INCREASED RISK OF ARTERIAL THROMBOEMBOLISM WITH SUNITINIB AND SORAFENIB

April 5, 2010 — Treatment of cancer patients with the targeted agents sunitinib (Sutent, Pfizer) and sorafenib (Nexavar, Bayer and Onyx) is associated with a significant increase in the risk for arterial thromboembolic events, according to a meta-analysis published online March 29 in the Journal of Clinical Oncology.

The meta-analysis, which consisted of 10,255 patients with a variety of cancers, found that the incidence of arterial thromboembolic events (ATEs) associated with sunitinib and sorafenib was 1.4% (95% confidence interval [CI], 1.2% - 1.6%), and that the relative risk for ATEs was 3.03% (95% CI, 1.25 - 7.37; P = .015), compared with control patients randomized to placebo.

"The overall incidence is very low — less than 5%. The relative risk is higher and is statistically significant, suggesting a 3-fold greater risk for developing ATEs with sorafenib or sunitinib, compared with controls," lead investigator Toni K. Choueiri, MD, director of the kidney cancer center at Dana-Farber/Brigham and Women's Cancer Center in Boston, Massachusetts, told Medscape Oncology. "These cases were in clinical trials. Could the incidence be higher in the general population? Probably, but we don't know. However, we have to recognize that ATEs do occur — that's the first thing."

Increased Bleeding Also a Risk

In October 2009, as reported by Medscape Oncology, Dr. Choueiri and colleagues published a study showing that the treatment of cancer patients with sunitinib and sorafenib doubled their risk of bleeding.

At the time, Dr. Choueiri noted that the risk for bleeding might even be higher in older and frailer cancer patients and in those receiving chemotherapy. He also stated that clinicians had scant awareness of the problem of bleeding with these drugs.

In the current study, he and his team analyzed 10 phase 2 and 3 trials published between January 1966 and July 2009 found with a PubMed search, and abstracts presented at the American Society of Clinical Oncology and the European Society of Medical Oncology meetings held between 2004 and 2009.

Six of the trials were on renal cell carcinoma; the others were on hepatocellular cancer, gastrointestinal stromal tumor, nonsmall-lung cancer, and neuroendocrine tumor.

The most reported event was cardiac ischemia or infarction (7 trials), followed by cerebral ischemia (3 trials). Two trials reported both cardiac and cerebral ischemia.

The doses of sunitinib and sorafenib, as well as the dosing schedules, were approved by the US Food and Drug Administration and consisted of sunitinib 50 mg orally once daily on a 4-weeks-on 2-weeks-off schedule, and sorafenib 400 mg orally twice daily.

The incidence of ATEs with sunitinib and sorafenib were similar — 1.3% (95% CI, 1.0% - 1.6%) for sunitinib and 1.7% (95% CI, 1.1% - 2.4%) for sorafenib. This difference was not statistically significant (P = .35).

Nor were there significant differences with regard to the type of malignancy or the type of clinical trial, Dr. Choueiri said.

The Good and the Bad of VEGF Inhibition

Speculating on the reasons for the increased incidence of ATEs, Dr. Choueiri told Medscape Oncology that he believes it is because these drugs disrupt the hemostatic balance.

"These drugs inhibit tumor angiogenesis, which has resulted in a major therapeutic advance for many cancers. The [vascular endothelial growth factor] VEGF pathway is vital for tumor angiogenesis, but it also plays an important part in regulating endothelial cells," he said. "Endothelial cells are important in vascular homeostasis for maintaining normal blood viscosity and preventing abnormal bleeding or abnormal clotting. If the balance is tipped toward clotting, arterial thromboembolic events, such as stroke and myocardial infarction, can occur. If it goes the other way, bleeding can occur."

VEGF also increases the production of nitric oxide, which has several vascular protective effects, such as antiplatelet activity and the inhibition of leukocyte adhesion.

"If you inhibit VEGF with these drugs, you disrupt, not in a major way but in a statistically significant way as we show in our study, this hemostatic balance and you tip it toward thrombosis or bleeding."

He added that he believes that this is a class effect. "I don't think folks can claim that one drug has less of an effect than the other."

Study Furthers Understanding of Vascular Effects

Commenting on this study for Medscape Oncology, Ming Hui Chen, MD, MMSc, an oncocardiologist who specializes in the cardiac care of cancer patients at Harvard Medical School in Boston, said that this study furthers our understanding the vascular effects of the small-molecule tyrosine kinase inhibitors.

She added that the study supports the observation of earlier trials that showed cardiac ATEs such as myocardial infarction.

With greater awareness of the ATE risk of these important anticancer agents, "clinicians and patients alike can partner in the early detection and management of any thrombolic events that occur," Dr. Chen added.

Cancer Patients Need These Drugs

Dr. Choueiri said care should be taken when using sunitinib and sorafenib, especially in patients who might be vulnerable to their effects.

"We should not stop using the drugs. Absolutely not. They have made an enormous difference to the way we treat these cancers. But we do have to exert caution, especially in a predisposed population," he told Medscape Oncology. "These would include people who have had a previous stroke, older people, those with uncontrolled hypertension, diabetes, a history of thrombolic events, and so on. The first thing is to know that ATEs can occur. The next most important thing is to monitor your patients. Don't just give them the drug and then see them 2 months later. Bring them back frequently and monitor closely."

Dr. Choueiri and Dr. Chen have disclosed no relevant financial relationships. In the paper, Dr. Choueri reports having had relationships with Bayer Pharmaceuticals/Onyx Pharmaceuticals, GlaxoSmithKline, Abbott Laboratories, Genentech, Agennix, Novartis, and Pfizer, but adds that he has received no compensation for these relationships.

J Clin Oncol. Published online March 29, 2010. Abstract

LIGIDAKIS SPEAKING

Surg Today. 2010 Apr;40(4):287-94. Epub 2010 Mar 26.
Strategies for treating liver metastasis from gastric cancer.
Kakeji Y, Morita M, Maehara Y.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

The prognosis of patients with liver metastasis from gastric cancer is dismal. This article reviews the characteristics of gastric cancer metastasizing to the liver, and multimodality of treatments. Differentiated adenocarcinoma, poorly differentiated adenocarcinoma with a medullary growth pattern, and special types, including endocrine carcinoma and hepatoid carcinoma, are likely to metastasize to the liver. The overexpression of growth factors or adhesion molecules is clinically significant for liver metastasis. Surgery for liver metastases arising from gastric adenocarcinoma is reasonable if a complete resection seems feasible after careful preoperative staging. A hepatic resection should always be considered as an option for gastric cancer patients with hepatic metastases. Newer generation cytotoxic agents such as S-1, irinotecan, and taxanes show promising activity for patients with metastases. Adjuvant chemotherapy or molecular targeted therapy will provide significant benefits to patients in the future.

VINFLUNINE FOR NSCLC

J Clin Oncol. 2010 Mar 29. [Epub ahead of print]
Phase III Trial Comparing Vinflunine With Docetaxel in Second-Line Advanced Non-Small-Cell Lung Cancer Previously Treated With Platinum-Containing Chemotherapy.
Krzakowski M, Ramlau R, Jassem J, Szczesna A, Zatloukal P, Von Pawel J, Sun X, Bennouna J, Santoro A, Biesma B, Delgado FM, Salhi Y, Vaissiere N, Hansen O, Tan EH, Quoix E, Garrido P, Douillard JY.

Centrum Onkologii Instytut, Warsaw; Regional Lung Disease Hospital, Poznan; Medical Academy Radiotherapy Clinic, Gdansk; Samodzielmy Wojewodzki Zaklad Opieki Zdrowotnej, Otwock, Poland; Klinika Pneumologie e Brudni Chir, Praha, Czech Republic; Asklepios Fachkliniken München-Gauting, Gauting, Germany; Hôpital André Boulloche, Montbéliard; Centre René Gauducheau, Saint-Herblain; Institut de Recherche Pierre Fabre, Boulogne; Hôpital Lyautey, Strasbourg; Centre René Gauducheau, Saint-Herblain, France; Instituto Clinico Humanitas, Rozzano, Italy; Jeroen Boch Ziekenhuis, Hertogenbosch, Netherlands; Odense Univesitetshospital, Odense, Denmark; National Cancer Centre, Singapore, Singapore; and Hospital Ramón y Cajal, Madrid, Spain.

PURPOSE: To compare vinflunine (VFL) to docetaxel in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) who have experienced treatment failure with first-line platinum-based chemotherapy. PATIENTS AND METHODS: Randomized, multicenter, phase III study, 551 patients received either vinflunine 320 mg/m(2) or docetaxel 75 mg/m(2) every 21 days until disease progression or serious toxicity. The primary end point was progression-free survival (PFS). The noninferiority analysis was based on a 10% difference (types I/II error rates: 5%/20%). Secondary end points included response rate (ORR), response duration, overall survival (OS), clinical benefit, quality of life (QOL), and safety. RESULTS: Median PFS was 2.3 months for each arm (HR, 1.004; 95% CI, 0.841 to 1.199). ORR, stable disease, median OS, were 4.4% versus 5.5%, 36.0% versus 39.6%, 6.7 versus 7.2 months (HR, 0.973; 95% CI, 0.805 to 1.176), respectively. No significant difference in patient benefit and QOL (Functional Assessment of Cancer Therapy-Lung). No unexpected adverse events were observed. Grade higher than 0 (vinflunine v docetaxel) anemia (82.1% v 79.8%), neutropenia (49.3 v 39.02%), thrombocytopenia (30.6% v 14.3%), febrile neutropenia (3.3% v 4.7%), constipation (39.2% v 11.7%), fatigue (36.6% v 33.9%), injection site reaction (31.9% v 0.7%), nausea (26.7% v 23.7%), vomiting (23.8% v 14.2%), alopecia (19.8% v 35.4%), stomatis (19.4% v 12.4%), abdominal pain (20.1% v 3.6%), myalgia (14.7% v 6.6%), peripheral neuropathy (10.7% v 15.0%), arthralgia (7.0% v 7.7%), diarrhea (6.2% v 12.4%), edema (1.5% v 5.4%), and nail disorders (1.1% v 5;1%) were observed. CONCLUSION: This noninferiority phase III study showed similar efficacy end points for vinflunine and docetaxel. Despite higher rates of some adverse effects (anemia, abdominal pain, constipation, fatigue) the overall toxicity profile of vinflunine was manageable. Therefore, VFL may be another option in the second-line treatment of patients with advanced NSCLC.

MEN1 PATIENTS FOLLOW UP

1. Periodic routine biochemical screening for adults with proven MEN 1
At least annually, fasting blood sample for:
Ionized Ca and albumin corrected Ca, PTH
Gastrin, glycoprotein alpha subunit
Glucagon, VIP, PP, chromogranin A
Prolactin, IGF-1, TSH, FT4
Glucose and insulin
Cholesterol, triglycerides and HDL
U&E, LFTs
2. Periodic routine imaging screening for adults with proven MEN 1
Annual abdominal ultrasonography-examining pancreas, liver and adrenals.
Third–fifth yearly CT or MRI of chest and abdomen for bronchopulmonary carcinoid, thymic carcinoid, adrenal and gastroenteropancreatic tumours
Third to fifth yearly pituitary MRI
Fifth yearly DXA BMD
3. General considerations
Depending on other clinical and familial factors and diagnoses, including symptoms, immediate family history and previous biochemical or radiological findings, the above protocol is modified for individual patient requirements. Children and adolescents without symptomatic disease generally undergo counselling for genetic testing at 10–12 years age, and if disease inheritance is confirmed, limited biochemical and nonionizing radiation imaging to identify presymptomatic hyperparathyroidism and pituitary disease.

CEP17 DUBLICATION AND RESPONSE OF BREAST CANCER TO ANTHRACYCLINES

NEW YORK (Reuters Health) Mar 26 - Breast cancer patients with duplication of the CEP17 gene are more likely to respond to anthracycline chemotherapy, investigators reported yesterday at the seventh European Breast Cancer Conference in Barcelona, Spain.

Adding an anthracycline to a regimen of CMF (cyclophosphamide, methotrexate, and fluorouracil) benefits about 10% of patients, presenter Dr. John Bartlett of the University of Edinburgh, U.K. told Reuters Health. Trials looking at HER2 and TOP2A (both on chromosome 17) as potential biomarkers of response produced conflicting results.

Dr. Bartlett's group conducted a meta-analysis of four phase III breast cancer trials looking at chromosome 17 CEP (CEP17), which is the alpha satellite repeat in the pericentromeric region. The investigators theorize that CEP17 duplication may indicate chromosome instability and enhanced sensitivity to DNA damage.

Out of 2574 patients, 27.5% had duplication of CEP17. Median follow-up ranged from 6.9 to 11.5 years.

"Our analysis showed that in each of the four trials, the effect was consistently the same in showing benefit from anthracycline in the CEP17-positive group of patients," Dr. Bartlett said.

According to his presentation, the risk ratio for recurrence-free survival ranged from 0.57 to 0.67 across the four trials among patients positive for CEP17 duplication treated with anthracycline. After adjustment for treatment, nodes, grade, stage HER2, and TOP2A, the overall risk ratio was 0.63 (p = 0.001).

Similarly, the adjusted risk ratio for overall survival ranged from 0.49 to 0.64. The overall adjusted risk ratio was 0.63 (p = 0.0036).

By contrast, patients with CEP17 "normal" status did not benefit from the addition of anthracycline therapy (hazard ratios close to one).

ZOMETA IN BREAST CANCER

In the randomized phase II trial, zoledronate appeared to limit dissemination of tumor cells to bone marrow, the investigators report.

The data released online today in The Lancet Oncology were first presented in preliminary form two years ago at a meeting of the American Society of Clinical Oncology (see Reuters Health eLine report, May 16, 2008).

Zoledronic acid is an osteoclast-inhibiting bisphosphonate. Two trials published last year showed a disease-free survival benefit from zoledronic acid treatment in women with early breast cancer receiving adjuvant endocrine therapy.

The current study included 120 women with stage II-III newly diagnosed breast cancer and no evidence of distant metastasis by CT or bone scan.

The authors, led by Dr. Rebecca Aft of Washington University School of Medicine, St. Louis, randomly assigned half the patients to receive intravenous zoledronate 4 mg every three weeks for one year. Starting at the same time, all patients received four cycles of neoadjuvant epirubicin plus docetaxel every three weeks with granulocyte-stimulating factor support.

At baseline, bone marrow from each anterior iliac crest showed disseminated tumor cells in 26 of 60 zoledronate-treated patients (43%) and 28 of 58 controls (48%). When bone marrow studies were repeated at 3 months (after 4 cycles of chemotherapy), these women did not have significant changes in detectable tumor cells.

But among the women with no detectable tumor cells in their bone marrow at baseline, 27 of 31 (87%) in the zoledronate group were still negative at 3 months, compared to 10 of 25 (40%) in the control group (p = 0.03).

The authors postulate that "chemotherapy leads to increased bone turnover and the release of growth factors, providing a favorable environment" for disseminated tumor cells, but "this effect is abrogated by treatment with bisphosphonates."

They caution, however, that their study was not designed for this comparison, and that false-negative bone marrow results cannot be excluded, so the findings should be confirmed in larger trials.

By 12 months, with only 79 women still evaluable, there was no difference between the groups in the proportion of patients with tumor cells in bone marrow.

The authors saw no significant differences in rates of pathological complete response or disease-free or overall survival at 12 and 24 months. Zoledronic acid did improve bone-mineral density at the hip and wrist at 12 months.

Rates of adverse events were similar in the two groups, although one woman treated with zoledronic acid developed osteonecrosis of the jaw.

The study was funded by Pfizer Inc. and Novartis Pharmaceuticals.

Lancet Oncol 2010.

GENE LINKED TO NSCLC IN NON SMOKERS

March 30, 2010 — Nonsmokers account for 10% to 15% of lung cancer cases in Europe and North America, 30% to 40% of cases in Asian countries, and 53% of all cases in women. Up to one third of these patients carry a newly identified susceptibility gene that reduces the expression of GPC5, a glypican gene that is suppressed in adenocarcinomas.

Ping Yang, PhD, and colleagues from the Mayo Clinic College of Medicine in Rochester, Minnesota, report the new cancer risk factor in the April issue of The Lancet Oncology. Dr. Yang led an international team in a 4-stage search for genetic variations that increase lung cancer risk in never smokers (defined as people who have smoked fewer than 100 cigarettes in their lifetime).

Dr. Yang told Medscape Oncology that "this study involved multiple institutions. Two had second-hand smoking information, and 2 did not. The role of the GPC5 gene in the risk for lung cancer among never smokers is independent of the effect of second-hand smoking; in other words, finding this gene did not diminish the risk for lung cancer linked to second-hand smoking. Larger studies are needed that can test the genetic effect separately in those who had been and those who had not been exposed to second-hand smoking."

Molecular oncologist Adi F. Gazdar, MBBS, who has also studied lung cancer in never smokers, was asked by Medscape Oncology to comment on the study. Dr. Gazdar, who is the W. Ray Wallace Distinguished Chair in Molecular Oncology Research at the University of Texas Southwestern Medical School in Dallas, said that "this is a good piece of work by experienced and competent scientists. It is the first large study that targets never smokers, and it identifies a previously unknown locus that may predispose to lung cancer in never smokers. A new putative tumor suppressor gene was identified."

"We know that genetic factors must predispose to lung cancer in never smokers. This study offers hope [that] those at increased risk [will be identified]," said Dr. Gazdar.

Separating Out Nonsmokers

For the current study, Dr. Yang and colleagues scanned and analyzed the genomes of 2272 participants who had never smoked, nearly 900 of whom were lung cancer patients. It took them 12 years to identify and enroll these study participants.

"It has been very hard to do this research because never smokers have been mingled with smokers in previous studies, and what usually pops up are genes related to nicotine dependence," Dr. Yang said.

The researchers began by examining DNA samples from 754 never smokers, and analyzed 331,918 DNA single-nucleotide polymorphisms (SNPs) in 377 matched case–control pairs to find the genetic variations most likely to alter the risk for lung cancer in never smokers. The scans looked at areas inside and outside genes, and at coding and noncoding regions. They turned up 44 "hits" that were substantially different between the lung cancer patients and the healthy control subjects.

The Mayo Clinic genome-wide association study used conditional logistical regression to identify associations between SNPs and lung cancer risk, while controlling for history of chronic obstructive pulmonary disease, exposure to second-hand smoke, and family history of lung cancer. SNPs rs2352028 and rs235209 were adjacent to each other on the same gene, which the researchers identified as a variant of GPC5.

"It was indeed a surprise that we found the specific gene. We believe other genes will emerge with more rigorous search and validation of the genomic hits," Dr. Yang said.

Validation in Independent Cohorts

To validate their findings, the researchers took the 44 most frequently occurring genetic alterations from the Mayo study and assessed them in 2 independent groups of never smokers: 735 people (328 patients and 407 healthy controls) from the University of Texas M.D. Anderson Cancer Center in Houston, and 253 people (92 patients and 161 healthy controls) from Harvard University in Boston, Massachusetts. The 2 SNPs remained significant in both these replication sets. Another replication of rs2352028 was done in 530 never smokers at the University of California in Los Angeles.

The authors estimate that more than 10% of lung cancer cases in never smokers could be attributed to genetic variations at this locus, and further analysis suggested that the top 2 SNPs were associated with lung cancer in never smokers through their regulation of GPC5 expression.

The final stage of the study involved understanding the function of the gene. "We had to understand whether these hits really represented the functional aspect of the gene, so we tested expression level of GPC5 and found it was significantly reduced," Dr. Yang said.

The GPC5 transcription level was 2-fold lower in adenocarcinoma than in normal lung tissue. "Interestingly, this reduced transcript expression level was not found in lung carcinoid tumors," Dr. Yang said.

Reduced GPC5 expression also led to tumor development in vitro. "If reduction of expression of this gene leads to the development of lung cancer, it suggests that this gene is normally a tumor suppressor," Dr. Yang said. "We believe it helps control cell proliferation and division, but we need to prove its function in animal models."

Important Trigger in One Third of Never Smokers

The researchers calculated that about one third of never-smoker lung cancer patients in this study had the same variation of the underperforming GPC5 gene. Dr. Yang suspects that this is an important cancer trigger in these patients, and that something else is going on in the remaining two thirds of never smokers. "We don't know what that is, but we now have 42 other hits to explore," she said.

The authors conclude: "Genetic variants at 13q31.3 alter the expression of GPC5, and are associated with susceptibility to lung cancer in never smokers. . . . Future studies are needed to investigate the regulatory effects of these SNPs (or tagged variants) and the functional role of GPC5 in lung tumorigenesis."

In an accompanying comment, Ramaswamy Govindan, MD, cautions that "even though this study reports a 2-fold reduction in GPC5 expression in adenocarcinoma tissues compared to matched normal controls, it is far from clear how reduced GPC5 expression could predispose individuals to lung cancer. More studies are needed to confirm these preliminary observations in the tumor samples from those with no history of tobacco smoking." Dr. Govindan is associate professor of oncology at Washington University School of Medicine in St. Louis, Missouri.

The study was supported by the US National Institutes of Health and by the Mayo Foundation. Dr. Yang and Dr. Gazdar have disclosed no relevant financial relationships. Dr. Govindan reports receiving consulting fees from Genentech and Astra-Zeneca.

Lancet Oncol. 2010;11:304-305, 321-330.

GEFITINIB FOR BREAST CANCER?

NEW YORK (Reuters Health) Mar 25 - Adding the epidermal growth factor receptor (EGFR) inhibitor gefitinib to anastrozole improves progression-free survival in postmenopausal women with hormone receptor-positive metastatic breast cancer, new research shows.

In the March 15th issue of Clinical Cancer Research, the researchers note that gefitinib inhibited HER2-overexpressing breast cancer cells in preclinical studies.

In a phase II trial, Dr. Massimo Cristofanilli from The University of Texas M. D. Anderson Cancer Center, Houston, and colleagues compared the combination regimen with anastrozole plus placebo. They randomized 93 postmenopausal breast cancer patients with hormone receptor-positive metastatic disease: 43 to the intervention group and 50 to the control group.

Women who received anastrozole plus gefitinib had longer median progression-free survival (14.7 vs 8.4 months) and higher clinical benefit rates (49% vs 34%).

The objective response rate was numerically lower with anastrozole plus gefitinib (2%) than with anastrozole plus placebo (12%), but the difference was not statistically significant.

In a post hoc analysis, a history of endocrine treatment had an adverse effect on survival in the gefitinib/anastrozole group. Among the women who received the two-drug regimen, median progression-free survival was 11.2 months with previous endocrine therapy, compared to 20.2 months without it.

Baseline biomarker levels, serum levels of HER2, and serum EGFR levels had no impact on progression-free survival or clinical benefit rates.

Adverse events were mostly mild, although the incidence of treatment-related adverse events was higher for anastrozole-gefitinib (79%) than for anastrozole-placebo (38%). Serious adverse events occurred with similar frequency in the anastrozole plus gefitinib (6/43, 14%) and anastrozole plus placebo (8/50, 16%) arms of the study.

"This study showed that anastrozole in combination with gefitinib was associated with a marked advantage in progression-free survival and a numerical improvement in clinical benefit rate compared with anastrozole plus placebo, in spite of smaller than planned patient numbers, and that the combination was tolerated in postmenopausal women with hormone receptor-positive metastatic breast cancer," the investigators conclude.

Clin Cancer Res 2010;16:1904-1914.

EVEROLIMUS FOR GASTRIC CANCER

NEW YORK (Reuters Health) Mar 25 - Everolimus may help control previously treated metastatic gastric cancer, according to a report in the March 15th Journal of Clinical Oncology.

"There are very limited treatment options for patients who progress despite the standard treatment for this aggressive cancer," lead author Dr. Toshihiko Doi from National Cancer Center Hospital East, Chiba, Japan, told Reuters Health in an email. "The results from this study demonstrate that everolimus has the potential to provide an effective new option for these patients."

In a single-arm phase II study, Dr. Doi and colleagues tested the safety and efficacy of everolimus monotherapy in 53 patients whose gastric cancer had progressed despite one or two prior chemotherapy regimens (with at least one containing fluorouracil or platinum derivatives, taxanes, or irinotecan).

Patients received 10 mg/day orally until progression, unacceptable toxicity, or study discontinuation for any other reason.

Twenty-eight of 50 patients (56.0%) in the per protocol analysis and 29 of 53 in the full analysis (54.7%) achieved some period of progression-free survival (median, 2.7 months). There were no complete responses.

Nearly half the patients (45%) had a decrease in tumor size, with the maximum best change reaching a 34% decrease in sum of longest diameters when compared with baseline.

The proportion of patients with stable disease (56.0%) and progressive disease (44.0%) was similar in the second-line and third-line treatment subgroups.

The median overall survival was 10.1 months.

The most common adverse events were stomatitis, anorexia, fatigue, rash, nausea, peripheral edema, diarrhea, and pruritus. Twenty patients (37.7%) had grade 3 adverse events, and 4 patients had grade 4 treatment-related adverse events.

At the time of the report, 36 (67.9%) of patients had died, 33 from gastric cancer, 2 from aspiration pneumonia unrelated to everolimus, and 1 from an unknown cause.

"We are now conducting a phase 3 trial for gastric cancer," Dr. Doi said. "GRANITE-1 (GastRic ANtItumor Trial with Everolimus-1) is a randomized, double-blind, placebo-controlled phase 3 clinical trial comparing continuous treatment with everolimus plus best supportive care versus placebo plus best supportive care in patients with advanced gastric cancer whose disease has progressed after prior systemic chemotherapy regimens for advanced disease."

J Clin Oncol 2010.

SAFE SEX AND OROPHARYNGEAL CARCINOMA

March 30, 2010 — The incidence of oropharyngeal carcinoma related to human papillomavirus (HPV) has been increasing in recent years, and there is speculation that this is the result of the "sexual revolution" of the 1960s.

This increase in the incidence of HPV-related oropharyngeal cancer has important public health implications, British experts warn in an editorial published online March 25 in the British Medical Journal.

HPV-related oropharyngeal carcinoma appears to be a new and distinct disease entity, with better survival than the classic non-HPV-related disease, they point out.

"These patients are typically younger and employed, and — because outcomes seem to be more favorable than for patients with non-HPV-related carcinoma — they will live longer with the functional and psychological sequelae of their treatment. Consequently, they need prolonged support from health, social, and other services, and may require help returning to work," write the authors, headed by Hisham Mehanna, BMedSc, MB ChB, FRCS, director of the Institute of Head and Neck Studies and Education at University Hospital in Coventry, United Kingdom.

However, currently, there is no good evidence to support managing patients with HPV-related head and neck cancer differently from those whose tumors are not HPV-related, the researchers write.

Several studies are being planned to evaluate different treatment options, and Dr. Mehanna and colleagues urge clinicians to offer all patients with oropharyngeal cancer the opportunity to enroll in a clinical trial. However, until data from those trials are available, "we suggest that clinicians should not change their current treatment policies."

Maura Gillison, MD, PhD, professor of medicine, epidemiology, and otolaryngology at Ohio State University in Columbus, who was approached for independent comment, told Medscape Oncology that she agrees.

Currently, patients should be treated the same, whether they are HPV positive or negative, she said, but they should be "strongly encouraged" to participate in trials.

Increase Linked to Sexual Behavior?

As evidence for the increasing incidence of HPV-related oropharyngeal carcinoma, the researchers cite several studies. One of these, conducted in Stockholm, Sweden, found a progressive proportional increase in HPV detected in biopsies taken to diagnose oropharyngeal cancer, from 23.3% in the 1970s, to 29% in the 1980s, 57% in the 1990s, 68% in 2000 to 2002, 77% in 2003 to 2205, and 93% in 2006 and 2007 (Int J Cancer. 2009:125:362-366).

One reason for this increase could be the sexual transmission of HPV, primarily through orogenital intercourse, Dr. Mehanna and colleagues write.

They also cite a recently published pooled analysis of 8 multinational studies conducted by the International Head and Neck Cancer Epidemiology (INHANCE) consortium (Int J Epidemiol. 2010;39:166-181). Using pooled data, this group compared 5642 patients with head and neck cancer and 6069 control subjects, and found that the risk of developing oropharyngeal carcinoma was associated with a history of 6 or more lifetime sexual partners, 4 or more lifetime oral sex partners, and — for men — an earlier age at first sexual intercourse.

The association between HPV-related oropharyngeal cancers and sexual behavior — having several sexual partners, and with oral sex and "French kissing" — has been reported in previous studies. Last year, American experts highlighting the increase in HPV-related oropharyngeal cancer suggested an association with an increase in the practice of oral sex among white, younger Americans, as reported previously by Medscape Oncology.

Dr. Gillison told Medscape Oncology that "it is clear that the strongest behavioral risk for [HPV-related oropharyngeal cancer] is the lifetime number of oral sex partners."

"However, there are no data to specifically link the increase in disease incidence to changes in oral sexual behaviors over time," she added, pointing out that sexual-behavior surveys in the United States did not collect this type of information before the 1990s.

"This is something that I have looked at carefully," Dr. Gillison said, and she believes that the available data suggest that the sharp increase in HPV-related oropharyngeal cancer is a result of the sexual revolution of the 1960s.

Legacy of the Sexual Revolution

"Our own work, using the [Surveillance, Epidemiology, and End Results] database, shows a strong cohort effect, which means the greatest determinant of risk in any age group is the year that you were born," Dr. Gillison reported.

"These cohort effects are largely driven by societal changes, and they tend to affect people first who are younger, because they are the people leading the behavioral changes," she explained.

During the 1960s, teenagers and young adults were more active sexually than previous generations, and having multiple sexual partners became more acceptable. "The more sexual partners you have, the greater the risk of contracting any sexually transmitted disease, including HPV," Dr. Gillison pointed out.

The time lag between an oral HPV infection and the development of HPV-related oropharyngeal cancer is between 15 and 30 years, and the age at which this cancer is usually diagnosed is 50 years or more.

So the increase in this cancer that was seen in the 1990s and the 2000s is likely to be the result of young people participating in increased sexual activity in the 1960s and 1970s, Dr. Gillison suggested.

"We saw a really sharp climb in the incidence in 2000," Dr. Gillison noted. "So you have to think: What were these people [now 50 or more years old] doing 20 to 30 years ago?"

Dr. Mehanna told Medscape Oncology that he "totally agrees."

The time line of the sudden increase in these cancers seen in the past decade and the 20 to 30 years that it takes for HPV-related cancer to develop points to changes in sexual behaviors that began in the 1960s and 1970s, he said. "The time frame fits," he said, although he added that "this is conjecture."

However, there are many points that are backed up with data. "What we know for sure is that HPV causes oropharyngeal cancer, and we understand the molecular mechanisms involved, so we know how it causes it," Dr. Mehanna explained. "We also know that patients who have HPV-related oropharyngeal cancers are more likely to have had 6 or more sexual partners or 4 or more oral sex partners," he said, and men are more likely to have started having sex at an earlier age. This [fits] with data for cervical cancer, also caused by HPV, which is more likely in women who become sexually active at an earlier age, he noted.

Rethink on HPV Vaccination?

Because a vaccine against HPV is already marketed for use in girls and young women to prevent cervical cancer, and was recently approved for use in boys to prevent genital warts, there has been speculation about whether this vaccine will also protect against HPV-related oropharyngeal cancer.

Dr. Gillison points out that there is no scientific evidence, as yet, to show that HPV vaccination does protect against HPV-related orophageal cancer. "It ought to," she explained, because this cancer is mainly associated with HPV type 16, and this is one of the virus types that the vaccines contain. "But science can be surprising, and things don't always work out as we expect," she warned. She pointed out that the oral cavity is very different from the genital area, and the differences in mucosal surfaces and in the antibodies in saliva and genital secretions might alter the response to vaccination.

"Whether the currently available HPV vaccines have the potential to prevent oral HPV infections that lead to cancer, and thereby reverse the current upward incidence trends documented now in the United States, the United Kingdom, and Sweden, is an important and unanswered question," Dr. Gillison commented.

"Unfortunately, the studies designed to evaluate this question that were slated to start next month in young men have recently been cancelled by the pharmaceutical sponsors," she added.

In their editorial, Dr. Mehanna and colleagues suggest that the recent rapid rise in HPV-related oropharyngeal carcinoma might alter some of the cost-effectiveness considerations about this vaccine and, in particular, its use in boys before they become sexually active.

The HPV vaccination of boys was judged to be not cost-effective in a recent analysis (BMJ 2009;339:b3884), but this decision was made on the basis of old data, Dr. Mehanna explained to Medscape Oncology. The data in that cost-effectiveness study only go up to 2003, but there has been a considerable increase — a doubling, in fact — since then, he said. There are data from 2009 that suggest that about 70% of oropharyngeal cancer is HPV-positive, compared with about 35% in 2003, he noted.

Hence, that study underestimated the incidence of HPV-related oropharyngeal cancer, Dr. Mehanna said, and a new cost-effectiveness analysis needs to be carried out to take these new incidence data into account. "It may well turn out to be cost-effective," he added.

Dr. Mehanna is director of the Institute of Head and Neck Studies and Education, which does contract work for GlaxoSmithKline. One of his coauthors, Terence Jones, from the Liverpool CR-UK Cancer Centre, School of Cancer Studies, Division of Surgery and Oncology, in the United Kingdom, is involved in a clinical trial in patients with HPV-related oropharyngeal carcinoma with a therapeutic vaccine that the manufacturer (Advaxis) is providing free of charge.

DUTASTERIDE PROSTATE CANCER PREVENTION

March 31, 2010 — New results showing that dutasteride (Avodart, GlaxoSmithKline) reduces the risk for prostate cancer have propelled the subject of chemoprevention for prostate cancer into the spotlight once again.

But the latest results do not convince an expert who has spoken out against this approach in the past; he does so again in an editorial accompanying the study in the March 31 issue of the New England Journal of Medicine.

The study, known as Reduction by Dutasteride of Prostate Cancer Events (REDUCE), was conducted in men considered to be at a high risk for prostate cancer because of their age (50 to 75 years of age), an elevated level of prostate-specific antigen (PSA), or because they had already had a prostate biopsy because of suspicion of prostate cancer.

Over the course of 4 years, significantly fewer prostate cancers were detected in men taking dutasteride than in those taking placebo, representing a relative risk reduction of 22.8% (P < .001).

The researchers, headed by Gerald Andriole, MD, chief of urologic surgery at Washington University School of Medicine in St. Louis, Missouri, conclude that dutasteride "may be considered as a treatment option for men who are at high risk of prostate cancer."

The data from this trial, which was sponsored by the manufacturer of dutasteride, have been submitted for approval for the indication of prostate cancer risk reduction, Dr. Andriole told Medscape Oncology. Currently, dutasteride is marketed for use in benign prostatic hyperplasia.

Nothing New?

Editorialist Patrick Walsh, MD, from the James Buchanan Brady Urological Institute at Johns Hopkins Medical Institutions in Baltimore, Maryland, told Medscape Oncology that the new data on dutasteride are similar to what has been seen with finasteride (Proscar, Merck & Co), and he believes that neither drug should be prescribed for the chemoprevention of prostate cancer.

"Dutasteride and finasteride do not prevent prostate cancer, but merely temporarily shrink tumors that have a low potential for being lethal," Dr. Walsh writes in his editorial.

Furthermore, the use of these drugs for prevention may be somewhat risky," he warned.

These drugs suppress PSA levels, Dr. Walsh told Medscape Oncology. This is "worrisome," he explained, because a decrease in PSA might convince men that the drug is preventing prostate cancer and lull them into a false sense of security that could delay a diagnosis "until they have disease that is difficult to cure," he said.

"Major Distinction" Between Findings

Dr. Andriole agreed that the broad results for the 2 drugs are similar — dutasteride was shown to reduce the risk for prostate cancer by 23%, which is close to the 25% reduction seen with finasteride.

But there is a "major distinction" between the 2 drugs in the findings of high-grade tumors, he told Medscape Oncology.

This has been a major concern with the finasteride data. The 7-year Prostate Cancer Prevention Trial found a reduction in low-grade tumors, but at the same time found an increase in high-grade tumors in the drug group over the placebo group. However, later analyses suggested that the effect of finasteride that reduced the size of the prostate made these high-grade tumors easier to find, rather than increasing their incidence.

In the just-published REDUCE trial, Dr. Andriole said there was "no increase in high-grade tumors in the raw data."

Although the numbers show a significant increase in high-grade tumors in the dutasteride group, compared with the placebo group (12 vs 1; P = .003), Dr. Andriole asserted that this imbalance can be explained by the men in the placebo group being excluded from the trial if their first biopsy found a tumor. If those men had remained in the study and been biopsied again a few years later, some of their tumors "likely would have been upgraded," he explained, and this would have resulted in the number of high-grade tumors in the 2 groups being comparable. "This so-called tumor upgrading has been observed in other studies," he said, adding that this point is elaborated upon in the discussion section of their paper.

Dr. Andriole also noted that if the mathematical modeling that was applied to the finasteride data was applied to the dutasteride data, it would actually show a statistically significant 38% reduction in the risk for high-grade tumors. This is not detailed in their paper, but is explained in a supplementary appendix, he said.

Recommended for Men at High Risk

Dr. Andriole told Medscape Oncology that he recommends prescribing dutasteride to men who are at high risk for prostate cancer (because of elevated levels of PSA, such as in this trial, or because of a family history of the disease). "This drug can reduce the man's chance of being overdiagnosed and overtreated for prostate cancer," he added.

In addition, he believes that the benefits of reducing the risk for prostate cancer and the improvement seen in outcomes related to benign prostatic hyperplasia outweigh the risk for adverse effects, which include sexual dysfunction and, in this trial, heart failure.

The sexual adverse effects, which include erectile dysfunction (reported in 9% of men taking dutasteride and in 5.7% of men taking placebo; P < .001), are reversible, Dr. Andriole said, and if they do appear, the drug can be discontinued, he added. Heart failure (reported in 0.7% of men taking dutasteride and in 0.4% of men taking placebo; P = .03) has not been reported as an adverse effect with these drugs, he noted. He suspects that the cases seen in this trial are related to the concomitant use of alpha blockers, although he admitted that this is "speculation."

Use Recommended by ASCO and AUA

The American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) jointly recommended the use of both dutasteride and finasteride in asymptomatic men to reduce the risk for prostate cancer in new guidelines issued in February 2009.

However, to date there has been little use of these drugs for this indication, several experts have told Medscape Oncology in previous interviews. This is an off-label use at present; both drugs are marketed for benign prostatic hypertrophy (finasteride is also marketed for male pattern baldness).

Dr. Andriole agreed that there has been little use of finasteride for reducing the risk for prostate cancer, and believes that this stems from concern over the high-grade tumor findings. He believes that the new data on dutasteride will "lay that anxiety to rest," and that these latest data will lead to an increase in the use of dutasteride for this indication.

Expert Discourages Use for Prevention

Dr. Walsh is firmly opposed to the use of these drugs for prostate cancer risk reduction. He has spoken out against finasteride in comments made in response to an article about the drug preventing cancer that made the front page of the New York Times (June 15, 2008).

"I am very concerned about encouraging patients and general physicians to use this drug," he wrote in the winter 2009 issue of Prostate Cancer Discovery. He notes finasteride does not prevent prostate cancer, "it just prevents men from knowing they have it!"

"First, it has no primary effect in reducing the number of men who will have a positive biopsy," he writes. "Second, men will believe that it prevents cancer, will be pleased that their PSA levels fall, and will not understand the potential danger of undiagnosed high-grade disease."

Dr. Walsh told Medscape Oncology that the comments he made about finasteride at that time apply equally to dutasteride.

"[REDUCE] showed that there was a 23% reduction in low-grade tumors that the patients would never have known they had," he said. "Does this sound like an indication to take a pill with sexual side effects that costs $4 a day?"

In his editorial, Dr. Walsh reviews previous studies on finasteride and the latest study on dutasteride. He points out that neither drug "significantly reduced the risk of prostate cancer among men who were followed closely and who underwent a biopsy because of an elevated PSA level (corrected for the effect of the drug) or an abnormal digital rectal examination." He adds that, "unfortunately, this is the setting that would be used for prevention."

But this approach "will continue to be pushed because of financial interests," he told Medscape Oncology. The clinical trials have been huge and the companies involved "must have spent a ton of money on it," he noted.

The REDUCE trial was supported by GlaxoSmithKline, manufacturer of dutasteride, and 4 of the coauthors are employees of the company. Dr. Andriole reports receiving consulting or advisory fees from GlaxoSmithKline and 8 other pharmaceutical companies; several coauthors report receiving consulting, advisory, or lecture fees from GlaxoSmithKline. Details are in the paper. Dr. Walsh has disclosed no relevant financial relationships.

N Engl J Med. 2010;363;1192-1202, 1237-1238.