QUINOLONE USE NAD BACTERIAL RESISTANCE

NEW YORK (Reuters Health) Jan 27 - Antibacterial therapy and prophylaxis in cancer patients is tied to bacterial resistance, and fluoroquinolones appear to be one of the biggest offenders, researchers report in a January 5th on-line publication in Cancer.

"This study reaffirms the challenge of balancing protection from infection for immunocompromised patients -- cancer, bone marrow transplant -- using broad spectrum antibacterials with the development of resistant organisms that are very difficult to treat," coauthor Dr. Bruno P. Granwehr, from the University of Texas M. D. Anderson Cancer Center, Houston, told Reuters Health by email.

Dr. Granwehr and colleagues analyzed isolates from 622 bacteremia episodes, 345 that were breakthrough episodes and 277 that occurred in patients who had not received antimicrobial drugs. Roughly 10% of episodes in each group were polymicrobial.

Breakthrough bacteremia was more likely than non-breakthrough bacteremia to be associated with multi-drug resistant (MDR) Escherichia coli, MDR Pseudomonas aeruginosa, and vancomycin-resistant enterococci.

On multivariate analysis, breakthrough bacteremia was significantly associated with hematologic malignancies (OR, 9.9) and neutropenia (OR, 3.0).

Monotherapy with fluoroquinolones, compared to treatment with any other regimen (including combination therapy with fluoroquinolones), was significantly linked to isolation of methicillin-resistant Staphylococcus aureus (MRSA) and MDR P. aeruginosa. Multivariate analysis showed that fluoroquinolones had the strongest association of any antibiotics with breakthrough bacteremia (odds ratio, 22.0).

Exposure to cephalosporins alone significantly increased the risk of isolating vancomycin-resistant enterococci.

The researchers also note that compared with no treatment at all, any combination regimen increased the risk of isolating MDR P. aeruginosa, MDR E. coli, and vancomycin-resistant enterococci.

Finding a balance between minimizing drug resistance and using antimicrobial prophylaxis appropriately "will require a commitment by institutions and health systems to monitor these relations and their impact on important outcomes," the authors conclude.

Cancer 2010.

GENETICS AND PROSTATE CANCER SURVIVAL

ONDON (Reuters) Jan 27 - A combination of three genetic abnormalities has a dramatic impact on prostate cancer survival and could help predict the best treatment, researchers said on Wednesday.

Scientists at Britain's Institute of Cancer Research (ICR) said their findings showed prostate cancer patients should be tested for specific genetic factors before doctors decide how aggressively to treat their tumors.

Dr. Alison Reid, who led the study, said it showed that patients with none of three specific genetic changes had good prospects, with 85.5% still alive after 11 years.

But those who had the all three gene abnormalities had a much worse prognosis, with only 13.7% still alive after 11 years.

Helen Rippon of the Prostate Cancer Charity said the study would help answer one of the most important questions in prostate cancer research -- "how to distinguish early, and with confidence, the potentially life threatening prostate tumors from the slow-growing form of the disease".

The ICR team employed fluorescence in situ hybridization (FISH) to analyze prostate tumor samples from 308 patients and look for three genetic changes -- loss of the PTEN gene and rearrangement of the ERG or ETV1 genes.

Previous studies have shown that deletions of the PTEN gene and ERG gene mutations are common in prostate cancer, but the combined impact of these on survival in a large group of patients had not been looked at previously.

Dr. Reid said around 6% of patients in the study had lost the PTEN gene and did not have either an ERG or ETV1 gene rearrangement.

In a paper published online January 26 in the British Journal of Cancer, she and her colleagues report: "The presence of PTEN gene loss in the absence of ERG/ETV1 gene rearrangements identified a patient population...with poorer cancer-specific survival that was highly significant (hazard ratio, 4.87; p <>

"Men diagnosed with prostate cancer could be tested for all three genetic alterations, and this information could be used to help determine how aggressively they should be treated," the researchers added.

Br J Cancer 2010.

CD44 POLYMORPHISM AND GASTRIC CANCER SURVIVAL

ORLANDO (Reuters Health) Jan 25 - Patients with gastric cancer who have a germline polymorphism in the CD44 gene have much more aggressive disease and are at higher risk for tumor recurrence than patients without this variation, according to new research presented at the American Society of Clinical Oncology's 2010 Gastrointestinal Cancers Symposium.

Being able to identify such patients could help guide their treatment and hopefully improve outcomes, said Dr. Thomas Winder, a postdoctoral research fellow at the University of Southern California Norris Comprehensive Cancer Center, Los Angeles.

The CD44 gene regulates the production of a protein associated with cellular adhesion and metastasis in digestive cancers, and high CD44 protein expression has been associated with poor prognosis, Dr. Winder explained. Altered CD44 may also make cancer cells more resistant to chemotherapy or radiation therapy.

The goal of his research was to discover whether germline variations within the CD44 gene are linked to clinical outcome in patients with localized gastric adenocarcinoma.

In 104 patients (63 males) with a median age of 57 years (range, 26 to 85), Dr. Winder and his colleagues sought to determine whether 4 genetic variations in the CD44 gene were associated with time to recurrence and overall survival.

They found that patients with the wild type A/A genotype in the first CD44 polymorphism (CD44 + 4883G>A) had a significantly longer time to tumor recurrence -- a median of 7.0 years after their diagnosis of resectable gastric cancer -- compared with just 2.1 years in patients who had the variant A/G or G/G genotypes (Log-Rank P value = 0.022).

Patients with the wild type A/A genotype also had longer median overall survival: 7 years, compared with 4.1 years for those with the A/G or G/G genotype (Log-Rank P value = 0.079).

These associations were also true for the second CD44 polymorphism (CD44 + 779G>A). Patients with the wild type G/G genotype had a significantly improved median time to tumor recurrence -- 7 years -- compared with 2.2 years for patients with the A/G or A/A genotype (Log-Rank P value = 0.045).

Median overall survival was 7.3 years for the wild type G/G genotype compared with 3.8 years for the variant A/G or G/G genotypes (Log-Rank P value = 0.018).

"Our results have clinical significance because we can now identify, with two single-nucleotide polymorphisms, those patients who are at high risk for tumor recurrence or metastasis. These patients might benefit from more aggressive treatment," Dr. Winder commented to Reuters Health.

"The CD44 test is reliable and the technique is available now, that's not a big deal. You have to collect blood, isolate the DNA, and then use PCR, which is available in every lab, to do the test. It's not expensive," he said.

But, he cautioned, "Our data are preliminary and have to be validated in prospective biomarker embedded clinical trials before they have immediate impact in actual clinical practice."

ALERT-REDUCE BORTEZOMIB DOSE FOR PATIENTS WITH LIVER IMPAIRMENT

January 26, 2010 — The US Food and Drug Administration (FDA) and Takeda Oncology issued a notification today to healthcare providers about Velcade (bortezomib), informing them that the starting dose for patients with multiple myeloma and moderate-to-severe hepatic impairment should be reduced.

The notification reads "dose-normalized mean [area-under-the-curve] values were increased by approximately 60% in patients with moderate or severe hepatic impairment."

Section 5.11, "Patients with Hepatic Impairment," now reads, "Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities."

New labeling will include full prescribing information for bortezomib for injection, with recommended dosages for patients with compromised liver function. Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated according to the current recommendations.

Patients with moderate or severe hepatic impairment (bilirubin levels > 1.5 - 3.0 × upper limit of normal) should be started on bortezomib at a reduced dose of 0.7 mg/m² per injection during the first cycle, with a subsequent dose escalation to 1.0 mg/m². Dose reduction to 0.5 mg/m² may be considered based on patient tolerance.

The new labeling will also include updated survival data at a median 36.7 months follow-up in patients with previously untreated multiple myeloma. The overall survival hazard ratio is 0.65 (95% confidence interval, 0.51 - 0.84; P = .00084). Median survival was 46.2 months for bortezomib compared with 34.8 months for melphalan and prednisone.

Bortezomib is indicated for the treatment of patients with multiple myeloma and for patients with mantle cell lymphoma who have received at least one prior therapy.

More information is available on the FDA's MedWatch Web site.

Adverse events related to Velcade should be communicated to MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.

DIMESNA FOR NSCLC?

January 26, 2010 — The investigational chemoprotective agent dimesna, also known as BNP7787 (Tavocept, BioNumerik), for advanced nonsmall-cell lung cancer (NSCLC) seems to improve survival, especially in patients with adenocarcinomas, according to a meta-analysis of 2 trials published in the December issue of European Journal of Clinical & Medical Oncology.

In other words, dimesna is also an "antitumor enhancing agent," according to the authors of the study.

"This doesn't happen," study coauthor Michael C. Perry, MD, told Medscape Oncology, referring to the fact that a chemoprotective agent might also provide survival benefit as an anticancer agent.

"The agent has been previously looked at to relieve toxicity — not as a primary therapy," said Dr. Perry, who is professor of medicine in the Division of Hematology and Oncology at the University of Missouri in Columbia, and a member of BioNumerik's scientific advisory board.

Dimesna was "envisioned" as an agent to reduce nephrotoxicity and neurotoxicity, and has been used in patients investigationally for "about 10 years," Dr. Perry added.

On the basis of the survival findings in the meta-analysis, BioNumerik has initiated an international phase 3 study of dimesna in patients with stage IIIB/IV primary adenocarcinoma of the lung.

The newly published meta-analysis examined overall survival outcomes for 346 newly diagnosed randomized patients with advanced NSCLC, including 211 with primary adenocarcinoma.

For the adenocarcinoma subtype in the combined analysis, patients treated with dimesna and taxane plus cisplatin chemotherapy (n = 107) had a median overall survival of 19.2 months, whereas those treated with chemotherapy alone (n=102) had a median overall survival of 11.5 months; the difference was statistically significant (P = .009).

Dimesna was not quite as impressive in all histopathologic subtypes of NCSLC included in the study but still showed effectiveness, write the study authors, led by Frederick Hausheer, MD, founder, chair, and chief executive officer of BioNumerik.

"Analysis of the combined study populations demonstrates a significant (P = .0392; power = .6588) overall survival benefit in favor of [dimesna]," write the study authors.

The survival benefit seen with dimesna is supported scientifically by "identified mechanisms of action," they report.

"We have elucidated that [dimesna] targets the thioredoxin and glutaredoxin systems, both of which are overexpressed in adenocarcinoma of the lung," the authors explain. "It is postulated that the presence of [dimesna] and its metabolites result in interference with the key components of the thioredoxin and glutaredoxin systems," they add.

Details of the 2 Studies in Meta-Analysis

Patients with advanced-stage IIIB/IV NSCLC were entered in 2 randomized, multicenter trials of dimesna — 1 in the United States (conducted by Cancer and Leukemia Group B [CALGB 30303]) and 1 in Japan.

In both studies, patients were treated with a taxane (docetaxel in the United States and paclitaxel in Japan) and cisplatin, administered with either dimesna vs no dimesna (United States) or dimesna vs placebo (Japan) for a maximum of 6 cycles. The 2 studies were very similar in design and included the same key inclusion criteria.

All patients enrolled in both trials were treatment naive and had not received any previous chemotherapy or primary therapy for their lung cancer.

All patients had a Zubrod performance status score of 0 to 1 and thus were among those "expected to do best on treatment," noted Dr. Perry. "Studies on anyone [with a Zubrod score] over 1 are not done," he added.

The mean age was 61.5 years in the American study and 60.6 years in the Japanese study. Again, the average ages were "typical" for lung cancer studies, said Dr. Perry.

All subtypes of NSCLC were represented in the study patients; however, adenocarcinoma was predominant.

"Adenocarcinoma was the largest of all of the NSCLC subtypes represented in each of the studies, and was equally distributed between treatment groups in each study," write the authors.

One of the limitations of the study was that data on second-line therapy was not gathered in the American study, say the authors. So, when patients failed in the study, they went back to community-based treatment. The only follow-up was to determine survival from the social security database. There might have been some kind of "substantial survival effect" from an "imbalanced" second-line treatment effect. But it is unlikely, said Dr. Perry, as is evidenced by the fact that, in the Japanese study, which collected second-line therapy data, no effect was seen.

All the authors of this study report being employed by, being in a leadership position at, or serving in a consultant/advisory role for BioNumerik Pharmaceuticals or ASKA Pharmaceuticals.

Eur J Clin Med Oncol. 2009;1:7-19.

GENE THERAPY FOR ESOPHAGEAL CANCER

January 25, 2010 (Orlando, Florida) — In the first clinical trial in locally advanced esophageal cancer, gene therapy, administered concurrent with chemotherapy and radiotherapy, led to high pathologic complete response (pCR) rates and a doubling in survival over historic controls. The multicenter study was presented here at the 2010 Gastrointestinal Cancers Symposium by Kenneth Chang, MD, from the University of California Irvine Medical Center, in Orange.

The meeting is sponsored by the American Gastroenterological Association, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

TNFerade Biologic is a second-generation replication-deficient adenovector carrying the transgene encoding human tumor necrosis factor (TNF)-α, which is regulated by the radiation-inducible promoter Egr-1. Intratumoral administration of TNFerade causes the secretion of TNF-α protein in tumors, which leads to the collapse of the tumor vasculature and the stimulation of proinflammatory and apoptotic pathways within the tumor. TNF-α also has a necrotizing and possibly immunomodulatory action, Dr. Chang said.

In a study of 24 patients, most with adenocarcinomas of T3 N1 stage, TNFerade was given weekly for 5 weeks by intratumoral injection under endoscopy or endoscopic ultrasound guidance, along with a 5.5-week course of cisplatin, 5-fluorouracil, and radiation (45 Gy total). Successive dosing cohorts received TNFerade at 4 × 10⁸, 4 × 10⁹, 4 × 10¹⁰, and 4 × 10¹¹ particle units weekly. Final follow-up data were available for all but the highest-dose group.

For the initial 3 dosing cohorts combined, the pCR rate was 36%, but reached 100% in some of the dosing cohorts. Two additional patients who were not resected had pCRs as well; these were shown radiographically. With their inclusion, the pCR rate was 47%. "They remain disease-free at 66 and 48 months," he noted.

"With these weekly injections, we were able to downstage the tumors," he said.

At 5 years, median overall survival was 56%, and median overall survival time was 47.7 months, he reported.

"This is in contrast to historic controls," Dr. Chang explained, "who have been shown to have median survival of 9.7 months, or up to 34 months at the most. This is much greater." He added that the 5-year survival rate is typically about 20%.

"[TNFerade] plus chemotherapy and radiotherapy yields an encouraging increase in survival over historic controls and warrants additional evaluation," Dr. Chang concluded.

During the discussion, however, Jaffer Ajani, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, who participated in the study early on, raised questions about the toxicity of the treatment; these data were not presented by Dr. Chang. Dr. Ajani said the study had been discontinued because of treatment-related deaths. He also explained that the treatment "is a big production," because it requires a gastroenterologist to deliver the treatment weekly, and questioned whether a survival advantage could be determined in a study of 24 patients.

Dr. Chang responded that the drug continues to be in development, and that after much review, the deaths were not attributed to the injection of TNF. "It appears that as an adjunct to treatment it is safe," he said, "and given the preliminary data, a larger trial is warranted."

In an interview with Medscape Oncology, Mark Thornton, MD, PhD, senior vice president of product development for GenVec, in Gaithersburg, Maryland, which manufacturers TNFerade, explained that early in the study, 1 patient died from a pulmonary embolism. Pending further investigation, the US Food and Drug Administration halted the study, but the drug is still being studied in larger pancreatic cancer trials. "Rigorous assessment" in that setting, including a comparison between the TNFerade and control groups, has shown no difference in thromboembolic events. The product is now in phase 3 trials for pancreatic cancer. Encouraging preliminary results were presented at the 2009 American Society of Clinical Oncology annual meeting (Abstract 4605), Dr. Thornton noted.

"This concern is ancient history," he said, adding that further studies in esophageal cancer are now expected.

The authors of the study report receiving consulting fees, being employed by, or owning stock in GenVec. Dr. Ajani reports receiving research funding from Sanofi-Aventis, Taiho, NS Pharma, and Adherex.

2010 Gastrointestinal Cancers Symposium (GICS): Abstract 45. Presented January 22-24, 2010.

STOP SMOKING IN EARLY LUNG CANCER

January 27, 2009 — "It is never too late for people to stop [smoking], even when they have lung cancer," proclaims an editorial published online January 21 in the British Medical Journal.

The editorial accompanies a meta-analysis that provides "preliminary evidence that smoking cessation after diagnosis of early-stage lung cancer improves prognostic outcomes," according to its authors.

The adjusted estimates suggest that the risk for death is halved in patients who stop smoking, say the researchers, led by Amanda Parsons, research fellow at the UK Center for Tobacco Control Studies at the University of Birmingham, United Kingdom.

"The estimated number of deaths prevented is larger than would be expected from a reduction of cardiorespiratory deaths after smoking cessation, so most of the mortality gain is likely to be due to reduced cancer progression," they write.

"These findings indicate that offering smoking-cessation treatment to patients presenting with early-stage lung cancer may be beneficial," they conclude.

The difference in survival between patients who stopped smoking and those who continued is "striking," said H. Jack West, MD, medical oncologist at the Swedish Cancer Institute in Seattle, Washington, and author of the Blowing smoke blog on Medscape Oncology. This effect is larger than that seen with postoperative chemotherapy, he added.

"If smoking cessation can improve true cure rates even modestly, it is absolutely an intervention worth pursuing," he said.

However, both the study authors and Dr. West emphasized that the finding pertains only to early-stage lung cancer patients.

Does Not Pertain to Advanced Disease

The situation is quite different for patients with advanced disease — and they form the majority of patients diagnosed with lung cancer.

Most patients diagnosed with lung cancer are in the last months of their lives, note editorialists Tom Treasure, MD, MS, professor of cardiothoracic surgery at University College Hospital in London, and Janet Treasure, MD, PhD, professor of psychiatry at King's College in London, United Kingdom, who are married.

"Fewer than 1 in 3 patients with lung cancer survive even 1 year," they add.

Some healthcare professionals might balk at discussing smoking cessation with this patient population, suggesting that it "is inhuman to dwell on the matter" because it "adds to feelings of guilt and takes away a life long comfort from the dying patient," they write in the editorial.

Elaborating further to Medscape Oncology, Dr. Tom Treasure, who was until recently chair of the National Confidential Enquiry into Patient Outcome and Death, said: "I get rather frustrated with people tormenting patients who are near to death, trying to jolly them along by saying we can give you some more chemotherapy. Is that really the best thing?"

"All patients know they should stop smoking, and we should make it clear to individuals that we approve this general message," Dr. Tom Treasure said.

"Getting down to the detail, we should emphasize that smoking cessation matters to most, perhaps nearly all, patients," he said. "They are entitled to know that it can make a difference."

However, he cautioned, "this general advice should be tempered with humanity."

Reduction in Risk for Death

The meta-analysis looked at 10 observational studies, 5 in patients with nonsmall-cell lung cancer (NSCLC; n = 860) and 5 in patients with small-cell lung cancer (SCLC; n = 1069). In 9 of the 10 studies, most of the patients were diagnosed as having early lung cancer, the researchers note.

Continued smoking was associated with a significantly increased risk for all-cause mortality (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.15 - 7.54) and recurrence (HR, 1.86; 95% CI, 1.01 - 3.41) in early-stage NSCLC, and for all-cause mortality (HR, 1.86; 95% CI, 1.33 - 2.59), development of a second primary tumor (HR, 4.31; 95% CI, 1.09 - 16.98), and recurrence (HR, 1.26; 95% CI, 1.06 - 1.50) in limited-stage SCLS.

Life-table modeling on the basis of these data estimated that, for early-stage NSCLC, the 5-year survival for 65-year-old patients was 33% if they continued to smoke and 70% if they stopped smoking. For limited-stage SCLC, these estimates were 29% for those who continued to smoke and 63% for those who quit.

This is the first study to have estimated the effect of smoking cessation on prognosis after a diagnosis of lung cancer, note the researchers. "Although unadjusted estimates suggest that the associated increase in risk of continuing (or the benefit of cessation) is modest, at around 20%, the adjusted estimates suggest a more than doubling in the risk of death from continued smoking," they add.

"These estimated effects are large," the editorialists note. "Patients and those caring for them should be given this information because the potential benefit is great," they explain.

In an interview with Medscape Oncology, Dr. Tom Treasure wondered about the magnitude of this effect on survival, and whether it was likely. "In such a cancer, where there have been years of exposure, it does seem a little strange that suddenly stopping smoking can have such a large effect," he said.

Need for Proper Context

The editorialists note that this new information "is valuable," but they add that "its application may be limited" because of the generally poor prognosis for most patients with lung cancer.

This is one of the issues with these latest findings — the results come from studies in which patients were mainly diagnosed and treated in the early stages of lung cancer — whereas in real life, most patients (75% to 80%) with lung cancer are diagnosed with advanced disease, as lead researcher Ms. Parsons acknowledged to Medscape Oncology.

"We are not suggesting" referral for smoking cessation for patients with advanced disease and poor prognosis, she emphasized.

However, for the 15% to 20% of patients who are diagnosed early enough to receive curative treatment (stages 1 to 3a NSCLC and limited-stage SCLC), the new findings "indicate that there may be a meaningful difference in survival when you compare those who quit with those who continue to smoke after diagnosis."

The figures that the British researchers report "do make sense in the context of nationally reported survival rates," Ms. Parsons said. For example, Cancer Research UK cites the following 5-year survival rates for early-stage NSCLC: 43% to 73% for stage 1, 25% to 46% for stage 2, and 19% to 24% for stage 3a disease.

"Our review found that a mixture of stage 1 to 3a NSCLC patients who smoked had a 5-year survival of 33%," she noted; quitting smoking increased this to 70%.

Ms. Parsons was responding to some of the criticism leveled at her teams' findings by the American Council on Science and Health (ACSH). In its newsletter, Gilbert Ross, MD, medical director at the ACSH, said the survival rates "are staggeringly high" and that they appear to be "outlandishly optimistic." He admitted that "we haven't analyzed the science of it . . . so we can't condemn the study outright, but these figures seem unlikely."

Ms. Parsons emphasized that the figures need to be taken in their proper context — i.e., just early-stage lung cancer patients rather than lung cancer patients as a whole.

Stopping Smoking in Early-Stage Patients

Ms. Parson noted that, because the studies were observational, causality cannot be assumed, but the review provides "preliminary evidence that stopping smoking may be beneficial in early-stage lung cancer patients."

"I hope that doctors will read the article and, in conjunction with their clinical judgment, decide whether it would be important to support their early-stage patients to stop on an individual basis," she told Medscape Oncology.

However, before smoking cessation for early-stage lung cancer can become part of standard practice, it needs to be tested in a large-scale randomized controlled trial, she explained. "Until then, data are encouraging that survival benefits can be seen in this group, and it is worthwhile encouraging patients to stop while assessing each case on its individual characteristics."

Approached for independent comment, Dr. West said that the new findings are "very promising and interesting, particularly as we compare the magnitude of benefit with approaches like chemotherapy."

"One central shortcoming of this work is the heterogeneity of patients studied, including those with NSCLC, SCLC, and advanced-stage disease, along with the majority who had early-stage NSCLC or limited-stage SCLC. Another is that this work is observational, and there were imbalances in the demographics of patients who quit [and those who] continued smoking in some studies," he said.

Therefore, he said, "we cannot state conclusively that the improved survival in patients who quit smoking was because of this change in behavior, but the magnitude of the survival difference, as well as the fact that these results were seen in such a broad range of patients with lung cancer, is striking."

"Given that these benefits of smoking cessation may eclipse the magnitude of such interventions as postoperative chemotherapy, it only adds to the limited information previously available to support quitting," Dr. West stated.

However, Dr. West also emphasized that these new findings apply only to patients with early-stage disease who are potentially curable.

The situation can be quite different in patients with advanced disease who are being treated with palliative intent. Here, he emphasized, "it is especially important to acknowledge the powerful addiction to nicotine that many patients have, and to respect that some may weigh the challenge of smoking cessation as having too negative an effect on their quality of life to justify a potential survival benefit."

"Nevertheless, chemotherapy and other systemic treatments that are the cornerstone of treatment for advanced lung cancer also entail a careful balance of quality of life with potential survival benefit; for many patients, smoking cessation may be associated with an improvement in pulmonary symptoms," he added.

"Overall, it is important to recognize that smoking is a charged issue in the lung cancer community. Lung cancer is reflexively associated with smoking, and many patients justifiably feel an element of 'blame the victim' from others and even themselves," Dr. West said.

"We need to approach counseling for smoking cessation constructively and without judgment," he concluded.

Ms. Parsons reports receiving reimbursement from Pfizer for attending a conference, and one of her coauthors, P. Aveyard, from the UK Centre for Tobacco Control Studies, reports carrying out consultancy work for the manufacturer of a smoking-cessation aid.

BMJ. 2010;340:b5569, b5630. Published online January 21, 2010. Abstract, Abstract

ANTI-EGFR ANTIBODIES IN COLORECTAL CANCER

January 26, 2010 (Orlando, Florida) — Further analyses of major trials of the 2 monoclonal antibodies against the epidermal growth-factor receptor (EGFR) — panitumumab (Vectibix, Amgen) and cetuximab (Erbitux, Bristol-Myers Squibb) — support their benefit as first-line treatment for metastatic colorectal cancer in patients with wild-type (normal) KRAS gene status, but found them futile in the small subset with BRAF mutations.

The updates were reported here at the 2010 Gastrointestinal Cancers Symposium (GICS), which is sponsored by the American Gastroenterological Association, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

In the primary survival analysis of the phase 3 PRIME trial, first-line treatment with panitumumab, given with 5-flurorouracil, leucovorin, and oxaliplatin (FOLFOX4), delayed progression by 1.6 months and extended overall survival to approximately 2 years in patients with wild-type KRAS, according to Salvatore Siena, MD, from the Ospedale Niguarda Ca' Granda in Milan, Italy.

In the PRIME trial of 1183 metastatic colorectal cancer patients, 60% had the wild-type KRAS gene, whereas 40% had mutated KRAS and therefore did not benefit from the addition of the drug. Patients were randomized to receive standard FOLFOX4 chemotherapy alone (control group) or FOLFOX4 chemotherapy plus panitumumab 6.0 mg/kg every 2 weeks.

The primary end point, median progression-free survival, was 9.6 months in wild-type KRAS patients in the panitumumab group and 8.0 months in the control group, for a 20% reduction in risk with panitumumab (P = .02). The secondary end point, median overall survival, was 23.9 months in the panitumumab group and 19.7 months in the control group.

"There was a 4.2-month advantage with panitumumab that was almost statistically significant (hazard ratio [HR], 0.83; P = .07)," Dr. Siena told Medscape Oncology. "It did not reach significance, probably because of our rigorous statistical design, which was a hierarchical sequential analysis," he explained.

"We had a very good control arm," he added. "In my opinion, this 4.2-month difference is clinically meaningful, although not statistically significant."

Response rates in wild-type patients were numerically higher: 55% in the panitumumab group and 48% in the control group (P = .07).

As expected, patients with mutated KRAS did not benefit from panitumumab. Progression-free survival in those patients was actually more favorable with FOLFOX4 alone than with FOLFOX4 plus panitumumab (8.8 months vs 7.3 months; P = .02).

In updated data from the OPUS trial, Carsten Bokemeyer, MD, from the University Hospital Hamburg-Eppendorf in Germany, reported that in KRAS wild-type patients (n = 82), cetuximab plus FOLFOX4 led to a median overall survival of 22.8 months, compared with 18.5 months for FOLFOX4 alone, although the 15% reduction in risk was not statistically significant. Disease progression, however, was significantly lower, by 43.3% (P = .0064), and tumor response rates were significantly higher (57.3% vs 34.0%; P = .0027) with the combination, Dr. Bokemeyer reported.

BRAF Mutations Associated With Poor Prognosis

In an update of the phase 3 CRYSTAL trial, principal investigator Eric Van Cutsem, MD, from University Hospital Gasthuisberg, in Leuven, Belgium, provided more evidence that BRAF mutations are prognostic indicators of worse outcomes in KRAS wild-type patients.

The BRAF mutation was present in 9% of the 666 patients with KRAS wild-type tumors in CRYSTAL, and these patients derived no benefit from treatment with cetuximab, he reported.

The main results of CRYSTAL (n = 1198), reported at the 2009 European Society for Medical Oncology/European CanCer Organization meeting in Berlin by Dr. Van Cutsem, showed that treatment with cetuximab plus folinic acid, fluorouracil, and irinotecan (FOLFIRI) was associated with a 30% reduction in progression (P = .0012) and a 20% reduction in mortality (P = .0093), compared with FOLFIRI alone, in the KRAS wild-type population.

In the analysis of FOLFIRI plus cetuximab in KRAS wild-type patients, median overall survival was 23.5 months overall and 25.1 months for patients with both KRAS and BRAF wild-type status, but just 14.1 months for KRAS wild-type patients who had BRAF mutations. Progression-free survival was, respectively, 9.9, 10.9, and 8.0 months.

"The findings suggest that BRAF tumor mutations are associated with poor prognosis in first-line metastatic colorectal cancer," Dr. Van Cutsem said.

CALBG 80405 May Determine Optimal Agent

In a lecture on metastatic treatment options for KRAS wild-type tumors, Cornelius J. Punt, MD, from Radboud University Nijmegen Medical Center in the Netherlands, said that because superiority has not been shown for anti-EGFR antibodies over bevacizumab in the first-line setting, panitumumab and cetuximab should not be chosen over bevacizumab unless they are proven to be preferable.

A head-to-head comparison of these agents is being conducted in the CALGB 80405 trial. The study will randomize patients to FOLFOX or to FOLFIRI plus bevacizumab, cetuximab, or bevacizumab and cetuximab, and the findings can be extrapolated to panitumumab, said Jordon Berlin, MD, clinical director of gastrointestinal oncology at Vanderbilt's Ingram Cancer Center in Nashville, Tennessee.

Dr. Berlin told Medscape Oncology that CALGB 80405 will be critically important in determining which first-line approach is optimal. "This head-to-head comparison will answer this question," he said. "Until these agents are compared head to head, bevacizumab has more momentum."

"There is a huge cosmetic factor with the EGFR inhibitors," he pointed out, notably skin toxicity, which the majority of responders develop. "While the side effects of bevacizumab are scary — stroke, bowel perforation, bleeding — they are very rare. If a patient is at high risk for these, they should not get bevacizumab; perhaps I would use an EGFR inhibitor. Clearly, for KRAS mutant tumors, there is no role for the EGFR inhibitors, so that is an easy answer for 40% of patients. However, for the 60% with KRAS wild-type tumors, we need the CALGB trial."

The PRIME trial was funded by Amgen. At least 1 author of this study reports employment, consultancy, stock ownership, honoraria, and research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co, ImClone Systems, Merck & Co, Merck Serono, Roche, Sanofi-Aventis, Pfizer, and Sanofi-Synthelabo.

2010 Gastrointestinal Cancers Symposium (GICS): Abstract 283. Presented January 22-24, 2010.

SUNITINIB FOR PANGREATIC NET

January 25, 2010 (Orlando, Florida) — In the final analysis of an international randomized phase 3 trial, the multikinase inhibitor sunitinib (Sutent, Pfizer) significantly prolonged both survival and progression-free survival in patients with advanced pancreatic neuroendocrine tumors (NET), investigators reported here at the 2010 Gastrointestinal Cancers Symposium.

The meeting is sponsored by the American Gastroenterological Association, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society for Surgical Oncology.

The study looked at 340 patients with advanced, progressive, well-differentiated pancreatic NETs. They were randomly assigned to continuous sunitinib 37.5 mg/d or placebo, along with best supportive care.

The median progression-free survival, which was the study's primary end point, was 11.4 months in the sunitinib group and 5.5 months in the placebo group, for a 58% reduction in risk (P < .001).

"With sunitinib, we improved progression-free survival by doubling it to 11.4 months, with a highly significant P value," said principal investigator Eric Raymond, MD, professor of medical oncology at Beaujon University Hospital in Clichy, France.

"Events occurred in 34.9% of the sunitinib arm versus 60% of the placebo arm," he noted, "meaning that the probability of being event-free at 6 months was 71.3% with sunitinib and 43% with placebo."

The overall response rate was 9.3% with sunitinib and 0% with placebo, with a median duration of response of 8.1 months with the drug. Stable disease rates were 34.9% and 24.7%, respectively.

The low response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria is in keeping with the finding from many other studies that this class of agents might be "destroying the inner tumor but not reducing the tumor's diameter," Dr. Raymond said. "The RECIST criteria underestimate the effect of this class of agents."

"After 1 cycle, we often saw hypodensity of the tumor on imaging, which translated into sustained tumor stabilization," he added. "Stable disease was a common feature of sunitinib treatment." Some of the patients in the trial are still stable after 2.5 years, he said in an interview.

Overall survival was a secondary end point, with sunitinib offering a survival probability of 92.6% and placebo offering a survival probability of 85.2%. This represented a statistically significant 59% reduction in risk (P = .0204), Dr. Raymond reported.

At a median follow-up of approximately 11 months, 9 patients in the sunitinib group had died, as had 21 in the placebo group.

"The study was stopped early because the number of events in the placebo arm was much higher, especially deaths," he said.

Preliminary results from this trial and the fact that the study was halted because of the benefit seen were reported by Medscape Oncology last year.

The phase 3 study findings have served as the basis for recent filings of supplemental applications for sunitinib in the treatment of NETs with the regulatory authorities in the United States, Europe, and Canada, according to the manufacturer, Pfizer.

Adverse Events Generally Tolerable

Adverse events were similar to those observed in other sunitinib studies. The most prominent events were diarrhea, nausea, vomiting, asthenia, hand-foot syndrome, and fatigue. Grade 3/4 events were uncommon, although they were slightly increased in the sunitinib group, most commonly neutropenia (12.0%), hypertension (9.6%), hand-foot syndrome (6%), and leukopenia (6%). Grade 5 treatment-related events occurred in 1 patient in each group (cardiac failure with sunitinib and dehydration with placebo).

"The adverse events were generally tolerable and manageable by dose interruption, dose reduction, and/or standard medical therapy," he added.

Asked to comment on the study, Jordan Berlin, MD, clinical director of gastrointestinal oncology at Vanderbilt's Ingram Cancer Center in Nashville, Tennessee, told Medscape Oncology that "this trial offers more than just an encouraging benefit in terms of time to progression and survival. What is most exciting is the proof of principle, that a targeted agent has a major effect in NET, and also that we can do these studies in this patient population."

He explained that NETs are not only rare, but that patients are a heterogeneous group that can be challenging to evaluate in a randomized phase 3 trial. "Some people have thought a phase 3 trial was not practical in this group."

The authors of the study report receiving support from Pfizer, the manufacturer of sunitinib. Dr. Berlin also reports receiving research support from Pfizer.

2010 Gastrointestinal Cancers Symposium (GICS): Abstract 127. Presented January 22–24, 2010.

CHEMORADIOTHERAPY FOR CERVICAL CANCER

January 26, 2010 — Adding chemotherapy to radiotherapy adds a modest but significant benefit in women with cervical cancer, according to a meta-analysis reported in the first 2010 issue of the Cochrane Database of Systematic Reviews. The results also suggest that adjuvant chemotherapy is beneficial, although more data are needed.

Data from 13 trials showed that patients treated with chemoradiotherapy had a 6% improvement in 5-year survival, compared with those treated with radiotherapy alone (hazard ratio (HR), 0.81; P < .001).

The researchers noted that in 2 other trials, a larger survival benefit was seen when chemotherapy was administered after chemoradiotherapy. The HR for these 2 trials was 0.46 (95% confidence interval [CI], 0.32 - 0.66; P < .001), which represents a 54% reduction in the risk for mortality and an absolute survival benefit of 19% at 5 years (range, 60% to 79%).

A third finding was that a significant survival benefit was observed for both platinum-based (HR, 0.83; P = .017) and nonplatinum-based (HR, 0.77; P = .009) chemoradiotherapy.

"The type of study that we did — a systematic review and meta-analysis using individual patient data — is often said to be the gold standard or yardstick of systematic reviews," said lead author Claire Vale, PhD, from the Meta-Analysis Group, MRC Clinical Trials Unit in London, United Kingdom. "Therefore, I think that what we have provided in doing this review is strong evidence about the use of chemoradiotherapy, and probably the best evidence available to date."

Even so, she told Medscape Oncology, the treatment of any individual woman with cervical cancer is based on many factors, including tumor stage, general health, and personal preference. "There are some women for whom chemoradiotherapy will not suitable, so for them, other treatments, such as radiotherapy alone, will necessarily be considered," she said.

The use of adjuvant chemotherapy might need to be further assessed in randomized controlled trials, Dr. Vale added. "As far as I am aware, there is considerable interest about this question in the research community."

Meta-Analysis Needed to Clarify Data

Following the publication of 5 clinical trials, the National Cancer Institute (NCI) issued a clinical alert in 1999 recommending that "concomitant chemoradiotherapy should be considered instead of radiotherapy alone in women with cervical cancer," the authors note. These recommendations led to a subsequent change in therapeutic regimens for many women diagnosed with cervical cancer.

Although 2 subsequent reviews reported improvements in several outcome measures, including overall survival, progression-free survival, and recurrence rates with chemoradiotherapy, the interpretation of results was complicated and left unanswered questions, write the authors. There was heterogeneity in trial results, inconsistency in the definition of outcomes between trials, and different control-group treatments in the studies included in these analyses.

Therefore, the Cochrane researchers conducted a meta-analysis that included updated individual patient data from all randomized controlled trials to better evaluate the effectiveness of chemoradiotherapy for all outcomes.

A total of 15 studies (3452 participants) met the eligibility criteria for inclusion in the analysis. The studies all looked at women with high-risk early-stage or locally advanced cervical cancer.

The median follow-up time for living patients across all 15 trials was 5.2 years, and data on overall survival, disease-free survival, locoregional disease-free survival, and metastases-free survival were available for all trials included in the analysis.

Benefit Seen Across All Outcomes

In addition to improving overall survival, chemoradiotherapy also reduced local and distant recurrence and progression, and improved disease-free survival. The HR of 0.78 (95% CI, 0.70 - 0.87; P < .001) for disease-free survival translated to an absolute benefit of 8% at 5 years (from 50% to 58%), and similar and significant absolute benefits for chemoradiotherapy were seen for 5-year locoregional disease-free survival (9%; P < .001), time to locoregional recurrence/progression (6%; P = .00009), and metastases-free survival (7%; P < .001).

The authors note that for time to metastases at 5 years, the improvement was smaller and "less convincing" (4%; P = .04).

A suggestion of a difference in the size of the survival benefit was observed with tumor stage, but not with other patient subgroups, note the authors.

The incidence of acute hematologic and gastrointestinal toxicity was higher with chemoradiotherapy, but only a few of the trials measured late toxicity. Thus, the data were insufficient to evaluate whether serious late toxicity is affected by the type of treatment, although available data suggest that only about 1% to 3% of women experience serious late toxicities.

"These results endorse the recommendations of the NCI alert, but also demonstrate their applicability to all women and a benefit of nonplatinum-based chemoradiotherapy," the authors conclude.

Cochrane Database Syst Rev. 2010;1:CD008285. Abstract

HYPERTENSION AND RESPONSE TO AVASTIN IN NSCLC

J Clin Oncol. 2010 Jan 19. [Epub ahead of print]

Clinical Course of Advanced Non-Small-Cell Lung Cancer Patients Experiencing Hypertension During Treatment With Bevacizumab in Combination With Carboplatin and Paclitaxel on ECOG 4599.

Dahlberg SE, Sandler AB, Brahmer JR, Schiller JH, Johnson DH.

Dana-Farber Cancer Institute, Boston, MA; Vanderbilt-Ingram Cancer Center, Nashville, TN; The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; and the University of Texas Southwestern Medical Center, Dallas, TX.

PURPOSE: Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) with demonstrated efficacy in combination with carboplatin and paclitaxel (PCB) for the treatment of advanced non-small-cell lung cancer (NSCLC). Administration of bevacizumab is postulated to decrease nitric oxide synthesis and lead to hypertension, which may be a physiological sign that the VEGF pathway is more actively being blocked and could result in improved outcomes. PATIENTS AND METHODS: Eastern Cooperative Oncology Group (ECOG) 4599 randomly assigned patients with nonsquamous NSCLC to carboplatin and paclitaxel (PC) versus PCB. Hypertensive patients were compared with nonhypertensive patients with respect to overall survival (OS) and progression-free survival (PFS) using blood pressure data and adverse event data separately. High blood pressure (HBP) by the end of cycle 1 was defined as blood pressure > 150/100 at any previous time or at least a 20-mmHg increase in diastolic blood pressure from baseline. RESULTS: In a multivariable Cox model adjusting for HBP as a time-varying covariate, comparing those on PCB with HBP with those on PC gave an OS hazard ratio (HR) of 0.60 (95% CI, 0.43 to 0.81; P = .001); comparing those on PCB without HBP with those on PC alone, the OS HR was 0.86 (95% CI, 0.74 to 1.00; P = .05). Comparing the PCB HBP group with PC gave an adjusted PFS HR of 0.54 (95% CI, 0.41 to 0.73; P < .0001) and comparing those on PCB without HBP to those on PC, the HR was 0.72 (95% CI, 0.62 to 0.84; P < .0001). The 6-month cumulative incidence of hypertension was 6.2% (95% CI, 3.9% to 8.6%). CONCLUSION: Data from ECOG 4599 suggest that onset of HBP during treatment with PCB may be associated with improved outcomes, and additional studies of the downstream effects of VEGF suppression and hypertension are needed.

TANDEM AUTOTRANSPANTATIONS FOR MULTIPLE MYELOMA

J Clin Oncol. 2010 Jan 19. [Epub ahead of print]

Long-Term Follow-Up of Autotransplantation Trials for Multiple Myeloma: Update of Protocols Conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences.

Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL.

University of Arkansas for Medical Sciences, Little Rock, AR; Cancer Research and Biostatistics, Seattle, WA; Cedar Sinai Medical Center, Los Angeles, CA; and Centre Hospitalier Universitaire, Nantes, France.

PURPOSE: The purpose of this study was to update outcomes of autotransplantation trials for myeloma conducted by the Intergroupe Francophone du Myelome (IFM), the Southwest Oncology Group, and the University of Arkansas for Medical Sciences (Total Therapy [TT]). METHODS: IFM90 (N = 194), IFM04 (N = 402), IFM9902 (N = 692), IFM9904 (N = 197), S9321 (N = 817), TT1 (N = 231), TT2 (N = 668), and TT3 (N = 303) were updated, and results were compared with original reports. RESULTS: Superior survival with single transplantation versus standard therapy in IFM90 was confirmed (P = .004), and a trend in favor of tandem versus single transplantation was maintained in IFM94 (P = .08). S9321 data were validated, with comparable survival in single transplantation and standard treatment arms (P = .35). A survival benefit from thalidomide maintenance in IFM9902 was not confirmed (P = .39) but emerged for the thalidomide arm of TT2 (P = .04). On multivariate analysis, survival was superior in TT2, TT3, and IFM9902 (all P < .001); tandem transplantations were superior to both single transplantations and standard therapies (P < .001), as were tandem transplantations with added thalidomide versus trials without thalidomide (P < .001). Postrelapse survival (PRS) was superior when initial event-free survival (EFS) exceeded 1280 days and when tandem transplantations had been administered, whereas PRS was shorter when EFS lasted 803 days or less and when trials had included thalidomide and bortezomib. CONCLUSION: These long-term follow-up data of transplantation trials provide a crucial framework of reference for outcome reporting of novel agent-based trials reportedly exhibiting remarkable short-term efficacy approaching high-dose therapy results.