- Clin Genitourin Cancer. 2009 Jan;7(1):39-42.
Phase II trial of carboplatin and paclitaxel in papillary renal cell carcinoma.
Bylow KA, Atkins MB, Posadas EM, Stadler WM, McDermott DF.
Department of Medicine, Section of Hematology/Oncology, University of Chicago, IL, USA. kbylow@mcw.edu
BACKGROUND: Cytotoxic chemotherapy has not been well investigated in non-clear-cell renal cell carcinoma (RCC). A phase II study was thus conducted to assess the efficacy of carboplatin and paclitaxel in such patients. PATIENTS AND METHODS: Patients were treated with carboplatin (area under the curve of 6) and paclitaxel 225 mg/m2 every 21 days and assessed for measurable disease response every 2 cycles. An initial 20 patients were planned to be enrolled to rule out a null hypothesized 15% response rate. RESULTS: Seventeen patients were enrolled, of which 16 patients had papillary and 1 had collecting duct histology. The patient with collecting duct histology had a complete response, but no responses were observed in patients with papillary histology and the trial was thus terminated early. Toxicities were as expected for the carboplatin and paclitaxel regimen. CONCLUSION: Carboplatin and paclitaxel is not an active regimen in patients with metastatic papillary RCC. Future studies should explore the role of this or similar regimens in collecting duct carcinoma.
Σάββατο 18 Ιουλίου 2009
CHEMOTHERAPY NOT EFFECTIVE FOR PAPPILARY RENAL CELL CARCINOMA
FINASTERIDE DOES NOT INCREASE RISK FOR HIGH GRADE PROSTATE CANCER
July 13, 2009 — Data from a new trial might help quell the fear that treatment with finasteride (Proscar, Propecia) increases the risk for high-grade prostate cancer.
As previously reported by Medscape Oncology, results of the Prostate Cancer Prevention Trial (PCPT) showed that finasteride treatment reduced the prevalence of prostate cancer by 25% when used as a chemopreventive agent in patients at high risk for the disease. At the same time, it also appeared to increase the incidence of high-grade prostate cancer.
The results of a new study, published online July 7 in Clinical Cancer Research, may shed some light on the controversial findings of the PCPT. They suggest that finasteride did not cause high-grade prostate cancers but simply made them easier to diagnose.
"Our results suggest that the PCPT findings, in which finasteride use was associated with an increase in diagnoses of high-grade cancers, was likely the result of a detection bias rather than an increase in de novo high-grade prostate cancer," said first author Christopher Elliott, MD, PhD, a urology resident at Stanford University, in California. "These results would suggest that the fear of promoting high-grade prostate cancer with finasteride is likely unfounded. This should make finasteride more attractive as a chemopreventive drug, especially given that finasteride is currently the only agent ever shown in a randomized trial to have a potential chemopreventive effect in inhibiting prostate cancer."
The researchers found that the level of prostate-specific antigen (PSA) declined steadily as prostate volume increased. At the same time, the level of PSA increased as prostate volume decreased. The results suggested that PSA performs better in smaller prostates for detecting both low- and high-grade disease, Dr. Elliott told Medscape Oncology.
They "also suggested that the chance of finding high-grade cancer was increased in men with smaller prostate glands, compared to those with larger glands," he said. "Finasteride has been shown to reduce prostate size by approximately 25% in men using the drug. Thus, our findings suggested that finasteride, by reducing prostate size, increased the likelihood of finding high-grade cancer in these men."
Other causes of an increased rate of high-grade cancer in men taking finasteride might exist, he added, but these were not supported by their data.
Inconsistent Findings in the PCPT
The PCPT tracked nearly 19,000 men over a 7-year period who were randomized to either finasteride or placebo. Although there was a 25% decrease in prostate cancer incidence among men taking finasteride, there was also a small but statistically significant increase in the rate of high-grade disease, compared with those taking placebo.
However, the increase in high-grade disease wasn't consistent across all groups and appeared to be limited to patients who underwent "for-cause biopsies," the researchers note. A biopsy was obtained during the PCPT for 1 of 2 reasons: "for cause," which patients underwent if they had an abnormal digital rectal exam or had a corrected PSA of 4 ng/mL or greater; or "end of study," which included all men not diagnosed with cancer during the trial. The latter group did not have abnormal digital rectal exams or elevated PSA levels.
There was a sharp difference between the 2 groups. Virtually no difference was seen in the diagnosis of high-grade cancers in the end-of-study biopsy cohort, which was 2.5% in the finasteride group and 2.3% in the placebo group. But the authors observed that there was a large difference in the for-cause biopsy group (11.5% in the finasteride group vs 7.7% in the placebo group). Thus, they write, the for-cause biopsy group drove the observation of an increased prevalence of high-grade cancer in the finasteride group.
Finasteride has been shown to decrease prostate volume by approximately 25%. In the PCPT, men in the finasteride group had a median prostate size of 25.5 cc at the time of biopsy, whereas men in the placebo group had a median prostate size of 33.6 cc. To better understand how volume changes in PSA test performance characteristics contribute to the PCPT findings, Dr. Elliott and colleagues conducted a retrospective review of 1304 men who had been referred for initial biopsy at their institution.
All of the patients had a PSA between 4 and 10 ng/mL or an abnormal digital rectal examination, and none of the participants had undergone a previous prostate biopsy or surgical therapy for benign prostatic hypertrophy. In addition, none of the patients used testosterone or 5-alpha reductase inhibitors.
Diagnosis of Cancer Improved as Prostate Volume Declined
To best approximate the PCPT study population, all of the men in this cohort, the authors note, had a PSA level of 10 ng/mL or less. Receiver-operator curves and positive predictive values (PPV) were ascertained for PSA stratified by diagnosis and prostate volume.
Within this cohort, 497 patients (38.1%) were diagnosed with prostate cancer; 247 (19%) were high grade (Gleason score ≥7) and 84 (6.4%) had a Gleason score of 8 or above. They noted that as prostate volume increased, the rates of any cancer diagnosis decreased in a statistically significant fashion.
The performance for the diagnosis of any prostate cancer improved as prostate volume decreased (area under the curve [AUC] <30 cc =" 0.758;" cc =" 0.629;">50 cc = 0.520), and this trend was statistically significant. A similar trend was seen for high-grade disease (AUC <30 cc =" 0.712;" cc =" 0.639;">50 cc = 0.497). Although it didn't reach statistical significance for the comparison of the <30>P = .123), it did become statistically significant for the comparison of the 30–50 cc group to the >50 cc group (P =.008).
The authors also found that the PPV of a PSA greater than 4 ng/mL was also affected by prostate volume, and trends for Gleason scores of 6 or less decreased as prostate volume increased (PPV <30 cc =" 25.0%;" cc =" 23.8%;">50 cc = 17.3%). A more significant trend was observed for high-grade disease (PPV <30 cc =" 39.0%;" cc =" 22.3%;">50 cc = 10.7%).
The researchers concluded that in their referral-based cohort of men undergoing extended-scheme prostate needle biopsy, the ability of PSA to detect any cancer or high-grade cancer is affected by prostate size. "PSA performance is significantly better in prostates less than 30 cc in size as compared to those greater than 30 cc in size," they write. "This finding could explain the differing high-grade prostate cancer diagnosis rates in the for-cause biopsy cohort of the PCPT, and supports the possibility of detection bias within the trial."
Finasteride Should Be Used if Deemed Beneficial
After returning to their data and analyzing their own results, the original cancer trial researchers reached similar conclusions, said Catherine Tangen, DrPH, the statistical principle investigator for the aPCPT from the Fred Hutchinson Cancer Research Center in Seattle, Washington, in a statement. She warned that without removing or analyzing the prostates of patients in the current trial, the true prevalence of undetected prostate cancer remains unknown and leaves the actual sensitivity of the PSA test open to question.
However, she noted that these observations "are consistent with everything we found," and suggest that men "should be given the opportunity" to take finasteride if they and their doctors agree that it may be beneficial to them.
The researchers have disclosed no relevant financial relationships.
Clin Cancer Res. 2009;15:4694-4699.
HORMONE THERAPY INCREASE RISK FOR OVARIAN CANCER
July 15, 2009 — New results suggest that hormone therapy increases the risk for ovarian cancer. The findings held true regardless of the duration of use, dose, formulation, or route of administration, according to a study published in the July 15 issue of JAMA.
However, the risk declines quickly once the therapy is discontinued, said first author Lina S. Mørch, MSc, from the Gynaecological Clinic, Rigshospitalet, Copenhagen, Denmark.
"For women having concerns about their risk because they are on hormone therapy or have been taking hormones, our data suggest their risk of ovarian cancer is similar to never users after 2 years' cessation," said Ms. Mørch. "That is, women currently taking hormones seem to reduce their risk of ovarian cancer by quitting hormone use."
In a nationwide prospective cohort study, Danish researchers found that women who have taken hormone therapy are at higher risk for epithelial ovarian cancer (range, 30% to 58%) than those who have not used them.
Ovarian cancer is still a rare disease, Ms. Mørch told Medscape Oncology. "So despite a 40% increased risk of ovarian cancer among current hormone-therapy users, each woman will still have a very low absolute risk of developing cancer [because of] her hormone use."
Indeed, the absolute risk increase was 0.12 per 1000 years, and if the association was causal, then hormone use resulted in approximately an extra 140 cases of ovarian cancer in Denmark over a mean follow-up time of 8 years. This averaged out to about 5% of the ovarian cancers in this study. But even though this number seems low, the authors note, ovarian cancer remains a highly lethal disease, so this risk should be considered when deciding whether or not to use hormone therapy.
Higher Risk Even With Short-Term Use
Their data show an increased risk for ovarian cancer even with short durations of hormone use (from 0 to 4 years), but this result differed from findings of previous studies that were unable to identify an increased risk when hormone therapy was used for less than 5 years.
"Our short-term users included women with a few months' use and women with more than 3 years' use," said Ms. Mørch. "Some previous studies defined short-term use as use less than 1 year or so. These differences in categories may explain some of the difference between this and previous studies."
"In addition, some previous studies did not distinguish sharply between current and previous use," she added. "Women who were current users at the start of a study were often classified as current users, even though they had become previous users during the follow-up period. In our study, the duration analyses were conducted only among women currently taking hormones."
As previously reported by Medscape Oncology, studies have suggested that there is an increased risk for ovarian cancer among women taking postmenopausal hormone therapy. However, data are limited as far as the differential effects of formulations, regimens, and routes of administration.
Risk Declines Over Time With Therapy Cessation
In the current trial, Ms. Mørch and colleagues evaluated the risk for ovarian cancer in perimenopausal and postmenopausal women receiving a variety of hormone therapies using data from the Danish Sex Hormone Register Study, which identified all Danish women 50 to 79 years who used hormone therapy from 1995 to 2005. Overall, the cohort was comprised of 909,946 women without hormone-sensitive cancer or bilateral oophorectomy. Prescription data were obtained from the National Register of Medicinal Product Statistics, and the National Cancer Register and Pathology Register provided ovarian cancer incidence data.
After an average follow-up of 8 years, 3068 incident ovarian cancers, of which 2681 were epithelial cancers, were detected. Compared with women who had never used hormone therapy, current users had incidence rate ratios for all ovarian cancers of 1.38 (95% confidence interval [CI], 1.26 - 1.51) and for epithelial ovarian cancer of 1.44 (95% CI, 1.30 - 1.58). The risk declined as the number of years since hormone therapy was last used increased.
Risk After Discontinuation of Hormone Therapy
| Number of Years Since Last Use | Relative Risk (95% Cl) |
| 0 - 2 | 1.22 |
| More than 2 - 4 | 0.98 |
| More than 4 - 6 | 0.72 |
| More than 6 | 0.63 |
The incidence rate was 0.52 in current hormone therapy users and 0.40 in never users. Ovarian cancer risk did not differ significantly with duration of use among current users, and risk did not differ according to the dose, route of administration, or type of therapy. Compared with women who had never used hormone therapy, the risk for estrogen-only therapies was 1.31 (95% CI, 1.11 - 1.54), and the risk for combined estrogen-plus-progestin therapy was 1.50 (95% CI 1.34-1.68). The difference between them was not statistically significant.
The authors do not recommend screening for ovarian cancer at this time on the basis of hormone therapy use. "Unfortunately, we have no reliable or effective screening technique for ovarian cancer," said Ms. Mørch. "Even the combination of CA125 and ultrasound examination gives many false-positive cases, with unnecessary surgery as a consequence."
This study was supported by the Danish Cancer Society. Coauthor Øjvind Lidegaard, MD, DrMSci, from the Gynaecological Clinic, Rigshospitalet in Copenhagen, Denmark, reports receiving a grant from Schering AG to cover research expenses, and has received fees for speeches from Schering Denmark and Novo Nordisk. None of the other coauthors have disclosed any relevant financial relationships.
JAMA. 2009;302:298-305.
BE CAREFUL WITH XOLAIR
July 16, 2009 — Results of an interim safety analysis of a clinical trial evaluating omalizumab (Xolair, Genentech/Novartis) in patients with moderate to severe asthma suggest that use of the drug may be associated with a disproportionate increase in the incidence of certain cardiovascular adverse events compared with control subjects, the US Food and Drug Administration (FDA) announced today.
The interim safety findings were from the ongoing Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma (EXCELS) trial, indicating increases in the incidence of ischemic heart disease, arrhythmias, cardiomyopathy and cardiac failure, pulmonary hypertension, cerebrovascular disorders, and embolic, thrombotic, and thrombophlebitic events in patients treated with omalizumab compared with control subjects, FDA announced.
The FDA is not recommending changes to safety labeling for for Xolair, and clinicians do not need to take their patients off the drug.
"Until the evaluation of the EXCELS study is completed, healthcare providers and patients should be aware of the risks and benefits described in the prescribing information, as well as the new information from the ongoing EXCELS study that may suggest a risk of cardiovascular and cerebrovascular adverse events," according to an alert sent today from MedWatch, the FDA's safety information and adverse event reporting program.
Omalizumab, an anti-immunoglobulin E monoclonal antibody, is approved for the treatment of moderate to severe persistent asthma in adults and adolescents older than 12 years who test positive for reactivity to a perennial airborne allergen and who do not achieve adequate control of symptoms with inhaled corticosteroids.
NEWS FOR ERLOTINIB MAINTENANCE COMING SOON
ZURICH (Reuters) Jul 13 - Tarceva improved the survival of patients with advanced lung cancer when used immediately after initial chemotherapy, Roche Holding AG said on Monday.
"Detailed data are not yet available, but delivering an overall survival benefit is well ahead of expectations," said JP Morgan analyst Geoff Meacham.
Treating patients immediately following first-line chemotherapy versus waiting for the cancer to grow or spread before giving additional treatment represents a new approach in advanced non-small cell lung cancer (NSCLC), Roche said.
Data from a late-stage study called SATURN showed Tarceva (erlotinib) met a key secondary target, showing a statistically significant improvement in overall survival. Full data will be presented at a lung cancer conference in San Francisco, which starts July 31.
"We have made no changes to our estimates, but this new data reinforces our view of Tarceva's approval and commercial potential," Sal Oppenheim analysts said.
Tarceva is already approved to treat pancreatic cancer in the United States and EUA VERY "LIGHT" REGIMEN
| Anticancer Res. 2009 Jul;29(7):2681-6. | Related Articles, LinkOut |
Cisplatin-Ifosfamide-gemcitabine as salvage chemotherapy in ovarian cancer patients pretreated with platinum compounds and Paclitaxel.
Polyzos A, Tsavaris N, Gogas H, Lagadas A, Polyzos K, Giannakopoulos K, Felekouras E, Tsigris C, Karatzas T, Papadopoulos O, Giannopoulos A.
Associate Professor, 1st Department of Propaedeutic Medicine, Athens University School of Medicine, Laiko General Hospital, 17, Agiou Thoma Str., GR 11527 Athens, Greece. panoraiap@med.uoa.gr and r-e-poly@hol.gr.
BACKGROUND: The role of combination chemotherapy regimens in the management of ovarian cancer patients with tumors previously exposed to platinum compounds and paclitaxel has not yet been defined. The present phase II study evaluated the activity and toxicity of a gemcitabine-ifosfamide-cisplatin combination in the aforementioned group of patients. Given the in vitro and in vivo synergism between the three agents, it was believed that using a three-drug combination would overcome tumor resistance to cisplatin. PATIENTS AND METHODS: Twenty-four patients were enrolled in the study. The median age was 56 years and the median performance status 1. Eight (34%) had potentially platinum-sensitive, 6 (24%) had primary platinum-resistant and 10 (42%) patients had secondary platinum-resistant tumors. Treatment consisted of gemcitabine 1 g/m(2) i.v. on days 1 and 8, cisplatin 75 mg/m(2) i.v. over 2 h fractionated over days 8 and 9, and ifosfamide 5 mg/m(2) i.v. over 1 h fractionated on days 8-9 with mesna uroprotection. Courses were administered every 3 weeks on an outpatient basis. Granulocyte colony-stimulating factor (G-CSF) was given at a dose of 5 mug/kg/day on days 10-14. A median of 4 cycles were administered with the delivered dose intensity at 85% of the planned dose for the three agents. RESULTS: Among 24 patients evaluable for response and toxicity, there were 8 partial responses with a response rate of 33% (95% confidence interval 16.4-55%). Stable disease was recorded in 6 (25.7) and progressive disease in 10 (42%) patients. Subgroup analysis revealed a response rate of 50% in potentially platinum-sensitive, 16.5% in primary platinum-resistant and 30% in secondary platinum-resistant tumors. The median response duration was 5 months (range 3-12 months), the median time to progression 6 months (range 3-16 months) and the median survival 12 months (range 3-24 months). Myelotoxicity was significant, with neutropenia grade 3 and 4 occuring in 35% and 20% of patients, respectively. Four episodes (3.5% of all cycles) of febrile neutropenia were documented and were well managed with oral antibiotics and G-CSF continuation until complete recovery. Grade 1, 2 and 3 peripheral neuropathy developed in 40%, 30%, and 10% of patients, respectively. CONCLUSION: The three-drug combination demonstrated a significant effectiveness in potentially platinum-sensitive tumors and a moderate efficacy in platinum-resistant tumors. The regimen, although myelotoxic, is tolerable with G-CSF support. Further investigation via comparative studies is required to define any superiority of the present regimen over doublets of the three agents in this group of patients.
AN INTERESTING FAILURE
Cancer Chemother Pharmacol. 2009 Jul 11. [Epub ahead of print] Related Articles, LinkOut
A phase II study of biweekly pemetrexed and gemcitabine in patients with metastatic breast cancer.
Dent SF, Gertler S, Verma S, Segal R, Young V, Goel R, Keller O, Canil C, Iscoe N.
The Ottawa Hospital Regional Cancer Centre, 501 Smyth Rd, Ottawa, ON, K1H 8L6, Canada, sdent@ottawahospital.on.ca.
PURPOSE: Pemetrexed (PEM) is a novel folate antimetabolite which inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. This phase II study was designed to assess the efficacy of Gemcitabine (GEM) and PEM given in a novel schedule in metastatic breast cancer (MBC) patients. METHODS: Eligible patients had MBC and received one prior chemotherapy regimen for metastatic disease; Performance status (PS) 0-2; measurable disease (RECIST criteria). PEM(500 mg/m(2)) was administered intravenously (IV) over 10 min prior to GEM(1,500 mg/m(2)) IV given over 30 min on day 1 every 14 days. RESULTS: Median age of the 16 patients in the study was 54 years (range 33-77). Fourteen patients had a PS of 0/1 and were evaluable for response. There were no reported complete or partial responses, seven patients with stable disease, six patients with disease progression and one patient with unknown response. Most common toxicities were skin rash: Grade 1/2(8) and Grade 3/4(1). Grade 3/4 non-hematological toxicities were fatigue(1); anorexia(1); pneumonia(1); peripheral ischemia(1) and elevation of liver transaminases(1). Three patients experienced febrile neutropenia (FN). This study did not meet the predefined criteria to proceed with additional accrual. CONCLUSIONS: This regimen of PEM and GEM showed no clinical activity in the dose and schedule tested.
ALERT FOR A NEW PROSTHETIC VALVE
July 15, 2009 (St Louis, Missouri) — A surgeon at the Washington University School of Medicine, in St Louis, MO, says she and her colleagues have no good explanation for what they term "alarmingly early stenosis" seen in patients treated with the Medtronic Mosaic bioprosthetic valve in the aortic position. According to a brief communication they've published in the June 2009 issue of the Journal of Thoracic and Cardiovascular Surgery, Dr Jennifer S Lawton and her coauthors, prompted by an initial case of early stenosis, followed all 122 patients in whom they'd used the device, ultimately turning up four cases of severe stenosis requiring valve replacement within just three to 44 months after implantation.
Durability of the Mosaic, a third-generation porcine valve, is typically assumed to be between 10 and 15 years, Lawton told heartwire . "We did not find any other reports of this: that's one of the reasons we felt we should try to get it into the literature; we felt others should know about it."
Medtronic, for its part, says Lawton et al's finding is solely related to patient-level factors, and the company staunchly defends the safety, durability, and efficacy of its product.
Early Stenosis
According to Lawton et al's report, all four valves, implanted by two different surgeons, have a "strikingly similar appearance of thickened material resulting in immobility of the leaflets."
Patient-prosthesis mismatch was excluded as a possible cause, as were other patient- or procedure-related factors, Lawton told heartwire . "Explanted valves were examined by a pathologist at the Washington University School of Medicine and by a pathologist after return of the valves to Medtronic, and no cause for the stenosis could be determined in any case," they write.
Contacted for comment, however, a Medtronic spokesperson pointed out that the Mosaic is the only stented heart valve with "proven third-generation performance," with more than three decades of tissue valve design improvements behind it.
"It is the valve of choice for many cardiac surgeons throughout the world," Joseph McGrath told heartwire . "Based upon the collective body of evidence of peer-reviewed journal articles that have demonstrated satisfactory clinical results with the device, Medtronic confidently stands behind its conviction that the Mosaic heart valve offers both surgeons and patients alike a safe and efficacious product."
The Medtronic analysis of the valves--sent to the company by Lawton and colleagues--indicated that pannus (a flap of tissue or scarring) and/or thrombus was the reason for explantation in all four cases. "These events are caused by patient factors extrinsic to the valve," McGrath said. Medtronic has subsequently published a formal statement about the Mosaic's durability online in response to Lawton et al's paper [2].
Lawton is not entirely reassured, however, and says she is not using the Mosaic--it had previously been her go-to device--until she has further information supporting its safety and durability, noting that there are many other options for valve replacement. She hopes other hospitals will be prompted to review their cases and see whether this phenomenon is occurring anywhere else. "I really didn't want to subject any of my patients to a similar problem, and I honestly don't know how to prevent it, so I've been choosing different types of valves."
She added that she didn't think there was any reason for alarm in patients who had already received the Mosaic, since the numbers of patients affected is seemingly so small. "Any patients with a valve replacement should follow up regularly with their physicians, and that means an echocardiogram periodically. If they have symptoms of shortness of breath, swelling in the legs, or chest pain, they should see their doctor and obtain an echocardiogram."
An Issue Worth Raising
Also asked to comment on the paper for heartwire , cardiothoracic surgeon Dr Jeff Tyner (Scripps Clinic, La Jolla, CA) emphasized that Lawton et al's report was "not enough to condemn the Mosaic, although it's a possible problem that you'd want to track."
He added that he himself has not used the Mosaic, because it has only eight to 10 years of data supporting its safety and durability. That said, he added, "It is a third-generation device, which means it should do very, very well long term. If others find this, however, it's a big deal. You have to wonder what the mechanism for this is."
Possible explanations, said Tyner, include underlying endocarditis (although patients with endocarditis were excluded from Lawton et al's series), subsequent chemotherapy, operator-related issues (including the kinds of rinses or other medicines/techniques used during the procedure), and finally something specific to the valve itself.
"I don't know what you do at this point other than raise the issue and get people to kind of track their patients," Tyner said. Since surgeons often do not end up following up with these patients, it's important for news of the potential problem to reach the cardiology and echocardiography communities, he added.
Τετάρτη 15 Ιουλίου 2009
BREAST CANCER OVERDIAGNOSED WITH MAMMOGRAPHY
July 14, 2009 — One in 3 breast cancers detected in publicly organized screening programs is overdiagnosed. And overtreatment inevitably occurs at the same rate, according to a meta-analysis of screening programs in Canada, Australia, Norway, Sweden, and the United Kingdom, published online July 9 in BMJ.
The new analysis is yet another study that adds to the controversy surrounding mammography's benefits and harms, which include overdiagnosis and overtreatment.
"The question is no longer whether overdiagnosis occurs, but how often it occurs," writes Gilbert Welch, MD, in an editorial accompanying the newly published analysis.
Overdiagnosis of cancer refers to cancers that grow so slowly that the patient dies of other causes before it produces symptoms or to cancer that is dormant or even regresses, explained Dr. Welch, who is a professor of medicine at Dartmouth Medical School in Hanover, New Hampshire.
Overdiagnosis is a "widely recognized problem" in prostate cancer screening, said Dr. Welch.
With regard to breast cancer, there is a growing body of evidence about overdiagnosis with which the new study is consistent, he added.
Namely, there are now 5 observational studies that indicate screening mammography is associated with increases in the incidence of breast cancer in women of screening age, but that there is "little or no subsequent decrease in the incidence of older women," notes Dr. Welch.
But is the rate of overdiagnosis really as high as 1 in 3 screen-detected cancers?
Dr. Welch says that that the "most compelling evidence to date" about overdiagnosis comes from an earlier randomized controlled trial of mammography versus observation (BMJ. 2006;332:689-692). In that study, overdiagnosis from screening occurred at a rate of 1 in 6, Dr. Welch notes.
Whatever the rate of overdiagnosis, both the study authors and the editorialist agree, overtreatment is likely to occur at the same rate.
"As it is not possible to distinguish between lethal and harmless cancers, all detected cancers are treated," write the study authors, Karsten Juhl Jørgensen, MD, and Peter C Gøtzsche, MD, from the Nordic Cochrane Center in Copenhagen, Denmark.
Close Call
The balance between the benefits and harms of mammography make it one of medicine's "close calls," adds Dr. Welch. It is a close call that has received a lot of public attention in the past year.
In the United Kingdom, there was public outcry over the lack of information about the harms of mammography in a public-health pamphlet about breast cancer screening. The protest led to a rewrite of the pamphlet, as reported by Medscape Oncology.
Furthermore, The New York Times and other media made front-page news out of a 2008 study from Norway that concluded that about 20% of screen-detected invasive breast cancers spontaneously regress. One of the Norwegian researchers told Medscape Oncology that such lesions are "pseudo-cancers."
In making decisions about whether or not to get screened, women are probably most interested in the "trade-off between the number of deaths from breast cancer avoided and the number of cancers overdiagnosed," suggested Dr. Welsh.
In an effort to provide physicians and their patients with a "balance sheet" of the harms and benefits of mammography, Dr. Welch included a tabular display along with his editorial. The credits and debits are for every 1000 women undergoing annual mammography for 10 years starting at the age of 50 years.
| Credits | Debits |
| 1 woman will avoid dying from breast cancer | 2–10 women will be overdiagnosed and treated needlessly 10–15 women will be told they have breast cancer earlier than they would otherwise have been told, but this will not affect their prognosis 100–500 women will have at least 1 "false alarm" (about half these women will undergo biopsy) |
New Study Details
To estimate the extent of overdiagnosis in organized screening programs, the Danish investigators compared trends in breast cancer incidence before and after the screening was initiated in the United Kingdom; Manitoba, Canada; New South Wales, Australia; Sweden; and parts of Norway.
The reason for this approach is based on the idea that, if screening was effective and did not produce overdiagnosis, then "the initial increase in cancers in the screened age groups would be fully compensated for by a similar decrease in the older age groups no longer offered screening," write the authors. Why is this so? Because the cancers in the older age groups would have been detected earlier on in life, as a result of screening, explain the authors.
The authors also note that such an approach must take into account changes in the background incidence of breast cancer and other factors.
One set of data offers an example of how the analysis was conducted. In Sweden, nationwide screening began in 1986, and in 1998, "almost all eligible women had been offered screening," the authors write. In 2000, the increase in invasive cancer after screening was implemented was 54% above expected rates for women aged 50 to 59 years and 21% for women aged 60 to 69 years. A drop in the incidence of breast cancer occurred among women aged 70 to 84 years, but the incidence "approached the expected rate," write the authors. In short, 88% of the increase among younger women was not compensated for by any drop in the older women, note the authors.
In summary, the total overdiagnosis of breast cancers, including ductal carcinoma in situ, from these public screening programs in different countries was 52%. The overdiagnosis of invasive breast cancer was 35%, report the authors.
The authors have disclosed no relevant financial relationships.
Δευτέρα 13 Ιουλίου 2009
MAYBE MORE IS BETTER
Duration of Chemotherapy for Advanced Non–Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Trials
From the Sydney Cancer Center, Royal Prince Alfred Hospital; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
Corresponding author: Michael J. Boyer, MB BS, Sydney Cancer Center, Royal Prince Alfred Hospital, Missenden Rd, Camperdown 2050, Sydney, New South Wales, Australia; e-mail: michael.boyer@sswahs.nsw.gov.au.
Purpose To determine if it is preferable to extend chemotherapy beyond a standard number of cycles in patients receiving first-line chemotherapy for advanced non–small-cell lung cancer.
Methods We searched biomedical literature databases and conference proceedings for randomized controlled trials (RCTs) comparing a defined number of cycles with continuation of the same chemotherapy until disease progression, a larger defined number of cycles of identical chemotherapy, and a defined number of cycles of identical initial chemotherapy followed by additional cycles of an alternative chemotherapy. Meta-analysis was performed using the fixed effect model. The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), adverse events (AE), and health-related quality of life (HRQL).
Results We found 13 RCTs including 3,027 patients. Extending chemotherapy improved PFS substantially (hazard ratio [HR], 0.75; 95% CI, 0.69 to 0.81; P < .00001) and OS modestly (HR, 0.92; 95% CI, 0.86 to 0.99; P = .03). Subgroup analysis revealed that effects on PFS were greater for trials extending chemotherapy with third-generation regimens rather than older regimens (HR, 0.70 interaction v 0.92 interaction; P = .003). Extending chemotherapy was associated with more frequent AE in all trials where it was reported and impaired HRQL in two of seven trials.
Conclusion Extending chemotherapy, particularly with a third-generation regimen, improved PFS substantially, but OS less so. Future trials should test extending treatment with more effective and/or better-tolerated agents.AN INTERESTING REGIMEN
Phase II Study of Pemetrexed and Carboplatin Plus Bevacizumab With Maintenance Pemetrexed and Bevacizumab As First-Line Therapy for Nonsquamous Non–Small-Cell Lung Cancer
From the Feinberg School of Medicine, Northwestern University, The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; Eli Lilly Pharmaceuticals; Hematology/Oncology of Indiana, Indianapolis, IN; and the Division of Hematology/Oncology, Rush University Medical Center, Chicago, IL.
Corresponding author: Jyoti D. Patel, MD, Northwestern University, Feinberg School of Medicine, 676 N St Claire, Suite 850, Chicago, IL, 60611; e-mail: jd-patel@northwestern.edu.
Purpose This study evaluated the efficacy and safety of pemetrexed, carboplatin, and bevacizumab followed by maintenance pemetrexed and bevacizumab in patients with chemotherapy-naive stage IIIB (effusion) or stage IV nonsquamous non–small-cell lung cancer (NSCLC).
Patients and Methods Patients received pemetrexed 500 mg/m2, carboplatin area under the concentration-time curve of 6, and bevacizumab 15 mg/kg every 3 weeks for six cycles. For patients with response or stable disease, pemetrexed and bevacizumab were continued until disease progression or unacceptable toxicity.
Results Fifty patients were enrolled and received treatment. The median follow-up was 13.0 months, and the median number of treatment cycles was seven (range, one to 51). Thirty patients (60%) completed 
METFORMIN BOOSTS pCR IN DIABETICS
Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer
From the Departments of Breast Medical Oncology, Biochemistry and Molecular Biology, Quantitative Sciences, Surgical Oncology, Pharmacy, Molecular and Cellular Oncology, and Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and the Department of Gynecology and Obstetrics, University of Muenster, Muenster, Germany.
Corresponding author: Ana M. Gonzalez-Angulo, MD, Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; e-mail: agonzalez@mdanderson.org.
Purpose Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this. Our purpose was to determine whether metformin use was associated with a change in pathologic complete response (pCR) rates in diabetic patients with breast cancer receiving neoadjuvant chemotherapy.
Patients and Methods We identified 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. Patients were compared by groups: 68 diabetic patients taking metformin, 87 diabetic patients not taking metformin, and 2,374 nondiabetic patients. pCR rates were compared between the three groups using 
Results The rate of pCR was 24% in the metformin group, 8.0% in the nonmetformin group, and 16% in the nondiabetic group (P = .02). Pairwise comparisons between the metformin and nonmetformin groups (P = .007) and the nonmetformin and nondiabetic groups (P = .04) were significant. Comparison of the pCR rates between the metformin and nondiabetic groups trended toward but did not meet significance (P = .10). Metformin use was independently predictive of pCR (odds ratio, 2.95; P = .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use.
Conclusion Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.
Supported by the Nellie B. Connally Breast Cancer Research Fund; an ASCO Breast Cancer Research Foundation Young Investigator Award, American Association for Cancer Research–Amgen Fellowship in Clinical/Translational Cancer Research, and Barbara Rattay Scholar Award (S.J.); the Deutsche Forschungsgemeinschaft (C.L.); and in part by an ASCO Career Development Award and National Cancer Institute Grant No. 1K23CA121994-01 (A.M.G.A.).SORAFENIB AND SURVIVAL IN RENAL CANCER PATIENTS
Sorafenib for Treatment of Renal Cell Carcinoma: Final Efficacy and Safety Results of the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial
From the From Institut Gustave Roussy, Villejuif; Hôpital Européen Georges Pompidou, Paris; Centre Léon Bérard, Lyon; Institut Claudius Regaud, Toulouse; Centre René Gauducheau, Saint-Herblain, France; Cambridge Research Institute, Cambridge; Royal Marsden Hospital, Surrey, United Kingdom; Military School of Medicine; Centrum Onkologii, Warsaw, Poland; Urologische Klinik und Poliklinik Klinikum der Universität Großhadern Ludwig-Maximilian-Universität, München, Germany; University of Chicago, Chicago, IL; Baylor Charles A. Sammons Cancer Center, Dallas, TX; Bayer HealthCare Pharmaceuticals, Montville, NJ; and Cleveland Clinic Taussig Cancer Center, Cleveland, OH.
Corresponding author: Bernard Escudier, MD, Department of Medicine, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France; e-mail: escudier@igr.fr.
Purpose Mature survival data and evaluation of vascular endothelial growth factor (VEGF) as a prognostic biomarker from the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) study in patients with renal cell carcinoma (RCC) are reported.
Patients and Methods Nine hundred three previously treated patients were randomly assigned to receive sorafenib versus placebo. On demonstration of progression-free survival (PFS) benefit with sorafenib, patients assigned to placebo were offered sorafenib. Overall survival (OS) was determined at two planned interim analyses and one final analysis, with a secondary OS analysis conducted by censoring placebo patients who crossed over to sorafenib. The relationships between baseline VEGF level and prognosis and efficacy were evaluated.
Results The final OS of patients receiving sorafenib was comparable with that of patients receiving placebo (17.8 v 15.2 months, respectively; hazard ratio [HR] = 0.88; P = .146); however, when post–cross-over placebo survival data were censored, the difference became significant (17.8 v 14.3 months, respectively; HR = 0.78; P = .029). Adverse events at 16 months after cross over were similar to those previously reported. Baseline VEGF levels correlated with Eastern Cooperative Oncology Group performance status (P < .0001), Memorial Sloan-Kettering Cancer Center score (P < .0001), and PFS and OS in univariate (PFS, P = .0013; OS, P = .0009) and multivariate (PFS, P = .0231; OS, P = .0416) analyses of placebo patients and with short OS by multivariate analysis of patients receiving sorafenib (P = .0145). Both high-VEGF (P < .01) and low-VEGF (P < .01) groups benefited from sorafenib.
Conclusion Although an OS benefit was not seen on a primary intent-to-treat analysis, results of a secondary OS analysis censoring placebo patients demonstrated a survival advantage for those receiving sorafenib, suggesting an important cross-over effect. VEGF levels are prognostic for PFS and OS in RCC. The results of TARGET establish the efficacy and safety of sorafenib in advanced RCC.MACROPHAGES AND SURVIVAL IN STAGES I/II MELANOMA
Macrophage Markers in Serum and Tumor Have Prognostic Impact in American Joint Committee on Cancer Stage I/II Melanoma
From the Cancer Immunotherapy Group and Departments of Oncology, Clinical Biochemistry, and Plastic Surgery, Aarhus University Hospital, Aarhus; the Finsen Laboratory, Rigshospitalet, Copenhagen; and Department of Pathology, Vejle Hospital, Vejle, Denmark.
Corresponding author: Trine O. Jensen, MD, Department of Oncology, Aarhus University Hospital, Norrebrogade 44, 8000 Aarhus C, Denmark; e-mail: trinejen@rm.dk.
Purpose To evaluate the prognostic role of soluble CD163 (sCD163) in serum and macrophage infiltration in primary melanomas from patients with American Joint Committee on Cancer (AJCC) stage I/II melanoma. The scavenger receptor CD163 is associated with anti-inflammatory macrophages, and it is shed from their surface.
Patients and Methods Serum samples from 227 patients with stage I/II melanoma obtained before definitive surgery (baseline) and during 5 years of follow-up were analyzed for sCD163 by enzyme-linked immunosorbent assay. Excised formalin-fixed, paraffin-embedded primary melanomas from 190 patients were available for immunohistochemical analyzes of CD163+ and CD68+ macrophage infiltration. They were estimated semiquantitatively in three different tumor compartments: tumor nests, tumor stroma, and at the invasive front of the tumor.
Results Serum sCD163 treated as an updated continuous covariate as well as the baseline value were analyzed together with the covariate's ulceration and thickness in a Cox proportional hazards model. sCD163 was an independent prognostic factor for overall survival (baseline, hazard ratio [HR] = 1.4; 95% CI, 1.1 to 1.7; P = .01; and updated, HR = 1.4; 95% CI, 1.1 to 1.8; P = .003). Melanomas with dense CD163+ macrophage infiltration in tumor stroma and CD68+ macrophage infiltration at the invasive front were associated with poor overall survival (CD163, HR = 2.7; 95% CI, 0.8 to 9.3; P = .11; and CD68, HR = 2.8; 95% CI, 1.2 to 6.8; P = .02) independent (borderline for CD163) of thickness and ulceration.
Conclusion Both serum levels of sCD163 and the presence of CD68+ macrophage infiltration at the tumor invasive front are independent predictors of survival in AJCC stage I/II melanoma. CD163+ cell infiltration in tumor stroma may be predictive of survival.COMPARING RHABDOMYOSARCOMA BETWEEN CHILDREN AND ADULTS
Comparing Adult and Pediatric Rhabdomyosarcoma in the Surveillance, Epidemiology and End Results Program, 1973 to 2005: An Analysis of 2,600 Patients
From the Departments of Pediatric Oncology and Medical Oncology, King Hussein Cancer Center, Amman, Jordan; Department of Pediatric Oncology, St Jude Children's Research Hospital, Memphis, TN; and the Pediatric Oncology Unit, Istituto Nazionale Tumori, Milan, Italy.
Corresponding author: Iyad Sultan, MD, King Hussein Cancer Center, Queen Rania Al Abdullah St, PO Box 1269, Amman 11941, Jordan; e-mail: isultan@khcc.jo.
Purpose To compare clinical features and outcomes of adults and children reported to have rhabdomyosarcoma.
Patients and Methods We analyzed data from 1,071 adults (age > 19 years) and 1,529 children (age 
Results Adults with rhabdomyosarcoma had significantly worse outcome than children (5-year overall survival rates, 27% ± 1.4% and 61% ± 1.4%, respectively; P < .0001). Tumors in adults were more likely to be at an unfavorable site (65% v 55%; P < .0001) and to have histologies that are unusual during childhood, particularly the pleomorphic subtype (19%) and not otherwise specified (43%). Regional and distant spread was not more frequent in adults. Adults had significantly worse outcome than children with similar tumors. The most significant difference was in localized disease; 5-year survival estimates were 82% ± 2.0% for children and 47% ± 2.9% for adults (P < .0001). Multivariate analysis showed that age, histologic subtype, primary site location, stage, and local control with surgery and/or radiation were significant predictors of survival. However, alveolar subtype and unfavorable primary site lost significance when analysis was restricted to adults.
Conclusion Adults reported to have rhabdomyosarcoma had worse survival than children with similar tumors. Predictors of poor outcome in children were valid in adults except for alveolar histology and unfavorable tumor site.A SAFER DRUG FOR ATRIAL FIBRILLATION
July 3, 2009 (Silver Spring, Maryland) — The US Food and Drug Administration (FDA) has approved dronedarone (Multaq, Sanofi-Aventis) to reduce the risk of cardiovascular hospitalization in the treatment of atrial fibrillation (AF) or atrial flutter.
The decision follows the recommendation of the Cardiovascular and Renal Drug Advisory Panel, which earlier this year voted 10-3 in favor of approval, a decision reported by heartwire . Dronedarone is envisioned as a safer alternative to amiodarone, a widely used antiarrhythmic agent in patients with AF.
The advisory panel recommendation and the FDA approval are based largely on the results of the ATHENA study. In that trial, treatment with dronedarone resulted in a 24% reduction in the risk of all-cause mortality or cardiovascular hospitalization when compared with placebo. The study, led by Dr Stefan H Hohnloser (JW Goethe University, Frankfurt, Germany), was published in the February 12, 2009 issue of the New England Journal of Medicine [1].
The FDA approval is good news for Sanofi-Aventis, which tried unsuccessfully to have dronedarone approved for use in patients with systolic heart failure. The current approval states that dronedarone is contraindicated in patients with severe heart failure or those with NYHA 2 or 3 heart failure with a recent decompensation requiring hospitalization. The ANDROMEDA trial, also reported by heartwire , showed that dronedarone increased the risk of mortality twofold among those treated with the drug.
STATINS FOR PRIMARY PREVENTION
July 3, 2009 (Rotterdam, The Netherlands) — Use of statins is associated with significantly improved survival and large reductions in the risk of major cardiovascular events in patients who have risk factors but who do not have established cardiovascular disease, according to a new meta-analysis of major statin trials published online June 30 in BMJ [1].
It shows that the relative risk reduction from long-term statin use in a primary-care setting is comparable to that observed in secondary prevention and confirms the results of the JUPITER study regarding the beneficial effects of statins across a range of patient groups, say the researchers.
"Our data suggest that people without established CVD should not be denied the relative benefits of long-term statin use," lead author Dr Jasper J Brugts (Thoraxcenter, Rotterdam, the Netherlands) told heartwire .
"However, the exact threshold for cost-effectiveness of such treatment should be investigated further and probably depends on the [individual] level of risk for cardiovascular disease due to specific combinations of risk factors," he added.
Statins Cut Deaths by 12%, Coronary Events by 30%, CV Events by 19%
Brugts said it is well-established that statins are effective in the setting of secondary prevention (ie, in patients with cardiovascular disease), "but whether the benefits apply to primary prevention is unknown, and previous research has provided ambiguous answers on statin use in people at relatively lower risk." In addition, there is debate about the efficacy of statins in certain subgroups, such as people aged over 65, women, and those with diabetes mellitus, he explained.
He and his colleagues combed the Cochrane controlled trials register, Embase, and Medline for studies on the clinical effects of statins compared with a placebo or control group and with follow-up of at least one year that also had at least 80% or more participants without established CVD and outcome data on mortality and major CVD events. They identified 10 trials including a total of 70 388 people, of whom 34% were women and 23% had diabetes mellitus. Mean follow-up was 4.1 years.
The trials included were: WOSCOPS, AFCAPS/TexCAPS, PROSPER, ALLHAT-LLT, ASCOT-LLA, HPS, CARDS, ASPEN, MEGA, and JUPITER.
The results are in line with those previously published on the effects of statins in secondary prevention, but the researchers note they were also able to include several recently published studies targeted at primary prevention that enrolled large numbers of women and diabetics and from which they were able to obtain data on clinically defined subgroups by contacting the principal investigators of each trial.
Overall, treatment with statins significantly reduced the risk of all-cause mortality (odds ratio 0.88), major coronary events (OR 0.70), and major cerebrovascular events (OR 0.81). "We demonstrated in 70 388 subjects without established cardiovascular disease but with risk factors that statin use improves survival and reduces the risk of major cardiovascular and cerebrovascular events," Brugt commented.
And the researchers saw the same effects of statins regardless of age, gender, or diabetic status. "It is reassuring that no significant treatment heterogeneity was found between the sexes, in elderly and young people, and between people with and without diabetes," they observe.
Cancer Numbers Reassuring But Not Unequivocal
Also important, says Brugts, "No increased risk of cancer was observed," something that has been of concern previously, sparked by an increased risk of cancer seen with use of statins in those aged over 70 in PROSPER. Follow-up of patients in WOSCOPS for 10 years, for example, did not show higher rates of malignancies.
But he and his colleagues caution, "Although our results show that statins do not seem to increase the risk of cancer, longer follow-up would be helpful to determine whether new cancer events could occur with time. This is especially critical when statins are used in primary prevention," they note.
And concerns might remain about the higher risk of cancer in elderly patients (70–82 years), as in PROSPER, "and further follow-up studies in such patients are required. Although this meta-analysis cannot fully remove that uncertainty, it confirms that the risk of cancer is not increased in middle-aged patients," they observe.
Cost/Benefits Must Be Weighed, As Ever
In conclusion, the authors say that despite their positive findings, the absolute overall treatment benefit in the current study population "would certainly be less than 1%, and significant numbers of participants would need to be treated to prevent one event."
It is not possible from these data to exactly define one group of people who would benefit most from statin use, and the correct identification of such people "remains a challenge," they add.
However, they also state "it is obvious that older men (>65 years) with risk factors or older women with diabetes and risk factors constitute the highest-risk group . . . [and] it is likely that a considerable number of such people would benefit from long-term statin use at reasonable costs."
INTENSIVE FOLLOW UP BENEFICIAL FOR EARLY STAGE COLORECTAL CANCER
NEW YORK (Reuters Health) Jul 07 - Patients with early (stage I and IIA) colon cancer derive similar benefits from intensive postoperative surveillance as those with late stage IIB and III colon cancer, clinicians report in the June 29 issue of the Journal of Clinical Oncology.
At present, it is unclear how best to treat postsurgical patients with early-stage colon cancer, Dr. Heidi Nelson, from the Mayo Clinic, Rochester, Minnesota, and colleagues note in their report. "We have demonstrated that patients with early-stage disease who develop a recurrence benefit to at least the same extent as their late-stage counterparts from intensive follow-up."
The findings are based on a secondary analysis of data from the Clinical Outcomes of Surgical Therapy (COST) trial for 537 patients with early-stage colon cancer and 254 with late-stage colon cancer.
The COST trial follow-up protocol included physical examination, including checking for recurrence at wound sites, plus carcinoembryonic antigen (CEA) testing every 3 months for the first year and then every 6 months for 5 years; chest x-ray every 6 months for 2 years and then annually; and colon evaluation, including colonoscopy or colon radiography, annually for the first year and then every 3 years if the colon was free of neoplasms; and computed tomography (CT) of the abdomen at the physician's discretion.
The cumulative incidence of recurrence at 5 years was 9.5% in patients with early-stage disease and 35.7% in those with late-stage disease, and the median time to recurrence was 1.8 years and 1.4 years, respectively.
Salvage rates for early- and late-stage disease patients with recurrence were similar --35.9% and 37%, respectively, Dr. Nelson and colleagues report.
"Our analysis of the COST trial database confirms what was reported by the (2007) Cochrane review; that is, roughly one third of patients who experience recurrences after primary colon cancer resection can be treated with secondary curative-intent surgery when followed intensively after primary surgery," the researchers write.
"Our report also confirmed that patients undergoing secondary surgery experience median survival of between 35.8 and 51.2 months," which is similar to median survivals reported in the literature.
The data also indicate that patients with early-stage colon cancer were significantly less likely than patients with late-stage disease to experience multiple sites of first recurrence (3.6% vs 28.6%).
They also report that the methods of first detection of recurrence were similar between the two groups: CEA (29.1% vs 37.4%), CT scan (23.6% vs 26.4%), chest x-ray (7.3% vs 12.1%) and colonoscopy (12.7% vs 8.8%), for early- versus late-stage disease, respectively.
The COST trial data "support the frequent use of CEA and colonoscopy and suggests greater emphasis on lung imaging with less certainty on the value of abdomen and pelvis CT," the investigators conclude.
"To our knowledge," they add, "this is the first prospective study to test and confirm the hypothesis that patients with early-stage disease experience the same benefits as those with late-stage disease after curative intent secondary resection."
J Clin Oncol 2009.
ANOTHER FAILURE OF COMBINATION CHEMOTHERAPY FOR PANCREATIC CANCER
- J Clin Oncol. 2009 Jul 6. [Epub ahead of print]
Phase III, Randomized Study of Gemcitabine and Oxaliplatin Versus Gemcitabine (fixed-dose rate infusion) Compared With Gemcitabine (30-minute infusion) in Patients With Pancreatic Carcinoma E6201: A Trial of the Eastern Cooperative Oncology Group.
Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd.
Cancer Institute of New Jersey, Brunswick, NJ; Dana-Farber Cancer Institute, Boston, MA; Vanderbilt University Medical Center, Nashville, TN; Pfizer; New York University Cancer Institute, New York, NY; Thomas Jefferson University; University of Pennsylvania, Philadelphia, PA; Mayo Clinic, Rochester, MN; and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.
PURPOSE: Single-agent gemcitabine (GEM) is standard treatment of metastatic pancreatic cancer. Fixed-dose rate (FDR) GEM and GEM plus oxaliplatin have shown promise in early clinical trials. E6201 was designed to compare overall survival (OS) of standard weekly GEM 1,000 mg/m(2)/30 minutes versus GEM FDR 1,500 mg/m(2)/150 minutes or GEM 1,000 mg/m(2)/100 minutes/day 1 plus oxaliplatin 100 mg/m(2)/day 2 every 14 days (GEMOX). METHODS: This trial included patients with metastatic or locally advanced pancreatic cancer, normal organ function, and performance status of 0 to 2. The study was designed to detect a 33% difference in median survival (hazard ratio [HR]
GENE POLYMORPHISMS AND GLIOMA RISK
July 9, 2009 — An international study of genetic variations involved in glioma, the most frequently occurring type of brain tumor, has identified 14 common gene variants in 5 genes associated with the occurrence of glioma.
Published online July 5 in Nature Genetics, the international investigation, led by researchers at the M.D. Anderson Cancer Center in Houston, Texas, analyzed data from 2 genomewide association studies from the United States and the United Kingdom. Together, the studies included 1878 patients with glioma and 3670 control individuals whose genotypes were obtained.
"[I]t's the first time we've had a large enough sample to understand the genetic risk factors related to glioma," said one of the senior authors, Melissa Bondy, PhD, professor, Department of Epidemiology, M.D. Anderson Cancer Center, University of Texas, in an M.D. Anderson press release.
The study contributes to understanding the possible cause of this common type of brain tumor, which constitutes approximately 80% of all primary brain malignancies. The only contributing factor identified previously was ionizing radiation. However, an increased familial risk had been recognized, leading to the US and UK genomewide association studies of glioma in populations with Western European heritage.
Beginning with the genotyping of more than a half-million single nucleotide polymorphisms (SNPs), the researchers found 34 SNPs demonstrating strong evidence of association with glioma (P <>−5). Replication studies were carried out in 3 case-control groups from French, German, and Swedish populations, totaling 2545 patients with glioma and 2953 control individuals.
Combined results from genomewide association and replication studies pointed to 14 SNPs in 5 genes that qualified for genomewide significance (P <>−7). Among these 14 SNPs, the 95% odds ratios (ORs) ranged from 1.18 to 1.36, with respective P values ranging from 1.07 × 10−8 to 2.34 × 10-18. The 5 genes implicated were TERT, CCDC26, CDKN2A/B, PHLDB1, and RTEL1.
The strongest association was found for a SNP in CCDC26, a gene on chromosome 8 that influences retinoic acid, thus reducing telomerase activity and increasing programmed cell death. A SNP in TERT showed the next strongest association with glioma (P = 1.50 × 10−17). TERT is necessary for telomerase activity and maintaining telomeres.
The third strongest association (P = 7.24 × 10−15) was for a SNP in CDKN2B. The CDKN2A/B region activates p53, a well-known tumor suppressor. Interestingly, half of all brain tumors have lost at least 1 copy of this gene — a deficit that usually indicates poor prognosis. The fourth-ranked SNP (P = 2.52 × 10−12) was located in RTEL1, a gene on chromosome 20 that normally functions to stabilize the genome. The fifth strongest signal (P = 1.07 × 10−8) was demonstrated for a SNP in PHLDB1 — a gene previously implicated in neuroblastoma, but not in glioma.
The only interactive effects detected in the study were between SNPs in CDCC26, and analysis of other pairs showed that their effects on glioma were independent. As rank-ordered here by their strength of association with glioma, the 5 genes increased the risk for glioma by 36%, 27%, 24%, 28%, and 18%, respectively.
Because their effects are largely independent, the variants' contributions to glioma risk are additive: "Individuals with eight or more risk alleles have an approximately fourfold increase in glioma risk compared to those with a median number of risk alleles," the report stated. However, this may be a low estimate because the model weighted the SNPs equally, which is unlikely in reality.
At present, the authors caution against using the results of their study for individual screenings. Not only is more research needed on the function of the individual genes, but factors such as demographics, environmental factors, and lifestyle should be included when identifying at-risk individuals.
The investigators will begin an even more comprehensive study next year, enrolling 6000 patients with glioma and 6000 control individuals. "We will be able to look at all of the potential risk and protective factors we've identified in much smaller studies over the years," said Dr. Bondy, "such as exposure to ionizing radiation, allergies, infections, and use of nonsteroidal anti-inflammatory drugs."
Dr. Bondy is also optimistic about the future: "Our findings give reasons for hope for those who might be affected and an incentive for a more comprehensive investigation of what has been a mysterious disorder."
Nat Genet. Published online July 5, 2009.
RF IMPROVES PFS IN COLORECTAL CANCER PATIENTS
Radiofrequency ablation with chemotherapy is safe and improves progression free survival in patients with unresectable colorectal cancer liver metastases
03.07.09
Category: Scientific News
Highlights of the ESMO Conference: 11th World Gastrointestinal Cancer Congress
The addition of radiofrequency ablation (RFA) to chemotherapy prolongs progression-free survival (PFS) and decreases local disease recurrence according to study results presented by Theo J. Ruers MD, of the Netherlands Cancer Institute in Amsterdam, The Netherlands, who headed an European Organization for Research and Treatment of Cancer (EORTC) study team that demonstrated the benefit of adding to chemotherapy in patients with unresectable colorectal cancer (CRC) liver metastases. Unresectable tumors were defined as those having no surrounding disease-free margin.
The primary endpoint was overall survival (OS) at 30 months and secondary endpoints included safety, OS and PFS.
Patients (n=119) with CRC liver metastasis and a maximum of 9 lesions and without extrahepatic disease were randomized to receive 6 months of FOLFOX plus, since October 2005, bevacizumab (n=59) or RFA plus the same chemotherapy regimen (n=60).
Baseline characteristics of the patients were similar in both groups; 60% of the patients had 4 liver metastases. In the RFA+chemotherapy arm, 30 patients (52.6%) received only RFA and in 27 patients (47.4%) RFA was combined with resection. Chemotherapy was administered to 51 patients (85%) in the RFA+chemotherapy arm. All 59 patients in the chemotherapy arm received a median number of 10 cycles of FOLFOX. The authors clarified that patients could be considered unresectable after undergoing surgical resection when there were remaining tumors that were unresectable.
The chemotherapy toxicity profiles were comparable between both arms and consistent with that seen in previous trials. Post-operative complications were observed in 10 patients who received RFA (33%) and in 9 patients (33%) who underwent RFA plus resection. Complications observed in patients were cardiac arrest (3) hemorrhage (2) and infection (6); 3 patients required re-operation. One patient died after surgery
At one year the PFS in the chemotherapy group was 39.35% compared to 60.06% in the RFA+chemotherapy arm (P=0.0267). At the interim analysis, the median PFS duration was 10 moths and 16.8 months in the chemotherapy and RFA+chemotherapy arms, respectively. Five patients had local recurrence at the RFA site and 10% of the tumors converted to being resectable. The 30 month time point has not yet been reached and the final analysis will be completed at that time.
The investigators concluded that this study demonstrates that a regimen of RFA combined with chemotherapy is safe, improves PFS and has a superior clinical benefit over FOLFOX treatment in patients with unresectable CRC liver metastases.
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