A NOVEL EFFECTIVE TREATMENT FOR ANAPLASTIC THYROID CANCER

J Clin Endocrinol Metab. 2010 Jun 30. [Epub ahead of print]
High Efficacy of Concomitant Treatment of Undifferentiated (Anaplastic) Thyroid Cancer with Radiation and Docetaxel.
Troch M, Koperek O, Scheuba C, Dieckmann K, Hoffmann M, Niederle B, Raderer M.

Department of Internal Medicine I, Division of Oncology and Cancer Center (M.T., M.R.), Department of Surgery, Division of General Surgery, Section of Endocrine Surgery (C.S., B.N.), and Departments of Pathology (O.K.), Radiotherapy and Radiobiology (K.D.), and Nuclear Medicine (M.H.), Medical University of Vienna, A-1010 Vienna, Austria.
Abstract

Context: Anaplastic thyroid carcinoma (ATC) is a rare but aggressive solid tumor with a very short survival time even with multimodality treatment. In view of in vitro data and the high rate of p53 mutations in ATC, we have used combined treatment with external beam radiation and docetaxel. Objective: The objective was to analyze the activity using radiation plus docetaxel. Design: The design was a retrospective analysis. Setting: The study was performed in a referral center of a university hospital. Patients: A total of six patients with ATC were treated at our institution. Intervention: Treatment consisted of standard external beam radiation of 60.0 Gy in 30 fractions along with docetaxel at a flat dose of 100 mg absolute every 3 wk for a total of six cycles starting within the first week of radiation. Outcome Measure: The outcome measure included clinical response and survival. Results: Five patients completed radiochemotherapy. One patient has completed radiation but is still on treatment with docetaxel. Four patients achieved complete remission and two partial response. During radiation therapy, four patients developed severe mucositis/stomatitis and two dermatitis, necessitating hospitalization. Two patients developed pneumonia and one urinary tract infection. All patients were hospitalized for a median of 17 d (range, 4-40 d) because of toxicites. After a median follow up of 21.5 months (range, 2-40 months), five patients are alive. Conclusion: The preliminary data suggest that the combination of radiation and concomitant docetaxel is highly effective in patients with ATC. However, a formal phase II study is needed to assess the therapeutic potential of this combination.

MOLECULAR MARKERS FOR CHEMOTHERAPY RESPONSE IN GEPs

Endocr Relat Cancer. 2010 Jun 22. [Epub ahead of print]
Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors (GEP).
O'Toole D, Couvelard A, Rebours V, Zappa M, Hentic O, Hammel P, Levy P, Bedossa P, Raymond E, Ruszniewski P.

D O'Toole, Department of Clinical Medicine & Gastroenterology, Trinity College Dublin, Dublin, P.O. Box 580, Ireland.
Abstract

Response rates to cytotoxics in gastro-entero-pancreatic (GEP) neuroendocrine tumors vary; recent trials demonstrated lack of objective response rates in up to 70% of patients. Identification of predictive therapeutic biomarkers would be beneficial in the treatment of GEP. Selected markers with known or suspected capability of predicting response to cytotoxics or prognosis (Ki-67, p53, MDR1, Akt, TS, PTEN, CA-9, CD34, VEGF, HIF1, hLMH1, Bcl2) were analyzed using immunohistochemisrtry in 60 treatment-naive patients receiving chemotherapy (n=46) or chemoembolisation (n=14) for inoperable advanced and/or metastatic GEP and correlated with prognosis (survival and response rates). Therapy included: systemic chemotherapy with streptozotocin (n=28), doxorubicin (n=14), 5-FU (n=18) and etoposide/cisplatinum (n=16); or chemoembolization (streptozotocin, 9; doxorubicin, 5). Factors associated with overall survival in the entire cohort were: Ki-67, p<0.001; tumor grade, p<0.001, tumor differentiation, p<0.001; CA9, p=0.004; Akt, p=0.01; HIF-1, p<0.001; p53, p<0.0001; hMLH1, p=0.005. Markers associated with treatment response included: overall group: Akt and PTEN (p=0.05 and p=0.05, respectively); streptozotocin: Akt (p=0.07), TS (p=0.02) and PTEN (p=0.017); doxorubicin: Ki-67 (p=0.05); Akt (p=0.06) and CA-9 (p=0.02). At multivariate analysis, Akt was significantly associated with a non-response to therapy (OR: 0.2 [0.05-0.8]). For patients receiving only systemic chemotherapy (n=46) PTEN (0.04) and hLMH1 (0.03) were correlated with treatment response; and for individual molecules were: streptozotocin: PTEN (p=0.008), hLMH1 (0.07); doxorubicin: Akt (p=0.09), CA-9 (p=0.09) and hLMH1 (p=0.09). These results demonstrate a number of new prognostic biomarkers in GEP-NET and in addition response to chemotherapy was correlated with a simple panel of selected markers (such as CA9, Akt, PTEN, TS and hLMH1).

T1 BLADDER CANCER SUBSTAGING

Prog Urol. 2010 Jun;20(6):440-9. Epub 2010 Mar 28.
[T1 bladder carcinoma: prognostic value of the muscularis mucosae invasion (T1a/T1b). A multicanter study by the French Urological Association (CCAFU)]

[Article in French]
Faivre d'Arcier B, Celhay O, Safsaf A, Zairi A, Pfister C, Soulié M, Rozet F, Rouprêt M, Fromont G, Mazerolles C, Gobet F, Fetissof F, Irani J.

Service d'urologie, hôpital Bretonneau, CHU de Tours, 2, boulevard Tonnellé, 37000 Tours, France. bfaivredarcier@gmail.com
Abstract

OBJECTIVE: The aim of this multicenter study was to determine the prognostic value of the depth of invasion of lamina propria and more specifically the influence of the invasion of the muscularis mucosae on survival parameters in T1 bladder carcinoma. PATIENTS: Six urological centers included patients between 1994 and 2004 who had an initial T1 bladder tumor. All T1 tumors were substaged according to the muscularis mucosae (MM) invasion into T1a (no invasion beyond the MM) and T1b (invasion beyond MM but preserving the muscle). Among the 387 patients included, 269 (69.5%) were found T1a and 118 (30.5%) T1b. Mean follow-up was 45.4 months. T1a and T1b groups were comparable except for tumor grade that was higher in T1b (p<0.001). RESULTS: Survival without recurrence was not significantly different between T1a and T1b groups (p<0.3) but T1a stage was found as an independent factor for survival without progression (RR=0.49; IC 95%=[0.71-0.90]), specific survival (RR=0.33; IC 95%=[0.16-0.67]) and global survival (RR=0.52; IC 95%=[0.32-0.85]). CONCLUSION: This study, the largest on the subject to our knowledge, have shown that muscularis mucosae invasion was a prognostic factor for survival without progression, specific survival, and global survival. We support that routine pathological assessment of the level of MM invasion in patients with stage T1 bladder cancer should be included in the histopathological report.

PSA SCREENING HALVES MORTALITY FROM PROSTATE CANCER?

July 1, 2010 — New data from a Swedish study show that population screening with prostate-specific antigen (PSA) in men between 50 and 69 years of age reduced prostate cancer mortality by almost half during a follow-up period of 14 years. The finding was published online today in Lancet Oncology.

"In this trial, prostate cancer screening was well accepted by the general population and can result in a relevant reduction in cancer mortality, greater than that reported in screening for breast and colorectal cancer," conclude the researchers, headed by Jonas Hugosson, MD, from the Department of Urology at the University of Gotenburg, Sweden.

This is the best mortality result ever seen with PSA screening — even better than the positive results reported from a large European study last year, which found a 20% reduction in prostate cancer deaths after 9 years. Those results came from the European Randomised Trial of Screening for Prostate Cancer (ERSPC) and provided for the first time "proof of the benefits of PSA screening," according to the investigators.

These new findings from Gotenburg provide the second proof after the ERSPC that PSA screening can save lives, David Neal MD, from the Department of Oncology at the University of Cambridge, United Kingdom, commented to Medscape Medical News.

Not Generalizable to the United States

However, there are several important caveats to the Gotenburg study, Dr. Neal writes in an accompanying editorial. It was small (n = 20,000), and more than half of the men were already included in the ERSPC study (n = 162,387, including 11,852 from the Gotenburg study). However, the 2 trials produced different results, probably because of the longer follow-up and younger age at screening in the Gotenburg study, he suggests.

Dr. Neal also emphasizes the context of the new finding. It comes from "a country with low levels of opportunistic PSA testing," which is in direct contrast to the situation in the United States, where there is already widespread PSA testing.

Hence, the results might be generalizable to other countries that have not had prior extensive PSA testing, but not to countries such as the United States, which already have such testing widely available, he said.

This may explain the negative results from the large study from the United States, the Prostate Lung Colorectal and Ovarian (PLCO), which found no reduction in prostate cancer mortality from PSA screening during a follow-up of 11 years. Those results have been discussed in some detail, with a major concern being potential contamination in the control group; the investigators noted that PSA testing had been widespread even before the study began.

The PCLO study is "flawed and will probably never show meaningful results," Dr. Neal commented to Medscape Medical News. "Many of the men were already screened with a PSA test."

The contradictory results from PLCO and ERSPC, which were published together in the New England Journal of Medicine last year, have fueled heated debate and controversy over the benefits vs harms of PSA screening.

However, Dr. Neal told Medscape Medical News that there is growing agreement that PSA screening does save lives from prostate cancer — at a price.

"The consensus is that PSA testing is a 'proof of principle' with a marker that has some defects. We need better biomarkers," he said. In the editorial, he mentions insulin-like growth factor or kallikrein family members, as well as genetic testing.

The new finding from Gotenburg shows that "PSA testing reduces death from prostate cancer in some circumstances," Dr. Neal concludes.

However, it does not imply that PSA screening programs should now be introduced internationally, he adds.

"One important finding in this study is that diagnosis of prostate cancer did not automatically result in men taking up radical treatment," Dr. Neal commented. About 40% of men were placed on active surveillance protocols, and 28% remain on these protocols. Hence, many of the men were managed conservatively, but despite this, there was a survival benefit in the groups that was screened, he pointed out.

Gotenburg Study "Mirrors Population Screening"

The Gotenburg study began in 1994 and enrolled 20,000 men who lived in the city and were older than 50 years (age range, 50 - 64 years; median age, 56 years). They were randomly assigned to either the screening or control group and then invited for screening with the PSA test. The invitations stopped at a median age of 69 years (range, 67 - 71 years).

This design "gives more representative results than does randomisation after informed consent, and mirrors the situation when screening is introduced in the population," the authors explain.

This study shows that a PSA-based screening program is acceptable to men aged 50 years or older, with 76% of men attending at least once, they report.

With such a participation rate, this screening program reduced prostate-cancer specific mortality "by as much as half over 14 years' follow-up."

During the median 14-year follow-up, prostate cancer was diagnosed in 12.7% of men in the screening group and 8.2% in the control group (hazard ratio, 1.64; P < .0001).

Most of the prostate cancer diagnosed in the screening group was early-stage disease, the researchers comment. More patients in the screening group had hormonal therapy, treatment with curative intent, and surveillance, they add.

According to the Cause of Death committee review, there were 44 deaths from prostate cancer in the screening group and 78 in the control group (according to death certificates, these numbers were 45 and 77, respectively).

"Half of the attendees who died from prostate cancer were diagnosed at their first screening visit," the researchers note.

The rate ratio (RR) of dying from prostate cancer was 0.56 in the screening group compared with the control group (P = .002).

The absolute cumulative-risk reduction (Kaplan-Meier estimates) of death from prostate cancer at 14 years was 0.40%, reduced from 0.90% in the control group to 0.50% in the screening group.

Compares Favorably With Other Cancer Screening

At 14 years of follow-up, the number who needed to be invited to screening (NNS) to prevent 1 prostate cancer death was 293, whereas the number needed to be diagnosed (corresponding to number needed to treat, NNT) was 12, the Swedish researchers report.

"These outcomes compare favourably with the well-established screening programs for breast and colorectal cancer," Dr. Neal comments in the editorial.

In their article, the Swedish researchers cite several papers for comparable figures.

Mammography for breast cancer screening has reported a NNS of 377 and an RR of 0.68 for women aged 60 to 69 years, and an NNS of 1339 and RR of 0.86 for women aged 50 to 59 years at 11 to 20 years of follow-up. A separate review reported an NNT for mammography of 10 over 10 years.

Colorectal cancer screening by fecal occult blood test has reported an RR of 0.84 in 2 separate reviews (after 11.7 - 18.4 years and 7.8 - 13 years, respectively), and an NNS of 1173 after 10 years.

Colorectal cancer screening by flexible sigmoidoscopy has reported an RR of 0.69 and an NNS of 489 at median follow-up of 11.2 years. However, as sigmoidoscopy removes any polyps that are found, it is associated with a reduced colorectal cancer incidence, and so an NNT cannot be calculated.

Differences Between Gotenburg and Previous Studies

The Swedish researchers discuss in some detail the discrepancy between their findings and those from the 2 large previous studies of PSA screening — the ERSPC and the PLCO — and offer potential explanations.

"First, the men in our study were younger (median age 56 years at baseline) than in both previous publications (median age>60years)," they point out.

"Younger men are less likely than older men to have incurable prostate cancer at the first screening, and are therefore more likely to gain the full benefit of screening," they comment.

In addition, the PSA threshold for biopsy was lower in the Gothenburg study, and so there was a "much higher rate" of biopsy for men with a positive screening result, the Swedish researchers note. There were also differences in the screening intervals, and the 2 previous studies also included digital rectal examination as a screening tool, whereas the Gotenburg study did not.

Perhaps the most important difference was the length of follow-up — a median of 14 years after randomization in the Gotenburg study compared with 9 years for ERSPC and 11.5 years for PLCO.

Dr. Hugosson and colleagues comment that the results for the first 10 years of follow-up from the Gotenburg study are similar to those from ERSPC, suggesting that most of the benefit from screening occurs after 10 years. "This is to be expected from a disease with a long lead-time and a long natural course," they add.

The NNT of 12 in the Gotenburg study is substantially lower than the NNT of 48 in the ERSPC, which suggests that NNT is very dependent on the length of follow-up, and "it is not easy to predict at which follow-up period the NNT will stabilise," they note.

As the NNT in prostate cancer screening mainly reflects the risk for overdiagnosis, the Swedish researchers suggest that this risk "is probably not as high as some have feared, at least if screening is restricted to the age groups included in this study" (ie, ages 50 - 69 years).

"Inviting men over the age of 70 for PSA screening seems questionable," the researchers comment. The benefit from prostate cancer screening takes a long time to achieve, they point out. Only marginal benefits are gained within the first 10 years, and the risk of overdiagnosis and overtreatment are still the major concerns in this field, so "one should be cautious to recommend that all elderly men have PSA screening."

Dr. Hugosson has received lecture fees from GlaxoSmithKline and Abbott Pharmaceuticals, and coauthor Hans Lilja, MD, has received honoraria from GlaxoSmithKline and holds patents for free PSA and hK2 assays. The other coauthors have disclosed no relevant financial relationships. Dr. Neal is one of the principal investigators on ProtecT, a trial of treatment of localized prostate cancer funded by the National Institute of Health Research.

Approached for independent comment, Philip Kantoff, MD, from the Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News that the new study "does strongly support the position that PSA-based screening reduces prostate cancer specific mortality."

"It also supports the previous findings that prostate cancer mortality in a screened population is low in the first 10 years, and that overtreatment appears to be a significant problem," Dr. Kantoff said. "The issues of refining who should be screened and how frequently — but most importantly, who needs to be treated — needs to be determined," he added.

Lancet Oncol. Published online July 1, 2010.

EARLY AGGRESSIVE THERAPY FOR RA RECOMMENDED

June 28, 2010 — Early, aggressive use of disease-modifying antirheumatic drugs (DMARDs) is recommended for patients with rheumatoid arthritis (RA), according to the results of a randomized controlled trial reported online June 24 in Arthritis Research and Therapy.

"Early therapy with combinations of conventional DMARDs has been shown to retard the radiologic progression of RA for a period of up to 5 years, but until now the effects of initial aggressive DMARD therapy on radiologic prognosis after that were unknown," said lead author Vappu Rantalaiho, MD, from Tampere University Hospital in Finland, in a news release. "We've shown that even after 11 years, early and aggressive therapy achieves excellent results for most patients."

The study goal was to assess radiologic progression beyond 5 years in 199 patients with early active RA initially treated with a combination of 3 DMARDs or with DMARD monotherapy. Participants were initially assigned to treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone (FINRACo), or treatment with a single DMARD (initially sulfasalazine) with or without prednisolone (SINGLE). The drug-treatment strategy after 2 years still targeted remission, but drug choice became unrestricted.

Outcome measures were Larsen score of hand and foot radiographs analyzed at baseline, 2, 5, and 11 years, and radiographic findings of large joints at 11 years. Radiographs of hands and feet were available at baseline and at 11 years for 65 patients in the FINRACo group and for 65 patients in the SINGLE group.

For the FINRACo group, mean change in Larsen score from baseline to 11 years was 17 (95% confidence interval [CI], 12 - 26) compared with 27 (95% CI, 22 - 33) in the SINGLE group (P = .037). There were no erosive changes in large joints at 11 years in 87% of the patients in the FINRACo group (95% CI, 74 - 94) and in 72% (95% CI, 58 - 84) of the patients in the SINGLE group.

"Targeting to remission with tight clinical controls results in low radiologic progression in most RA patients," the study authors write. "Patients treated initially with a combination of DMARDs have less long-term radiologic damage than do those treated initially with DMARD monotherapy."

Limitations of this study include a trend toward a lower Larsen score at baseline in the FINRACo group completers vs the SINGLE group completers.

"Probably the most important precondition to our excellent results in most patients was the active treatment policy aiming at remission at all time points," Dr. Rantalaiho concluded. "Our results emphasize the importance of early remission for long term outcome. In the present study, the patients who were in strict remission at 1 year had significantly less radiologic progression throughout the follow-up than the patients who were not."

The Medical Research Fund of Tampere University Hospital and the Finnish Society for Rheumatology supported this study. The study authors have disclosed no relevant financial relationships.

Arthr Res Ther. Published online June 24, 2010.

NEW DRUGS FOR NSCLC

June 30, 2010 — Two new experimental agents hold promise in the treatment of lung cancer, according to data presented here during the American Society of Clinical Oncology 2010 Annual Meeting.

The results of a phase 2 trial show that the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor PF299804 (Pfizer) appears to be more effective than erlotinib (Tarceva) in improving progression-free survival in patients with nonsmall-cell lung cancer (NSCLC) who have failed chemotherapy.

A second phase 2 study found that when ARQ197 (ArQule), a selective non-ATP-competitive inhibitor of c-MET, was combined with erlotinib, progression-free survival was prolonged in patients with advanced NSCLC, compared with those who received erlotinib alone.

However, 2 other investigational agents failed to improve outcomes. In a phase 3 trial, the addition of figitumumab (Pfizer) to paclitaxel and carboplatin did not increase overall survival in patients with advanced nonadenocarcinoma NSCLC. In addition, the trial was halted early because of serious adverse effects and increased mortality associated with the experimental agent.

In a phase 2 trial, combining mapatumumab (Genome Sciences) with carboplatin and paclitaxel as first-line therapy in advanced NSCLC did not improve response rate or progression-free survival.

PF299804

In the first study, 188 patients with advanced NSCLC who had failed at least 1 chemotherapy regimen were randomized to receive either oral PF299804 45 mg or erlotinib150 mg once daily until disease progression or toxicity.

Progression-free survival was 12.4 weeks (range, 8.3 to 16.1) for patients receiving PF299804 and 8.3 weeks (range, 8.0 to 11.4) for patients receiving erlotinib (hazard ratio [HR], 0.681; P = .019). The benefit was also consistent across several subgroups, including EGFR wild-type.

"Overall survival data are being collected, but are not yet mature," lead author Michael Boyer, MBBS, PhD, clinical professor of medicine at the University of Sydney in Australia, told Medscape Oncology. "Further follow-up will be required before we have this information."

The objective response rate also favored PF299804 over erlotinib (17% vs 4.3%; 2-sided P = .009).

Neither group has reached the median duration of response. One patient who received PF299804 achieved a complete response of 48-plus weeks, as of April 15, 2010, explained Dr. Boyer.

The number of patients achieving clinical benefit (complete response, partial response, or stable disease for 24 or more weeks) was significantly higher for those who received PF299804 than for those who received erlotinib (27.7% vs 13.8%; P = .03).

The results of this study lend support to phase 3 trials of PF299804. "A phase 3 trial of PF299804 is currently active — the CAN-NCIC-BR26 study — and is being carried out in Canada and Australia," said Dr. Boyer. "It compares single-agent PF299804 with placebo in patients who have failed erlotinib."

"The design of other potential phase 3 trials is currently under discussion," he added.

The majority of treatment-related adverse events were grade 1 or 2, although 9 patients discontinued therapy because of them: 6 in the PF299804 group and 3 in the erlotinib group. Four treatment-related grade 5 adverse events were reported: 2 in the PF299804 group (1 pneumonia and 1 pneumonitis) and 2 in the erlotinib group (1 pneumonia and 1 pulmonary embolism).

"The adverse events were easily manageable and not problematic," said Dr. Boyer, "and 94% of patients were able to continue with planned treatment, with the discontinuation rate being only 6%."

ARQ197

In the second study, Joan H. Schiller, MD, professor of medicine at Southwestern Medical School in Dallas, Texas, and colleagues conducted a randomized trial comparing erlotinib plus ARQ197 with erlotinib plus placebo. Archival tissue was collected for all patients so that KRAS, EGFR, and c-MET could be analyzed. The cohort included 167 patients with advanced EGFR-inhibitor-naïve NSCLC.

"c-MET is a receptor tyrosine kinase that is implicated in a number of abnormal cellular behaviors," said Dr. Schiller during her presentation. "c-MET amplification is associated with poor prognosis in NSCLC and resistance to EGFR kinase inhibitors."

Progression-free survival, the study's primary end point, favored the combination therapy over single-agent erlotinib in the intent-to-treat population (median, 16.1 vs 9.7 weeks; HR, 0.81; 95% confidence interval [CI], 0.57 - 1.15; P = .23).

"This was statistically significant when adjusting for key prognostic factors in Cox regression analysis," said Dr. Schiller.

Adjustment for prognostic factors such as histology and genotype yielded a progression-free survival HR of 0.68 (95% CI, 0.47 - 0.98; P < .05).

Progression-free survival was improved in patients with nonsquamous histology, EGFR wild-type status, and KRAS mutations.

"Improvements in median overall survival paralleled those of progression-free survival and were pronounced in nonsquamous patients," said Dr. Schiller.

Overall survival was 36.2 weeks in the ARQ197 plus erlotinib group and 29.4 weeks in the erlotinib group. Among nonsquamous patients, there was a 9.2 week improvement in progression-free survival in the combination group (18.9 vs 9.7 weeks) and a 13.7 week improvement in overall survival (43.1 vs 29.4 weeks).

Thus far, a preliminary safety analysis has revealed no major differences between the 2 study groups; rash was 64% in the combination group and 52% in the single-agent group; diarrhea was 48% and 53%, respectively; fatigue was 33% and 37%; nausea was 26% and 26%; and anemia was 14% and 13%.

"Benefits in EGFR wild-type and KRAS-mutation-positive patients were intriguing and merit further investigation, and have been submitted for presentation at the upcoming European Society for Medical Oncology meeting," she concluded.

In a Highlights of the Day session, Charles Rudin MD, PhD, from Johns Hopkins University in Baltimore, Maryland, noted that "the results are exciting but clearly need confirmation."

The investigation showed a hint of benefit for overall survival, he said. "The results were interesting overall for a phase 2 trial, with a very intriguing exploratory subset analysis."

Figitumumab

The insulin-like growth-factor type I receptor (IGF-IR) plays an important role in normal cellular growth and development, and is implicated in the regulation of tumor growth. Figitumumab is a monoclonal antibody that targets the IGF-IR. In this study, a planned enrollment of 820 patients were to be randomized in a 1:1 manner to receive paclitaxel (200 mg/m2), carboplatin (area under the curve [AUC] 6), and figitumumab (20 mg/kg), or paclitaxel and carboplatin alone.

However, accrual was permanently suspended at 681 patients because of a lack of efficacy and the serious adverse effects and death associated with figitumumab.

"The study was stopped early by the Independent Data Monitoring Committee due to excessive deaths," said Dr. Rudin. "It was not predicted or seen in the phase 2 trial, and it is disappointing and concerning."

Dr. Rudin noted that "many of us in the lung cancer community were hopeful about figitumumab" because of the results of the earlier phase 2 trial. It had "striking data for a phase 2 trial in NSCLC, with an overall response rate of 64%," he said, but then the drug went on to fail in a phase 3 trial.

"But does this mean we should be give up and go home?" he asked. "Not yet. This target is too clearly implicated in disease to not be further explored."

The researchers, led by Jacek Jassem, MD, professor of medicine and at the Medical University of Gdansk in Poland, observed serious adverse effects in the experimental group, which included dehydration, hyperglycemia, and hemoptysis. In addition, there was an excess of treatment-related deaths in group receiving figitumumab (8 vs 0).

"There were also more cardiac events in the experimental group (15 vs 5)," explained Dr. Jassem.

The overall survival showed a trend toward the control group, which was close to being significant (10.3 vs 8.5 months; P = .051), said Dr. Jassem during his presentation.

However, survival HR estimates favored patients with low baseline insulin-like growth factor (IGF)-1 levels in the standard chemotherapy group, but favored those with high baseline IGF-1 levels in the experimental group.

The study closed permanently after a planned interim analysis at 225 events because of a survival HR that "showed there was no sense in continuing the study," he said. "Biomarker analysis continues to design possible future studies."

"There is probably some potential benefit of figitumumab, but it is highly compromised by its side effects," Dr. Jassem said. "The risk/benefit of figitumumab in addition to standard chemotherapy appears to be related to the levels of circulating free IGF-1."

He added that additional research is needed to verify the potential benefit in patients with high levels of free IGF-1.

Mapatumumab

In the fourth trial, Joachim von Pawel, MD, from the Asklepios Klinikum Gauting in Munich, Germany, and colleagues evaluated the efficacy and safety of mapatumumab, in combination with carboplatin and paclitaxel, as first-line therapy in patients with advanced NSCLC.

Mapatumumab is a fully human agonist monoclonal antibody that targets and activates the death receptor TRAIL-R1. In this study, 119 patients with stage IIIB or IV advanced primary NSCLC were randomized to 1 of 3 study groups: paclitaxel 200 mg/m2 + carboplatin AUC 6.0; the same dose of paclitaxel/carboplatin plus mapatumumab 10 mg/kg; or the same dose of paclitaxel/carboplatin plus mapatumumab 30 mg/kg.

The patients completed up to 6 cycles in the absence of evidence of disease progression or unacceptable toxicity, and participants in the groups receiving mapatumumab could receive additional cycles of the drug in the absence of disease progression.

The researchers found that adding mapatumumab to paclitaxel/carboplatin therapy did not improve either the response rate or progression-free survival.


"It's a pity that we have no benefit from adding mapatumumab to paclitaxel/carboplatin in unselected patients with advanced NSCLC," said Dr. von Pawel.

Overall, the combination was well tolerated. "The adverse-event profile of the combination was similar to chemotherapy alone, and there were some numerical differences across treatment groups," he said.

"The pharmacokinetic and biomarker analyses are ongoing, as are clinical trials in other indications," Dr. von Pawel added.

This trial was similarly disappointing, said Dr. Rudin. "Again, it had a great clinical suggestion of efficacy; unfortunately, there did not appear to be a benefit."

Dr. Boyer reports relationships with Human Genome Sciences, AstraZeneca, Lilly, Merck, Roche, and Bristol-Myers, Squibb. The ARQ197 study was funded by ArQule and Daichi Sankyo Co. Dr. Schiller reports relationships with Celegene, Genentech, Geron, Novartis, Pfizer, Synta, ArQule, AstraZeneca, Bayer, Biodesix, Daiichi Sankyo, GSK, Merck, Onyx, and Syndax. Dr. Jassem reports a relationship with Pfizer. Dr. von Pawel reports relationships with Genentech, Lilly, Merck Serono, Pfizer, Roche, and AstraZeneca.

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstracts 7500, LBA7501, LBA7502. Presented June 5, 2010. Abstract LBA7523. Presented June 7, 2010.

GENOMIC ANALYSIS OF PROSTATE CANCER ONLINE

June 30 2010 — In what its creators call a "unique public resource for the cancer research community," a genomic analysis of prostate cancer is now available online.

The immediate significance of this resource stems from the fact that the disease has a "high prevalence" and there is a "relative paucity of large comprehensive genomic datasets in prostate cancer," according to the authors of a review of the analysis published online June 24 in Cancer Cell.

There might be future significance as well, suggest the authors.

Other projects that characterize genomes for glioblastoma, lung, colon, pancreas, and breast cancers have "provided critical insights into the molecular classification of cancers" write the authors, led by Barry Taylor, PhD, from Memorial Sloan-Kettering Cancer Center in New York City.

These other projects have led to improvements in patient care and create a hope for the same in prostate cancer, suggested one of the study's other authors.

"Genomic studies in other cancer types have resulted in new drug targets and strategies to classify patients into clinically meaningful subgroups that improve treatment decisions," said coauthor Charles Sawyers, MD, PhD, in a press statement. "This first-ever database of its type brings us one step closer to achieving that goal in prostate cancer." Dr. Sawyers is from the Howard Hughes Medical Institute in Chevy Chase, Maryland.

The authors note that there have been fewer genomic studies in prostate cancer than in some other tumor types, in part because of the "special challenges" of prostate cancer, including the "relatively small tumor size and admixture with stroma that requires careful pathologist-guided dissection."

No Common Mutation

The new analysis used 218 primary and metastatic prostate cancer samples and 12 cell lines and xenografts. The samples were obtained from patients treated with radical prostatectomy at Memorial Sloan-Kettering. There was a 5-year median follow-up with the tumor set, which allowed the authors to attempt to address matters of prognosis using the various data.

The investigators defined transcriptomes, copy-number alterations, and exon resequencing and/or focused mutation detection for 157 "high-interest" genes.

One of the observations from the exon resequencing data is that somatic point mutations in prostate cancer might be rare relative to other tumor types, such as lung cancer and melanoma. "No single gene emerged as commonly mutated," write the authors.

Also, mutations in commonly mutated oncogenes and tumor suppressor genes, such as PIK3CA, KRAS, BRAF, and TP53, are present but rare, say the authors.

Nonetheless, an integrative analysis of mutations, copy-number alterations, and expression changes revealed changes in the PI3K, RAS/RAF, and androgen-receptor pathways in nearly all metastatic samples and a high frequency of primary samples, report the authors.

Finding such alterations in primary tumors — and not just metastatic tumors, as expected — extends the "potential importance of androgen-receptor pathway perturbation to disease initiation."

Dr. Sawyers summarized a number of the findings. "These data clarify the role of several known cancer pathways and provide important clues into others. We have gained insight into the importance of androgen-receptor status."

The genomic-profiling project is dedicated to the memory of Memorial Sloan-Kettering researcher William Gerald, who initiated it.

The research was supported in part by a Memorial Sloan-Kettering Cancer Center Prostate SPORE grant and by the David H. Koch Foundation.

Cancer Cell. Published online June 23, 2010. Abstract

A NICE SOUP

Int J Radiat Oncol Biol Phys. 2010 Jun 26. [Epub ahead of print]
Bevacizumab, Capecitabine, Amifostine, and Preoperative Hypofractionated Accelerated Radiotherapy (HypoARC) for Rectal Cancer: A Phase II Study.
Koukourakis MI, Giatromanolaki A, Tsoutsou P, Lyratzopoulos N, Pitiakoudis M, Kouklakis G, Chloropoulou PA, Manolas K, Sivridis E.

Departments of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis, Greece.
Abstract

PURPOSE: Bevacizumab has established therapeutic activity in patients with metastatic colorectal cancer, and anti-vascular endothelial growth factor therapy enhances the activity of radiotherapy in experimental models. We assessed the feasibility and efficacy of preoperative radiochemotherapy combined with bevacizumab in patients with rectal cancer. METHODS AND MATERIALS: Nineteen patients with radiologic T3 and/or N+ rectal carcinoma were treated with preoperative conformal hypofractionated accelerated radiotherapy (3.4 Gy in 10 consecutive fractions) supported with amifostine (500-1,000 mg daily), capecitabine (600 mg/m(2) twice daily, 5 days per week), and bevacizumab (5 mg/kg every 2 weeks for 2 cycles). Surgery followed 6 weeks after the end of radiotherapy. A cohort of 14 sequential patients treated with the same regimen without bevacizumab was available for comparison. RESULTS: Grade 2 or 3 diarrhea was noted in 7 of 19 patients (36.8%), which was statistically worse than patients receiving the same regimen without bevacizumab (p = 0.01). A higher incidence of Grade 2 or 3 proctalgia was also noted (21.1%) (p = 0.03). Bladder and skin toxicity was negligible. All toxicities regressed completely within 2 weeks after the end of therapy. Pathologic complete and partial response was noted in 7 of 19 cases (36.8%) and 8 of 19 cases (42.1%). Within a median follow-up of 21 months, none of the patients has had late complications develop and only 1 of 18 evaluable cases (5.5%) has had locoregional relapse. CONCLUSIONS: Bevacizumab can be safely combined with hypofractionated radiotherapy and capecitabine as a preoperative radiochemotherapy regimen for patients with rectal cancer. The high pathologic complete response rates urges the testing of bevacizumab in randomized studies. Copyright © 2010 Elsevier Inc. All rights reserved.

MDS AT RISK FOR PROGRESSION

Leuk Res. 2010 Jun 21. [Epub ahead of print]
The lower risk MDS patient at risk of rapid progression.
Mittelman M, Oster HS, Hoffman M, Neumann D.

Department of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, 6 Weizmann St., Tel Aviv 64239, Israel.
Abstract

Most patients with myelodysplastic syndrome (MDS) are classified at diagnosis as having a low/INT-I or INT-II/high risk disease, based on the classical International Prognostic Scoring System (IPSS) criteria. The low/INT-I risk patients are usually managed mildly with supportive care, including red blood cell (RBC) transfusions, erythroid stimulating agents (ESAs), other cytokines (G-CSF, platelet stimulating agents), as well as thalidomide and lenalidomide. Some patients receive immunosuppressive therapy, and iron chelation is indicated in iron overloaded patients. Aggressive approach (hypomethylating agents, chemotherapy and stem cell transplantation) is usually not applied in such patients. Occasionally, we observe a "low risk" patient with rapid progression of disease and poor outcome. Can we identify demographic, clinical, laboratory, cellular-biological and/or molecular parameters that can predict "poor prognostic features" (PPF) in "low risk" MDS patients? Clinical and laboratory parameters have been reported to be associated with poor prognosis, in addition to the known "classical" IPSS criteria. These include older age, male gender, poor performance status, co-morbidities, degree of anemia, low absolute neutrophile count (ANC) and platelet counts, RBC transfusion requirements, high serum ferritin, high LDH, bone marrow (BM) fibrosis, increased number of BM CD34+ cells and multi-lineage dysplasia. Certain immunophenotypes (low CD11b, high HLA-Dr, CD34, CD13 and CD45), clonal granulocytes, multiple chromosomal abnormalities, chromosomal instability, short telomeres and high telomerase activity were also reported as PPF. Studies of apoptosis identified Bcl-2 expression and high caspase 3 as PPF, while the reports on survivin expression have been confusing. Recent exciting data suggest that methylation of p15 INK4b and of CTNNA1 (in 5q-), high level of methylation of other genes, absence of the TET2 mutation, down regulation of the lymphoid enhancer binding factor 1 (LEF1), mutation of the polycomb-associated gene ASXL1 and a specific 6-gene signature in gene expression profiling - are all associated with poor prognosis in MDS. Do we have data suggesting a different treatment for "low risk" MDS patients displaying PPF? Two teams, the combined Nordic-Italian and the GFM groups have reported an improved survival with ESAs. The GFM has achieved prolonged survival with iron chelation. Recently, encouraging data with survival advantage in azacitidine-treated patients have been published, including a few INT-I patients. Finally, data suggest that low/INT-I MDS patients who undergo stem cell transplantation (SCT0 do better than INT-II/high risk patients). In summary, some patients, classified as "low risk MDS" carry PPF. An appropriate therapeutic approach is indicated. Future updated classifications and prospective trials may lead to a better outcome. Copyright © 2010 Elsevier Ltd. All rights reserved.

A SURVIVING MYTH

Scand J Gastroenterol. 2010 Jun 22. [Epub ahead of print]
"A surviving myth" - corticosteroids are still considered ulcerogenic by a majority of physicians *
Martínek J, Hlavova K, Zavada F, Seifert B, Rejchrt S, Urban O, Zavoral M.

Department of Internal Medicine of the First Medical Faculty and Central Military Hospital, Charles University, Prague, Czech Republic.
Abstract

Abstract Objective. Evidence does not support an association between systemic corticosteroid use and the development of peptic ulcer disease (PUD) and prophylactic anti-ulcer therapy is not routinely indicated. The aim was to find out the opinion of physicians in the Czech Republic on corticosteroid-induced ulcers. Materials and methods. A questionnaire-based study targeting 360 physicians of different specialties (100 from Gastroenterology, 100 from General Practice, 80 from Pneumology/Immunology, and 80 from Neurology/Neurosurgery). Results. Eighty-two percent of the physicians considered corticosteroids ulcerogenic, 7.5% of the responders considered them ulcerogenic only in patients with a family history of PUD, and 10.3% of the physicians considered corticosteroids non-ulcerogenic. Seventy-five percent of the responders would administer concomitant antisecretory treatment. Sixty-seven percent of the physicians thought that PUD was a frequent complication of corticosteroid therapy. If the ulcerogenic potential of ibuprophene, diclofenac, and prednisone was a subject of the physicians' judgment, a majority (40.5%) considered prednisone to be the most ulcerogenic substance. Thirty percent of gastroenterologists (vs. 1.9% of others; p < 0.001) did not consider corticosteroids to be ulcerogenic; 27.4% (vs. 4.3%; p < 0.01) would not administer an antisecretory prophylaxis routinely. Conclusions. Although there is no evidence showing an association between PUD and the use of corticosteroids, a majority of physicians consider corticosteroids gastrotoxic. This applies, to a lesser extent, to gastroenterologists. Action should be taken to explode the myth about the gastrotoxicity of corticosteroids and to minimize useless expenses on concomitant prophylaxis.

LEPTOMENIGEAL METASTASES

Semin Neurol. 2010 Jul;30(3):236-44. Epub 2010 Jun 24.
Leptomeningeal metastasis.
Chamberlain MC.

Department of Neurology and Neurological Surgery, Division of Neuro-Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1023, USA. chambemc@u.washington.edu
Abstract

Leptomeningeal metastasis occurs in ~5% of all patients with cancer and is the third most common metastatic complication of the central nervous system. Staging of leptomeningeal metastasis includes contrast-enhanced brain and spine magnetic resonance imaging and radionuclide cerebrospinal fluid (CSF) flow study. Treatment, when clinically indicated, often requires administration of involved-field radiotherapy to bulky or symptomatic disease sites as well as intra-CSF and systemic chemotherapy. The use of high-dose systemic therapy may benefit selected patients with breast- or lymphoma-related leptomeningeal metastasis and obviate the need for intra-CSF chemotherapy. Intra-CSF drug therapy primarily utilizes one of three chemotherapeutic agents (e.g., methotrexate, cytosine arabinoside, and thiotepa) administered by a variety of schedules either by intralumbar or intraventricular drug delivery. Beginning to be utilized are novel intra-CSF agents, such as the targeted monoclonal antibodies rituximab (anti-CD20 for B-cell lymphoma-related leptomeningeal metastasis) and trastuzumab (anti-Her2/neu for breast cancer-related leptomeningeal metastasis). Although treatment of leptomeningeal metastasis is palliative with median patient survival of 2 to 3 months, treatment may afford stabilization and protection from further neurologic deterioration in patients with leptomeningeal metastasis. Thieme Medical Publishers.

BOUBOUKAS SPEAKING

J Neurooncol. 2010 Jun 20. [Epub ahead of print]
Prolonged survival of neoplastic meningitis from breast cancer with letrozole and intrathecal methotrexate: a case report.
Peroukides S, Onyenadum A, Starakis I, Koutras A, Makatsoris T, Bouboukas G, Kalofonos H.

Department of Medical Oncology, School of Medicine, University of Patras, 26504 Rio, Patras, Greece, panio@upatras.gr.
Abstract

Neoplastic meningitis from breast cancer has a dismal prognosis and short survival. Treatment is based on the intrathecal administration of chemotherapeutic agents, cranial or craniospinal radiotherapy, and systemic chemotherapy. In this report we describe the case of a woman with neoplastic meningitis from breast carcinoma who developed an excellent response to letrozole combined with intrathecal methotrexate, resulting in long-term survival of more than 36 months. Based on the findings of this case report, we suggest that addition of letrozole to the standard therapeutic approach may be beneficial for some patients.

SECOND LINE CHEMOTHERPY FOR ENDOMETRIAL CARCINOMA

Cancer Chemother Pharmacol. 2010 Jun 20. [Epub ahead of print]
Second-line chemotherapy for advanced or recurrent endometrial carcinoma previously treated with paclitaxel and carboplatin, with or without epirubicin.
Ueda Y, Miyake T, Egawa-Takata T, Miyatake T, Matsuzaki S, Yokoyama T, Yoshino K, Fujita M, Enomoto T, Kimura T.

Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan, ZVF03563@nifty.ne.jp.
Abstract

PURPOSE: A combined chemotherapy of taxane and platinum, with or without anthracycline, has been used as a standard first-line regimen. The purpose of this study was to investigate the effectiveness of second-line chemotherapy for treatment of advanced or recurrent endometrial carcinoma previously treated with a combined chemotherapy of taxane and platinum, with or without anthracycline. METHODS: During the 2000-2008 study period, 723 patients were diagnosed with endometrial cancer at the Departments of Obstetrics and Gynecology of the Osaka University and the Osaka Rosai Hospitals, Osaka, Japan. The subset of these cases that eventually required treatment by second-line chemotherapy was retrospectively analyzed. RESULTS: Response rate to second-line chemotherapy was 25%. Treatment-free interval (TFI) of >/= or <6 months was demonstrated to be significantly associated with the response to second-line chemotherapy (P = 0.0026), progression-free survival (P = 0.0003) and overall survival (P = 0.025). The second-line chemotherapy similar to the first-line regimen was ineffective in all the 7 cases (100%) whose TFI was shorter than 6 months. Multivariate analysis showed that TFI was the most significantly important factor predicting the effectiveness of second-line chemotherapy (the adjusted hazard ratio of TFI on PFS and OS: 3.482, 95% CI, 1.641-7.388, P = 0.0012, and 2.341, 95% CI, 1.034-5.301, P = 0.042, respectively). CONCLUSIONS: Our present study provides, for the first time, evidence that the majority of refractory or recurrent diseases, if they occur within 6 months of a first-line chemotherapy using taxane and platinum with or without anthracycline, are non-responsive to the current regimens of second-line chemotherapy.

METAANALYSIS OF BEVACIZUMAB THERAPY IN COLORECTAL CANCER

From Annals of Oncology
Bevacizumab Combined with Chemotherapy for Patients with Advanced Colorectal Cancer: A Systematic Review

S. Welch; K. Spithoff; R. B. Rumble; J. Maroun

Abstract

Background: Fluoropyrimidine-based chemotherapy is considered standard treatment of advanced colorectal cancer. Recent studies indicate benefit to the addition of bevacizumab, a recombinant monoclonal antibody targeting vascular endothelial growth factor.
Methods: Medline, EMBASE, Cochrane Library, and conference proceedings were searched to identify randomized trials in advanced colorectal cancer comparing chemotherapy plus bevacizumab with chemotherapy alone. A meta-analysis of published data was carried out.
Results: Five trials comparing chemotherapy plus bevacizumab with chemotherapy alone as first- or second-line treatment were identified. Our meta-analysis indicates an advantage in favor of the addition of bevacizumab to chemotherapy in terms of overall survival (OS) [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.69–0.90; P = 0.0005], progression-free survival (PFS) (HR 0.63; 95% CI 0.49–0.81, P = 0.0004), and response rate (RR 1.50; 95% CI 1.06–2.10, P = 0.02). The most commonly observed adverse effects related to bevacizumab included hypertension, proteinuria, bleeding, and thrombosis. Gastrointestinal perforation and poor wound healing were also observed; however, their incidence was rare.
Conclusions: For patients with advanced colorectal cancer receiving first- or second-line fluoropyrimidine-based chemotherapy, the addition of bevacizumab improves PFS and OS at the expense of increased incidence of toxicity. The magnitude of benefit may differ based on the chemotherapy regimen with which bevacizumab is partnered.

LOW ADHERENCE FOR HORMONAL THERAPY IN BREAST CANCER

June 30, 2010 — Only half of the women with early-stage breast cancer who were prescribed tamoxifen and/or aromatase inhibitors completed the full course of treatment, putting themselves at increased risk for breast cancer recurrence.

The new finding comes from a study of 8769 patients in the Kaiser Permanente of Northern California healthcare system, published online June 28 in the Journal of Clinical Oncology.

Over the 4.5 year follow -period, 30% of women discontinued therapy. Of those who continued, 28% were nonadherent.

Hence, overall, only 49% were fully adherent for the entire 4.5 years.

Discontinuation rates were similar for women taking tamoxifen alone and aromatase inhibitors alone, although women who took a combination of the 2 were less likely to stop early, the researchers note.

The study was carried out from 1996 to 2007; 43% of patients were prescribed tamoxifen alone, 26% aromatase inhibitors alone, and 30% a combination of the 2.

Highest Rates in Youngest Patients

The highest rate of discontinuation (32%) was seen in women younger than 40 years of age.

"We were surprised to see that so many young women stopped treatment early, despite the fact that the therapy has a proven track record in reducing breast cancer recurrence," lead researcher Dawn Hershman, MD, associate professor of medicine and epidemiology at Columbia University Medical Center in New York City, said in a press release.

"It's very disturbing that patients under 40 had the highest discontinuation and nonadherence rates, because those patients have the longest life expectancy," she added.

Two previous studied of tamoxifen also found younger age to be a predictor of early discontinuation, the researchers note, and suggest that "young adults with cancer may be a particularly vulnerable group."

Consistent With Previous Results

"Our results are consistent with other studies that have shown high discontinuation and nonadherence rates among women on adjuvant hormonal therapy," the researchers write. Despite differences in methodology, previous studies have all consistently reported discontinuation rates in the range of 30% to 50%.

One reason for the high rate of discontinuation might be toxicity, the researchers suggest. They cite a previous study of 622 postmenopausal women, which found a 30% discontinuation rate for aromatase inhibitors, in which 84% of those who discontinued said they did so because of adverse effects (Breast Cancer Res Treat. 2007;106[Suppl 1]:abstract 3131).

"We found that 4% of patients filled only 1 prescription for their hormonal therapy," Dr. Hershman and colleagues note, adding that early treatment toxicities might be the cause.

"We found that 13% of patients who continued hormonal therapy were nonadherent from the first refill," they also note, and suggest that "it might be helpful to identify interventions to improve adherence at this time point."

Another point the researchers emphasize is that "adherence to hormonal therapy is highly dependent on communication between the physician and the patient."

Understanding Noncompliance Is Important

Understanding why patients don't take their medicines as directed is becoming increasing important in the cancer field, as more treatment is moving out of the clinic and into the home, said Jennifer Obel, MD, attending physician at NorthShore University Health System in Evanston, Illinois, and a member of the American Society of Clinical Oncology Communications Committee.

"We now have more than 50 oral anticancer medications," Dr. Obel notes.

"This new study reaffirms some worrisome trends for women completing hormonal therapy, and brings up the larger issue of noncompliance for cancer therapies in general," she said in a statement.

A recent British study found noncompliance with imatinib (Gleevec) in the treatment of chronic myeloid leukemia in 25% of patients, putting those patients at risk for poorer outcomes. Those researchers expressed surprise at this rate of nonadherence among cancer patients, although it is similar to that seen with other chronic diseases. "You would think that cancer patients would be more motivated to keep taking their drug, so the finding is rather counterintuitive," said Nick Barber, PhD, professor of practice and policy at the School of Pharmacy, London.

Dr. Hershman and colleagues echo this sentiment, and say it is surprising that nonadherence appears to be almost as significant a problem in oncology, with potentially life-saving medications, as it is in other disease areas.

Dr. Hershman and colleagues have disclosed no relevant financial relationships.

J Clin Oncol. Published online July 28, 2010. Abstract

UNDERUSE OF ANTHARCYCLINES IN HER2+ BREAST CANCER

Oncologist. 2010 Jun 24. [Epub ahead of print]
Underuse of Anthracyclines in Women with HER-2+ Advanced Breast Cancer.
Montemurro F, Rossi V, Nolè F, Redana S, Donadio M, Martinello R, Verri E, Valabrega G, Rocca MC, Jacomuzzi ME, Viale G, Sapino A, Aglietta M.

Institute for Cancer Research and Treatment, Division of Medical Oncology I, Candiolo, Italy;
Abstract

Abstract Anthracyclines are among the most active drugs in breast cancer. Because of excessive cardiotoxicity, their use in combination with trastuzumab has been discouraged in patients with human epidermal growth factor receptor (HER)-2(+) metastatic breast cancer. We sought to describe how this treatment paradigm influenced the use of anthracyclines in this patient setting. We analyzed a multi-institutional database containing the treatment history of 450 patients who received at least one trastuzumab-based regimen for HER-2(+) metastatic breast cancer. Patients were considered eligible for anthracyclines for metastatic disease if they were never exposed (NE) or had been previously exposed (PE) to an anthracycline in the neoadjuvant or adjuvant setting and had relapsed after 12 months from the last dose. We then assessed the use of anthracycline-based therapy after failure with the first trastuzumab-based regimen in eligible patients. Three-hundred twenty-one patients were considered eligible for anthracyclines. In total, 190 eligible patients developing disease progression during the initial trastuzumab-based therapy were analyzed. An anthracycline was administered as first salvage treatment in 14 NE and two PE patients. Another 15 NE and nine PE patients received an anthracycline as a further line of therapy. Of 119 eligible patients who died from breast cancer, only 30 received an anthracycline for metastatic disease. In conclusion, despite the fact that two thirds of the patients receiving trastuzumab-based therapy for HER-2 metastatic breast cancer are eligible for anthracyclines, these drugs are infrequently used nowadays to treat trastuzumab-refractory disease. A role for these compounds should be redefined in this patient subset.

GUIDELINESS FOR TB TESTING

June 30, 2010 — The US Centers for Disease Control and Prevention (CDC) have issued updated guidelines for testing for Mycobacterium tuberculosis infection in adults and children using interferon gamma release assays (IGRAs), approved by the US Food and Drug Administration (FDA). The updated recommendations, published in the June 25 issue of Morbidity and Mortality Weekly Report, offer guidance to US public health officials, healthcare providers, and laboratory workers.

"Before 2001, the tuberculin skin test (TST) was the only practical and commercially available immunologic test for Mycobacterium tuberculosis infection approved in the United States," write Gerald H. Mazurek, MD, and colleagues from the Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, CDC. "Recognition that interferon gamma (IFN-γ) plays a critical role in regulating cell-mediated immune responses to M. tuberculosis infection led to development of ...IGRAs for the detection of M. tuberculosis infection. IGRAs detect sensitization to M. tuberculosis by measuring IFN-γ release in response to antigens representing M. tuberculosis."

Since the CDC published 2005 guidelines for use of the QuantiFERON-TB Gold test (QFT-G), 2 new IGRAs were FDA approved to assist in diagnosing latent and active M tuberculosis infection: QuantiFERON-TB Gold In-Tube test (QFT-GIT) and the T-SPOT.TB test (T-Spot). For these assays, the antigens, methods, and interpretation criteria are different from those for previously FDA-approved IGRAs.

The updated recommendations for IGRA use were developed by a group of experts convened by the CDC to review available evidence including data submitted to FDA, published reports, and expert opinion concerning IGRAs. Studies of sensitivity, specificity, and agreement for IGRAs and tuberculin skin test yielded varying results regarding superiority of any of these tests.

"In brief, TSTs and IGRAs (QFT-G, QFT-GIT, and T-Spot) may be used as aids in diagnosing M. tuberculosis infection," the guidelines authors write. "They may be used for surveillance purposes and to identify persons likely to benefit from treatment. Multiple additional recommendations are provided that address quality control, test selection, and medical management after testing."

Recommendations for use of IGRAs in these guidelines include the following:

* To assist in diagnosing infection with M tuberculosis, tuberculin skin tests and IGRAs may be used for surveillance or to identify persons likely to benefit from treatment (those who are or will be at increased risk for M tuberculosis infection or for progression to active tuberculosis if infected).
* Established protocols using FDA-approved test formats are required for performance and interpretation of IGRAs in compliance with Clinical Laboratory Improvement Amendment standards.
* To facilitate more refined evaluation of test results and better understanding of implications and limitations of the tests, both the standard qualitative test interpretation and the quantitative assay measurements should be reported along with the criteria used for test interpretation.
* Before blood draw, arrangements for IGRA testing should be made so that the specimen is collected in the proper tubes and so that testing can be performed within the required timeframe.
* Before implementing testing with IGRAs, each institution and tuberculosis-control program should consider availability, overall cost, potential benefits of IGRAs, and characteristics of the test population in their own setting.
* Neither the tuberculin skin test nor the IGRAs should typically be used to test persons at low risk for both infection and progression to active tuberculosis if infected, unless they are likely to be at increased risk in the future. Screening such persons is likely to cause a higher number of false-positive results and diversion of resources from higher-priority activities. When testing low-risk patients, the test with the greatest specificity should be chosen.
* The most suitable test or combination of tests to diagnose M tuberculosis infection should be chosen based on the reasons and the context for testing, test availability, and overall cost effectiveness.
* An IGRA may be used instead of a tuberculin skin test in all situations in which the CDC recommends the tuberculin skin test as an aid in diagnosing M tuberculosis infection.
* An IGRA is preferred for testing persons from groups that typically have low rates of returning to have tuberculin skin tests read and for those who have received Bacille Calmette-Guérin (BCG) as a vaccine or as cancer treatment. In the latter group, the tuberculin skin test has a higher false-positive rate.
* IGRAs or the tuberculin skin test (without preference) may be used to test recent contacts of persons with infectious tuberculosis.
* IGRAs or the tuberculin skin test (without preference) may be used for periodic screening for occupational exposure.
* For testing children younger than 5 years, the tuberculin skin test is preferred vs the IGRA. To increase diagnostic sensitivity in this age group, however, some experts recommend using an IGRA as well as the tuberculin skin test.

"Although substantial progress has been made in documenting the utility of IGRAs, additional research is needed that focuses on the value and limitations of IGRAs in situations of importance to medical care or tuberculosis control," the guidelines authors write.

MMWR Morb Mortal Wkly Rep. 2010;59(RR-5):1-28.

ANOTHER "TARGETED" FAILURE

Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial.
Herbst RS, Sun Y, Eberhardt WE, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE.

University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract

BACKGROUND: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC). METHODS: Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB-IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m(2) intravenously every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov, number NCT00312377. FINDINGS: 1391 patients received vandetanib plus docetaxel (n=694 [197 women]) or placebo plus docetaxel (n=697 [224 women]). Vandetanib plus docetaxel led to a significant improvement in PFS versus placebo plus docetaxel (hazard ratio [HR] 0.79, 97.58% CI 0.70-0.90; p<0.0001); median PFS was 4.0 months in the vandetanib group versus 3.2 months in placebo group. A similar improvement in PFS with vandetanib plus docetaxel versus placebo plus docetaxel was seen in women (HR 0.79, 0.62-1.00, p=0.024); median PFS was 4.6 months in the vandetanib group versus 4.2 months in the placebo group. Among grade 3 or higher adverse events, rash (63/689 [9%] vs 7/690 [1%]), neutropenia (199/689 [29%] vs 164/690 [24%]), leukopenia (99/689 [14%] vs 77/690 [11%]), and febrile neutropenia (61/689 [9%] vs 48/690 [7%]) were more common with vandetanib plus docetaxel than with placebo plus docetaxel. The most common serious adverse event was febrile neutropenia (46/689 [7%] in the vandetanib group vs 38/690 [6%] in the placebo group). INTERPRETATION: The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy. FUNDING: AstraZeneca. Copyright © 2010 Elsevier Ltd. All rights reserved.

PROGNOSTIC FACTORS IN N+ BREAST CANCER

Clin Cancer Res. 2010 Jun 24. [Epub ahead of print]
BCIRG001 Molecular Analysis: Prognostic Factors in Node-Positive Breast Cancer Patients Receiving Adjuvant Chemotherapy.
Dumontet C, Krajewska M, Treilleux I, Mackey JR, Martin M, Rupin M, Lafanechere L, Reed JC.

Faculté de Médecine Rockefeller, INSERM.
Abstract

PURPOSE: There are currently no validated factors predictive of response to taxanes in patients with breast cancer. We analysed specimens from patients included in the BCIRG 001 trial, a randomized study which demonstrated superiority of docetaxel/ doxorubicin/ cyclophosphamide over fluorouracil/doxorubicin/ cyclophosphamide as adjuvant therapy for node positive operable breast cancer in terms of disease free and overall survival.Experimental design: Immunohistochemical assessment of biological markers included histological grade, tumor size, estrogen and progesterone receptors, lymph node status, HER2, MUC1, Ki-67/MIB-1, p53, Bcl-2, Bax, Bcl-XL, BAG-1, beta tubulin isotypes II, III and IV, tau protein and detyrosinated alpha tubulin. Associations between selected parameters and survival were tested through univariate analyses, then completed with multivariate analyses and a bootstrap resampling technique.RESULTS: In univariate analysis histological grade, tumor size, number of involved nodes, estrogen and progesterone receptor status, p53, Ki-67, tubulin III and tau protein were associated both with DFS and with OS. In multivariate analysis estrogen and progesterone receptors, tumor size, number of involved nodes, Ki-67 protein were associated both with DFS and with OS while tau levels were correlated with DFS and tubulin III and P53 were correlated with OS. No interaction was observed between Ki-67 and treatment allocation.CONCLUSIONS: We conclude that the protein expression in primary tumors of Ki-67 and P53 protein, as well as of the microtubule-related parameters tau and tubulin III, are independent prognostic factors in patients receiving adjuvant chemotherapy for node positive breast cancer but are not predictive of benefit from docetaxel-containing adjuvant chemotherapy.

BE CAREFUL WITH NEW DRUGS

June 29, 2010 (Seattle, Washington) — During the daylong discussion of last year's controversial Food and Drug Administration (FDA) advisory panel on prasugrel (Efient, Lilly/Daiichi Sankyo), one agency official asked: "Does prasugrel cause cancer?" While his answer, as well as the consensus reached by the expert panel, was that prasugrel did not appear to cause cancer, a couple of researchers continue to warn about the possibility that prasugrel might be a promoter of cancer and that physicians should be aware of these risks, especially in patients prescribed the drug long term [1].

In a new report in the June 29, 2010 issue of the Archives of Internal Medicine, Drs James Floyd (University of Washington, Seattle) and Victor Serebruany (Heart Drug Research Laboratories, Towson, MD) present data from an analysis of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38) and show that use of prasugrel was associated with an increase in cancer risk, particularly a 62% increase in the rate of new and worsening cancers.

"There are data suggesting a strong signal of new and worsening solid cancers in the prasugrel arm, which grow exponentially and begin to occur at four months and even faster in women, independent of how you look at this," Serebruany told heartwire . "If you look at the centrally adjudicated events, if you look at events the investigators reported, or if look you at the FDA review of the data, there is a very straightforward solid increase in cancer-associated death and the existence of new and worsening cancer."

"Nobody Can Say There Is No Risk of Cancer"

The new report is based on the TRITON-TIMI 38 analysis performed by Dr Thomas Marciniak, a medical reviewer for the FDA, first included in the February 3, 2009 briefing document for the meeting of the Cardiovascular and Renal Drugs Advisory Committee. The analysis, summarized briefly by Floyd and Serebruany in Archives, documents all solid cancers, including nonhematologic malignant cancers, and excludes nonmelanoma skin cancer, which carries a benign prognosis and is usually excluded from clinical trials, and brain tumors.

Overall, there were 92 new solid cancers among patients treated with prasugrel and 64 new solid cancers among the patients treated with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis), a significant 44% increase in risk. Excluding nonmelanoma skin cancers and brain tumors, there were 112 treatment-emergent cancers in the prasugrel arm and 69 treatment-emergent cancers in the clopidogrel-treated patients, a difference that translates into a significant 62% increase in risk of these new and worsening solid cancers. In addition to these findings, there was a nonsignificant 57% increase in deaths from cancer among patients treated with prasugrel.

To heartwire , Serebruany said some have suggested ascertainment bias could explain the difference in cancer rates in the two treatment arms. Because prasugrel is associated with a significant increase in bleeding, more cancers might be detected with the bleeding event, although Serebruany said the data do not show this to be true. After cancers detected by bleeding events were excluded, the difference in cancer rates persisted. Moreover, other trials do not support this theory.

"The data show that in the CHARISMA trial, in the combination group, the patients treated with clopidogrel and aspirin, there was less cancer than in the clopidogrel-group only, even though the combination patients had more bleeding," he said. "If the pattern is there, if there is really something going on with thienopyridines, where bleeding will cause the increased detection of cancer signal, this didn't happen with clopidogrel."

In the past, Serebruany suggested that the high level of platelet inhibition with prasugrel might impair defenses against tumor growth, but recent data from the PLATO study with ticagrelor (Brilanta, AstraZeneca) does not support this. Studies assessing the antiplatelet potency of ticagrelor vs prasugrel, however, are still needed, he said.

Concern About the Long-Term Use

Speaking with heartwire , Dr Sanjay Kaul (Cedar Sinai Medical Center, Los Angeles, CA) said that while the risk of cancer can't be ruled out, "there was already some uncertainty about whether the benefit outweighed the risk associated with prasugrel." Adding more uncertainty with the cancer signal adversely alters the risk/benefit profile of the drug and strengthens the idea that it should be used only short term.

Kaul, famously disinvited from the 2009 advisory panel meeting because of an incomplete vetting process that left unanswered questions about his possible "intellectual biases" with regard to prasugrel but who was later exonerated when the FDA apologized and admitted his removal was a mistake, wrote an editorial, along with Dr George Diamond (Cedars Sinai Medical Center), accompanying the Archives report by Floyd and Serebruany [2]. In it, as he stated to heartwire , Kaul runs through numerous possible scenarios: that prasugrel causes cancer, promotes cancer, triggers the detection of cancer, or is completely unrelated to cancer. Little is truly known right now, he said, leaving physicians to make inferences from the existing data.

"We just don't know about the long-term risks of cancer; it's not sufficiently addressed," said Kaul. "We are in the dark ages with regard to the science of tumor promotion."

In response to the new report, Lilly and Daiichi Sankyo emailed a statement to heartwire , pointing out that the FDA has already concluded it is unlikely prasugrel caused cancer and that the drug's label highlights the imbalance of newly diagnosed malignancies, which primarily occurred in the colon and lung. Also, preclinical data are "not indicative of tumor-growth enhancement," while "oncology experts have concluded that there is no biologic plausibility that prasugrel would be a tumor stimulator," according to the company.

Need to Systematically Collect Data

Commenting on the new report on prasugrel and cancer, Dr Magnus Ohman (Duke Clinical Research Institute, Durham, NC), chair of the ongoing TRILOGY-ACS study comparing prasugrel vs clopidogrel in medically treated acute coronary syndrome patients, said his group is prospectively collecting cancer information at baseline and throughout the course of the trial with a detailed case-report form.

"We need to realize that cancer and coronary disease coinhabit the same sphere, and we need to at least get the data correct," he said. "Whether there is an association or not, that's a much harder thing to prove, but at least we can collect the data."

Asked about the possibility of a link between prasugrel and cancer, Ohman said that researchers and clinicians need to be careful balancing what is known and what still needs to be determined. He questioned why some cancers are excluded from the analysis, such as brain tumors, saying this can alter the relative risks observed in statistical analyses. Ohman also noted that the FDA is seemingly of two voices with prasugrel, with Dr Ellis Unger (Office of New Drugs, FDA, Silver Spring, MD), one of the agency's main reviewers, stating that prasugrel is "unlikely [to be] carcinogenic" and does not promote tumor growth [3], while the Marciniak data raise some concerns. Regardless, Ohman said that "debate is always healthy" and that the issue reminds researchers that "cancer should always be addressed in clinical trials and never forgotten.

"We need to be careful not to overstate it one way or to understate it the other way," he told heartwire . "Nobody would ever want to sweep this under the rug and say this isn't a problem. A systematic, careful assessment of clinical trials is the only way we can move toward the truth."

Serebruany, however, does not believe the TRILOGY study, with an expected enrollment of 10 300 patients, of whom approximately half are enrolled, will answer the cancer question. Based on his calculations, if 280 cancer events are needed to detect a 50% increased risk of cancer, and assuming a control event rate of 1% annually, TRILOGY would need to include 22 000 patients to definitively detect a cancer signal. Kaul told heartwire that if researchers wanted to detect a 33% increase in cancer risk, TRILOGY would require nearly 40 000 patients.

"The leadership of the FDA has said that the cancer signal will be watched very carefully in TRILOGY, but TRILOGY is not powered enough to answer this question," Serebruany pointed out. "If the cancer signal were the same in TRILOGY as it was in TRITON, the study would need to be doubled in size. Stating that TRILOGY will clearly answer the question is a joke."