BENDAMUSTINE FOR CLL

NEW YORK (Reuters Health) Aug 11 - As first-line therapy for advanced chronic lymphocytic leukemia (CLL), bendamustine produced significantly higher response rates and longer progression-free survival than chlorambucil in a phase III clinical trial.

Bendamustine also evoked a "manageable toxicity profile," Dr. Wolfgang U. Knauf of the Frankfurter Diakonie Klinken and co-investigators report in the August 3rd online issue of the Journal of Clinical Oncology.

"Bendamustine is a novel agent, synthesized with the intent of combining the alkylating properties of mechlorethamine and the purine antimetabolite properties of benzimidazole," the European research team explains. Based on promising phase I/II trial results, they conducted a randomized, open-label study comparing the two drugs.

The study population included 319 previously untreated patients (mean age 63 years) with advanced (Binet stage B or C) stage disease, 162 randomly assigned to bendamustine and 157 to chlorambucil. The safety population comprised 312 treated patients: 1 in the bendamustine group and 6 in the chlorambucil group did not receive treatment. Median observation time was 35 months (range, 1 to 68).

Bendamustine 100 mg/m�/d was administered intravenously on days 1 and 2, whereas chlorambucil 0.8 mg/kg was given orally on days 1 and 15 (or broken into smaller doses on days 1 and 2 and on days 15 and 16.) Treatment cycles were repeated every 4 weeks for a maximum of 6 cycles.

Overall, 68% of the bendamustine group and 31% of the chlorambucil group achieved a complete or partial response. Median progression-free survival was 21.6 months and 8.3 months, respectively (p <>

More time under observation will be required to determine differences in overall survival, the authors note.

Hematologic grade 3 to 4 adverse events occurred more often in the bendamustine group (40% vs 19% in the chlorambucil group). The corresponding incidence of grade 3 to 4 severe infections were 8% vs 3%.

Two cases of tumor lysis syndrome occurred during the first cycle of treatment with bendamustine. The patients recovered and continued treatment. However, the authors emphasize that this condition is potentially fatal, and advise that, at least in patients with a high tumor burden, that prophylactic therapy against hyperuricemia be administered, and that adequate fluid intake be provided.

Dr. Knauf and his associates point out that, based on these data, the US Food and Drug Administration approved bendamustine in March 2008 for the treatment of chronic lymphocytic leukemia.

J Clin Oncol 2009;27.

PET TESTING REDUCES FUTILE RESECTIONS FOR COLORECTAL LIVER METASTASES

NEW YORK (Reuters Health) Aug 17 - Use of 18F-FDG PET imaging can reduce the rate of futile laparotomies in patients with colorectal liver metastases from 45% to 28%, according to a report in the July issue of The Journal of Nuclear Medicine.

"This is the first and only randomized controlled clinical trial on the efficacy of FDG-PET to select patients with liver metastases from colorectal cancer for liver surgery," senior author Dr. Wim J. G. Oyen, from Radboud University Nijmegen Medical Centre, the Netherlands, told Reuters Health.

"The biggest finding," Dr. Oyen added, "is that FDG-PET detects additional disease that deems liver surgery futile in 1 in 6 patients, who would have been taken to surgery when CT alone was used. Furthermore, the addition of FDG-PET in every patient did not result in an increase of overall health care costs."

The results stem from a study of 150 patients with colorectal liver metastases who were randomly assigned to preoperative evaluation with CT alone or combined with FDG-PET. The subjects were followed for at least 3 years after randomization.

Futile laparotomy, the main outcome measure, was defined as a laparotomy that did not lead to complete tumor removal, showed benign disease, or that did not improve disease-free survival by longer than 6 months.

Thirty-four patients (45%) in the control group had a futile laparotomy compared with 21 (28%) in the PET group, a risk reduction of 38% (p = 0.042).

"Every patient with liver metastases from colorectal cancer to whom liver surgery is offered, should ask for FDG-PET before the final decision to actually go ahead with liver surgery is made," Dr. Oyen emphasized.

"Future research will focus on the role of neoadjuvant chemotherapy and the role of novel surgical procedures such as radiofrequency ablation of tumors," he added.

J Nucl Med 2009;50:1036-1041.

NSCLC AND GEFITINIB

The study, headed by Rafael Rosell, MD, from the Catalan Institute of Oncology in Badalona, Spain, was published online August 19 in the New England Journal of Medicine.

Erlotinib is already indicated for use in NSCLC in patients who have failed at least 1 chemotherapy regimen, but as a second-line treatment. This new study suggests using it as first-line therapy in patients with EGRF mutations (who made up 16% of the Spanish study population).

However, an accompanying editorial points out that the study was not randomized, and the outcomes for patients with EGRF mutations who were treated with erlotinib were compared with outcomes for historic controls.

Another study, also published online August 19 in the New England Journal of Medicine, was randomized; it showed that patients with EGRF mutations responded better to a targeted agent, gefitinib (Iressa, AstraZeneca), than to chemotherapy. Headed by Tony Mok, MD, from the Chinese University of Hong Kong, this study concluded that in the largely female nonsmoking Asian population that was studied, gefitinib was superior to chemotherapy as a first-line treatment, and that the benefit was greatest in patients with EGRF mutations (who made up 59.7% of the study population).

Erlotinib and gefitinib are both tyrosine kinase inhibitors, targeted agents that have milder adverse effects than chemotherapy and have the advantage of oral administration.

Both of the studies showed that NSCLC patients with EGRF mutations had an increase in the response rate and improved progression-free survival when treated with the targeted agent instead of chemotherapy. The nonrandomized Spanish trial showed an improvement in overall survival, but the randomized Asian trial did not.

These results leave several questions unanswered, according to Adi Gazdar, MD, from the University of Texas Southwestern Medical Center in Dallas, who wrote an accompanying editorial. It is unclear whether the results from Asian and Western populations can be extrapolated to one another, and whether erlotinib and gefitinib can be substituted for one another.

In addition, the relation between EGRF mutations and responsiveness to tyrosine kinase inhibitors (which include erlotinib and gefitinib) is complex, he writes. There are several different EGFR mutations, and 1 is involved in secondary resistance to these agents. "Almost all NSCLCs that respond initially to tyrosine inhibitors eventually relapse and resist further treatment," he notes.

Nevertheless, these 2 studies and others suggest that carefully selected subgroups of patients with NSCLC should be considered for first-line treatment with tyrosine inhibitors instead of chemotherapy, Dr. Gazdar notes.

Preliminary results from both of these studies were presented last year at the European Society for Medical Oncology meeting, and were reported at that time by Medscape Oncology. Experts at the meeting welcomed the results for erlotinib and gefitinib, but emphasized the need for further study.

Large-Scale Screening Feasible

In the Spanish study, Dr. Rosell and colleagues screened lung cancer tissue from 2105 NSCLC patients in 129 institutions over the course of 3 years, and found 350 patients (16.6%) with EGFR mutations. These patients had stage IIIB disease with pleural effusions or stage IV disease.

EGFR mutations were significantly more frequent in women (representing 69% of the subgroup with mutations), in patients who had never smoked (66.5%), and in those with adenocarcinomas (80.9%) (P < .001 for all comparisons).

Patients with EGFR mutations were eligible for erlotinib (150 mg daily) but, for various reasons, not all of them received it, the researchers explain. In total, 217 patients received erlotinib and 197 could be evaluated for a response.

These 197 patients had a median progression-free survival of 14 months and a median overall survival of 27 months. In addition, 70% showed a complete or partial response to the drug.

Both of these are an improvement on what is usually seen with lung cancer, the researchers state, and they cite historic control data that suggest that this improvement is more than double. In NSCLC patients without the EGFR mutation, chemotherapy normally yields progression-free survival of 5 months, overall survival of 12 months, and a response rate of about 30%, they note.

"These results highlight the idea that EGRF-mutant lung cancer is a distinct class of nonsmall-cell lung cancer," Dr. Rosell and colleagues write.

They conclude that screening for EGFR mutations is warranted in women with lung cancer, in those who have never smoked, and in those with nonsquamous tumors. Large-scale screening is "feasible and improves outcomes," they add.

Results Cannot Be Taken Out of Context

The Asian study by Dr. Mok and colleagues, known as IPASS (Iressa Pan-Asian Study), involved 1217 previously untreated patients with advanced pulmonary adenocarcinoma who had never smoked or who had been only light smokers (≤10 pack-years of smoking and no smoking for at least 15 years). They were randomized to receive gefitinib (250 mg daily) or a standard first-line chemotherapy doublet (carboplatin and paclitaxel).

Gefitinib was superior to chemotherapy as an initial treatment in this patient population, the researchers report. The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with chemotherapy.

About half of the trial participants provided tissue samples, and EGFR mutation data could be evaluated in 437 patients (35.9%). Of these, 261 (59.7%) were positive for EGFR mutations.

This subgroup of 261 patients who were positive for EGFR mutations showed a "remarkably high" response rate (71.2%) and prolonged progression-free survival with gefitinib, the researchers note. In contrast, patients without the EGRF mutation showed a poor response rate to gefitinib (1.1%), and progression-free survival favored chemotherapy.

"Our trial confirms the predictive value of EGFR mutations for the responsiveness of pulmonary adenocarcinoma to gefitinib as compared with carboplatin–paclitaxel," Dr. Mok and colleagues explain. "Patients in whom an EGFR mutation has been identified will benefit most from first-line therapy with gefitinib," they add.

Dr. Mok presented details of these EGRF mutation results recently at the 13th World Conference on Lung Cancer (WCLC), as reported by Medscape Oncology. At the time, David Gandara, MD, WCLC program chair and professor of medicine at the University of California-Davis, said: "This is an extraordinarily helpful trial because we can now learn more about lung cancer biology. But at the same time, it can't be taken out of context. The trial was done in Asia, entirely in those with adenocarcinoma, 94% of whom were never smokers and 80% of whom were female."

"This is not a typical lung cancer population — especially in the United States," he added. Only 15% of American lung cancer patients have an EGFR mutation, "and gefitinib has a restricted indication for use only in patients who have previously benefited from the drug, he noted. Whether it should be used here in advanced lung cancer patients with EGFR mutations is controversial, Dr. Gandara noted.

The Asian IPASS study was supported by AstraZeneca. Dr. Mok reports receiving consulting fees from Roche, AstraZeneca, Pfizer, and Eli Lilly; lecture fees from Roche, AstraZeneca, and Eli Lilly; and a research grant from AstraZeneca Hong Kong. Some of his coauthors declare relevant financial relationships and some are employees of AstraZeneca, as detailed in the paper. Dr. Rosell and coauthors have disclosed no relevant financial relationships. Editorialist Dr. Gazdar reports receiving consulting fees from AstraZeneca.

N Engl J Med. Published online before print August 19, 2009

LIMB SPARING AND AMBUTATION FOR SARCOMA PATIENTS

August 12, 2009 — Limb-sparing surgery is not necessarily the best option for patients with bone and soft-tissue sarcomas. In fact, say researchers, even though it appears that amputations are now less common, it cannot be assumed that limb-sparing surgery will offer a better functional outcome or higher quality of life for young people with this type of cancer.

A new analysis, published online August 10 in Cancer, recommends that patients and physicians carefully consider the pros and cons of limb-sparing surgery and amputation. The rates of survival and local disease recurrence are similar, but limb-sparing surgery is associated with a higher rate of complications, which could lead to a poorer quality of life, say the researchers.

"The overall marginal difference in functional outcomes and health-related quality of life [HRQoL] between amputees and those who had undergone limb-salvage procedures, as assessed by the patients, was something of a surprise," study coauthor Ronald D. Barr, MB, ChB, MD, professor of pathology, pediatrics, and medicine at McMaster University in Hamilton, Ontario, told Medscape Oncology.

In recent years, the improved survival in patients with bone and soft-tissue sarcomas has put more of a focus on quality-of-life issues and patient-reported outcomes. Also, these tumors primarily afflict adolescents and young adults, who have potentially lengthy life expectancies, the researchers note.

"The literature attests to the ever-smaller number of amputations being performed and the apparent advantages of limb salvage as assessed by the surgeons," Dr. Barr explained. But this simply emphasizes the need for patient-related outcomes, as promulgated by the Institute of Medicine in the United States.

Studies should include measurement of function and HRQoL, and should stratify patients by age, so that the results will be useful in the decision-making process faced by clinicians and patients.

But for now, "clinicians need to customize the intervention to the needs of the individual," Dr. Barr said.

"Clinicians need to provide patients with all necessary information to allow them to make the best decision for themselves," he continued. They also need to "recognize that this is an evolving story, thanks to the capability of the orthopedic surgical oncologists and the imagination and expertise of the bioengineers who work on these challenges."

Challenges and No Consensus

Dr. Barr and coauthor Jay S. Wunder, MD, MSc, from Mount Sinai Hospital and the University of Toronto, in Ontario, conducted a literature review of all published papers on limb-sparing surgery that also measured patients' functional health and quality of life.

They acknowledged that there were a number of challenges facing this type of assessment, one being the relatively small number of cases. Even though bone and soft-tissue sarcomas are relatively common in the adolescent and young adult age group, they still represent only a small fraction of the total cancer burden. Therefore, sample sizes present a major limitation to outcomes research in this population.

Another challenge is the numerous confounders that need to be addressed when attempting to measure HRQoL. These include age (particularly pre- vs postpuberty), sex (women often report poorer quality of life), tumor characteristics, type of pre- and postsurgical treatment, time elapsed since surgery (related to functional adaptation), and when the study was conducted.

Unfortunately, there were no studies of sufficient size and design that addressed all of the confounding variables and "perhaps there never will be," the researchers write. But even though the quality of the evidence is necessarily imperfect, they note that "some fairly clear messages are apparent."

For instance, there appears to be general agreement that limb-sparing techniques are the preferred approach for patients with upper-extremity tumors, but the evidence is less defined for the lower limb, which is a far more common disease site.

Overall, many of the studies found that the differences in disability between patients who underwent amputation and those who underwent limb-sparing surgery were smaller than expected, and did not show significant differences in psychological health or quality of life. The researchers found no consensus on the preferred approach, although there did appear to be greater advantages to limb-sparing surgery than to amputation for higher surgical sites in the lower limb.

Quality of life was also assessed using multiple survey tools, making it even more difficult to evaluate the data. For example, the instrument most commonly used to assess functional outcome is the one developed by the Musculoskeletal Tumor Society (MSTS). However, since it relies on the subjective ratings of clinicians, its validity has been called into question, the researchers point out. In one study, members of the MSTS used the tool to assess function and HRQoL measures in 29 cancer survivors. Their results showed that although functional outcomes were better after limb-sparing surgery than after above-knee amputation or hip disarticulation, psychosocial outcomes were no different.

Another study from the Childhood Cancer Survivor Study, a cohort of about 15,000 individuals diagnosed with cancer as children and adolescents from 1970 to 1986, used the Toronto Extremity Salvage Score (TESS). In contrast to MSTS, TESS is an instrument for functional self-assessment, measuring physical disability and activity limitations. No difference was seen in TESS scores between amputees and individuals who had undergone limb-sparing surgery, and there was good correlation between TESS scores and HRQoL.

In addition, some studies highlighted the discordance between scores from the various assessment tools. Two recent studies found that patients undergoing limb-sparing surgery had better functional outcomes on MSTS, but there were no statistical differences in TESS or Short Form (SF)-36 (a tool used to assess health outcomes and quality of life) scores. A third study reported no difference in MSTS, TESS, or SF-36 scores between the 2 patient groups, but those with amputations had lower scores on objective functional outcome using another survey, the Functional Mobility Assessment tool.

The authors also noted that studies from a single institution raise issues of "referral and patient bias." In one such study, a higher proportion of limb-sparing patients than amputees were pleased with their outcomes. However, some patients were reportedly "concerned about the surgeon's investment in the limb and did not want to disappoint him."

Economic Evaluation

Several papers included in the analysis evaluated cost-effectiveness, comparing amputation with limb salvage. The up-front expenses for surgical cost, duration of rehabilitation, and the need for revisions are all more extensive for limb-sparing surgery, whereas long-term costs are greater for amputation. These expenses include artificial limb manufacture, maintenance, and replacement.

The economic evaluation of surgical options for young patients with tumors in the lower extremities "is likely to reveal a tradeoff between the up-front costs of limb-sparing surgery and the maintenance costs associated with amputation," the authors write.

Old Study Has "Never Been Bettered"

The first report that addressed quality of life in patients with extremity sarcoma was published in 1982, and it has "never been bettered with respect to study design," Drs. Barr and Wunder note. In the study, sponsored by the National Cancer Institute, 21 patients younger than 21 years with nonmetastatic nonrhabdomyosarcoma soft-tissue sarcomas of the lower limb were randomized to amputation plus chemotherapy or to limb-sparing surgery plus chemoradiotherapy (Surgery. 1982;91:17-23).

Using the Sickness Impact Profile, a well-validated measure of HRQoL, the amputees self-reported better emotional behavior, body care and movement, and sexual functioning than the patients who had undergone limb-sparing surgery. The assessment was conducted 1 to 3 years after surgery. The trial researchers stated that there were no differences in the costs incurred in the 2 study groups.

The authors of the latest review wonder if a study of "such admirable rigor" could be repeated today, and add: "therein lies the 'call to arms' — or at least legs.''

The researchers have disclosed no relevant financial relationships.

Cancer. Published online before print August 10, 2009.

BREASTFEEDING AND BREAST CANCER RISK

August 13, 2009 — Women with a family history of breast cancer who have ever breastfed reduce their risk of getting premenopausal breast cancer by nearly 60%, according to a new study.

''For women with a family history of breast cancer, this suggests an extra benefit [of breastfeeding] is, it may reduce the risk of breast cancer," says Alison Stuebe, MD, an assistant professor of obstetrics and gynecology at the University of North Carolina at Chapel Hill, the lead author of the study. It is published in the Archives of Internal Medicine.

While previous studies have also suggested a link between breastfeeding and reduced breast cancer risk, results have been mixed, Stuebe writes. Studies in which women who already have breast cancer are asked about their breastfeeding history can be flawed by "recall bias," she says.

''Our goal was to collect information before the diagnosis and follow women," Stuebe tells WebMD.

Stuebe and her colleagues drew information from 60,075 women who were participants in the Nurses' Health Study II from 1997 to 2005 and had given birth.

The women answered questions about demographics, body measurements, and lifestyle factors every two years, and described their breastfeeding practices. They were asked about family history of breast cancer and if they had been diagnosed with invasive breast cancer.

By the end of the follow-up in June 2005, Stuebe's team found 608 cases of premenopausal invasive breast cancer, with 99% of the cases verified by medical records. The woman's average age at diagnosis was 46.

''Overall, in the whole group of women we studied, women who had breastfed were 25% less likely to develop premenopausal breast cancer than women who had never breastfed," says Stuebe, who conducted the research while at Brigham and Women's Hospital and Harvard Medical School in Boston.

Family History of Breast Cancer

When the researchers looked separately at the women without a family history and those with a family history of breast cancer (mother, sister, or grandmother), they found ''almost the entire effect could be accounted for by women with a family history," she tells WebMD.

Among those with a family history, those who had breastfed had a 59% reduced risk for premenopausal breast cancer compared to those who never breastfed. The breastfeeding did not have to be exclusive breastfeeding, without formula use.

To understand better the difference between the overall risk reduction and the reduction in those with a family history, Stuebe offers this analogy: Suppose the Los Angeles Lakers and a group of 5-year-olds had a free-throw contest. Overall, the group may have made, say, 60% of the free throws. But when you look separately at the successful free throws made by the basketball stars vs. those made by the kids, the results will undoubtedly be driven entirely by the Lakers.

The risk reduction for women with a family history of breast cancer who breastfeed, Stuebe says, is comparable to that found in high-risk women who take hormonal treatments such as tamoxifen.

''For women without a family history," she tells WebMD, ''it may be that their rates of breast cancer are so low we don't detect a difference or there may not be a protective association."

The protective effect began with three months of breastfeeding, she tells WebMD. That's three months total, she says, not just for a single child. So a mother may have breastfed two children for a month and a half each and gotten the benefit, for instance.

Second Opinion

''It is a huge reduction in risk," says Amanda Phipps, a pre-doctoral research associate at the Fred Hutchinson Cancer Research Center in Seattle, of the nearly 60% decreased risk in women who breastfeed and have a family history of breast cancer.

''I find it very interesting," says Phipps, who has researched the link, too. "But I think because it is a rather novel finding it would need to be replicated in the literature."

In a study published in Cancer last year, Phipps and her colleagues found that certain breast cancer types may be rarer among women who breastfeed their babies for at least six months.

The biology to explain the link is not yet clear, Phipps says.

Even so, she calls the association "exciting" because breastfeeding is an action women can take to reduce their breast cancer risk, while many other risk factors -- such as having a family history -- are not modifiable.

GEFITINIB FOR NSCLC

August 20, 2009 (San Francisco, California) — Two large studies on the oral agent gefitinib (Iressa, AstraZeneca) affirm its use as a treatment in select lung cancer patients with mutations of epidermal growth-factor receptor (EGFR) — particularly female Asian patients with advanced nonsmall-cell lung (NSCLC) adenocarcinoma who have never smoked or who have smoked very little. The findings were presented here at the 13th World Conference on Lung Cancer (WCLC), organized by the International Association for the Study of Lung Cancer. But whether or not the results of these studies will have an impact on lung cancer patients in the United States is open to debate, say experts.

Results from 1 of the studies, the Iressa Pan-Asia Study (IPASS), conducted in 87 centers in Asia, were announced in late 2008 at the European Society for Medical Oncology Congress, as reported by Medscape Oncology. The IPASS randomized phase 3 trial involved 1217 patients with advanced NSCLC with adenocarcinoma histology who had never smoked or who had smoked very little. In these chemotherapy-naïve patients, gefitinib was compared with the standard regimen of carboplatin and paclitaxel. Although overall survival did not differ between the 2 groups, progression-free survival at 1 year was superior in the gefitinib group (25% vs 7%; hazard ratio [HR], 0.74; P < .0001).

Importance of EGFR Mutation

The IPAAS study also found that patients with the EGFR mutation fared better with gefitinib than those without (overall response rate, 71.2% vs 1.1%). In new results announced at the WCLC meeting, researchers took their analysis a step further and looked at response rates in those with different types of EGFR mutations — exon 19 deletions, exon 21 L858R deletions, and exon 20 T790M deletions.

"We've demonstrated previously that the presence of the EGFR mutation is vital for the success of the drug," said Tony Mok, MD, lead author and professor of clinical oncology at the Chinese University of Hong Kong. "Targeted therapy is much better than chemotherapy as long as there is a target. Now we have details on the target," he added.

Information on EGFR status was available for about a third of the trial participants (n = 437), and among those, a high percentage — 60% — were EGFR positive. Further analysis of those receiving gefitinib revealed that those with an exon 19 deletion fared better than those with an exon 21 deletion. In patients with an exon 19 deletion, progression-free survival HR was 0.38 (gefitinib:carboplatin plus paclitaxel), but in those with an exon 21 deletion, it was 0.55. Also, patients receiving gefitinib with an exon 19 deletion had a better overall response rate (85% vs 43.2%) than those receiving chemotherapy. "That's the highest response rate ever documented with gefitinib," Dr. Mok noted.

In patients with an exon 21 deletion, the overall response rate was 60.9% in the gefitinib group and 53.2% in the chemotherapy group.

"Overall, there's a benefit for gefitinib with both exon 19 and 21 [deletions], but there's a greater benefit with the exon 19 deletion," Dr. Mok said. Also, the researchers reported that 3 of 5 patients with an exon 20 T790M deletion experienced partial responses to gefitinib. It was previously reported that this mutation is resistant to EGFR tyrosine kinase inhibitors.

"This is an extraordinarily helpful trial because we can now learn more about lung cancer biology. But at the same time, it can't be taken out of context. The trial was done in Asia, entirely in those with adenocarcinoma, 94% of whom were never smokers and 80% of whom were female," noted David Gandara, MD, WCLC program chair and professor of medicine at the University of California-Davis, in an interview with Medscape Oncology. "This is not a typical lung cancer population — especially in the United States." Dr. Gandara noted that that only 15% of American lung cancer patients have an EGFR mutation, and the results of the IPASS trial should be interpreted with caution in the United States.

Gefitinib is currently approved in the United States only for those who have previously benefited from the drug, and whether it should be used here in advanced lung cancer patients with EGFR mutations is controversial, Dr. Gandara said. The drug is licensed for use elsewhere, such as in China, Japan, and the European Union.

Second Trial is Complementary

In another phase 3 randomized clinical trial reported here at the WCLC meeting, the First-SIGNAL study, oral gefitinib failed to show a benefit in terms of overall survival, although it improved progression-free survival. This Korean trial involved 313 NSCLC patients with adenocarcinoma who had never smoked and who had stage IIIB or IV lung cancer; nearly 89% of the patients were female. Patients were randomized to gefitinib or standard chemotherapy with gemcitabine and cisplatin.

Overall survival was similar in both groups, although progression-free survival at 1 year was superior in the gefitinib group than in the chemotherapy group (20.3% vs 5.0%). The objective response rate was also significantly better in the gefitinib group (53.5% vs 45.3%; odds ratio, 1.385; P = .1533). Patients in the gefitinib group showed improved quality of life compared with those in the chemotherapy group, although there were 2 grade 5 interstitial lung disease events in the gefitinib group.

In nearly a third of the patients in this trial, EGFR mutation status was known (n = 96), and the subgroup of patients who were EGFR positive did dramatically better when treated with gefitinib than those who were negative for the mutation. Overall survival was 30.6 months in EGFR-positive patients and 18.4 months in EGFR-negative patients (HR, 0.845; P = .643), and median progression-free survival was 8.4 months and 2.1 months, respectively (HR, 0.394; P = .0006). Overall response rate was also dramatically better among EGFR-positive than among EGFR-negative patients (84.6% vs 25.9%).

"EGFR mutation status is a strong predictive marker for overall response and progression-free survival. Because of its high overall response rate and better toxicity, gefitinib is a good therapy for these Asian nonsmokers," said lead researcher Jin S. Lee, MD, from the National Cancer Center Korea in Goyang.

The First-SIGNAL trial is complementary and very similar to IPASS, Dr. Gandara remarked. "It's valuable in that it gives us more assurance that the results of IPASS are reproducible," he said.

Need to Consider Molecular Markers

"Both these trials point out that we need to be looking at molecular markers in lung cancer patients, rather than just clinical parameters," said Heather Wakelee, MD, assistant professor of medicine and codirector of the Thoracic Oncology Program at Stanford University in California, and a member of the organizing committee for the WCLC, in an interview with Medscape Oncology. "Hopefully, in 5 years, we'll be able to test every patient for their mutation status and pick the best treatment based on those results," she said.

She noted that even in these 2 trials where the patient populations were very similar — most patients were Asian, female, never smokers with adenocarcinoma — there were clear differences in treatment response based on the presence and type of EGFR mutation. "Molecular analysis is clearly the future of lung cancer treatment," she said.

The IPASS study and First-SIGNAL studies were sponsored by AstraZeneca. Dr. Gandara is a consultant for Response Genetics, Sanofi-Aventis, Bayer, AstraZeneca, Lilly Oncology, Amgen, Genentech, Bristol-Myers Squibb, and Pfizer; and has received research support from Lilly, Bristol-Myers Squibb, Genentech, Pfizer, and Abbott Oncology. Dr. Mok is a consultant to Roche, AstraZeneca, Merck Serono, Eisai, and Pfizer. Dr. Lee and Dr. Wakelee have disclosed no relevant financial relationships.

13th World Conference on Lung Cancer: Abstracts PRS.4 and B9.5. Presented August 1 and 3, 2009

R-FCM REGIMEN FOR CLL

J Clin Oncol. 2009 Aug 24. [Epub ahead of print]

Related Articles, LinkOut

Rituximab, Fludarabine, Cyclophosphamide, and Mitoxantrone a New, Highly Active Chemoimmunotherapy Regimen for Chronic Lymphocytic Leukemia.

Bosch F, Abrisqueta P, Villamor N, Terol MJ, González-Barca E, Ferra C, Diaz MG, Abella E, Delgado J, Carbonell F, García Marco JA, Escoda L, Ferrer S, Monzó E, González Y, Estany C, Jarque I, Salamero O, Muntañola A, Montserrat E.

Department of Hematology, Hospital Clínic, Institut de Investigacions Biomèdiques "August Pi i Sunyer"; Department of Hematopathology, Hospital Clinic; Hospital "Duran y Reynals," L'Hospitalet; Hospital del Mar; Hospital de Sant Pau, Barcelona; Departments of Hematology, Hospital Clínic; Hospital General Universitario; Hospital Dr Peset; Hospital "Arnau de Vilanova"; Hospital "La Fe," Valencia; Hospital "Germans Trias y Pujol," Badalona; Hospital Clínico Universitario, Salamanca; Hospital Universitario Puerta de Hierro, Madrid; Hospital Joan XXIII, Tarragona; Hospital "Josep Trueta," Girona; and Hospital Mutua de Terrassa, Terrassa, Spain.

PURPOSE: The addition of monoclonal antibodies to chemotherapy has significantly improved treatment of chronic lymphocytic leukemia (CLL). Based on excellent results with the chemotherapy-only regimen fludarabine, cyclophosphamide, and mitoxantrone (FCM), we built a new chemoimmunotherapy combination-rituximab plus FCM (R-FCM). We report a phase II clinical trial consisting of an initial treatment with R-FCM followed by rituximab maintenance. PATIENTS AND METHODS: Seventy-two untreated CLL patients age 70 years or younger received rituximab 500 mg/m(2) on day 1 (375 mg/m(2) the first cycle), fludarabine 25 mg/m(2) IV on days 1 to 3, cyclophosphamide 200 mg/m(2) on days 1 to 3, and mitoxantrone 6 mg/m(2) IV on day 1, given at 4-week intervals with up to six cycles supported with colony-stimulating factor. Patients achieving response received maintenance with rituximab 375 mg/m(2) every 3 months for 2 years. RESULTS: The overall response, minimal residual disease (MRD) -negative complete response (CR), MRD-positive CR, and partial response rates were 93%, 46%, 36%, and 11%, respectively. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Advanced clinical stage, del(17p), or increased serum beta2-microglobulin levels correlated with a lower CR rate. CONCLUSION: R-FCM is highly effective in previously untreated CLL, with an 82% CR rate and a high proportion of MRD-negative CRs (46%). Treatment toxicity is acceptable. Parameters correlating with a lower response rate were advanced clinical stage, high serum beta2-microglobulin levels, and del(17p). Based on these results, R-FCM warrants further investigation in randomized clinical trials.

PERFORMANCE STATUS 2 NSCLC

J Clin Oncol. 2009 Aug 24. [Epub ahead of print]

Related Articles, LinkOut

Randomized Phase II Trial of Docetaxel Plus Cetuximab or Docetaxel Plus Bortezomib in Patients With Advanced Non-Small-Cell Lung Cancer and a Performance Status of 2: CALGB 30402.

Lilenbaum R, Wang X, Gu L, Kirshner J, Lerro K, Vokes E.

Mount Sinai Cancer Center, Miami Beach, FL; Duke University, Durham; Southeast Cancer Control Consortium, Winston-Salem, NC; Hematology-Oncology Associates of Central New York, Syracuse, NY; University of Chicago, Chicago, IL.

PURPOSE: A randomized phase II trial of two novel treatment strategies in the first-line management of advanced non-small-cell lung cancer patients with performance status (PS) 2. PATIENTS AND METHODS: Patients were assigned to docetaxel 30 mg/m(2) on days 1, 8, and 15 every 28 days in combination with either cetuximab 400 mg/m(2) loading dose followed by 250 mg/m(2) weekly (D + C) or bortezomib 1.6 mg/m(2) on days 1, 8, and 15 every 28 days (D + B) for up to 4 cycles. Patients with responding or stable disease continued cetuximab or bortezomib until progression. The primary end point was progression-free survival (PFS) rate at 6 months. RESULTS: Sixty-four patients were enrolled and 59 were included in this analysis. Complete or partial response rates were 13.3% and 10.3% for D + C and D + B, respectively. Median PFS was 3.4 months in the D + C arm and 1.9 months in the D + B arm. Corresponding figures for 6-month PFS were 27.8% and 13.8% and 5.0 and 3.9 months for median survival, respectively. Grade 3/4 hematologic toxicity was 16% for D + C and 21% for D + B, whereas nonhematologic toxicities were observed in 63% and 44% of patients, respectively. There was one treatment-related death in each arm. CONCLUSION: These results confirm the poor prognosis associated with a PS of 2 and the difficulty in translating recent advances in targeted therapy to this subset of patients. While the results in the D + C arm are numerically superior, neither combination met the prespecified PFS end point to justify further research in this setting.

PROSTATE CANCER SCREENING DEBATED AGAIN

September 1, 2009 — More than 1 million additional men have been diagnosed with and treated for prostate cancer since the introduction of prostate-specific antigen (PSA) screening in the 1980s. And the "vast majority of these additional 1 million men did not benefit from early detection," write the authors of a new study published online August 31 in the Journal of the National Cancer Institute.

"Prostate cancer screening has resulted in substantial overdiagnosis and in unnecessary treatment," Otis W. Brawley, MD, medical director of the American Cancer Society, writes in an editorial that accompanies the new study.

These new findings once again question the benefits of prostate cancer screening, says Dr. Brawley.

"'Does prostate cancer screening save lives?' is still a legitimate question," he states.

The new study examines national prostate cancer incidence and treatment data in the United States from 1986 — the year before prostate-antigen screening (PSA) was introduced — to 2005.

The study's conclusions stem from the idea that, for cancers detected early in a population, there should be a reduction in the number of cancers detected later in that same population.

In the United States, that offsetting reduction has not occurred in prostate cancer.

Instead, overall incidence rose rapidly after 1986, before peaking and declining in 1992 — but the decline was to levels "considerably higher than those in 1986," write the study authors, H. Gilbert Welch, MD, PhD, from Dartmouth Medical School in Hanover, New Hampshire, and Peter C. Albertsen, MD, from the University of Connecticut Health Center in Framingham.

The excess incidence — and thus overdiagnosis — has been worst in young men. The relative incidence rate (2005 relative to 1986) was 7.23 in men younger than 50 years. This rate is considerably higher than the relative incidence rates found in older men — 0.56 in men 80 years and older, 1.09 in men 70 to 79 years, 1.91 in men 60 to 69 years, and 3.64 in men 50 to 59 years.

Men Need to Be Informed

Drs. Welch and Albertsen believe that clinicians should "explicitly communicate," to men considering the screening, the relative magnitude of the number of deaths averted to the number overdiagnosed.

However, this is a difficult task, the authors admit. "Estimating the trade-off between a mortality benefit and an overdiagnosis is problematic when there is uncertainty about whether the benefit exists at all," they write.

The current study conservatively estimates that 1 death is averted for every 20 men overdiagnosed, say the authors. A recent European study suggests a 1 to 50 ratio, which is a "more plausible" estimate, write Drs. Welch and Albertsen, because it is from a randomized clinical trial (screened vs unscreened groups). "Given the European trial report that 1410 men need to be screened to avoid 1 death, this translates into a trade-off of approximately 1 death averted to 50 men overdiagnosed with prostate cancer," write the authors, referring to the study from the European Randomized Study of Screening for Prostate Cancer (New Engl J Med. 2009;360:1320-1328).

However, in a recent major American randomized cancer screening trial, prostate cancer screening did not provide a mortality benefit (New Engl J Med. 2009;360:1310-1319).

Thus, with the possibility that the true mortality benefit "approaches 0," the estimate of the ratio of deaths averted to men overdiagnosed "approaches 1 to infinity," write Drs. Welch and Albertsen

Findings Are Probably Underestimates

The investigators of the new study used data on age-specific incidence and initial course of therapy for prostate cancer from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. They then used age-specific male-population estimates from the US Census to determine the excess in the number of men diagnosed and treated in each year after 1986.

Since 1986, an estimated additional 1,305,600 men were diagnosed with prostate cancer; of that number, 1,004,800 were definitively treated for the disease, say the authors.

Excess incidence does not provide an exact figuring of overdiagnosis, admit the authors. However, in time, it is still a fairly good estimate, they suggest. "Although excess incidence is only a proxy for overdiagnosis — because some of the excess may simply reflect the lead time of diagnosis — the 2 measures become increasingly equivalent with the passage of time," they write.

During the entire study period of 1986 to 2005, prostate cancer incidence rose 26% (from 119 to 150.5 per 100 000), they observe.

To calculate how many men needed to be overdiagnosed to avert 1 death from prostate cancer, the authors used "the most optimistic assumption about the benefit" that was possible — "that the entire decline in prostate cancer mortality observed during this period is attributable to screening" (and none was related to improved therapies, techniques, clinician skill, and so on). Thus, they estimated "that approximately 56,500 prostate cancer deaths had been averted and that approximately 23 men had to be diagnosed and approximately 18 treated for each man experiencing the presumed benefit" — a death averted.

These numbers related to the benefit of screening are probably an underestimate because, in addition to the fact that they ignore progress made in prostate cancer treatment, they also ignore the fact that prostate cancer would have declined after 1986 if PSA had not been introduced.

How would prostate cancer incidence have declined?

The authors explain that prostate cancer was slowly increasing, at a rate of about 2% per year, in the decade before 1986. However, this increase was almost entirely due to cancers found incidentally when men were treated surgically (with transurethral resection) for benign prostatic hyperplasia. Half of all prostate cancer in 1986 was found during this surgery. When the surgery fell out of favor, the number of prostate cancers discovered this way dropped by 50% — a drop large enough to have caused an overall decline in prostate cancer incidence had PSA screening not arrived at the same time.

In short, because the investigators used 1986 as their base year, a year in which prostate cancer incidence numbers were inflated because of a specific surgery, their estimates of the effect of PSA screening represent underestimates, they say.

Whatever the exact numbers, many men have undergone unnecessary treatment and other difficulties, say Drs. Welch and Albertson. "All overdiagnosed patients are needlessly exposed to the hassle factors of obtaining treatment, the financial implications of the diagnosis, and the anxieties associated with becoming a cancer patient," they write

The researchers have disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online before print August 31, 2009.

STAGE I TRIPLE NEGATIVE BREAST CANCER

Breast J. 2009 Sep-Oct;15(5):454-60. Epub 2009 Aug 4.

Related Articles, LinkOut

Comment in:

• Breast J. 2009 Sep-Oct;15(5):451-3.

T1N0 triple negative breast cancer: risk of recurrence and adjuvant chemotherapy.

Kaplan HG, Malmgren JA, Atwood M.

Swedish Cancer Institute at Swedish Medical Center, Seattle, Washington 98104, USA. hank.kaplan@swedish.org

Adjuvant treatment of T1N0 breast cancer (BC) has evolved in recent years with chemotherapy options dependent on tumor size and cellular characteristics. Our goal is to describe the difference in outcome between T1N0 triple negative (TriNeg) and estrogen/progesterone receptor positive/her2/neu-negative BC. From our institute's registry, we identified primary BC patients diagnosed from 1998 to 2005, estrogen/progesterone receptor negative (ER-/PR-)/her-2/neu negative (her2-) (TriNeg = 110) and ER+/PR+/her2- (HR+/her2- = 919). Clinical diagnosis and treatment variables were chart abstracted. Vital and disease status were updated annually. Pearson chi-squared tests were used for bivariate analysis. Hazard ratios were calculated using the Cox proportional hazards model. Average patient age was 59 years, range 23-93 years and average length of follow-up was 4.22 years. T-stage distribution for HR+/her2- patients was 9% T1a (>0.1, < or =" 0.5">0.5 cm, < or =" 1">1 cm, < or =" 2" test =" 27.77," style="border-bottom: 1px dashed rgb(0, 102, 204); background: transparent none repeat scroll 0% 0%; cursor: pointer; -moz-background-clip: border; -moz-background-origin: padding; -moz-background-inline-policy: continuous;" class="yshortcuts" id="lw_1252532318_11">hazard ratio for recurrence in the TriNeg group was 6.57 (95% CI = 2.34, 18.49) adjusted for age, tumor size, and adjuvant chemotherapy. Triple negative T1N0 patients have greater recurrence risk in spite of more aggressive therapy by both number treated and adjuvant chemotherapy type even in a low-risk category. New treatment modalities specific for triple negative disease are urgently needed.

FALSE ALARM?

September 1, 2009 (Barcelona, Spain) — The proton-pump inhibitor (PPI) data from the large-scale TRITON-TIMI 38 trial, suggesting no effect of these agents on cardiovascular event rates in either the clopidogrel or prasugrel groups, has now been presented at the European Society of Cardiology (ESC) 2009 Congress and published online in the Lancet [1].

These data have been cited on several occasions in the controversy surrounding the issue of whether PPIs affect the action of clopidogrel, but this is the first time that they have been officially made available.

Also published in the same Lancet paper but not presented at the ESC meeting is an analysis of platelet aggregation in the much smaller PRINCIPLE-TIMI 44 study, showing that inhibition of platelet aggregation was modestly reduced with both clopidogrel and prasugrel in patients taking a PPI.

Lead author of the Lancet paper, Dr Michelle O'Donoghue (Brigham and Women’s Hospital, Boston, MA), told heartwire that the data from the TRITON trial were much more clinically relevant than the PRINCIPLE data, as the TRITON trial involved 13 600 patients and studied clinical events, while the PRINCIPLE study only involved 201 patients and focused on platelet aggregation as its primary end point.

She commented: "In TRITON-TIMI 38, we did not find use of a PPI to be associated with a higher risk of cardiovascular events for patients on either clopidogrel or prasugrel. This is in contrast to prior studies that have shown a higher risk of adverse events for patients on clopidogrel in combination with a PPI. This is also the first study to show that it appears to be safe to combine a PPI with prasugrel. However, as with prior studies, use of a PPI was not randomized in the current study. As such, these data can provide some early reassurance to clinicians that these two classes of drugs may in fact be safe to use in combination for patients who have a strong indication to be on both drugs. However, only a randomized trial of a PPI can provide definitive evidence regarding the safety of combining these two classes of drugs."

On the modest attenuation of the antiplatelet effects for both clopidogrel and prasugrel shown with PPIs in the PRINCIPLE study, O'Donoghue said: "This is consistent with findings from prior studies. The fact that this modest attenuation of the antiplatelet effects did not translate into a higher risk of clinical outcomes in TRITON highlights the fact that we should not rely solely on surrogate end points." She added: "Rather, these findings illustrate that there remains much to be understood about the exact nature of the relationship between platelet-function studies and clinical events. This is highly analogous to the situation that we observed a few years ago with atorvastatin, whereby atorvastatin appeared to modestly attenuate the antiplatelet effects of clopidogrel, but this was not associated with a higher risk of adverse outcomes."

O'Donoghue explained that the PRINCIPLE data were not presented at the ESC meeting because "it was required that we submit data from a single clinical trial. As well, our presentation was restricted to only 10 minutes." She added: "For these two reasons, we restricted our presentation to the results of the TRITON-TIMI 38 study. We believe, however, that the platelet-function studies provide additional intriguing mechanistic insight, so we included these data in the Lancet paper."

"Impressive" Data

Coauthor of an accompanying Comment article in the Lancet [2], Dr Dirk Sibbing (Deutsches Herzzentrum, Munich, Germany), who has conducted some of the platelet-function studies of PPIs and clopidogrel, told heartwire that he thought the TRITON data were "impressive."

"There have been lots of anxious discussions about an interaction, but I think these TRITON data have taken some of the hysterical reaction out of the matter," he commented.

He said that while the platelet aggregation data should not be ignored, it appears that PPIs have only a modest effect on platelet inhibition with the thienopyridines, and there would likely have to be a greater effect to have any influence on clinical events. He suggested a "two-hit" hypothesis. "I think you probably have to have another problem that can affect platelets in order for the PPI effect to matter. The average patient in TRITON did not have such problems, so I would say the TRITON data suggest that in a moderate-risk population it is safe to use PPIs with clopidogrel and prasugrel."

Sibbing added: "But clinicians should always err on the safe side, and I would still advise that doctors choose a PPI that has been associated with the least interactions with thienopyridines if coprescribing these drugs, ie, not omeprazole. And if a patient is at high risk of having intrinsic platelet problems, for example if they are diabetic, I would be more cautious."

Sibbing also suggested that the increase in cardiovascular events seen in some of the prior observational studies in patients taking PPIs with clopidogrel could have been due to compliance issues. "Patients taking PPIs are more likely to have symptoms of gastric pain and therefore may stop taking the thienopyridines for a few days. That might cause the event rather than the PPI itself. TRITON was a randomized trial that was closely monitored, so patients have to be more compliant, and therefore this effect would not have shown up as much in this setting."

"I would say these new TRITON data nicely demonstrate that moderate risk patients who are compliant with their thienopyridine therapy can safely be put on a PPI," he commented.

Sibbing noted that the PRINCIPLE data showing a small reduction in platelet inhibition with prasugrel as well as clopidogrel when given with PPIs was "interesting and surprising. . . . I believe this is the first time such an effect has been reported with prasugrel and shows that it is not just a clopidogrel issue, but prasugrel is a much more potent antiplatelet drug, and therefore this modest effect should not be a problem," he commented to heartwire .

TRITON Data

The current Lancet paper reports that of the 13 608 acute coronary syndrome (ACS) patients randomized to prasugrel or clopidogrel in TRITON TIMI 38, 4529 (33%) were on a PPI at randomization. O'Donoghue et al used a multivariable Cox model with propensity score to assess the association of PPI use with clinical outcomes. Results showed no association between PPI use and risk of the primary end point (a composite of cardiovascular death, myocardial infarction [MI], or stroke) for patients treated with either drug.

TRITON-TIMI 38: Rate of the Primary End Point as Related to PPI Use

Drug	PPI (%)	No PPI (%)	Unadjusted HR (95% CI)	p
Clopidogrel	11.8	12.2	0.98 (0.84–1.14)	0.80
Prasugrel	10.2	9.7	1.05 (0.89–1.23)	0.58

Patients who were treated with a PPI were significantly more likely to be older, female, and white; have an index diagnosis of unstable angina/non-ST-elevation MI; and live in North America or Western Europe than those not treated with a PPI. Patients treated with a PPI were also significantly more likely to have a history of peptic ulcer disease and have a lower baseline hemoglobin concentration at the time of randomization.

After adjustment for potential confounders and the propensity to treat with a PPI, the authors found no significant association remaining between use of a PPI and risk of the primary end point, both for patients treated with clopidogrel (HR 0.94; 95% CI 0.80–1.11; p=0.46) and for those treated with prasugrel (HR 1.00; 95% CI 0.84–1.20; p=0.97). Use of a PPI was also not associated with increased risk of MI, stent thrombosis, or a decreased risk of bleeding for patients treated with either clopidogrel or prasugrel.

Because PPIs could be started or discontinued at any time during follow-up, additional analyses were conducted to look at different time points and after varying durations of follow-up, and similar results were found. Another analysis showed no difference with different PPIs or other gastric antacid drugs, including H₂ receptor antagonists. Yet another analysis focused on patients with a single reduced-function CYP2C19 allele, and this also suggested no interaction between either clopidogrel or prasugrel and PPIs.

PRINCIPLE TIMI 44 Results

In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention (PCI) were randomized to prasugrel or clopidogrel 600-mg loading doses. In both arms, there was a modest reduction in inhibition of platelet aggregation in patients on a PPI compared with those not on a PPI.

PRINCIPLE-TIMI 44: Inhibition of Platelet Aggregation Related to PPI Use

Drug	PPI (%)	No PPI (%)	p
Clopidogrel	23.2	35.2	0.02
Prasugrel	69.6	76.7	0.054

BEVACIZUMAB AND CAMPTO FOR GBM

J Clin Oncol. 2009 Aug 31. [Epub ahead of print]

Related Articles, LinkOut

Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma.

Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T.

Brain Tumor Center, Duke University, Durham, NC; Department of Neurosurgery, University of California, San Francisco, San Francisco; Genetech Inc, South San Francisco; and Department of Neurology, University of California, Los Angeles School of Medicine, Los Angeles, CA; Department of Neurology, Brigham and Women's Hospital and Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA; Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI; Department of Neurology, University of Virginia, Charlottesville, VA; Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Neuro-Oncology, M. D. Anderson Cancer Center, Houston, TX; Division of Neurology, Evanston Northwestern Healthcare, Evanston, IL; Department of Neurology, University of Chicago, Chicago, IL; and University of Utah Hospital, Salt Lake City, UT.

PURPOSE: We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial. PATIENTS AND METHODS: One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m(2) or 125 mg/m(2) (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. RESULTS: In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade >/= 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively). CONCLUSION: Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.

ALIMTA CARBOPLATIN NOT GOOD ENOUGH FOR SCLC

J Clin Oncol. 2009 Aug 31. [Epub ahead of print]

Related Articles, LinkOut

Phase III Study of Pemetrexed Plus Carboplatin Compared With Etoposide Plus Carboplatin in Chemotherapy-Naive Patients With Extensive-Stage Small-Cell Lung Cancer.

Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, Blakely J, Serwatowski P, Karaseva NA, Ciuleanu T, Jassem J, Dediu M, Hong S, Visseren-Grul C, Hanauske AR, Obasaju CK, Guba SC, Thatcher N.

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; Vrije University Medical Center, Amsterdam; Eli Lilly Netherlands, Utrecht, the Netherlands; Christie Hospital, Manchester, United Kingdom; US Oncology, Houston, TX; Hospital Grosshansdorf, Grosshansdorf; Department of Medicine and Medical Oncology, St Georg Hospital, Hamburg, Germany; Mazovian Center of Lung Diseases and Tuberculosis, Otwock; Sokolowski Specialist Hospital in Szczecin-Zdunowo; Medical University of Gdask, Gdask, Poland; The West Clinic, Memphis, TN; St Petersburg Oncology Center, St Petersburg, Russian Federation; Cancer Institute "Ion Chiricuta," Cluj-Napoca; "A. Trestioreanu" Oncology Institute, Bucharest University, Bucharest, Romania; Eli Lilly and Company, Indianapolis, IN.

PURPOSE: Following a phase II trial in which pemetrexed-platinum demonstrated similar activity to that of historical etoposide-platinum controls, a phase III study was conducted to compare pemetrexed-carboplatin with etoposide-carboplatin for the treatment of extensive-stage small-cell lung cancer (ES-SCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with ES-SCLC and an Eastern Cooperative Oncology Group performance status of zero to 2 were randomly assigned to receive pemetrexed-carboplatin (pemetrexed 500 mg/m(2) on day 1; carboplatin at area under the serum concentration-time curve [AUC] 5 on day 1) or etoposide-carboplatin (etoposide 100 mg/m(2) on days 1 through 3; carboplatin AUC 5 on day 1) every 3 weeks for up to six cycles. The primary objective of the study was noninferiority of pemetrexed-carboplatin overall survival with a 15% margin. RESULTS: Accrual was terminated with 908 of 1,820 patients enrolled after results of a planned interim analysis. In the final analysis, pemetrexed-carboplatin was inferior to etoposide-carboplatin for overall survival (median, 8.1 v 10.6 months; hazard ratio [HR],1.56; 95% CI, 1.27 to 1.92; log-rank P < .01) and progression-free survival (median, 3.8 v 5.4 months; HR, 1.85; 95% CI, 1.58 to 2.17; log-rank P < .01). Objective response rates were also significantly lower for pemetrexed-carboplatin (31% v 52%; P < .001). Pemetrexed-carboplatin had lower grade 3 to 4 neutropenia, febrile neutropenia, and leukopenia than etoposide-carboplatin; grade 3 to 4 thrombocytopenia was comparable between arms and anemia was higher in the pemetrexed-carboplatin arm. CONCLUSION: Pemetrexed-carboplatin is inferior for the treatment of ES-SCLC. Planned translational research and pharmacogenomic analyses of tumor and blood samples may help explain the study results and provide insight into new treatment strategies.