enriched in inflammatory cytokines. Lapatinib, an inhibitor of HER2 and EGFR, was more effective in inhibiting growth of cholangiocarcinoma cell lines than trastuzumab.

CONCLUSION:

We provide insight into the pathogenesis of cholangiocarcinoma and identify previously unrecognized subclasses of patients, based on KRAS mutations and increased levels of EGFR and HER2 signaling, who might benefit from dual-target tyrosine kinase inhibitors. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes that regulate proteasome activity, indicating new therapeutic targets.
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

PRADAXA-MORE BAD NEWS

2012-01-14T13:47:00.002+02:00

January 9, 2012 (Frankfurt, Germany and Cleveland, Ohio) — The question of MI risk with dabigatran (Pradaxa, Boehringer Ingelheim) is in the spotlight once again, with two new papers on the subject published within the last few days.
In one paper--published online on January 3, 2012 in Circulation--RE-LY investigators looked more closely at their data for any type of ischemic event and at the subgroup of patients with existing ischemic heart disease and found reassuring results for dabigatran [1]. "We have scrutinized the RE-LY data as much as we can, and I think these latest results alleviate the worry somewhat," lead author, Dr Stefan Hohnloser (J W Goethe University, Frankfurt, Germany), told heartwire .
But in the other paper, published online today in the Archives of Internal Medicine, a meta-analysis of seven trials of dabigatran appears to confirm an MI signal with the drug [2].
Data Not Conflicting?
However, lead authors of both papers agreed that they did not think the two new studies were conflicting. Hohnloser said: "There is a signal of MI with dabigatran in the RE-LY results, no question, and the same thing is seen in this new meta-analysis. We are not arguing about that. But when we look at the totality of all ischemic events in RE-LY there is no signal at all. We have also shown that the MI issue is not increased in patients with a history of ischemic heart disease, and there is a net clinical benefit of dabigatran over warfarin, regardless of whether patients have coronary heart disease or not."
Lead author of the meta-analysis, Dr Ken Uchino (Cleveland Clinic, OH) had a similar viewpoint. "Our paper shows an increase in MI when other studies are considered as well as RE-LY. And the Circulation paper looks into greater detail of those events in RE-LY and emphasizes the overall benefit of dabigatran. It is important to note that the increase in MI risk is small, and if used for AF, there is a net clinical benefit for dabigatran. When we wrote our paper, we weren't aware of this new data from RE-LY, and I think there was a concern about dabigatran in patients with ischemic heart disease. I think the Circulation paper has helped clarify that the risk of MI is not increased more in people who had a history of coronary heart disease, but the benefit of dabigatran is still there. It is reassuring on that point. On the basis of that data, I would not be concerned about using dabigatran in patients with ischemic heart disease."
However, he added: "The RE-LY data only deals with the AF population, and I think that if dabigatran is used in other indications, questions still remain and this needs more study. In the venous thromboembolism [VTE] population, the absolute risk of MI is very low, and I would doubt the benefit-risk ratio would be reversed, but I would like to see more data on this."
A Comprehensive Analysis of Ischemic Events
Hohnloser explained to heartwire that the Circulation paper was a much more comprehensive analysis of ischemic events in RE-LY. "We included all types of ischemic events--CABG, PCI, unstable angina, cardiac arrest, and cardiac death--as well as MI."
The MI numbers in RELY (previously reported) showed 80 such events in the 5983 patients in the dabigatran 110 mg group, 79 events in the 6059 patients in the dabigatran 150 mg group, and 63 events in the 5998 patients in the warfarin group. "Because the MI numbers were actually very low, we went back and added in every other type of ischemic event to give more statistical power," Hohnloser noted. Results showed no difference between the three groups.
"In addition, when you look at the totality of benefits with dabigatran--the reduction in hemorrhagic stroke, ischemic stroke, and bleeding vs the increased number of MI--there is clearly a net clinical benefit in favor of dabigatran over warfarin," Hohnloser said.
RE-LY: Cardiac Events and Net Clinical Benefit (Rate Per 100 Person-Years)

Events/benefit	Dabigatran 110 mg	Dabigatran 150 mg	Warfarin
All ischemic events	3.38	3.53	3.60
Net clinical benefit	7.34	7.11	7.91

Net clinical benefit: composite of stroke, MI, CV death, pulmonary embolism, systemic embolism, or major bleeding.
The researchers examined the timeframe over which the ischemic events in RE-LY occurred and found that one-third of events happened well after the study drug was discontinued. "So they were probably completely unrelated to the medication," Hohnloser commented.
They also looked at just those patients who had a history of coronary disease, and this group showed the same benefit in terms of stroke prevention and bleeding reduction with dabigatran vs warfarin than in those without coronary heart disease. "The net clinical benefit is in favor of dabigatran in both patients with and without coronary artery disease," Hohnloser said.
On the possible reason for the numerical increase in MIs in the dabigatran group, Hohnloser suggested that this may have been because warfarin is more effective at preventing MI than dabigatran. "Other studies have shown that warfarin is very effective at preventing MIs. It is known to be better than aspirin in this regard, but aspirin is used in preference (in CAD patients) because of all the difficulties with warfarin."
Meta-Analysis of Seven Studies
In the meta-analysis, Uchino and his colleague Dr Adrian Hernandez, combined data from seven studies of dabigatran--the RELY and PETRO trials vs warfarin in AF patients; three studies of short-term prophylaxis of deep venous thrombosis with enoxaparin as control; one study in acute VTE with warfarin as control; and one study in ACS vs placebo.
Results showed dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group.
Meta-Analysis: MI Risk With Dabigatran vs Control

End point	Dabigatran	Control	HR (95% CI)	p value
MI incidence	237/20 000 (1.19%)	83/10 514 (0.79%)	1.33 (1.03–1.71)	0.03

Commenting to heartwire , Hohnloser said: "I do believe this meta-analysis is helpful in that it is always good to have people raising safety issues so we get as much information as possible, but meta-analyses have their own problems. In this case, they have combined very different patient populations--those with AF and those with VTE. There are also different control groups--warfarin, enoxaparin, or placebo." He noted that Boehringer Ingelheim had conducted various meta-analyses and found that in trials comparing dabigatran to warfarin, there was a signal of increased MI, but in studies comparing dabigatran to enoxaparin or placebo, there was no difference in MI.
On this point, Uchino commented: "We can't say anything about MI risk in the studies which used enoxaparin and placebo as controls in isolation, as there were too few events. The increase seen in the meta-analysis could be due to a better preventative effect with warfarin, but we cannot conclude this for sure."
Hohnloser added: "The message from the meta-analysis is that there does appear to be an increased risk of MI with dabigatran vs warfarin. We would not argue with that. But if you compare all the bad things that can happen with both drugs, then dabigatran definitely has the advantage."
Editorialists Cautious
In an editorial accompanying the meta-analysis [3], Drs Jeremy Jacobs and Jochanan Stessman (Hadassah-Hebrew University Medical Center, Jerusalem, Israel) express concern about the "enthusiasm--nearly to the level of euphoria--to embrace the new, which must be restrained by the old aphorism: primum non nocere."
To heartwire , Jacobs added: "I think caution is needed with dabigatran, especially among patients with known active ischemic heart disease. High quality data from clinical use will be the way to clarify the as yet unresolved issues concerning its effect upon MI rates, and how significant this may or may not be in regard to its noninferiority for bleeding."
But Hohnloser argued: "There will always be people who are looking for reasons not to prescribe an expensive new drug, especially one like [dabigatran] that could be used in a huge amount of people, which has major cost issues. And these people will take ammunition from this meta-analysis. But they are forgetting about all the problems with warfarin and the fact that only half the patients with AF actually get it because it is so difficult to use. The Archives editorialists were not aware of our paper when they wrote their article, and if they were, I think they may have changed their conclusions somewhat."
After having seen the new data from RE-LY, Jacobs said it was "an interesting, albeit posthoc analysis, which successfully manages to smooth over the observed effect." He added: "The authors themselves suggest that a trial designed to compare cardiac outcomes might be necessary to resolve the issue."

References

A RARE MUTATION THAT INCREASE PROSTATE CANCER RISK

2012-01-14T13:46:00.000+02:00

January 11, 2012 — Researchers have discovered a "rare but recurrent" genetic mutation that is associated with a significantly higher risk for hereditary prostate cancer.
A report on the finding appears in the January 12 issue of The New England Journal of Medicine.
The discovery has no immediate impact on clinical practice because a commercial test is not available.
"Our findings need to be reproduced in additional populations before...there are sufficient data to support developing a clinical test," Kathleen Cooney, MD, one of the study's senior authors, told Medscape Medical News. She is professor of internal medicine and urology at the University of Michigan Medical School in Ann Arbor.
Still, the discovery is big news. "This is the first major genetic variant associated with inherited prostate cancer," said Dr. Cooney in a press statement.
Prostate cancer has long been identified as having a "strong familial component," but identifying a genetic basis for the phenomenon has been elusive in the past, write Dr. Cooney and her coauthors in their paper.
In their preliminary work, the investigators found that in 4 selected families with a pronounced history of prostate cancer, all 18 males with the disease had a G84E mutation in the HOXB13 gene, which is important in prostate development.
This HOXB13 G84E mutation, now also identified as rs138213197, is novel; it has not been reported elsewhere in major gene sequencing databases.
Dr. Cooney and colleagues looked for the newly documented mutation in 5083 white men who had prostate cancer (but who were unrelated to each other) and in 1401 control subjects without prostate cancer.
They found the mutation in 72 men (1.4%) with and in 1 man without (0.1%) prostate cancer. Thus, the carrier rate was 20 times higher in men with than in men without prostate cancer.
The investigators analyzed these 5083 men with prostate cancer by age at disease onset and by the presence of any history of prostate cancer in their families. The mutation was significantly more common in men with early-onset familial prostate cancer (3.1%) than in those with late-onset nonfamilial prostate cancer (0.6%) (P = 2.0 × 10⁻⁶).
The HOXB13 G84E mutation is rare, the authors point out; it apparently occurs in only 1.4% of all men with prostate cancer. However, the relative rarity of the mutation has not dampened the spirits of the investigators.
"It's what we've been looking for over the past 20 years," said William B. Isaacs, PhD, the study's other senior author. He is professor of urology and oncology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. "It's long been clear that prostate cancer can run in families, but pinpointing the underlying genetic basis has been challenging, and previous studies have provided inconsistent results."
The investigators hope that other groups will attempt to validate their findings. Dr. Cooney and her team are already doing further studies. But a test for the genetic mutation will have to overcome some hurdles, she explained.
"If our findings hold up, it may be possible to offer testing to unaffected men within a family in which the proband [the first member identified with prostate cancer] carries a HOXB13 mutation," she said.
But this is currently "premature," given the unknowns at the moment. "Because we do not know the penetrance of any of the HOXB13 mutations, we would not be able to offer clinical advice to men found to be mutation carriers. In other words, we would not be able to tell them the likelihood of being diagnosed with prostate cancer in their lifetime or if PSA testing would be useful," she said.
Other Rare Variants Could Be Found
This study might lead to more discoveries of the genetic causes of inherited prostate cancer, say the authors.
"This work suggests that future DNA sequencing studies using next-generation technology and study populations enriched for genetic influence (as evidenced by an early age at onset and positive family history) may identify additional rare variants that will contribute to familial clustering of prostate cancer," they write.
This "next-generation technology" was pivotal to the discovery of the HOXB13 G84E mutation.
Improved gene sequencing technologies allow for more "rapid and comprehensive" investigation of genomics, the authors say. In this case, the researchers sequenced the DNA of more than 200 genes in a human chromosome region known as 17q21–22. This has been "one of the most intensely investigated regions of the genome for prostate cancer susceptibility," they point out.
The study received funding support from William Gerrard, Mario Duhon, John and Jennifer Chalsty, P. Kevin Jaffe, and the Patrick C. Walsh Prostate Cancer research fund. The Department of Network and Computing Systems at TGen, with support from National Institutes of Health grants, facilitated the use of supercomputing resources.
N Engl J Med. 2012;366:141-149. Abstract

STATINS INCREASE DIABETES RISK

2012-01-14T13:43:00.001+02:00

January 9, 2012 (Boston, Massachusetts) — Statin use in postmenopausal women is associated with a significantly increased risk of diabetes mellitus, research shows [1]. New data from the Women's Health Initiative (WHI) hints that the risk of diabetes is higher than suggested by previous studies, with investigators reporting a 48% increased risk of diabetes among the women taking the lipid-lowering medications.
"With this study, what we're seeing is that the risk of diabetes is particularly high in elderly women, and this risk is much larger than was observed in another previous meta-analysis," senior investigator Dr Yunsheng Ma (University of Massachusetts Medical School, Boston) told heartwire . "For doctors treating patients, we would like them to really look at the risk-benefit analysis, especially in different age groups, such as older women."
Annie Culver (Mayo Clinic, Rochester, MN), a pharmacist and lead investigator of the study, published online January 9, 2012 in the Archives of Internal Medicine, said that "close monitoring and an individualized risk-versus-benefit assessment is really a good thing, as well as an emphasis on continued lifestyle changes." Culver added that as the population ages, and because these patients have a higher vulnerability to diabetes anyway, monitoring for diabetes in statin-treated patients becomes more important.
"I think the risk [of diabetes] is definitely there for statins," Culver told heartwire , "and I think physicians are probably aware of this risk. I think we now need more information and more research about precisely how this risk translates to different people and different populations."
Previously Published Data on Statins and Diabetes Risk
Recently published data reported by heartwire highlighted the potential risk of diabetes with statin therapy. In June, Dr Kausik Ray (St George's University of London, UK) and colleagues published a meta-analysis of PROVE-IT, A to Z, TNT, IDEAL, and SEARCH--five trials testing high-dose statin therapy--and found a significant increase in risk of diabetes with higher doses of the lipid-lowering drugs. A meta-analysis published in the Lancet in 2010 by Dr Naveed Sattar (University of Glasgow, UK) also showed that statin therapy was associated with a 9% increased risk of diabetes.
In the present study, Culver, Ma, and colleagues analyzed data from the WHI, an analysis that included 153 840 postmenopausal women aged 50–79 years old. Information about statin use was obtained at enrollment and year three; the current analysis includes data up until 2005. At baseline, 7.0% of women were taking statins, with 30% of women taking simvastatin, 27% taking lovastatin, 22% taking pravastatin, 12.5% taking fluvastatin, and 8% taking atorvastatin. During the study period, 10 242 incident cases of diabetes were reported.
In an unadjusted risk model, statin use at baseline was associated with a 71% (95% CI 1.61–1.83) increased risk of diabetes. After adjusting for potential confounding variables, the risk of diabetes associated with statin therapy declined to 48% (95% CI 1.38–1.59). The association was observed for all types of statins.
"The association between diabetes risk and statin therapy was not observed with any one type of statin, and it seems to be a class effect," said Ma.
Subgroup Risk
A significantly increased risk of diabetes was observed in white, Hispanic, and Asian women (an increased risk of 49%, 57%, and 78%, respectively). Among African Americans, who made up 8.3% of the population studied, there was a nonsignificant 18% increased diabetes risk associated with statin use at baseline. Statin use and diabetes risk was also observed in women across a range of body mass indices (BMIs <25.0, 25.0–29.9, and >30.0 kg/m²). Women with the lowest BMI (<25.0 kg/m²), appeared to be at higher risk of diabetes compared with obese women, a finding the investigators speculate is related to phenotype or hormonal differences between the women.
In an editorial [2], Dr Kirsten Johansen (University of California, San Francisco), Editor of the Archives, noted that the increased risk of diabetes in women without CVD has "important implications for the balance of risk and benefit of statins in the setting of primary prevention in which previous meta-analyses show no benefit on all-cause mortality."
Ma agreed, noting to heartwire that statins are used with increasing frequency, including in primary prevention, and--based on the JUPITER trial--in patients with normal LDL cholesterol, but elevated C-reactive protein (>2.0 mg/L). In the present study, baseline statin therapy was associated with a significant 46% and 48% increased risk of diabetes in women with CVD and without CVD, respectively.
Just 7% of women in the WHI study were taking statins in the analysis, but today that number would be significantly higher, making the potential risk of diabetes at the population level much more widespread. Ma said that physicians need to evaluate the risk of diabetes as well as the potential benefits of statin therapy in elderly female patients, and start statins after lifestyle interventions have been attempted.

ADJUVANT CHEMOTHERAPY IMPROVES PFS IN GASTRIC CANCER

2012-01-14T13:42:00.000+02:00

Lancet. 2012 Jan 6. [Epub ahead of print]

Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial.

Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, Mok YJ, Kim YH, Ji J, Yeh TS, Button P, Sirzén F, Noh SH; for the CLASSIC trial investigators.

Source

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.

Abstract

BACKGROUND:

D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II-IIIB gastric cancer.

METHODS:

The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II-IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m(2) twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m(2) on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov (NCT00411229).

FINDINGS:

1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34·2 months (25·4-41·7) in the chemotherapy and surgery group and 34·3 months (25·6-41·9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69-79) in the chemotherapy and surgery group and 59% (53-64) in the surgery only group (hazard ratio 0·56, 95% CI 0·44-0·72; p<0·0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294).

INTERPRETATION:

Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer.

A GREEK STUDY

2012-01-14T13:38:00.003+02:00

Breast Cancer Res Treat. 2011 Dec 21. [Epub ahead of print]

Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial.

Gogas H, Dafni U, Karina M, Papadimitriou C, Batistatou A, Bobos M, Kalofonos HP, Eleftheraki AG, Timotheadou E, Bafaloukos D, Christodoulou C, Markopoulos C, Briasoulis E, Papakostas P, Samantas E, Kosmidis P, Stathopoulos GP, Karanikiotis C, Pectasides D, Dimopoulos MA, Fountzilas G.

Source

1st Department of Medicine, "Laiko" General Hospital, University of Athens, Medical School, P.O. Box 14120, Athens, 11510, Greece, hgogas@hol.gr.

Abstract

To explore the impact of dose intensity (DI) in the adjuvant setting of breast cancer, a randomized phase III trial was conducted comparing postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide, methotrexate and fluorouracil (CMF)in high-risk breast cancer patients. From Oct 2000 to June 2005, 1,121 node-positive patients were randomized to dose-dense sequential epirubicin 110 mg/m(2) and paclitaxel (Taxol(®), Bristol Myers-Squibb, Princeton, NJ) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of "intensified" combination chemotherapy with CMF. By protocol design total cumulative dose and duration of treatment were identical in both groups. Dose intensity of epirubicin and paclitaxel was double in the dose-dense arm. Prophylactic treatment with granulocyte colony-stimulating factor was given with the dose-dense treatments. Disease-free survival (DFS) was the primary endpoint. At a median follow-up of 76 months, 253 patients (23%) had documented disease relapse (123 vs. 130 in groups A and B, respectively) and 208 deaths (101, group A and 107, group B) had been observed. The 5-year DFS rate of 74 and 74% and OS rate of 86 and 85% were observed for group A and group B, respectively. No differences were found in DFS or OS between the two treatment groups (P = 0.78 and P = 0.45 for DFS and OS, respectively). Safety analysis results showing that both regimens were well tolerated and safe have been previously published (Fountzilas et al. Ann Oncol 2008). No DFS or OS benefit from the dose-dense sequential epirubicin and paclitaxel was detected when compared to the concurrent administration of the same drugs. No additional safety issues were raised with long-term follow-up.

PROSTATE BIOMARKERS TO REDUCE REPEAT BIOPSIES

2012-01-14T13:37:00.003+02:00

January 12, 2012 — In men who are strongly suspected of having prostate cancer, a pair of biomarkers has the potential to prevent up to 30% of repeat biopsies after an initial negative biopsy, according to an exploratory cohort study.
The study was published online November 11, 2011, in the British Journal of Urology International.
The biomarkers identify a biochemical process in prostate tissue, known as DNA hypermethylation, and could eventually serve as an adjunct to biopsy histopathology, say the investigators, led by Bruce Trock, MD, from the Brady Urological Institute, Johns Hopkins School of Medicine, in Baltimore, Maryland.
It has been previously established that DNA hypermethylation of 2 genetic markers — known as glutathione-S-transferase P1 (GSTP1) and adenomatous polyposis coli (APC) — occurs with "high frequency" in prostate tumor tissue but is "much less common in the benign prostate," write Dr. Trock and his coauthors.
Thus, GSTP1 and APC were good candidates for study in men in a nettlesome circumstance — those with high-risk features for prostate cancer (such as an elevated prostate-specific antigen [PSA] level) but initial negative biopsy histologically.
These men often get biopsied repeatedly, even though only 10% to 36% of second biopsies detect cancer and the chance of cancer detection decreases with each subsequent round of testing, the authors report.
To identify men who can forgo repeat biopsies, methods that have a high negative predictive value (NPV) and a low false negative rate are needed, the authors point out.
Dr. Trock and colleagues noted that the APC marker looked especially promising because it has a high NPV (96%), a low false-negative rate (5%), and a high sensitivity (95%).
GSTP1 is of value because it has a higher specificity than APC, "suggesting that methods be sought to exploit the advantages of both markers," write the authors.
But they also issue a caveat that should be applied to all early, small studies: "Validation in a larger independent study is needed" to proceed to a clinical trial.
The study represents a first in this promising area of research, say the authors. "This is the first prospective study in a defined clinical cohort with rigorous inclusion criteria to evaluate the potential usefulness of DNA methylation markers to predict outcome on repeat biopsy in this clinically important cohort," they write.
The study has a number of limitations, including the fact that the threshold of APC methylation that served as the indicator of whether or not cancer was present was "determined post hoc."
The authors give fair warning about this: "Use of optimum thresholds can overstate diagnostic biomarker performance and so warrant cautious interpretation until independently validated."
Study Details
The study enrolled 86 men (40 to 75 years) from Johns Hopkins Hospital, Walter Reed Army Medical Center, and the Cleveland Clinic. They all had a high index of suspicion for a missed prostate cancer after their first biopsy.
The suspicion was based on 3 factors, leading to 3 study groups: men with suspicious digital rectal examination [DRE] or high-risk PSA level (PSA ≥ 8.0 ng/mL; and prostate volume < 50.0 mL, PSA density ≥ 0.2 ng/mL per cm³, or percent free PSA ≤ 10.0); men with high-grade prostatic intraepithelial neoplasia (HGPIN); and men with atypical small acinar proliferation (ASAP) on initial biopsy.
All of the men underwent a second (repeat) 12-core ultrasonography-guided biopsy. DNA methylation of GSTP1 and APC was determined by comparing tissue from the initial negative biopsy with that from the repeat biopsy.
On repeat biopsy, 21 of 86 (24%) men were found to have prostate cancer. In the suspicious DRE/high-risk PSA, HGPIN, and ASAP groups, the incidence was 14%, 21%, and 39%, respectively.
The authors were reassured about this incidence of cancer; it suggests that the study group was representative of American men in the study age range with a high index of suspicion for prostate cancer. "The prostate cancer rate in our study overall, and within subgroups, is consistent with values reported for similar populations," they write.
The APC and GSTP1 methylation ratios below the threshold (predicting no cancer) produced a NPV of 96% and 80%, respectively. The relative NPV was 1.2 (95% confidence interval, 1.06 to 1.36), "indicating APC has significantly higher NPV," the authors report.
APC also exhibited a higher sensitivity and NPV than the percentage of free PSA in the subset of participants with data available on PSA. This is important, explain the authors, because the percentage of free PSA "is often used to determine the need for biopsy" by clinicians.
The study was funded by Veridex (now MDx Health). Senior author Alan Partin, MD, from Johns Hopkins School of Medicine, reports receiving funding from Veridex.
Br J Urol Int. Published online November 11, 2011. Abstract

METFORMIN'S ANTITUMOR EFFECT IN OVARIAN CANCER

2012-01-14T13:37:00.000+02:00

NEW YORK (Reuters Health) Jan 06 - In a review of ovarian cancer outcomes, women with diabetes survived longer if they took metformin -- and on progression-free survival the diabetics who used metformin did better even compared to women who didn't have diabetes at all.
Dr. Iris L. Romero and colleagues from the University of Chicago, Illinois say their observations add to a "growing body of evidence" from epidemiologic and preclinical studies indicating that metformin has antitumor effects.
"There is also a biologically plausible mechanism mediating metformin's protective effect in cancer through AMPK (adenosine monophosphate-activated protein kinase) activation and inhibition of insulin signaling," Dr. Romero noted in an email to Reuters Health.
The study team looked at data on 341 women with stage I to IV epithelial ovarian (n = 273), fallopian (n = 34), or peritoneal (n = 34) cancer treated at their institution between 1992 and 2010. The cohort included 16 diabetics who used metformin and another 28 who did not.
Women received same treatment for ovarian cancer regardless of whether they had diabetes. Rates of primary cytoreductive surgery with residual disease smaller than 1 cm after surgery, the type of chemotherapy used, and the average number of chemotherapy cycles were similar among the groups. Nearly all of the women (95%) received both platinum-based and taxane-based chemotherapy, most commonly carboplatin and taxol.
But as the study team reports this month in Obstetrics and Gynecology, five-year progression-free survival rates were 51% in diabetic patients who used metformin, 8% in diabetic patients who did not use metformin, and 23% in nondiabetics (p=0.03).
Overall survival at five years was 63% in metformin users, 23% in non-metformin users and 37% in the nondiabetic group (p=0.03).
After controlling for "standard clinicopathologic parameters," metformin use remained significantly associated with progression-free survival, but not with overall survival, the investigators said.
In a survival analysis adjusted for confounding factors, comparing diabetic metformin users to diabetic nonusers, the risk of disease recurrence was significantly decreased in metformin users (hazard ratio 0.38). The metformin group also had a lower risk of dying during the study (hazard ratio 0.43), although this difference failed to reach statistical significance.
The risk of disease recurrence and death were also lower in patients with diabetes who used metformin when compared with the nondiabetic group, but this reduction was not statistically significant.
In contrast, patients with diabetes who did not take metformin were more apt to have their cancer recur (hazard ratio, 1.42) and to die of their disease (hazard ratio, 1.33) when compared with patients without diabetes.
These findings, note the researchers, are in line with other studies that have demonstrated anticancer effects of metformin in several cancers including breast, prostate, colon and ovarian cancer.
Clinical and laboratory studies have also suggested that metformin may improve response to chemotherapy. In the current study, the best response to chemotherapy occurred in metformin users, Dr. Romero and colleagues say.
Given the retrospective nature of the study, the results should be considered hypothesis-generating and should not be generalized to clinical practice, the authors emphasize.
Also, they say, the small sample size limited their ability to find a difference in survival between diabetic metformin users and nondiabetic patients and kept them from analyzing the effects of diabetic medications other than metformin. Furthermore, the researchers could not control for diabetes severity.
Despite these limitations, the researchers say the idea that specific anti-diabetes treatments affect cancer survival is clinically relevant given the increasing prevalence of diabetes.
The World Health Organization estimates that 171 million people worldwide have type 2 diabetes, a number that is expected to double by 2030.
"If future studies continue to support the protective effect of metformin in cancer, then this will be an important consideration when managing diabetic patients with cancer," Dr. Romero and colleagues conclude.
"It is also important to note that metformin has a strong track record of safety, is inexpensive and is already widely used," Dr. Romero told Reuters Health.
She added that prospective randomized clinical trials are needed looking at metformin as chemoprevention for patients at high-risk of developing ovarian cancer and as adjuvant treatment and maintenance during and after chemotherapy. Such trials are already under way in breast cancer, she said.
The study was supported by grants from the National Institutes of Health and the Gynecologic Cancer Foundation/St. Louis Ovarian Cancer Awareness. The authors have disclosed no relevant conflicts of interest.
SOURCE: http://bit.ly/A9smFS
Obstet Gynecol 2012;119:61-67.

CARBOPLATIN PHARMACOKINETICS IN HEMODIALYSIS PATIENTS

2012-01-14T13:36:00.000+02:00

Cancer Chemother Pharmacol. 2011 Dec 23. [Epub ahead of print]

Pharmacokinetics of carboplatin in a hemodialysis patient with small-cell lung cancer.

Hiraike M, Hiraki Y, Misumi N, Hanada K, Tsuji Y, Kamimura H, Karube Y, Kashiwabara K.

Source

Department of Pharmacy, National Hospital Organization Kumamoto Medical Center, 1-5 Ninomaru, Kumamoto, Kumamoto, 860-0008, Japan, hiraike@kumamoto2.hosp.go.jp.

Abstract

PURPOSE:

We examined a method to determine the dose of carboplatin and the timing of hemodialysis in carboplatin-based chemotherapy for a hemodialysis patient with cancer.

METHODS:

Carboplatin-based chemotherapy was performed for a patient with small-cell lung cancer who was receiving hemodialysis. The dose of carboplatin was calculated based on body surface area in the first cycle (480 mg/body, Day 1) and based on the Calvert formula with the aim of achieving AUC of 5 mg/ml min in the second cycle (170 mg/body, Day 1). Carboplatin was continuously infused for 1 h on Day 1 of each cycle. Hemodialysis was performed for 4 h beginning 1 h after administration of carboplatin.

RESULTS:

The AUC of free carboplatin administered in the first and second cycles was 13.45 and 5.74 mg/ml min, respectively, and t (1/2) was 24.66 and 21.84 h, respectively. Protein binding ratio depended on the time after administration and reached a value ≥50% only at ≥24 h administration.

CONCLUSION:

Based on the results of this study, a value close to the targeted AUC can be obtained in a hemodialysis patient with cancer when carboplatin is administered at a dose determined based on the Calvert formula. These results may be useful to achieve a targeted AUC in hemodialysis patients. A certain amount of carboplatin can be eliminated by performing hemodialysis in an early phase when protein binding ratio is low after transition to the elimination phase to enable stable the concentration.

IT RUNS INTO THE GENES-A GREEK DOCTOR IN FLORIDA

2012-01-14T13:34:00.001+02:00

January 6, 2012 (Bonita Springs, Florida) — Florida cardiologist, Dr Zannos Grekos (Regenocyte Therapeutic, Bonita Springs, FL), stands accused of contributing to a patient's death by administering an unjustified stem-cell therapy. In the latest twist in the case, Florida Department of Health (FDOH) lawyers are questioning whether the patient ever signed off on the novel therapy in the first place.
In a formal complaint filed in August, the FDOH states that Grekos treated a 69-year-old patient who had breast cancer and 0% to 29% bilateral stenosis of the carotid arteries with an "experimental stem-cell procedure" that included injecting autologous bone-marrow aspirate into the patient's cerebral circulation. The patient was discharged without fully waking from sedation, the complaint alleges, and then later fell and hit her head at home. She died in the hospital soon after, and CT scan and MRIs confirmed the presence of a severe brain stem injury and infarct of the cerebellum. The complaint states that the patient's death resulted from the infarcts of her left cerebella and left medulla.
The FDOH alleges "the treatment provided by Dr Grekos to [the patient] was neither authorized nor recognized by the Federal Drug Administration, [and] Dr Grekos's medical records did not contain medical justification for the injection of autologous bone-marrow aspirate into [the patient's] cerebral circulation as a treatment for [her] neuropathy. Dr Grekos's treatment of [the patient's] neuropathy by the injection of autologous bone-marrow aspirate into the cerebellar circulation had no substantiated medical and/or scientific value."
The FDOH is asking the state's board of medicine to either permanently revoke or suspend Grekos's license and administer fines or "any other relief that the board deems appropriate."
In February 2011, the FDOH issued Grekos an emergency restriction order. The order restricts Grekos from "providing any stem-cell treatment, including but not limited to the injection of autologous bone-marrow aspirate." The order does not bar Grekos from seeing patients if he does not provide the restricted treatment.
The case is working its way through an administrative court in Tallahassee, FL. On January 4, Administrative Law Judge Susan Belyeu Kirkland agreed to schedule the final hearing on the case for March 20–23. Grekos's attorney Richard Brooderson had asked the judge to move the hearing back from the original dates of January 18–20 because of issues that arose during discovery that require Grekos's lawyers to hire additional experts to help mount a defense.
As reported by Naples Daily News, one of the important issues that arose in the depositions is that the husband of the deceased patient believes the signature on certain key documents, including the patient informed-consent form, is not the patient's signature. So Brooderson and the FDOH will both likely be hiring handwriting experts to testify [1].
The lawyers for the FDOH and Grekos have not yet responded to heartwire 's request for comments.

References

ANOTHER URBAN LEGEND-GnRH AGONISTS TO REDUCE INFERTILITY RISK OF CHEMOTHERAPY

2012-01-14T13:33:00.002+02:00

January 12, 2012 — Infertility as a result of chemotherapy for breast cancer is not improved with the use of a gonadotropin-releasing hormone (GnRH) agonist, according to a new study.
In the Suppression of Ovarian Function With Triptorelin (SOFT) trial, the rate of premature menopause among women treated with a GnRH agonist was similar to that in the control group. The trial was stopped early because of futility, and the researchers conclude that this approach "should not be recommended."
The SOFT results were published online January 9 in the Journal of Clinical Oncology.
This negative trial joins 2 others that also failed to show a benefit with GnRH agonists, although these 3 negative trials are in contrast to 2 others that were positive, according to an accompanying editorial. In view of these conflicting data, the role of ovarian suppression through chemotherapy "remains uncertain," writes the editorialist, Ann Partridge, MD, from the Dana-Farber Cancer Institute and Brigham and Women's Hospital in Boston, Massachusetts.
Results From the SOFT Trial
The SOFT trial, conducted by Pamela Munster, MD, from the University of California, San Francisco, and colleagues, originally aimed to enroll 124 patients, but it was stopped after 49 patients were enrolled.
The participants were premenopausal women younger than 45 years who had been newly diagnosed with early-stage breast cancer (stage I to III). All the women received 1 of 4 adjuvant chemotherapy regimens: AC (4 cycles of doxorubicin plus cyclophosphamide), AC-T (4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of a taxane), FEC (6 cycles of fluorouracil plus epirubicin plus cyclophosphamide), or FAC (6 cycles of fluorouracil plus doxorubicin plus cyclophosphamide).
In addition, women with estrogen-receptor-positive tumors were offered tamoxifen.
Study patients in the treatment group received an intramuscular injection of the GnRH agonist triptorelin (Trelstar Depot) 3.75 mg every 28 to 30 days, starting before and continuing throughout the chemotherapy.
When the trial was halted, there was an imbalance in the number of patients available for analysis between the triptorelin group and the control group (26 vs 21).
The median follow-up was 18 months (range, 5 to 43 months) after completion of chemotherapy.
There was no difference in the rate of amenorrhea between the triptorelin and control groups (10% vs 12%). Three women in the triptorelin group and 2 in the control group stopped menstruating and their menses did not return; all 5 were taking tamoxifen.
For many of the remaining patients, menstruation stopped and then restarted. The median time to return of menses was 5.8 months in the triptorelin group and 5.0 months in the control group; the difference was not statistically significant (P = .58). One woman in the triptorelin group and 5 in the control group continued to menstruate throughout the trial.
Two of the patients in the control group subsequently became pregnant, which resulted in unassisted and normal-term deliveries. No pregnancies or miscarriages were reported in the triptorelin group.

"These results suggest that use of GnRH agonists in premenopausal patients treated with contemporary (neo)adjuvant chemotherapy does not offer a benefit in preserving ovarian function, compared with patients not treated with GnRH agonists, and it should not be recommended," Dr. Munster and colleagues conclude.
Mixed Results From Other Trials
The approach of using GnRH agonists to suppress ovulation during chemotherapy was based on several nonrandomized phase 2 studies, which had reported high rates (67% to 90%) of preserved menstruation in treated patients, the researchers note.
"Our data are consistent with these findings," they note: 88% of women receiving triptorelin resumed menstruation. However, this study was randomized and found no difference between patients in the triptorelin group and those in the control group (90% of women resumed menses).
Results from other randomized trials have been mixed. "This study is 1 of 6 recently completed or ongoing trials that have been designed to address this important question," notes the editorialist, adding that 2 other randomized trials have also shown no clear benefit.
The recently published results from the Zoladex Rescue of Ovarian Function (ZORO) trial (J Clin Oncol. 2011;29:2334-2341), which involved 60 women with hormone-negative breast cancer, found a nonsignificant difference in the rate of menses resumption between women in the goserelin (Zoladex) group and those in the control group (70.0% vs 56.7%; P = .42). Two women in each group became pregnant.
In addition, preliminary data from the Ovarian Protection Trial in Estrogen Negative (OPTION) study, which involved 140 women and also used goserelin, showed no clear benefit (J Clin Oncol. 2010;28[suppl]:15s [abstr 590]). In fact, in the subgroup of women who were younger than 40 years, the treatment group fared worse; at 12-month follow-up, 34.7% of women in the goserelin group had not resumed menses, compared with 15.8% in the control group (P ≤ .05).
Dr. Munster and colleagues note that the negative results from the SOFT trial were similar to those from the ZORO and OPTION trials, which "support our findings that GnRH agonists do not preserve ovarian function as measured by resumption of menses."
However, there have also been 2 positive studies reported.
One of these positive trials, conducted in Italy by the Gruppo Italiono Mammella, involved 281 patients and used triptorelin (JAMA. 2011;306:269-276). The researchers report a significant (17%) difference with treatment — 25.9% of women in the goserelin group had early menopause, compared with only 8.9% in the triptorelin group (P < .001).
The other positive trial was reported a few years ago (Fertil Steril. 2009;91:694-697). It involved 78 women and used goserelin. The researchers reported that within 3 to 8 months of treatment termination, 89.6% of women resumed menses and 69.2% resumed spontaneous ovulation in the goserelin group, compared with 33.3% and 25.6%, respectively, in the control group,.
One randomized trial is still ongoing — the Prevention of Early Menopause (POEMS), in women with hormone-receptor-negative breast cancer.
In view of the conflicting data, and while mature results from ongoing studies are awaited, the role of this treatment approach remains "uncertain," Dr. Partridge notes in her editorial.
"Given the current level of evidence, women who are interested in future fertility, and the providers who are assisting them in these often difficult decisions, should not rely on GnRH agonist treatment during chemotherapy for preservation of menstrual and ovarian function or fertility," she concludes.
The SOFT trial was supported by a grant from the National Cancer Institute. Dr. Munster reports receiving research funding from Pfizer. Dr. Partridge has disclosed no relevant financial relationships.
J Clin Oncol. Published online January 9, 2012. Abstract, Editorial

RADIOTHERAPY FOR N+ GASRIC CANCER IMPROVES PFS

2012-01-14T13:31:00.000+02:00

NEW YORK (Reuters Health) Jan 10 - Adding radiotherapy to capecitabine-cisplatin chemotherapy after complete resection of gastric cancer did not significantly improve disease-free survival for most patients in the ARTIST trial.
The randomized study, by Dr. Won Ki Kang from Sungkyunkwan University School of Medicine in Seoul, Korea and colleagues, involved 458 patients.
The researchers reported online December 19 in the Journal of Clinical Oncology that 75.4% of patients in the chemotherapy-only arm and 81.7% in the chemoradiotherapy arm completed treatment as planned.
After a median follow-up of 53.2 months, there were 55 recurrence events in the chemoradiation group and 72 in the chemotherapy group. The estimated three-year disease-free survival rates were 78.2% with radiation and 74.2% without it (P=0.0862).
For the 396 patients with positive lymph nodes, however, three-year disease-free survival was significantly higher with chemoradiotherapy (77.5% vs 72.3%; P=0.0365).
"Because these findings were from a subgroup analysis, the data should be interpreted with caution," the researchers warn. They say they're planning "a subsequent phase III trial (ARTIST-II) to compare chemotherapy versus chemotherapy with radiotherapy in patients with D2 lymph node dissection and pathologic lymph node-positive disease... to confirm the benefit of adjuvant chemoradiotherapy."
Rates of locoregional recurrence and distant metastases did not differ significantly between the treatment arms.
Grade 3 or 4 vomiting, stomatitis, hand-foot syndrome, and diarrhea occurred in up to 12% of patients in both study arms. Grade 4 neutropenia affected 5.7% of patients in the chemotherapy arm and 4.8% in the chemoradiotherapy arm.
There were two treatment-related deaths, one from neutropenic septic shock during chemotherapy and one from non-neutropenic pneumonia in the chemoradiotherapy group.
"The postoperative capecitabine-cisplatin regimen was well tolerated, and the safety data presented here are comparable to those observed in a previous study of the capecitabine-cisplatin regimen in patients with advanced gastric cancer," the investigators conclude. "Patients in the ARTIST trial will continue to be observed for recurrence and survival."
SOURCE: http://bit.ly/zwBazO
J Clin Oncol 2011.

GENETIC SIGNATURES-RETRACTIONS CONTINUE

2012-01-14T13:29:00.001+02:00

By Ivan Oransky, MD
NEW YORK (Reuters Health) Jan 09 - In a reminder of how much a once-heralded area of cancer research has crumbled, a former Duke oncologist and his colleagues issued their eighth study retraction late last week.
Like the others, it was related to validation of gene signatures that predict treatment outcomes.
On Friday, Dr. Anil Potti and his co-authors formally withdrew a 2008 study in the Journal of the American Medical Association that purported to offer a genetic signature that would show which patients with breast cancer would respond to a particular treatment.
The authors write in a statement on the JAMA website -- available at http://bit.ly/AeIufY -- that they are retracting the paper because it was based on a method they now believe is unreliable. That approach -- which no one has been able to reproduce -- was described in a now-withdrawn paper in the journal Nature Medicine in 2006.
The case is yet another example of researchers -- some with financial interests in the results -- being overly enthusiastic about findings that did not hold up to scrutiny.
The retraction by Dr. Potti is the eighth of what Duke officials said this past summer would be about a dozen - most related to genetic signatures for lung cancer -- along with another dozen corrections and partial retractions. The Duke team had published about 40 papers, many of which have been cited hundreds of times by other scientists, according to Thomson Scientific's Web of Knowledge.
One of the retractions was of a 2006 paper in Blood that claimed to identify a gene expression profile linked to antiphospholipid antibody syndrome accompanied by venous thrombosis. Reuters Health originally reported on that paper on March 23, 2006.
The now-retracted JAMA study garnered a fair amount of media coverage, too, including a story by Reuters Health on April 1, 2008.
Journals and universities began subjecting Dr. Potti's work to intense scrutiny, however, after it emerged that he had claimed awards and scholarships that he never received, in biographical sketches for grant applications.
The whole episode has been a "huge setback," said Dr. Otis Brawley, chief medical officer of the American Cancer Society.
"What happened at Duke is that you have a whole bunch of folks worried that this genomic information is just too complicated, making it too easy for someone to basically create fraudulent science," Dr. Brawley told Reuters Health.
UNDONE BY RESUME 'INACCURACIES'
Dr. Keith Baggerly, who studies genomics at the M.D. Anderson Cancer Center in Houston, has been looking into the Duke team's data since shortly after the Nature Medicine report came out. At that time, a colleague excitedly approached Dr. Baggerly and Dr. Kevin Coombes, hoping to use the work to improve the treatment of patients at M.D. Anderson.
But Drs. Baggerly and Coombes found numerous problems in the research, including mislabeling of data. They began asking Dr. Potti's group for the data, but the Duke team was slow to respond. Eventually, some journals began publishing critiques by Baggerly and Coombes, often alongside defenses of the work by Dr. Potti and his colleagues. Meanwhile, clinical trials making use of the genetic signature continued at Duke.
Questions from Dr. Baggerly and Dr. Coombes went largely unheeded until July 2010, when The Cancer Letter, a trade publication, reported that Dr. Potti had falsely claimed to be a Rhodes Scholar on an American Cancer Society grant application. Within months, the trials were halted, and Duke returned $729,000 to the cancer organization.
Dr. Potti resigned from Duke in November 2010, and has since joined a private oncology practice with offices in North Carolina and South Carolina. He and his colleagues, along with Duke, face two lawsuits from nine patients who took part in the trials. Eleven other such cases have already been settled for at least $75,000 each, according to the North Carolina Medical Board, which reprimanded Dr. Potti for the "inaccuracies" on his biographical sketch and CV.
According to the JAMA retraction notice, Dr. Potti works at the Myrtle Beach, South Carolina office of Coastal Cancer Center. But a person answering the phone there said he did not work in that office and was unavailable because he was in clinic.
For plaintiffs' attorneys, proving that patients were actually harmed by being in the trials will be difficult, said Dr. Brawley.
"I don't myself think that patients were harmed by being steered to a particular chemotherapy, at one level," he said. The choices in the trial were widely accepted therapies that their own doctors would have likely given them.
That wasn't the only risk, however.
"I'm a little bit concerned that some of the patients may have gone back and had new biopsies, for new analysis in the laboratory," Dr. Brawley said. "If that was purely for this trial, those were unnecessary procedures, with risks. I hope no one was harmed by that."
MOVING FORWARD
The episode is fueling soul-searching at Federal agencies.
There are "some positive things coming out of this whole mess," Dr. Baggerly said. For example, the U.S. Institute of Medicine (IOM) may require genetic tools such as the one the Duke team used to go through the same approvals that a medical device would go through at the Food and Drug Administration.
A report by the IOM is expected out in the next few months, and there are similar changes being considered at the National Cancer Institute -- which funded some of the Duke team's work -- and the Food and Drug Administration. Duke itself has created a team to establish new safeguards as genetic research moves into the clinic.
But the dark lessons remain.
"To a certain extent, what I'm worried about is that this may show aspects of how it is becoming increasingly difficult to check the scientific literature and how that difficulty stems at least in part from lack of immediate access to data but also lack of code and documentation," Dr. Baggerly told Reuters Health.
Given the highly technical nature of the work, it's not surprising that the flaws in the papers weren't caught before they were published, according to Dr. Baggerly.
"That's actually OK," he said. "It's not OK that it took so long for the challenges to be accepted once the research was questioned."
"The other thing that is not OK is the fact that it made it into guiding clinical trials," Dr. Baggerly added.
Dr. Brawley said the story "is a tragedy in a number of different ways."
"I'm actually more concerned right now with the systemic issue across the country that it's up to universities to police their researchers," he said. "But as science progresses, those universities are more and more interested in how many patents they have, and how many licenses they have for those patents."
"The universities that are responsible for assuring academic integrity actually have a conflict of interest," said Dr. Brawley, pointing out that Duke had an ownership stake in CancerGuide Diagnostics (formerly Oncogenomics, Inc.).
CancerGuide, which cut ties with Dr. Potti in July 2010 after the Rhodes misrepresentation came to light, had licensed technology based on his work at Duke, the student newspaper The Duke Chronicle reported in 2010. Duke has since divested from the company.
'A 21ST CENTURY DEFINITION OF CANCER'
Despite the setback, cancer treatment will continue to make more and more use of genetic information, Dr. Brawley said. Oncologists already use tools such as the OncotypeDX genetic test to tailor treatments for breast cancer and colon cancer.
"Since the 1840s, we've been using a light microscope to define cancer," he said. "Now with all the other advances we have, even the needle biopsy, we often find a one-centimeter tumor, and we're saying 'this looks like cancer,' according to a 19th-century definition. What we need is a 21st century definition of cancer."
"We've got these new tools, and people are very excited about using them," Dr. Baggerly said. "Some of these genetic level screw-ups are indeed what cause the disease, so there is the potential there. That said, some of the initial claims about how quickly we're going to be able to turn these (findings) into clinically useful assays have been overoptimistic."
"We're going to get there, but a number of the early studies thought this would be an easy problem," he said. "The biology turns out to be quite complex."

LOCOREGIONAL TREATMENT OF STAGE IV BREAST CANCER DEBATE

2012-01-14T13:28:00.000+02:00

From Expert Review of Anticancer Therapy

A Debate on Locoregional Treatment of the Primary Tumor in Patients Presenting With Stage IV Breast Cancer

David H Nguyen; Pauline T Truong

Key Issues

With improved survival with modern systemic treatment for metastatic breast cancer, the incentive to avoid adverse effects of uncontrolled locoregional disease in patients with stage IV breast cancer has increased.
Locoregional treatment of the primary breast disease has the potential to improve locoregional control in patients with metastatic breast cancer.
Some retrospective registry-based studies and institutional series suggest an association between locoregional treatment and improved survival. However, the results must be interpreted with caution due to selection bias and limited ability to control for confounding factors.
The available data suggest that locoregional treatment may be considered in subsets with favorable clinicopathologic characteristics, including young age, good performance status, estrogen receptor-positive tumors, bone-only involvement or limited metastatic disease burden.
Consensus is lacking regarding the optimal timing of locoregional treatment relative to systemic therapy.
Prospective randomized controlled trials are underway internationally to address this clinically relevant debate.

BENEFITS AND HARMS OF CHEMOTHERAPY FOR AML TREATMENT

2012-01-14T13:26:00.000+02:00

January 13, 2012 — New research into the behavior of leukemic cells during and after treatment has led to some "very interesting and provocative" observations about they way acute myeloid leukemia (AML) evolves, according to one of the researchers involved.
Although there are no immediate therapeutic implications from the research, the study opens up a "Pandora's box of questions, and we will need to test various new hypotheses," senior author John DiPersio, MD, PhD, chief of the division of oncology at the Washington University School of Medicine, St Louis, Missouri, said in an interview.
The research was published online January 11 in Nature.
The study involved 8 patients with AML, all of whom received cytarabine and anthracycline for induction therapy and additional cytotoxic chemotherapy for consolidation. All 8 patients subsequently relapsed.
The researchers sequenced the genomes of leukemic cells taken before and after chemotherapy, and compared them with each other and with healthy cells taken from each patient before chemotherapy (to act as a control).
The results suggest that chemotherapy damages the DNA in leukemic cells and leads to new mutations. "The mutations in AML patients who have relapsed are different from those present in the primary tumor, and they are more likely to have a tell-tale signature of DNA damage," Dr. DiPersio said in a statement.
"This suggests that the mutations in relapsed cells are influenced by the chemotherapy drugs the patients receive," he added.
However, causality has not been proven, Dr. DiPersio emphasized to Medscape Medical News. The new mutations observed in relapse occurred after the patients received chemotherapy, but it is not proven that they were caused by chemotherapy, he elaborated.
That is suspected to be the case, but to prove it they will have to study other drugs that have different modes of action, he said, such as hypomethylating agents like azacitidine and the novel agent lenalidomide, which are already used in the treatment of AML in elderly patients.
Different Mutations on Relapse
Chemotherapy offers a very successful treatment for AML, Dr. DiPersio continued. In patients younger than 60 years of age, it results in a cure in more than 40% of patients. However, for the other patients, a remission is usually followed at some stage by a relapse, sometimes several relapses, and eventually death.
It is this relapse phenomenon that the new research helps explain. The genome sequencing revealed 2 major patterns of evolution of leukemic cells.
In this study, all 8 patients studied had a single founding clone of cells, all with the same mutations. In all cases, chemotherapy failed to eradicate the founding clone, the cluster of leukemic cells that drive the disease.
The genome sequencing revealed that in some patients, this founding clone developed new mutations that enabled it to survive chemotherapy and to evolve into a new clone. However, in other patients, a subclone broke off from the founding clone, developed new mutations, and evolved to become the dominant clone at relapse.
"It's the same tumor coming back but with a twist," explained coauthor Richard Wilson, PhD, director of the Genome Institute at Washington University School of Medicine.
"It's always the founding clone or a subclone that comes back with new mutations that give the cells new strategies for surviving attack by whatever drugs are thrown at them. This makes a lot of sense, but it's been hard to prove without whole-genome sequencing," he added in a statement.
"Our preconceived notion of the clonal evolution of AML and other cancers has been altered by our study, which suggests that it is much more complicated and dynamic than we initially suspected, and can even be affected by the therapy that is given to treat the disease," Dr. DiPersio explained.
"Chemotherapy drugs are absolutely necessary to get leukemia patients into remission, but we also pay a price in terms of DNA damage," coauthor Timothy Ley, MD, professor of oncology at Washington University, said in a statement.
The findings reach beyond AML, he suggested. Chemotherapy might contribute to disease progression and relapse in many different cancers, he said, "which is why our long-term goal is to find targeted therapies based on the mutations specific to a patients' cancer, rather than to use drugs that further damage DNA."
The study was funded by the National Human Genome Research Institute, the National Cancer Institute, and the Barnes-Jewish Hospital Foundation. The authors have disclosed no relevant financial relationships.
Nature. Published online January 11, 2012. Abstract

NO BENEFIT OF ROBOT PROSTATECTOMY (ONLY FOR SURGEON WALLET)

2012-01-14T13:25:00.001+02:00

NEW YORK (Reuters Health) Jan 09 - In a recent survey, men who had robotic surgery for prostate cancer and men who had lower-tech surgeries were equally likely to have sexual problems and urinary leakage afterward.
"I wasn't surprised at all," said Dr. Otis Brawley, chief medical officer of the American Cancer Society, who wasn't involved in the study.
"Unfortunately, robotic prostatectomy -- like many things in prostate cancer -- has gotten a lot more hype than it should."
Robotic prostatectomy has caught on rapidly in the U.S., despite the fact that there isn't enough data to prove it's better than traditional approaches. It is, however, much more costly, adding some $2,000 in hospital costs per procedure.
The new study, published online January 3 in the Journal of Clinical Oncology, is based on responses from more than 600 prostate cancer patients on Medicare, including roughly 400 who had robotic-assisted laparoscopic prostatectomy.
Nearly 90% had a moderate or major problem with sexual functioning 14 months after their surgery, Dr. Michael Barry of Massachusetts General Hospital in Boston and colleagues found. And about 33% reported incontinence afterward.
Overall, there were no differences between the two patient groups, although urinary problems appeared to be slightly more common after the robot procedure.
An editorial in the journal called the findings "sobering" but added that it's hard to compare the two procedures directly based on the survey results. It's possible, for instance, that men with high hopes for the robot procedure would be particularly bothered by side effects afterward.
"The problem that is revealed in this paper is this question of expectations," said Dr. Matthew Cooperberg, a urologist who co-wrote the editorial. "There is a known issue of regret related to robotic surgery."
Part of the problem is heavy promotion, which has catapulted robot surgery to its current status. Out of the tens of thousands prostate removals done annually in the US, some 85% are estimated to be robotic.
"To an extent it's the manufacturer, to an extent it's surgeons, to an extent it's a culture that tends to put great faith in technology, even when the patient doesn't understand it," Dr. Cooperberg, of the University of California, San Francisco, told Reuters Health.
The robots, which cost a couple of million dollars each, do have some advantages, such as less blood loss. But Dr. Cooperberg, who uses the technology himself, readily acknowledges that it probably doesn't treat cancer any better than the old surgery and doesn't have proven benefit in terms of side effects.
SOURCES: http://bit.ly/wf5iCM and http://bit.ly/wf5iCM
J Clin Oncol 2012.

TKIs MAY BE CAN BE STOPPED IN SOME RENAL CANCER PATIENTS

2012-01-14T13:23:00.001+02:00

NEW YORK (Reuters Health) Jan 10 - Patients with less aggressive metastatic renal cell carcinoma may be able to discontinue treatment with vascular endothelial growth factor (VEGF)-targeted agents, a new study suggests.
"These data support a hypothesis that there may be a select group of metastatic renal cell carcinoma patients who can safely hold VEGF-targeted therapy and maintain disease control off therapy for a reasonable period of time," Dr. Brian I. Rini, from Ohio's Cleveland Clinic, told Reuters Health by email.
"Such a strategy," he added, "takes advantage of a more indolent underlying disease biology in these patients, with the advantage of reduced toxicity while off therapy."
In a December 2 online paper in Cancer, Dr. Rini and colleagues report on 40 patients who discontinued VEGF-targeted therapy. All had clear cell histology, and all had stable disease or better. The median duration of VEGF-targeted therapy was 14.6 months (range, 2.8 to 79). The drugs were stopped mainly due to toxicity (in 73%); no one stopped because of disease progression.
Median progression-free survival overall was 13.5 months. Twenty-five patients (63%) had disease progression, after a median interval of 10 months. In eight of these patients (32%), progression occurred at sites that were not previously involved, but there was no evidence of rapid disease progression in any patient.
Seventeen patients with progression were treated with local and systemic therapies. The other eight patients "chose to continue expectant management given the low volume and pace of disease," the authors reported.
The 15 patients with no progression also continued to be managed expectantly.
The researchers conclude that in patients achieving at least stable disease on VEGF-targeted therapy, a select subset "can be observed off therapy."
More specifically, they said, "only more favorable Heng risk group" -- which takes into account anemia, thrombocytosis, neutrophilia, hypercalcemia, Karnofsky performance status and time from diagnosis to treatment -- "and achievement of a complete response prior to discontinuing therapy were independent predictors of a longer progression-free survival off therapy."
SOURCE: http://bit.ly/AlR8Gm
Cancer 2011.

PROVING THE OBVIOUS-LIVING NEAR NUCLEAR PLANTS INCREASE LEUKEMIA RISK

2012-01-14T13:22:00.002+02:00

PARIS (Reuters) Jan 11 - The incidence of leukemia is twice as high in children living close to French nuclear power plants as in those living elsewhere in the country, a study by French health and nuclear safety experts has found.
But the study, released online January 5 in the International Journal of Cancer, fell short of establishing a causal link between the higher incidence of leukemia and living near nuclear power plants.
France has used nuclear power for three decades and is the most nuclear-reliant country in the world, with 75% of its electricity produced by 58 reactors.
The study, conducted by the French health research body INSERM, found that between 2002 and 2007, 14 children under the age of 15 living in a five-kilometer radius of France's 19 nuclear power plants had been diagnosed with leukemia.
This is double the rate of the rest of the country, where a total of 2,753 cases were diagnosed in the same period.
"This is a result which has been checked thoroughly and which is statistically significant," said Dominique Laurier, head of the epidemiology research laboratory at France's nuclear safety research body (IRSN).
INSERM has carried out similar research with the IRSN since 1990, but has never before found a higher incidence of leukemia in children living near nuclear power plants.
"But we are working on numbers which are very small and results have to be analyzed with a lot of care," said Laurier, one of the authors of the study.
Laurier said the findings indicated no difference in risk between sites located by the sea or by rivers, nor according to the power capacity of the plant.
The IRSN said it recommended a more thorough study of the causes of the leukemia cases found near nuclear power stations and hoped to set up international research collaboration.
"It's a rare disease and working on a bigger scale would allow more stable results," said Laurier.
A 35-year British study published last year found no evidence that young children living near nuclear power plants had an increased risk of developing leukemia.
That research, conducted by scientists on the Committee of the Medical Aspects of Radiation in the Environment (COMARE), found only 20 cases of childhood leukemia within 5 km (3.1 miles) of nuclear power stations between 1969 and 2004.
The scientists said the rate was virtually the same as in areas where there were no nuclear plants.
Studies have been conducted around the world into possible links between the risk of childhood blood cancers and living near nuclear plants.
A study on Germany, published in 2007, did find a significantly increased risk, but the COMARE team said these findings were probably influenced by an unexplained leukemia cluster near a nuclear plant in Krummel, northern Germany, that lasted from 1990 to 2005.
Excluding Krummel, evidence for an increased leukemia risk among young children living close to German nuclear power plants was "extremely weak," it said.
SOURCE: http://bit.ly/AvmVdX
Int J Cancer 2012.

PSA SCREENING DEBATE CONTINUES

2012-01-14T13:21:00.000+02:00

January 6, 2012 — New longer-term follow-up from the American Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) Trial continues to indicate that annual prostate-specific antigen (PSA) screening for 6 consecutive years does not provide men with a mortality benefit.
The massive study now has 13-year data on 57% of the men who originally enrolled. The updated data are reported online today in the Journal of the National Cancer Institute.
Despite this conclusion, the study's senior author said in an interview with Medscape Medical News this week that "maybe there is a benefit."
"The lack of a reduction in mortality could be explained, in part, by screening in the control arm," said Philip Prorok, PhD, from the National Institutes of Health in Bethesda, Maryland.
Dr. Prorok reported that the 76,000-men trial "didn't have a pure control group," that many of men in the control group underwent PSA testing, and that some might have gained a mortality benefit from the testing and subsequent biopsy and treatment.
The investigators did not plan it that way.
Dr. Prorok explained that, beginning in 1993, men were randomized to an intervention group (receiving annual PSA tests for 6 years and 4 digital rectal exams) or to a control group (receiving no testing). But then "PSA testing took off" in the United States, he said. By year 6 of the study, 53% of the control group had had at least 1 PSA test. The authors call this "opportunistic testing."
Dr. Prorok said that when the PLCO trial was designed in the early 1990s, PSA testing was rarely used. But then urologists promoted the testing nationally "without any justification of benefit."
PLCO essentially became a different randomized trial, comparing annual PSA testing plus digital rectal exams (intervention group) with usual care and opportunistic testing (control group).
Because of this "contamination" of opportunistic testing in the control group, the trial data are so flawed that the study lacks clinical significance, critics of the study told Medscape Medical News.
"People are putting a lot of weight on a study that is uninterpretable," said Anthony D'Amico, MD, from Brigham and Women's Hospital in Boston, Massachusetts, referring, in part, to the US Preventative Services Task Force, which recently recommended that healthy men not routinely be offered screening, using the PLCO data as part of their argument.
Dr. D'Amico also pointed out that 15% of the men randomized to screening in PLCO never attended a screening. Thus, the trial was a comparison of 2 groups: one in which 85% of men were screened and one in which 53% of men were screened. In the end, the PLCO study lost its statistical power, he noted. "It's a dataset that you cannot make any conclusions about," Dr. D'Amico summarized.
The problem of opportunistic testing of men in the control group is probably worse than reported, said another expert.
"The contamination rate has probably increased," said Philip Kantoff, MD, from the Dana-Farber Cancer Institute in Boston, referring to the fact that the study's published rate of opportunistic testing was recorded by the investigators only after 6 years.
PSA testing is "enormous" in the United States, Dr. Kantoff observed, and would have afforded the men in the control group repeated opportunities after those first 6 years to learn their PSA level and possibly act on that information to seek biopsy and treatment.
Investigator Dr. Prorok said that the PLCO team will update information on the contamination rate; he was unsure if it had worsened.
He also disagreed with Dr. D'Amico's assessment that the trial is uninterpretable.
"The study provides information about what happens when you add annual screening on top of what a population is already getting in terms of screening," he said, referring the study's eventual and accidental design.
New Results
The PLCO results indicate, among other things, that PSA screening leads to overdiagnosis of prostate cancer, said Dr. Prorok.

At 13 years, 4250 participants have been diagnosed with prostate cancer in the intervention group, compared with 3815 in the control group.
The cumulative incidence rates for prostate cancer in the intervention and control groups were 108.4 and 97.1 per 10 000 person-years, respectively, resulting in a relative increase of 12% in the intervention group (relative risk [RR], 1.12; 95% confidence interval [CI], 1.07 to 1.17), the authors report. "This overdiagnosis from screening is probably an underestimate because there was probably some overdiagnosis in the control group too [because of opportunistic PSA testing]," said Dr. Prorok.
There were also more prostate cancer deaths in the screening group than in the control group (158 vs 145), Dr. Prorok noted. This raises the question of whether or not screening might actually increase the risk for death, he said. However, the difference was slight and could be related to chance, he added.
Specifically, the cumulative mortality rates from prostate cancer in the intervention and control groups were 3.7 and 3.4 deaths per 10,000 person-years, respectively, resulting in a nonstatistically significant difference between the 2 groups (RR, 1.09; 95% CI, 0.87 to 1.36).
Authors Always Pointed Out the Contamination
The PLCO investigators first published their results in 2009, and concluded that "after 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the 2 study groups." (N Engl J Med. 2009; 360:1310-1319).
This conclusion echoes the findings in the new paper by the PLCO team.
However, back in 2009, they also pointed out that many of the men in the control group received prostate cancer screening, which might have obscured the results and hidden any benefit of screening.
"The level of screening in the control group could have been substantial enough to dilute any modest effect of annual screening in the screening group," they wrote.
But this message was largely lost in the media coverage of the study, which generally declared that the PLCO study was a "negative" study, and that its counterpart, the European Randomized Study of Screening for Prostate Cancer (ERSPC), which was published simultaneously, was a "positive" study.
The ESPRC found a significant decrease in the rate of prostate cancer mortality between the screening and control groups (rate ratio, 0.80; 95% CI, 0.65 to 0.98; P = .04), or a relative reduction of 20% in the rate of death from prostate cancer.
Importantly, the ESPRC had less contamination because the percentage of men in the control group who got an opportunistic PSA test in the European trial was significantly lower, said Dr. Kantoff. "PSA testing is not as widely available there as it is here," he said.
"The aggregate information is that there is a reduction in mortality from prostate cancer with screening," said Dr. Kantoff, referring to the 2 major randomized trials of prostate cancer screening.
However, the ESPRC also has multiple flaws, all of the experts interviewed for this article pointed out.

Dr. Kantoff summarized what he believes is the current state of thinking about prostate cancer screening. "The jury is still out on the efficacy of the whole process," he said. That process includes not only PSA testing but subsequent biopsies, monitoring, and the many decision points that lead to treatment.
J Natl Cancer Inst. Published online January 6, 2012. Abstract

RITUXIMAB COMBO FOR INDOLENT NHL

2012-01-14T13:19:00.002+02:00

NEW YORK (Reuters Health) Jan 09 - For advanced, untreated indolent B-cell nonfollicular non-Hodgkin lymphomas (INFL), induction with fludarabine, cyclophosphamide, and rituximab, and a short course of rituximab maintenance, is "highly effective," according to Italian researchers.
This heterogeneous group of diseases includes small lymphocytic lymphoma, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia), and marginal zone lymphoma.
In a December 16 online paper in Cancer, Dr. Luca Baldini of the University of Milan and colleagues noted that treatment for these cancers traditionally has been derived from therapies that work for chronic lymphocytic leukemia (CLL). There is no definitive regimen.
The new study was a phase II trial with 46 evaluable patients. Therapy consisted of six cycles of fludarabine and cyclophosphamide and eight cycles of rituximab, followed by four maintenance doses of rituximab every two months.
Twenty-one patients had small lymphocytic lymphoma (SLL), 19 had lymphoplasmacytic lymphoma, and six had nodal marginal zone lymphoma.
SLL reportedly accounts for no more than 6% of non-Hodgkin lymphomas, or around 400 a year in the U.S. The other two subtypes are even less common.
The overall response rate after maintenance was 89.1%. Of these 41 patients, 47.8% had complete remission, 19.6% had unconfirmed complete remission, and 21.7% had a partial response.
After a median follow-up of 41 months, only one patient had died of disease progression. On intent-to-treat analysis, progression-free survival and failure-free survival were each 90.1%. Overall survival was 97.4%.
Fourteen patients (29.8%) required dose modification because of adverse events. More than half the patients (55.3%) had treatment-related grade 3 and 4 neutropenia.
"Rituximab maintenance plays an important role in reducing residual tumor burden, thereby improving the quality and duration of response," the authors write.
Overall, they conclude, the combination "is the best treatment option for patients with (indolent B-cell nonfollicular lymphomas) to date, producing higher remission and survival rates compared with previous treatment regimens tested in this subset of patients."
SOURCE: http://bit.ly/AehPtN
Cancer 2011.

LIMITED BENEFIT OF CHEMOTHERAPY FOR MESOTHELIOMA

2012-01-14T13:19:00.000+02:00

NEW YORK (Reuters Health) Jan 10 - New chemotherapy combinations have prolonged the median survival of patients with malignant mesothelioma by only a few months, researchers from The Netherlands have found.
As reported online December 1 in the European Respiratory Journal, Dr. R. A. Damhuis from the Rotterdam Cancer Registry and colleagues assess the use of chemotherapy in 4731 patients treated for malignant mesothelioma between 1995 and 2006, and its impact on their survival.
"Response to single-agent or combination chemotherapy used to be limited until a novel agent was introduced, pemetrexed, that showed a response rate of 32% in combination with carboplatin," the researchers note. Early reports of pemetrexed started appearing around 2002.
Indeed, they found, chemotherapy use increased from 8% (in 1995-1998) to 36% (in 2005-2006). Only 11% of 70- to 79-year-olds and only 3% of patients 80 years and older received chemotherapy, however.
At the same time, median survival increased over time from 7.1 to 9.2 months. With chemotherapy, median survival increased from 10.1 to 13.3 months. (But, the authors point out, "By definition, chemotherapy patients cannot die between diagnosis and their first cycle, hence getting a survival head start.)
The survival difference with chemotherapy faded after controlling for age and tumor type, the researchers note.
Median survival was markedly lower for peritoneal vs pleural mesothelioma (3.9 vs 8.1 months). Male gender and older age predicted worse survival in peritoneal mesothelioma, whereas younger age, epithelioid tumor type, and chemotherapy in the latter periods predicted better survival in pleural mesothelioma.
"Despite introduction of novel chemotherapy regimens," the investigators conclude, "malignant mesothelioma is still a fatal disease with a median prognosis of less than a year. With disease incidence at its peak, now is the time to test new treatment options, preferably in randomized controlled trials."
"Within 10 years, the number of mesothelioma patients will decrease and the aging of the patient population will make them less suitable for inclusion in trials with toxic treatment," they add. "Quality of life should be a major endpoint in these trials, and prevention remains the best option to decrease mortality from mesothelioma."
SOURCE: http://bit.ly/yt6Rdp
Eur Resp J 2011.

MOLECULAR TESTING AS PART OF SCREENING FOR BREAST CANCER

2012-01-14T13:18:00.000+02:00

January 13, 2012 — There has been a significant increase in "low-risk" and "ultra-low-risk" breast cancers among women 49 to 60 years of age in the era of population-wide mammography screening, suggests a new study that examined molecular profiling evidence.
"Screening appears to preferentially identify the low-risk lesions in the population today," the authors conclude.
The study, published in the December issue of Breast Cancer Research and Treatment, provides the "first molecular evidence of the increased detection of very-low-risk lesions over time," say the authors, led by Laura Esserman, MD, MBA, from the University of California, San Francisco.
The study used data from the Netherlands, and compared a cohort of women diagnosed with breast cancer from 1984 to 1992 (when mammography was not routinely offered) with a cohort of women diagnosed from 2004 to 2006 (the mammography-screening era).
When women 49 to 60 years of age in the 2 cohorts were compared, there was less low-risk breast cancer in the earlier cohort (40.6%; 67 of 165) than in the later cohort (58%; 119 of 205).
The study was limited to women with node-negative breast cancer. Risk was assessed using the Netherlands Cancer Institute's 70-gene breast cancer prognosis test, now commercially known as MammaPrint (marketed by Agendia). The test, which has been proven to be predictive of overall survival and the development of distant metastases, also identifies ultra-low-risk disease.
The investigators reported on a subset of ultra-low-risk women in the 2 cohorts and, once again, found increasing numbers over time.
In the earlier cohort, 10% of women 49 to 60 years of age had ultra-low-risk breast cancer, compared with 30% of women in the same age range in the later cohort.
Notably, among women younger than 40 years, there was no significant increase in low-risk disease between the 2 time cohorts.
What do these results mean? The authors believe they should lead to changes in breast cancer screening and care. They suggest that because there has been an increase in less-aggressive breast cancer, there needs to be an associated increase in less-aggressive treatment and even, in some cases, less-aggressive diagnosis.

"The study provides information that will allow us to improve screening," write the authors. They suggest that molecular tests such as MammaPrint and Oncotype DX (marketed by Genomic Health) could be used at the time of screening "to help identify low-risk tumors." Currently, the tests are used after diagnosis to help guide treatment.
An expert not associated with the study balked at the idea of using these tests at the time of screening.
"The concept of adding molecular profiling to screening sounds very attractive," said Kandace McGuire, MD, from the division of surgical oncology at the Magee-Womens Hospital of University of Pittsburgh Medical Center in Pennsylvania. But molecular tests require biopsies, she explained, which would be inappropriate at the screening level.
"Using this technology would actually not save women biopsies. It could be used to guide treatment, but not diagnosis," she said about the 70-gene test.
Despite the fact that the authors of the paper present "a rationale for integrating molecular testing at the time of screening," the primary purpose of the 70-gene test is to avoid overtreatment, said senior author Laura van 't Veer, PhD, who is also from the University of California, San Francisco.
Criticisms aside, Dr. McGuire admires the research. "In general, I think this is a thought-provoking paper. It does suggest that most of the screening-detected tumors are indolent and may have never amounted to clinically significant cancers in postmenopausal women," she said.
Avoiding Biopsies
Dr. Esserman and coauthors believe that their finding that many breast cancers are slow- to moderate-growth tumors "should enable us to reset thresholds for biopsy for very-low-risk mammographic lesions." The authors are referring to BI-RADS (Breast Imaging Reporting and Data System) 4A lesions, which are by definition suspicious but "almost always turn out to be benign," they say.
Dr. McGuire is not comfortable with any proposed change in management without evidence.
Both the study authors and Dr. McGuire agree that further study is needed to see how clinicians can modify the screening and management of low-risk cancers and lesions.
Also, Dr. McGuire said that the development of biomarkers that allow biopsies to be avoided would be a huge boon to women.
"Many centers, including Pittsburgh, are actually looking for circulating serum markers that may act as a surrogate for these molecular profiles, so that a biopsy is not required for risk stratification, and might actually lead to a change in diagnosis and biopsy rates," she said.
Good News for Aging Women
The MammaPrint 70-gene test was developed to predict long-term outcome in the absence of systemic therapy on a consecutive series of breast cancer patients from the Netherlands Cancer Institute. The test divides scores into 2 categories: good (low risk) and poor (high risk) prognosis.
The test was validated in a cohort of patients from 5 European centers in the TRANSBIG study. Over a median follow-up period of 13.6 years, a poor-prognosis signature was associated with a hazard ratio (HR) of 2.32 (95% confidence interval [CI], 1.35 to 4.00) for time to distant metastasis and a HR of 2.79 (95% CI, 1.60 to 4.87) for overall survival.
In this study, 866 patients were analyzed in the 2 cohorts and were divided into groups by age (younger than 40 years, 40 to 48 years, 49 to 60 years, and older than 60 years). Regardless of the cohort, a good prognosis with the 70-gene test significantly increased as age increased (P < .01).
The proportion of T1, grade 1, hormone-receptor-positive tumors also significantly increased with age. In other words, there is "an increase in the likelihood of having a good-prognosis tumor as a woman ages," the authors write. This was true for the combined population and for each individual age-based and time-based cohort.
Dr. McGuire believes that molecular testing and risk stratification are especially helpful to older women making treatment decisions. In women older than 70 years with breast cancer, one study indicates that recurrence is extremely low at 12 years, with or without radiotherapy, she said (N Engl J Med. 2004;351:971-977).

"I think it would be of benefit to further stratify 'older' patients into low- and high-risk [categories], not only to tailor therapy like radiation, but also to inform us...about the benefit of various adjuvant systemic therapies. The opportunity to spare an older woman cytotoxic chemotherapy cannot be underestimated," she said.
This study is not encouraging for young women with breast cancer. More than 70% of tumors in women younger than 40 years had a poor-prognosis signature; this proportion was found in both the earlier cohort and the later cohort. In other words, the proportion has remained constant over the past 20 years, the authors point out.
This study was supported by the Early Detection Research Network, the UCSF Dean's Medical Student Summer Research Fellowship, and the Dutch Genomics Initiative Cancer Genomics Center. Senior author Laura van 't Veer, PhD, is the original creator of the 70-gene prognosis signature. Coauthor Annuska Glas is an employee of Agendia, which markets MammaPrint.
Breast Cancer Res Treat. 2011;130:725-734. Abstract

NO USE OF PANITUMUMAB AFTER CETUXIMAB FAILURE

2012-01-09T18:18:00.000+02:00

Oncologist. 2011 Dec 30. [Epub ahead of print]

Panitumumab in Patients with KRAS Wild-Type Colorectal Cancer after Progression on Cetuximab.

Wadlow RC, Hezel AF, Abrams TA, Blaszkowsky LS, Fuchs CS, Kulke MH, Kwak EL, Meyerhardt JA, Ryan DP, Szymonifka J, Wolpin BM, Zhu AX, Clark JW.

Source

Boston, Massachusetts, USA;

Abstract

AbstractPurpose Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type metastatic colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab.Patients and Methods We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies.Results We treated twenty patients for a median of two cycles (range 1-4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. Panitumumab was well tolerated. Thirteen patients (65%) had grade 1-2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies.Conclusions Panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab.Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. Cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents.

CETUXIMAB IS EFFECTIVE IN ELDERLY PATIENTS WITH COLORECTAL CANCER

2012-01-09T18:15:00.000+02:00

Br J Cancer. 2012 Jan 3. doi: 10.1038/bjc.2011.554. [Epub ahead of print]

Cetuximab-based therapy in elderly comorbid patients with metastatic colorectal cancer.

Jehn CF, Böning L, Kröning H, Possinger K, Lüftner D.

Source

Medizinische Klinik und Poliklinik m. S. Onkologie & Hämatologie; Charité Campus Mitte, Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.

Abstract

Background:Clinical trials under-represent patients (pts) >65 years. Non-interventional studies (NISs) help to evaluate therapies in daily practice. This NIS evaluates efficacy and safety of cetuximab in combination with chemotherapy in metastatic colorectal cancer (mCRC) pts aged >65 years vs 65 years.Methods:A total of 657 pts were recruited into the NIS and analysed applying descriptive statistics and χ(2) or Fisher's exact test.Results:A total of 309 and 305 pts aged 65 and >65 years, respectively, were documented; 80% showing a reduced ECOG status of 1-2 and 95% having received at least one palliative treatment. Cetuximab was combined with irinotecan according to approval status. Grade III/IV toxicities occurred in 20% of pts without any difference between age groups although the older pts had significantly more pre-existing comorbidities (P=0.001). A total of 64.2% of the pts developed skin rash, which was strongly related to response (P<0.0002) without any difference between age groups (P=0.34). The objective response rates were 37.9% for ages 18-65 years vs 35.4% for >65 years. Progression-free survival (PFS) did not differ between pts 18-65 years old (6.5 months) in comparison with pts >65 years (7.0 months). In a multivariate analysis only ECOG status had a negative impact on PFS (HR: 0,675; 95% Cl, 0.53-0.87; P=0.0019).Conclusion:This NIS reports one of the largest mCRC collectives >65 years and reduced performance status. Cetuximab has a similar efficacy and safety profile for pts aged 65 and >65 years.British Journal of Cancer advance online publication, 3 January 2012; doi:10.1038/bjc.2011.554 www.bjcancer.com.

RISK OF CONTRALATERAL TESTICULAR CANCER

2012-01-06T20:54:00.002+02:00

Int J Cancer. 2011 Dec 15;129(12):2867-74. doi: 10.1002/ijc.25943. Epub 2011 May 28.

Risk of metachronous contralateral testicular germ cell tumors: a population-based study of 7,102 Norwegian patients (1953-2007).

Andreassen KE, Grotmol T, Cvancarova MS, Johannesen TB, Fosså SD.

Source

Department of Etiological Registry, Cancer Registry of Norway, Oslo, Norway. krea@kreftregisteret.no

Abstract

The purpose of the study was to identify overall incidence and risk of developing a metachronous contralateral testicular germ cell tumor (TGCT) and compare the risk for patients treated before and after 1980 (cisplatin became available for patients with metastatic TGCT). Our hypothesis was that the risk of metachronous TCGT would be reduced for patients with metastatic disease diagnosed after 1980. We included 7,102 men with unilateral TGCT, recorded in the Cancer Registry of Norway. Allowing for competing risk, cumulative incidence and adjusted hazard ratio (HR) were estimated for different subgroups, and the diagnostic periods 1953-1979 (I) and 1980-2007 (II). Relative risks were assessed by standardized incidence ratio (SIR). In Period I and Period II, 38 and 137 males, respectively, were diagnosed with metachronous contralateral TGCT. Corresponding 20-year cumulative incidences were 1.9% and 3.9%. In Period II, risk of a second TGCT was halved [HR = 0.5, 95% confidence interval (95% CI) = 0.33-0.77] for patients with metastatic compared to localized disease. For patients presenting with localized and metastatic disease, the SIRs for Period I were 14.6 (95% CI = 9.6-21.2) and 25.3 (95% CI = 12.1-46.5), respectively. In Period II, the corresponding numbers were 19.0 (95% CI = 15.6-22.9) and 9.8 (95% CI = 6.4-14.5). In conclusion, the risk of metachronous contralateral TGCT was halved for patients with metastatic compared to localized disease in Period II, whereas this protective effect of extent of disease lacked significance for Period I. These findings support our hypothesis that cisplatin-based chemotherapy reduced the risk of a second TGCT for patients with metastatic TGCT diagnosed after 1980.

A SECOND LINE REGIMEN FOR KAPOSI SARCOMA

2012-01-06T20:53:00.003+02:00

J Cancer Res Clin Oncol. 2011 Dec 11. [Epub ahead of print]

Etoposide, vincristine, doxorubicin and dexamethasone (EVAD) combination chemotherapy as second-line treatment for advanced AIDS-related Kaposi's sarcoma.

Zhong DT, Shi CM, Chen Q, Huang JZ, Liang JG, Lin D.

Source

Department of Medical Oncology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, Fujian, People's Republic of China.

Abstract

OBJECTIVE:

To evaluate through retrospective analysis the efficacy and toxicity of combination chemotherapy with etoposide, vincristine, doxorubin and dexamethasone (EVAD) as second-line therapy in patients with advanced AIDS-related Kaposi's sarcoma (AIDS-KS) after failure of first-line chemotherapy.

METHODS:

Eighty-eight patients with poor-risk AIDS-KS were treated intravenously with combination chemotherapy with EVAD; etoposide at a dose of 100 mg/m(2) on three consecutive days, vincristine 1.4 mg/m(2) with a maximum single dosage of 2.0 mg on day one, doxorubicin 30 mg/m(2) on day one and dexamethasone 40 mg on three consecutive days, with a three week cycle. All eligible patients had relapsed or progressed after prior two to six cycles of combination chemotherapy with doxorubicin, bleomycin and vincristine (ABV) or bleomycin and vincristine (BV).

RESULTS:

Assessment of the response of all the patients was made. The overall objective response rate was 59.1% (95% CI 48.83-69.37%), with five complete responses and 47 partial responses. Twenty-six cases of stable disease and 10 of progressive disease were observed in the remaining patients. The median follow-up period was 27 months (range 8-52 months). The median time to progression was 6.80 months (95% CI 2.04-11.56 months), and the median overall survival was 14.24 months (95% CI 10.26-18.22 months). Leucopenia was seen in 92.0% of patients, of which 20 patients had grade 3 and 12 had grade 4. Conclusions Combination chemotherapy with EVAD offers a new, active and safe therapeutic approach for the treatment of advanced AIDS-related KS.

ANOTHER FRAUD REVEALED BY A GREEK SCIENTIST

2012-01-06T20:53:00.000+02:00

January 5, 2012 — A cloud has descended over research into a biomarker for prostate cancer — early prostate cancer antigen-2 (EPCA-2) — which was described as "amazing" and appeared to overcome some of the shortcomings of prostate-specific antigen.
A paper about the biomarker was published several years ago in Urology (2007;69:714-720), but was retracted in October 2011 because data from the study could not be verified. "The article contains findings that may be unreliable," the study authors write in their retraction.
The move was highlighted in the Retraction Watch blog.
The paper's lead author is Robert H. Getzenberg, PhD, director of research of the James Buchanan Brady Urological Institute and professor of urology at the Johns Hopkins University School of Medicine in Baltimore, Maryland.
Dr. Getzenberg holds a patent for the assay technology that detects EPCA-2. The patent is owned by the University of Pittsburgh and Johns Hopkins University and has been licensed to Onconome Inc. Dr. Getzenberg received research funding from Onconome, which, in 2009, sued him and the 2 institutions for scientific fraud.
Dr. Getzenberg at one time reportedly described EPCA-2 as "amazing" because of its very high sensitivity and specificity, according to Retraction Watch.
A critic of EPCA-2 said that he has attempted for some time to publish a letter in Urology on the shortcomings of the assay used by Dr. Getzenberg and colleagues in their EPCA-2 research.
"This letter was accepted for publication, but has never been published and the reasons for the delay not resolved," said Eleftherios Diamandis, PhD, from the Department of Laboratory Medicine and Pathobiology at the University of Toronto in Ontario, Canada, in an essay published in Clinical Chemistry last year.
Dr. Diamandis said that he knew that the assay used to detect EPCA-2 was not capable of its touted abilities "as soon as the first paper on EPCA-2 was published."
"By analyzing what we know about ELISA assay design and performance, I concluded that the assay would not be either a sensitive or a specific measure of any analyte present in serum at the low ng/mL concentrations," he writes.
When his letter languished at Urology, he turned to Clinical Chemistry to publish his insights.
In his essay, Dr. Diamandis frames the EPCA-2 debacle in a larger cultural context: few biomarkers are validated but many are touted as the next great thing.
"The literature is full of reports of high-profile papers that have reported excellent diagnostic discrimination between groups, but subsequent independent validation was a failure," he writes.
In most cases, various biases were critical factors, he says. One example is the nuclear magnetic resonance profiling of urine for cancer detection, which has failed repeated validation efforts.
Dr. Diamandis has commented on this issue in other papers. Last year in the Journal of the National Cancer Institute, he pointed out that that not a single new "major cancer biomarker" has been approved for clinical use in the past 2 decades, despite large amounts of funding and plenty of public-relations hype, as reported at the time by Medscape Medical News.

PERITONEAL CARCINOMATOSIS IS AN ADVERSE PROGNOSTIC FACTOR

2012-01-06T20:52:00.001+02:00

NEW YORK (Reuters Health) Jan 03 - Peritoneal carcinomatosis in patients with metastatic colorectal cancer is associated with a poorer prognosis following chemotherapy than other disease manifestations, researchers report in a paper online December 12 in the Journal of Clinical Oncology.
"Patients with peritoneal carcinomatosis have 30% shorter survival as compared with other subtypes of metastatic colorectal cancer," Dr. Jan Franko, who worked on the study, told Reuters Health by email. "That is A LOT worse."
Nevertheless, he added, "systemic chemotherapy is still beneficial for these patients."
Dr. Franko, of Mercy Clinics in Des Moines, Iowa, estimated that of the 20,000 or so metastatic colorectal cancer patients newly diagnosed with or developing carcinomatosis in 2011, about a quarter would develop isolated peritoneal carcinomatosis (pcCRC).
He and his colleagues examined outcomes of such patients enrolled in two prospective randomized trials of chemotherapy compared with patients with other manifestations of metastatic colorectal cancer. In total, nearly 2,000 patients were included.
Both groups were similar overall, but liver metastasis was significantly less common in the pcCRC patients (63% vs. 82%). This was also true of lung cancer (27% vs. 34%).
However, pcCRC patients had shorter median overall survival (12.7 vs. 17.6 months, p<0.001) and progression-free survival (5.8 vs. 7.2 months, p=0.001). This remained the case after adjusting for factors including age, performance status, and liver metastases.
In both groups of patients, infusional fluorouracil, leucovorin, and oxaliplatin was superior to irinotecan, leucovorin, and fluorouracil as first-line treatment.
Given this performance, the team notes that the "choice of systemic chemotherapy should be independent of (the) presence or absence of peritoneal carcinomatosis."
"Molecular and genetic profiling of colorectal cancers," they add, "may establish a gene signature that is predictive of a propensity for peritoneal carcinomatosis colorectal cancer and may lead to selection of alternative adjuvant or advanced disease management strategies" for these patients.
In an accompanying editorial, Dr. Andrea Cercek of Memorial Sloan-Kettering Cancer Center and Dr. Leonard Saltz of Weill Cornell Medical College in New York write that optimal treatment will continue to be a subject of debate.
However, they add, "we could not agree more" that "molecular and genetic profiling may help guide our choice of regional and systemic therapies for CRC in all of its various forms and manifestations in the future."
SOURCE: http://bit.ly/xpXlCc
J Clin Oncol 2011.

ANOTHER DRUG FOR KIDNEY CANCER

2012-01-06T20:51:00.001+02:00

(Reuters) Jan 03 - Aveo Pharmaceuticals Inc said its experimental kidney cancer drug was safer and more effective than an already-approved drug marketed by Bayer and Onyx Pharmaceuticals Inc.
Aveo is currently testing the drug tivozanib in a late-stage trial in patients with advanced renal cell carcinoma.
J.P. Morgan analyst Geoff Meacham said in a note to clients that he expects tivozanib to emerge as the first-line standard of care in renal cell carcinoma, which has a market of about $2 billion.
Tivozanib showed a median progression-free survival (PFS) of 11.9 months compared with a median of 9.1 months for those treated with Bayer and Onyx's Nexavar, also known as sorafenib, in the overall study population.
"Based on discussions with physicians, we believe a drug that prolongs disease progression or death by greater than one year will be very well received," Meacham said.
Pfizer Inc is currently awaiting approval for Inlyta -- its experimental drug for patients with advanced kidney cancer. The drug is also being tested as a treatment for liver cancer.
In February 2011, Aveo signed a deal worth up to $1.3 billion with Japan's Astellas Pharma to develop treatments for a broad range of cancers.
Based on the latest data, Aveo and Astellas plan to submit for marketing approval of tivozanib in the United States and Europe in 2012.
Meacham, who reiterated his "overweight" rating on Aveo's stock, said he expects a smooth regulatory process for tivozanib with a likely launch in 2013 and bringing in revenue of about $590 million in 2015.

BRCA AND MI SEVERITY

2012-01-06T19:07:00.001+02:00

January 4, 2012 (Toronto, ON) — Canadian researchers have discovered that the BRCA1 gene is an essential regulator of cardiac function, at least in mice, and may therefore represent a new therapeutic target for heart failure [1].
The findings are also important for cancer patients who have mutations in the BRCA1 and BRCA2 genes — who are at higher risk of breast and ovarian cancer — because it means these individuals could be at increased risk of heart problems as well, say Dr Praphulla C Shukla (St Michael's Hospital, Toronto, ON) and colleagues in their paper published online December 20, 2011 in Nature Communications.
Shukla et al found that mice with BRCA1/2 mutations had much more severe MIs than those without the mutations and a subsequent three to five times higher rate of death, largely due to the development of heart failure.
The results may explain recent observations that BRCA1/2 mutation carriers have an increased risk of nonneoplastic death, particularly in older age, say the researchers.
And they likely have implications for those undergoing chemotherapy too, in that BRCA1 and 2 mutation carriers could be even more susceptible to the cardiotoxic effects of such treatment than average cancer patients, Shukla et al suggest. Mice with the mutations had a twofold increase in heart failure when treated with doxorubicin.
Oncologist and coauthor Dr Christine Brezden-Masley (St Michael's Hospital) says the research is already making her think twice about particular chemotherapy regimens in BRCA mutation carriers.
"When a patient has the mutated gene, I now have to think about how much doxorubicin I'm going to give them or whether we should consider an alternative therapy," she says in a hospital statement [2].

DANGEROUS EXPERIMENTS

2012-01-06T19:06:00.002+02:00

LONDON (Reuters) Dec 30 - The World Health Organization issued a stern warning on Friday to scientists who have engineered a highly pathogenic form of the deadly H5N1 bird flu virus, saying their work carries significant risks and must be tightly controlled.
The United Nations health body said it was "deeply concerned about the potential negative consequences" of work by two leading flu research teams who this month said they had found ways to make H5N1 into a easily transmissible form capable of causing lethal human pandemics.
The work by the teams, one in The Netherlands and one in the United States, has already prompted an unprecedented censorship call from U.S. security advisers who fear that publishing details of the research could give potential attackers the know-how to make a bioterror weapon.
The U.S. National Science Advisory Board for Biosecurity has asked two journals that want to publish the work to make only redacted versions of studies available, a request to which the journal editors and many leading scientists object.
In its first comment on the controversy, the WHO said: "While it is clear that conducting research to gain such knowledge must continue, it is also clear that certain research, and especially that which can generate more dangerous forms of the virus....has risks."
H5N1 bird flu is extremely deadly in people who are directly exposed to it from infected birds. Since the virus was first detected in 1997, about 600 people have contracted it and more than half of them have died.
But so far it has not yet naturally mutated into a form that can pass easily from person to person, although many scientists fear this kind of mutation is likely to happen at some point and will constitute a major health threat if it does.
MUTATIONS
Flu researchers around the world have been working for many years trying to figure out which mutations would give H5N1 the ability to spread easily from one person to another, while at the same time maintaining its deadly properties.
The U.S. National Institutes of Health funded the two research teams to carry out research into how the virus could become more transmissible in humans, with the aim of gaining insight on how to react if the mutation occurred naturally.
The WHO said such research should be done "only after all important public health risks and benefits have been identified" and, "it is certain that the necessary protections to minimize the potential for negative consequences are in place."
The agency also said it was vital that new rules on the sharing of viruses and scientific know-how were enforced to ensure those countries at most immediate risk from H5N1, mainly developing countries in Asia such as Indonesia, Vietnam and others, would benefit from advances in research.
During the novel-H1N1 flu pandemic in 2009-2010, many developing countries complained they had no life-saving antivirals or vaccines to combat the new virus, despite having made samples of the virus available to researchers and pharmaceutical companies to develop the medicines.
It is normally laboratories in wealthy developed countries that have the level of scientific expertise needed to work on complex flu viruses, while bird, or avian, flu viruses themselves often come from less well-developed Asian countries.
A new Pandemic Influenza Preparedness Framework was agreed and adopted by all WHO member states in May 2011 to set rules for sharing flu viruses that have pandemic potential, and sharing the benefits of the expertise gained.
"WHO considers it critically important that scientists who undertake research with influenza viruses with pandemic potential samples fully abide by the new requirements," the U.N. agency said in its statement.

NEOADJUVANT PERTUZUMUAB AND TRASTUZUMAB COMBINATION

2012-01-06T19:06:00.000+02:00

Lancet Oncol. 2011 Dec 6. [Epub ahead of print]

Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.

Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P.

Source

Oncologia Medica, San Raffaele Cancer Centre, Milan, Italy.

Abstract

BACKGROUND:

Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting.

METHODS:

In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2), escalating, if tolerated, to 100 mg/m(2) every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688.

FINDINGS:

Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1-55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6-38·5]; p=0·0141). 23 of 96 (24·0% [15·8-33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3-25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15-20 serious adverse events per group in 10-17% of patients) but lower in group C (four serious adverse events in 4% of patients).

INTERPRETATION:

Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer.

CANCER DEATH DROP BUT INCIDENCE RISES

2012-01-06T19:05:00.000+02:00

January 5, 2012 — The good news is that overall cancer death rates have declined for both men and women. The not so good news is that the incidence rates for some cancer types appear to be increasing.
According to a report issued by the American Cancer Society (ACS), and published online January 4 in 2 parts in CA: A Cancer Journal for Clinicians, cancer-specific mortality rates from 1999 to 2008 have declined in both men and women of every racial/ethnic group, with the exception of American Indians/Alaska Natives, for whom rates have remained stable.
One part of the report notes that the overall reduction in cancer deaths rates since 1990 in men and 1991 in women extrapolates to the prevention of about 1,024,400 deaths from cancer.
Of note, the most rapid decrease in annual mortality rate was observed among black (2.4%) and Hispanic men (2.3%).
Death rates continue to decline for all 4 major cancer sites — lung, colorectum, breast, and prostate. Lung cancer alone accounted for nearly 40% of the total decline in men and breast cancer accounted for 34% of the total decline in women.
For all 4 major cancer sites, incidence rates declined, with the exception of breast cancer in women, which remained relatively stable from 2005 to 2008 after decreasing by 2% per year from 1999 to 2005.
Mortality rates reflect changes in incidence, as well as progress and advances in treatment and diagnosis, explained Elizabeth Ward, PhD, national vice president of intramural research for the ACS.
Incidence trends are more difficult to interpret, she told Medscape Medical News. For example, incidence rates for breast cancer have fluctuated, she noted. The sharp decline of almost 7% from 2002 to 2003 has been attributed to the decrease in use of hormone replacement therapy after the publication of the results of the Women's Health Initiative in 2002.
In addition, the introduction of screening programs might have led to an increased incidence, said Dr. Ward. "Incidence rates went up for prostate cancer when PSA screening was introduced, for instance. But mortality rates are going down for all 4 major cancer sites, even if incidence trends do not correlate."
Rising Rates for 7 Cancers
Unfortunately, incidence rates for other cancers have been rising. In the other part of the report, ACS researchers examined trends in incidence rates from 1999 to 2008 for 7 cancers.
During the past decade, the incidence rates of cancers of the pancreas, liver, thyroid, and kidney, and of melanoma have gone up. In addition, there was a rise in esophageal adenocarcinoma and in certain subtypes of oropharyngeal cancer that are associated with human papillomavirus (HPV) infection. Racial/ethnic differences were observed for some but not all of the cancers with rising incidence rates.
For example, increased incidence rates for HPV-related oropharyngeal cancer and melanoma were seen only among whites; increased rates for esophageal adenocarcinoma were seen among whites and Hispanic men. Rates of hepatic cancer rose in white, black, and Hispanic men and in black women. Conversely, rising incidence rates of thyroid and kidney cancers were observed in all racial/ethnic groups except Native American and Alaska Native men.
The ACS found that people 55 to 64 years of age had the highest increase in incidence rates for liver and HPV-related oropharyngeal cancers; people 65 years and older had an increase in incidence rates for melanoma. For men with HPV-related oropharyngeal cancer and women with thyroid cancer, rising incidence rates were highest among people 55 to 64 years of age.
The reasons for these increasing trends are not entirely clear, said Dr. Ward, adding that there might be a number of underlying reasons. The increased incidence of HPV-related oropharyngeal cancers, for example, might be associated with changes in sexual behaviors that increase the risk for HPV exposure.
"Esophageal adenocarcinoma may be related to rising obesity rates and an increased prevalence of gastroesophageal reflux disease," she said. "This in turn can lead to Barrett's esophagus."
The increased incidence rates of thyroid and kidney cancer are far less clear. "There has been suspicion that part of the reason is an increase in detection as our technology improves," explained Dr. Ward. "That may be part of the explanation, or there may really be a true increase and we just don't know the real causes yet."
"Thyroid cancer is really a puzzle," she said. "It is increasing fast, and research is now being conducted to determine the reasons for this increase. For other cancers, we may have a better handle on the reasons they are increasing and there are some public-health measures that can be taken."
Variations by Ethnic/Racial Groups
There were a total of 565,469 recorded cancer deaths in the United States in 2008, which is the most recent year for which data are available. Cancer accounted for 23% of all deaths recorded in the United States, which makes it the second leading cause of death, right behind cardiovascular disease. From 2007 to 2008, there was a decline in the age-standardized cancer death rate of 1.5%, from 178.4 to 175.8 per 100,000.
There are considerable regional/geographic variations in cancer incidence and mortality, the report notes. Lung cancer, for example, has the greatest variation in rates, which reflects smoking prevalence. In Kentucky, which has the highest prevalence of smoking, lung cancer is almost 4 times as high as it is in Utah, which has the lowest prevalence of smoking.
Cancer incidence and mortality rates continue to show considerable variation by racial and ethnic groups. As previously reported by Medscape Medical News, racial and ethnic disparities continue to exist in cancer care, even after factors such as insurance and socioeconomic status are controlled for, and a disproportionate number of cancer-related deaths occur in racial/ethnic minorities.
Most striking is the fact that for all cancer sites combined, black men have a 15% higher incidence rate and a 33% higher death rate than white men in the United States. Black women have an incidence rate that is 6% lower than white women, but a 16% higher death rate.
In the United States, incidence and death rates are consistently higher in blacks than in whites, with the exception of women with breast (incidence) and lung (incidence and mortality) cancer, and of men and women with kidney (mortality) cancer. However, both incidence and death rates are lower in other ethnic/racial groups than in whites and blacks in the United States for all cancer subtypes and the 4 most common sites.
The exception is incidence and mortality of cancers associated with infectious agents, such as stomach, liver, and cervix, which tend to be higher in minority groups than in whites. As an example, incidence and mortality rates are twice as high in Asian Americans and Pacific Islanders as in whites, which reflects a higher degree of chronic infection with Helicobacter pylori and hepatitis B and C.
Projections for 2012
These current statistics give a bit of mixed message, said Richard Schilsky, MD, past president of the American Society of Clinical Oncology (ASCO) and current executive editor of the ASCO Web site CancerProgress.Net. "The big news is that cancer mortality rates continue to go down, and have been for quite some time," he told Medscape Medical News. "This is true for cancer in general, and especially for the most common cancers."
However, it is clear that other cancers are on the rise, said Dr. Schilsky, who is professor of medicine, chief of hematology/oncology, and deputy director of the Comprehensive Cancer Center, University of Chicago, Illinois. "We also haven't seen these declines in some segments of the population, especially African Americans."
Identifying the rising incidence of some cancers can be helpful. "At least in some cases, there may be an underlying explanation that we can work with and hopefully resolve," he said.
Dr. Schilsky added that some of the best news is that more than 1 million deaths attributable to cancer have been averted over the past decade. "That is very encouraging."
For 2012, the ACS estimates that there will be 1.6 million new cases of invasive cancers, and 577,190 cancer-related deaths — corresponding to more than 1500 deaths per day.
For men, prostate, lung and bronchus, and colorectum cancers will be the most common cancers diagnosed, and will account for approximately 50% of all newly diagnosed cases. Prostate cancer alone will account for 29% (241,740) of incident cases.
For women, breast, lung and bronchus, and colorectum cancers will be the 3 most commonly diagnosed types of cancer, and will also account for approximately half of all new cases. Breast cancer alone is expected to account for 29% (226,870) of all newly diagnosed cancers.
"The importance of trends is that they point us in the right direction," said Dr. Ward. "If a cancer type is increasing, it is important to know the causes. This will encourage more studies to investigate these findings."
The authors have disclosed no relevant financial relationships.
CA Cancer J Clin. Published online January 4, 2012. Abstract, Abstract

AP-2 AND RESISTANCE TO CHEMOTHERAPY

2012-01-06T19:04:00.000+02:00

January 4, 2012 — A new way of predicting which patients with colorectal cancer are unlikely to respond to chemotherapy regimens containing fluorouracil is reported in the January 4 issue of the New England Journal of Medicine.
Patients with colorectal or rectal cancer whose tumors show hypermethylation of the gene encoding transcription factor AP-2 epsilon (TFAP2E) are clinically nonresponsive to fluorouracil-based chemotherapy, say the researchers, headed by Matthias Ebert, MD, from the University of Mannheim, Germany.
This genetic alteration was found frequently in the 4 cohorts of patients studied, occurring in 27% to 63% in patients with metastatic colorectal cancer and in 45% to 46% of patients with rectal cancer.
Patients whose tumors showed TFAP2E hypermethylation had a significantly lower response to fluorouracil-based chemotherapy regimens than patients without this alteration, the researchers report.
They suggest that testing for this mutation could be used to predict which patients are unlikely to respond to fluorouracil-based regimens. "However, before our published association between TFAP2E methylation and chemotherapy response can be used for the clinical management of cancer patients, our data need to be confirmed in prospective studies," Dr. Ebert emphasized.
"These studies were done in tissue samples stored from patients treated with chemotherapy or chemoradiation," he explained to Medscape Medical News. "We do not have data from prospective trials, which are required for further validation of our results."
Four Cohorts Studied
Dr. Ebert and colleagues analyzed tumor samples and clinical data from 4 independent cohorts of patients being treated at a number of university hospitals in Germany.
Cohort 1 (in Bochum) consisted of 76 patients with metastatic colorectal cancer who were participating in a trial comparing oral capecitabine and oxaliplatin (CAPOS) with intravenous fluorouracil and oxaliplatin (FUFOX).
Cohort 2 (in Dresden) consisted of 44 patients with metastatic colorectal cancer treated with either leucovorin, fluorouracil, and irinotecan (FOLFIRI) or folinic acid, fluorouracil, and oxaliplatin (FOLFOX).
Cohorts 3 (in Mannheim) consisted of 50 patients with rectal cancer undergoing chemoradiation with fluorouracil in combination with irinotecan and cetuximab.
Cohort 4 (in Munich) consisted of 70 patients with primary rectal cancer who underwent chemoradiation with intravenous fluorouracil and 45 Gy of radiation.
In all 4 cohorts there was a negative association between TFAP2E hypermethylation and treatment response rates, the researchers report.
Patients who had this genetic alteration (hypermethylation) had a significantly lower response to chemotherapy than patients who did not (hypomethylation).
For example, in cohort 2, of the 36 (of 44) patients for whom data were sufficient for analysis, 23 were found to have hypermethylated TFAP2E, and only 1 had a response to chemotherapy; the remaining 22 patients did not respond. The other 13 patients were found to have hypomethylated TFAP2E, and all 13 showed a response to chemotherapy. None of the hypomethylated TFAP2E tumors failed to respond.
There was "a substantial effect size," the researchers note. The probability of response to treatment was 6 times as high in patients with hypomethylation as in those with hypermethylation.
TFAP2E methylation might be valuable for predicting response to chemotherapy in both colorectal and rectal cancer, the researchers suggest. "Overall, our data indicate that fluorouracil-based chemotherapy is largely ineffective in patients with colorectal cancer with TFAP2E hypermethylation," they conclude.
This is the first time that a link between TFAP2E hypermethylation and chemoresistance to fluorouracil-based regimens has been reported, Dr. Ebert noted. However, there have been several previous reports linking such resistance to the gene that encodes for dickkopf homolog 4 protein (DKK4), "which we identified as a potential downstream target of TFAP2E," he added.
The team speculates that targeting this downstream DKK4 gene might be useful in these patients. "It would be an interesting option to make a potentially resistant cancer sensitive again," Dr. Ebert explained. "We are looking into this with cell-culture studies and animal models," he told Medscape Medical News. "Antibodies against DKK4 are available, and we speculate that the development of anti-DKK4 antibodies or other targeted agents would be of interest."
The authors have disclosed no relevant financial relationships.
N Engl J Med. 2012;336:44-53. Abstract

TAMIFLU RESISTANT INFLUENZA SPREADING IN AUSTRALIA

2012-01-06T19:02:00.002+02:00

December 29, 2011 — A variation of the pandemic 2009 A(H1N1) influenza virus that is resistant to oseltamivir (Tamiflu, Roche) appears to be spreading in Australia, at least in the state of New South Wales, according to a letter to the editor published online today in the New England Journal of Medicine.
The report adds extra weight to a recent analysis by the US Centers for Disease Control and Prevention (CDC) that shows an uptick in the same oseltamivir-resistant influenza strain in the United States. If such resistance becomes widespread, it would deprive clinicians of a tried and true antiviral drug to treat serious influenza infections.
The 2 new studies on antiviral resistance comes on the heels of a CDC report released December 23 that describes yet another way in which influenza viruses are mutating. The CDC has disclosed that since July 2011, 12 patients have been infected with a swine-origin A(H3N2) virus that borrows a gene from the pandemic 2009 A(H1N1) virus (the latter virus is now considered seasonal, and seasonal influenza vaccines are designed to guard against it).
In the Australian study, 29 (16%) of 182 patients infected with the pandemic influenza virus between May 2011 and August 2011 harbored a version of the virus that was oseltamivir-resistant, write Aeron Hurt, PhD, a researcher at the World Health Organization Collaborating Centre for Reference and Research on Influenza in Melbourne, Australia, and colleagues. The 182 patients hailed from the New England–Hunter region of New South Wales. Of the 29 patients with the oseltamivir-resistant virus, only 1 had received the antiviral medicine before a virus sample was collected.
According to earlier studies, the oseltamivir-resistant virus is detected in less than 1% of patients with the pandemic 2009 A(H1N1) virus who have not been treated previously with the antiviral. In addition, "transmission has been documented only in closed settings or settings involving close contact with infected persons."
Among the patients with the resistant strain, 2 had shared a short car ride, and 8 belonged to 4 households with 2 members each. The remaining 19 patients had no known epidemiological link with each other. Most of the 29 patients lived within 31 miles of the city of Newcastle.
The virus strains of these 29 patients were closely related, "suggesting the spread of a single variant," Dr. Hurt and colleagues write.
Although the virus was resistant to oseltamivir, it was still susceptible to the antiviral medication zanamivir (Relenza, GlaxoSmithKline).
The Australian study was conducted during that country's influenza season, coinciding with winter in the Southern Hemisphere. The authors write that as the Northern Hemisphere heads into winter, public health authorities there should rapidly analyze pandemic virus strains from the outset to determine whether an oseltamivir-resistant version is spreading.
Resistant Strains in the United States no Longer Linked to Prior Drug Exposure
Public health authorities in the United States do not need too much nudging to watch for antiviral resistance. On December 19, Emerging Infectious Diseases, a CDC journal, published an article online reporting that from October 2010 through July 2011, 1.0% of pandemic 2009 A(H1N1) virus strains tested resistant to oseltamivir, up from 0.5% during the 2009 to 2010 influenza season.
Although the increase is small, the epidemiology behind the numbers suggests a low level of community transmission of the rogue virus, according to the authors. During the 2009 to 2010 influenza season, most patients with the resistant virus had been previously exposed to the antiviral drug, and many were severely immunocompromised, which may have increased the risk of developing resistance during oseltamivir treatment. During the 2010 to 2011 period, however, the opposite was true: most patients with the resistant virus had no history of oseltamivir exposure.
The authors call the rise of pandemic 2009 A(H1N1) virus strains with oseltamivir resistance "concerning," in light of how prepandemic versions had mutated to gain this edge. They note that the prevalence of such oseltamivir-resistant strains had risen to 12% in the 2007 to 2008 influenza season, and had topped 99% in the 2008 to 2009 season. This increase was not linked to prior exposure to the antiviral drug.
The loss of oseltamivir from the clinical arsenal would leave physicians and patients with only 1 effective antiviral drug, zanamivir, to treat a severe infection caused by the pandemic virus now in seasonal circulation, write the authors. They note that more than 99% of the strains of this virus are "inherently resistant" to the adamantane family of antivirals.
More information about antiviral resistance in influenza viruses is available at the CDC's Web site.
Several authors have reported various relationships to industry, such as receiving antiviral drugs free of charge from manufactures to conduct susceptibility assays, receiving research grants from the International Federation of Pharmaceutical Manufacturers and Associations, and having ownership stakes in influenza vaccine manufacturer CSL Limited. A complete conflict-of-interest statement is available on the journal's Web site.
N Engl J Med. 2011;365:2541-2542. Full text

IS 4 MONTH INCREASE IN PFS WORTHING 50000€-EMA SAYS YES BUT FDA SAYS NO

2011-12-30T23:25:00.000+02:00

December 23, 2011 — Bevacizumab (Avastin, Roche) has been approved for a new indication, newly diagnosed ovarian cancer, by the European Commission. The drug is already marketed for several other cancers.
The new EU approval is for use of bevacizumab as first-line treatment together with standard chemotherapy (carboplatin and paclitaxel) in women with advanced cancer. It is based on data from 2 clinical trials (GOG0218 and ICON-7) that found women who had bevacizumab added to chemotherapy and then continued to receive bevacizumab alone have significantly improved progression-free survival compared with those who received chemotherapy alone.
Updated results from the ICON-7 (International Collaborative Ovarian Neoplasm) trial were reported at this year's annual meeting of the American Society of Clinical Oncology (ASCO) and showed, at a median follow-up of 28 months, progression-free survival of 19.8 months in the bevacizumab group compared with 17.4 months with chemotherapy alone (hazard ratio, 0.87; P = .039). There was also a trend toward improved overall survival, but this did not reach statistical significance; these study patients continue to be followed, and a final analysis has not yet been completed. ASCO highlighted these results as one of the "major clinical cancer advances" of 2011 in its recent annual report.
"Today's approval of Avastin marks the first major treatment advance in newly diagnosed ovarian cancer in 15 years," commented Hal Barron, MD, chief medical officer and head of global product development at Roche.
Bevacizumab has also been studied in recurrent ovarian cancer, and the OCEANS (Ovarian Cancer Evaluation of Avastin and Safety) trial showed significant improvement in progression-free survival when the targeted drug was added to chemotherapy in this setting. Those results were also presented at the ASCO annual meeting and were highlighted as a major advance in the annual report. Recurrent ovarian cancer could be another potential new indication for the drug.

2011-12-30T23:21:00.003+02:00

December 28, 2011 ( UPDATED December 29, 2011 ) — Two phase 3 trials have demonstrated that bevacizumab (Avastin, Genentech/Roche) slows the progression of ovarian cancer in women with advanced disease and may offer clinicians a new class of treatment. Both trials were published in the December 29 issue of the New England Journal of Medicine.
Data from these 2 trials formed the basis of the recent approval in Europe of bevacizumab for use in women with advanced ovarian cancer.
However, Genentech may not be pursuing an indication for bevacizumab in ovarian cancer in the United States, according to a news report from the Associated Press. "We do not believe the data will support approval," said a spokesperson for Genentech, who also added that the decision was not final.
The fact that bevacizumab has yet to show an improvement in overall survival among women with ovarian cancer may be giving the company pause, suggests the report. The situation echoes the circumstances with the drug in breast cancer, which resulted in the Food and Drug Administration revoking bevacizumab's related indication.
The 2 new trials are complementary but differ in a number of ways. However, both studies investigated the addition of bevacizumab to standard chemotherapy in the first-line treatment of ovarian cancer. Both trials were also cosponsored by Roche.
"Bevacizumab blocks the growth factor [vascular endothelial growth factor], which is important in the process of ovarian cancer progression," said Robert A. Burger, MD, one of the bevacizumab investigators, in a press statement. He is director of the Women's Cancer Center at Fox Chase Cancer Center in Philadelphia, Pennsylvania.
Dr. Burger was the lead investigator of the Gynecologic Oncology Group (GOG) study 0218. The 1873-patient study took place at 336 sites located primarily in the United States, but also in Canada, South Korea, and Japan.
In the GOG0218 study, the use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy extended the median progression-free survival (PFS) by 3.8 months in patients with advanced epithelial ovarian cancer.
Specifically, the median PFS was 10.3 months in the chemotherapy-alone control group and 14.1 months in the group that received chemotherapy plus bevacizumab for a prolonged maintenance period. This prolonged, "bevacizumab-throughout" group had a hazard ratio (HR) for progression or death of 0.717 (95% confidence interval [CI], 0.625 - 0.824; P < .001). The median follow-up was 17.4 months.
"This approach can be looked upon as a third major component of treatment for ovarian cancer," summarized Dr. Burger, referring to the use of bevacizumab in addition to the current standard of chemotherapy and debulking surgery. (All of the women in both studies first received surgery.) "This represents a new way for us to control the disease," he added.
In the second study, PFS (restricted mean) at 36 months was 20.3 months with standard therapy and 21.8 months with standard therapy plus bevacizumab (HR for progression or death with bevacizumab added, 0.81; 95% CI, 0.70 - 0.94; P = .004). Overall, the treatment difference was described as "modest" by the study authors, led by Timothy Perren, MD, from the University of Leeds in the United Kingdom.
This study, known as the Gynecologic Cancer InterGroup International Collaboration on Ovarian Neoplasms 7 (ICON7) trial, involved 1528 women and took place at 263 international sites.
The ICON7 investigators noted that the treatment effect was maximized earlier in the study, at 12 months, coinciding with the end of the bevacizumab treatment. In fact, the effect disappeared at 24 months, which led the investigators to use the novel statistical method of restricted mean difference for their calculations at 36 months. The method accounts for "nonproportional hazards."
The fact that the addition of bevacizumab was most effective at 12 months, with a resounding 15.1% (95% CI, 10.7 - 19.5) improvement in PFS compared with standard therapy, led the investigators to speculate about possible continuous maintenance treatment. They said that the findings raised the "possibility that prolonged therapy beyond 12 months, perhaps until disease progression, might further improve outcome."
The GOG0218 investigators called bevacizumab a "front-line treatment option," but also said that much more work is needed in evaluating bevacizumab in this setting. They cited the need to optimize duration and timing of treatment, examine cost-effectiveness, and "perhaps most important, identify potential tumor or host biologic factors predictive of efficacy and adverse events with the ultimate goal of decreasing morbidity and mortality from this disease."
Earlier data from both studies have been previously reported by Medscape Medical News: Data from ICON7 were reported from the American Society of Clinical Oncology 2011 Annual Meeting and at the 35th European Society for Medical Oncology Congress, and data from GOG0128 were reported from the American Society of Clinical Oncology 2010 Annual Meeting.
Differences in the 2 Studies
The ICON7 trial differed from the GOG trial in a number of ways.
The ICON7 study enrolled patients with advanced-stage cancer (70%) who had no visible residual disease, as well as some patients with high-risk, early-stage disease (9%). In the GOG0218 study, all of the patients had advanced disease: stage 3 (incompletely resectable, and thus some residual disease) or stage 4. All of the women in GOG0218 had epithelial disease; 90% in ICON7 did so.
Also important is that in the ICON7 study, half the dose of bevacizumab was used (7.5 mg/kg vs 15 mg/kg in the GOG0218 study) for a shorter maintenance period (12 vs 16 cycles).
Notably, the prognosis for patients at high risk for progression in the ICON7 study was similar to that for all patients in the GOG study. A 3.6-month (restricted mean) improvement in PFS was observed with bevacizumab in ICON7, "similar to that seen in the GOG-0128 study," write Dr. Perren and coauthors. "The apparently greater effect of bevacizumab in patients with a poor prognosis is encouraging," they add.
Overall Survival and Adverse Events
The primary outcomes were also different in the 2 studies. In GOG0218, the primary endpoint was PFS, but the trial is also tracking survival. At the time of the new analysis (median follow-up, 17.4 months), 76.3% of the patients were still alive, with no significant differences in overall survival.
In ICON7, PFS is a secondary outcome and overall survival is the primary outcome; these data are not yet final and are due in 2013. However, in their updated analysis, the investigators report that Kaplan-Meier estimated rate of 1-year survival was 92% in the bevacizumab group and 86% in the standard therapy group (HR, 0.85; 95% CI, 0.69 - 1.04; P = .11).
Bevacizumab did not affect the delivery of chemotherapy in either trial. However, the drug did, as the ICON7 authors worded it, "expand the range of toxic effects." Most notably, bevacizumab increased hypertension and bowel perforation. For instance, in the GOG0218 study, the rate of hypertension requiring medical therapy was higher in the bevacizumab-throughout group (22.9%) than in the control chemotherapy group (7.2%). Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2% and 2.6% of patients in the control group and the bevacizumab-throughout group, respectively.
Study Designs
In GOG, all patients received chemotherapy consisting of intravenous paclitaxel at a dose of 175 mg/m² body-surface area, plus carboplatin at an area under the curve of 6, for cycles 1 through 6, plus a study treatment (either placebo or bevacizumab) for cycles 2 through 22, with each cycle having 3 weeks' duration.
The study actually had 3 groups: 1 with chemotherapy alone and 2 with differing lengths of bevacizumab.
The control treatment was chemotherapy with placebo added in cycles 2 through 22. Another group, known as "bevacizumab-initiation" treatment, was chemotherapy with bevacizumab (15 mg/kg body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22.
The third group, known as "bevacizumab-throughout" treatment was chemotherapy with bevacizumab added in cycles 2 through 22.
The bevacizumab-initiation group had less improvement in PFS than the more treatment-intensive bevacizumab-throughout group.
In ICON7, patients were randomly assigned to receive carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg/m² body-surface area), given every 3 weeks for 6 cycles, or to receive this regimen plus bevacizumab (7.5 mg/kg body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease.
GOG0128 was supported by Roche/Genentech and the National Cancer Institute. ICON7 was supported by Roche/Genentech and the National Institute for Health Research, through the National Cancer Research Network in the United Kingdom. The lead authors of both GOG0128 and ICON7, as well as some of their coauthors, have disclosed financial relationships with the study sponsor, Roche. The lead authors also report relationships with other pharmaceutical companies.
N Engl J Med. 2011;365:2473-2496. GOG full text, ICON7 full text

ALISKERIN UNDER REVIEW

2011-12-30T23:20:00.004+02:00

LONDON (Reuters) Dec 23 - The European Medicines Agency said it would review the use of aliskiren-containing medicines after blood pressure drug Rasilez made by Novartis was shown in an independent study to increase the risk to patients with heart or kidney problems.
The regulator said on Thursday it would assess data from the ALTITUDE study, which was terminated early after patients showed no benefit from using the drug.
There were more cases of stroke, renal complications, hyperkalemia and hypotension in patients who received aliskiren compared with patients who received a placebo.
Novartis was not immediately available to comment on Thursday.
On Tuesday, the company said it was recommending the removal from patients' treatment of products based on aliskiren, which it markets as Rasilez in Europe and Tekturna in the United States, and a review of their high blood pressure medication.
Eight medicines containing aliskiren, a type of renin inhibitor, are licensed for use in Europe.

PSA SCREENING:DEBATE CONTINUES

2011-12-30T23:20:00.002+02:00

December 29, 2011 — The debate about PSA screening for prostate cancer, which has reached a crescendo in recent months after the US Preventive Services Task Force (USPSTF) recommended against it, continues now in a series of opinion articles published in the December 28 issue of JAMA.
Most of the commentators take issue with recommendation.
Although the USPSTF "deserves credit for sharpening the focus on the risks and harms of prostate screening," the committee did not get it quite right, suggests an opinion piece from Robert Volk, PhD, from the Department of General Internal Medicine at the University of Texas M.D. Anderson Cancer Center in Houston, and Anthony Woolf, MD, from the Department of Medicine at the University of Virginia School of Medicine in Charlottesville.
This was a grade D recommendation, which indicates that physicians have no obligation to mention the issue of prostate cancer screening because testing of asymptomatic men should not occur, the commentators point out. It would be better to have a grade C recommendation, which also recommends against routine screening but would allow for individualized decision making, they note. This would permit physicians to apprise men of the potential benefits and harms of screening, and then the patient and physicians could decide in partnership whether or not to proceed.
A grade C recommendation would have put the USPSTF in line with virtually all other medical organizations, including the American Cancer Society and the American Urological Association, in recommending against routine screening but promoting actively engaging men in the decision, Dr. Volk and Dr. Woolf comment.
Cannot Go Uncontested
The USPSTF recommendations "miss the mark," according to another set of authors, David Miller, MD, MPH, and Brent Hollenbeck, MD, both from the Department of Urology at the University of Michigan, Ann Arbor.
They point out that during the last 2 decades, and concurrent with the dissemination of PSA screening, there has been a significant decline in prostate cancer–specific mortality in the United States ( Lancet Oncol. 2008;9:445-452).
"This well-established epidemiological trend is difficult, if not impossible, to explain without accepting that early detection strategies built around PSA screening have allowed the identification and successful treatment of patients who would have otherwise died of biologically aggressive, clinically significant prostate cancers," they write.
"[T]his advance apparently was barely recognized in the deliberations and communications from the task force," they comment.
However well-intentioned, the USPSTF recommendation against PSA screening cannot go uncontested, say Dr. Miller and Dr. Hollenbeck. Although emphasizing the need to avoid harm associated with detection and treatment, which is without question a laudable goal, the task force is essentially "relegating some men to an avoidable death from prostate cancer, including the morbidity associated with metastatic disease."
"Clinicians must preserve the ability to detect aggressive prostate cancer while these tumors are still at an early stage," they write. "At the present time, PSA screening is the best tool available to achieve this objective, even if it means some men may experience morbidity and mortality associated with diagnosis and treatment."
Change in Management
Eliminating PSA-based screening is premature, write Jeri Kim, MD, from the Department of Genitourinary Medical Oncology, and John Davis, MD, from the Department of Urology, University of Texas M.D. Anderson Cancer Center, in a third commentary.
"Until each man's risk for prostate cancer can be individually assessed (as it will be in the future), a new model is needed for managing the disease in PSA-screened men, " they write.
They suggest changes at the low-grade-disease end of the spectrum, as this is where the problem of overdiagnosis and overtreatment occurs. Low-risk patients could be managed with active surveillance, and some could be treated with 5-alpha reductase inhibitors finasteride and duasteride.
At present, in the United States, about 90% of men with localized disease (including about 75% with lower-risk cancers) undergo surgery or radiation therapy, according to another commentary by Robert Chou, MD, from Oregon Health & Sciences University, Portland, and Michael LeFevre, MD, from the University of Missouri School of Medicine in Columbia. They note that those estimates are based on actual US data ( J Clin Oncol. 2010;28:1117-1123), and whether these rates can be substantially reduced in practice has "yet to be determined."
The controversies behind prostate cancer screening may never be fully resolved, they comment, but they, and many of the other authors, emphasize that "[n]o man should be screened without his explicit consent."
The Right Call
One of the opinion pieces supports the USPSTF recommendation against PSA screening and comes, unsurprisingly enough, considering his well-known stance on cancer screening, from H. Gilbert Welch, MD, MPH, from the Dartmouth Institute for Health Policy & Clinical Practice, Hanover, New Hampshire. (Dr. Welch is author of Should I Be Tested for Cancer? Maybe Not and Here's Why, and a coauthor of Overdiagnosed: Making People Sick in the Pursuit of Health).
"If I was pressed to get off the fence, it's the call I would have made," he writes.
"The United States now needs the medical profession to make more calls like this," he writes. "[T]he nation also needs the profession to communicate the nuances of medicine. Most tests and treatment are neither unambiguously good nor unambiguously bad. Instead, their effect is modified by how they are used."
Dr. Wolf served as a chair to the American Cancer Society Prostate Cancer Advisory Committee when it developed its 2010 prostate screening guideline, and Dr. Volk served as a consultant to that committee. Dr. Miller is a member of the National Comprehensive Cancer Network Prostate Cancer Treatment Guidelines Committee. Dr. Kim reports receiving research support from Merck. Dr. Davis has acted as a consultant to Baxter and has grants pending with Genprobe and Jansen. Dr. Chou was lead author on the evidence review commissioned by the USPSTF on prostate cancer screening. Dr. LeFevre is the co–vice chair of the USPSTF.
JAMA. 2011;306:2715-2722, 2649-2650. Volk and Wolf extract, Kim and Davis extract, Miller and Hollenbeck extract, Chou and LeFevre extract, Welch extract

DIAGNOSIS OR RCC INCREASING IN USA

2011-12-30T23:19:00.002+02:00

NEW YORK (Reuters Health) Dec 23 - The incidence of kidney cancer has increased significantly over the past three decades in the United States, according to a report in the November 16 online issue of The Journal of Urology.
"As imaging tests are ordered for a variety of reasons, incidental renal cancers are being increasingly found," Dr. Seth A. Strope from Washington University School of Medicine in St. Louis, Missouri, told Reuters Health by email.
"Since most of these tumors are now found in an asymptomatic state, internists should be vigilant for these findings on their scans."
Dr. Strope and colleagues used National Cancer Institute SEER cancer registry data for 1975 to 2006 to determine the kidney cancer incidence by age.
During this interval, the overall age-adjusted kidney cancer incidence increased 238%, from 7/100,000 to 17.6/100,000 adults. The annual rise was higher between 1976 and 1990 (3.6% annually) than between 1991 and 2006 (2.9% annually).
Renal tumors diagnosed after 1991 were more likely to be smaller and localized to the kidney than tumors diagnosed earlier.
All age groups showed an increase in renal cancer diagnoses during the more contemporary periods, with the most rapid increases appearing in the younger age groups during the second half of the study.
The fastest increase in renal cancer incidence was in the 20- to 39-year-old group, followed by the 60-to-69- and 70-to-79-year-old groups.
"The trend toward increased exposure to risk factors for kidney cancer at earlier ages combined with imaging may help explain why the youngest age group had the fastest increase in renal cancer relative to the other age groups," the researchers note.
"Rising incidence of kidney cancer points to the need to appropriately tailor therapy to individual patients," Dr. Strope said. "Younger patients would most benefit from kidney preservation through removal of only the tumor, while older patients may benefit from surveillance of small renal masses."
"Further research into the rising incidence of kidney cancer will need to focus on new risk factors," Dr. Strope added. "Exploration of large cohort studies with focus on risk factors in past versus more current years will be needed to determine these risk factors."
SOURCE: http://bit.ly/s3edud
J Urol 2011;187:32-38.

LMWH FAILURE IN ACUTELY ILL

2011-12-30T23:18:00.003+02:00

December 28, 2011 — The low–molecular weight heparin enoxaparin did not reduce the rate of death from any cause among hospitalized, acutely ill medical patients, according to the findings of the large, randomized International, Multi-Center, Randomized, Double Blind Study to Compare the Overall Mortality in Acutely Ill Medical Patients Treated With Enoxaparin Versus Placebo in Addition to Graduated Elastic Stockings (LIFENOX) trial.
Ajay K. Kakkar, MBBS, PhD, from the Thrombosis Research Institute and University College London, United Kingdom, and colleagues reported their findings in the December 29 issue of the New England Journal of Medicine.
According to the researchers, thromboprophylaxis has been shown to reduce the rate of venous thromboembolic events in both surgical and medical patients, and current guidelines clearly recommend its use in both these patient populations. However, lower use in acutely medically ill patients "may reflect a lack of evidence for a mortality reduction associated with pharmacologic prophylaxis in acutely ill medical patients."
The current study sought to evaluate the effect of thromboprophylaxis enoxaparin on the rate of death from any cause in acutely ill medical patients.
A total of 8307 patients were included in the trial. Participants were at least 40 years of age with 1 of the following conditions: acute decompensation of heart failure, active cancer, or severe systemic infection in addition to chronic pulmonary disease, obesity, history of venous thromboembolism, or an age of 60 years or older. Expected duration of hospitalization was at least 6 days.
Patients were randomly assigned to receive either subcutaneous enoxaparin, given at a dose of 40 mg/day, or placebo, and all patients were assigned to wear elastic stockings with graduated compression.
The primary endpoint of rate of death from any cause at day 30 was comparable with enoxaparin vs placebo (4.9% vs 4.8%; risk ratio, 1.0; 95% confidence interval [CI], 0.8 - 1.2; P = .83). The rate of major bleeding was also similar, at 0.4% in the enoxaparin group and 0.3% in the placebo group (risk ratio with enoxaparin, 1.4; 95% CI, 0.7 - 3.1; P = .35).
"These findings appear to be counterintuitive, given the fact that pharmacologic prophylaxis has been shown to reduce the risk of venous thromboembolism, including asymptomatic deep-vein thrombosis, by at least 45% in hospitalized, acutely ill medical patients," Dr. Kakkar and colleagues report.
They add that their study "may have been underpowered to show a between-group difference in mortality."
According to the researchers, although no reduction in risk for death was observed in the current trial, pharmacologic thromboprophylaxis is known to prevent venous thromboembolism, thus reducing the need for treatment with high doses of anticoagulant agents during a prolonged period.
Frank A. Lederle, MD, director of the Minneapolis VA Center for Epidemiological and Clinical Research in Minnesota, was lead author on a recent independent systematic review of heparin prophylaxis (various types, not just enoxaparin) that also showed little or no net benefit in improving mortality.
"As we noted, the available data do not indicate a clinically important net benefit from heparin prophylaxis in medical or stroke patients," he told Medscape Medical News. "We did observe a nonsignificant trend toward lower overall mortality with heparin, but the new findings by Kakkar and colleagues suggest this trend may not be meaningful," he added.
"In my view, the strongly prescriptive guidelines that put great pressure on physicians to use heparin prophylaxis are not justified and should be changed in favor of individual judgment," he said. "In particular, the Joint Commission standard that requires prophylaxis or an explanation of why not for any inpatient over 18 years old is seriously misguided."
According to Dr. Lederle, the overall answers of no reduction in mortality and no important net gain in morbidity are "unlikely to be wrong." He added that for those who still wish to use heparin prophylaxis in medical patients, it would be useful to know in which patients the practice is most likely to be favorable. "However, without significant effects in large combined populations, the chance of identifying favorable subgroups is unfortunately rather small," he said.
The study was supported by sanofi-aventis, the manufacturer of enoxaparin. Dr. Kakkar reports receiving consulting fees, grant support through his institution, and lecture fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, GlaxoSmithKline, Pfizer, and sanofi-aventis. The other authors also report multiple commercial relationships. Dr. Lederle has disclosed no relevant financial relationships.
N Engl J Med. 2011;365:2463-2472.