DIFFERENCES BETWEEN ANASTRAZOLE AND LETROZOLE

Br J Cancer. 2011 Mar 1. [Epub ahead of print]

Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole - of clinical importance?

Geisler J.

Institute of Clinical Medicine, University of Oslo, Faculty Division at Akershus University Hospital, Sykehusveien 27, Lørenskog N-1478, Norway.

Abstract

Aromatase inhibition is the gold standard for treatment of early and advanced breast cancer in postmenopausal women suffering from an estrogen receptor-positive disease. The currently established group of anti-aromatase compounds comprises two reversible aromatase inhibitors (anastrozole and letrozole) and on the other hand, the irreversible aromatase inactivator exemestane. Although exemestane is the only widely used aromatase inactivator at this stage, physicians very often have to choose between either anastrozole or letrozole in general practice. These third-generation aromatase inhibitors (letrozole/Femara (Novartis Pharmaceuticals, Basel, Switzerland) and anastrozole/Arimidex (AstraZeneca, Pharmaceuticals, Macclesfield, Cheshire, UK)), have recently demonstrated superior efficacy compared with tamoxifen as initial therapy for early breast cancer improving disease-free survival. However, although anastrozole and letrozole belong to the same pharmacological class of agents (triazoles), an increasing body of evidence suggests that these aromatase inhibitors are not equipotent when given in the clinically established doses. Preclinical and clinical evidence indicates distinct pharmacological profiles. Thus, this review focuses on the differences between the non-steroidal aromatase inhibitors allowing physicians to choose between these compounds based on scientific evidence. Although we are waiting for the important results of a still ongoing head-to-head comparison in patients with early breast cancer at high risk for relapse (Femara Anastrozole Clinical Evaluation trial; 'FACE-trial'), clinicians have to make their choices today. On the basis of available evidence summarised here and until FACE-data become available, letrozole seems to be the best choice for the majority of breast cancer patients whenever a non-steroidal aromatase inhibitor has to be chosen in a clinical setting. The background for this recommendation is discussed in the following chapters.British Journal of Cancer advance online publication, 1 March 2011; doi:10.1038/bjc.2011.58 www.bjcancer.com.

INTERMITTENT ANDROGEN SUPPRESSION AS EFFECTIVE AS CONTINUOUS TREATMENT FOR PROSTATE CANCER

A phase III randomized trial comparing intermittent versus continuous androgen suppression in patients with PSA progression after radical radiotherapy

22.02.11

Category: Scientific News

Intergroup trial shows that intermittent androgen suppression is non-inferior to continuous androgen deprivation in men with PSA recurrence after radical therapy

In men with PSA recurrence after radical radiotherapy, intermittent androgen suppression has been suggested by phase II trials to improve quality of life (QoL) but effects on survival were unknown. In the NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/UK intercontinental CRUKE/01/013 randomized phase III trial, investigators compared intermittent androgen suppression vs continuous androgen deprivation to test for non-inferiority with respect to overall survival.

Eligible men had rising PSA > 3.0 ng/ml more than one year after radical radiotherapy, either initial or salvage, for localized prostate cancer. Patients could receive up to 1 year of neo/adjuvant androgen deprivation therapy. Stratification factors were time since radical radiotherapy, initial PSA, prior radical prostatectomy and prior androgen deprivation therapy. Intermittent androgen suppression was delivered for 8 months in each cycle with restart when PSA reached >10 ng/ml off treatment. Primary endpoint was overall survival; secondary endpoints included time to hormone refractory state, QoL, cholesterol/HDL/LDL, duration of treatment/non-treatment intervals, time to testosterone and potency recovery. The independent Data and Safety Monitoring Committee recommended halting the trial after a planned interim analysis demonstrated that a pre-specified stopping boundary for non-inferiority was crossed.

Investigators randomized 1,386 patients, 690 to intermittent and 696 to continuous androgen deprivation. Arms were balanced for important baseline factors.  Median follow up was 6.9 years. Intermittent androgen suppression patients completed a median of 2 x 8 month cycles. A total of 524 deaths were observed (268 on intermittent vs 256 on continuous androgen deprivation). Median overall survival was 8.8 vs 9.1 years on intermittent and continuous androgen deprivation arms, respectively (p=0.009). The intermittent androgen suppression arm had more disease related (122 vs 97) and fewer unrelated (134 vs 146) deaths. Time to the hormone refractory state was statistically significantly improved on the intermittent androgen suppression arm (p=0.024). Intermittent androgen suppression patients had reduced hot flashes, but otherwise there was no evidence of differences in adverse events, including myocardial events or osteoporotic fractures.

The authors, who presented results at the fourth annual Genitourinary Cancers Symposium (17-19 February 2011, Orlando, USA), concluded that in men with PSA recurrence after radical radiotherapy, intermittent androgen suppression, given as described herein, is non-inferior to continuous androgen deprivation with respect to the overall survival.

The Genitourinary Cancers Symposium was co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology and the Society of Urologic Oncology.

DENOSUMAB FOR PROSTATE CANCER WITH BONE METASTASES

Lancet. 2011 Feb 24. [Epub ahead of print]

Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study.

Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C.

Institut Gustave Roussy, University of Paris Sud, Villejuif, France.

Abstract

BACKGROUND: Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer.
METHODS: In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed.
FINDINGS: 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9-18·5) for patients on denosumab and 11·2 months (IQR 5·6-17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8-24·9) with denosumab compared with 17·1 months (15·0-19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71-0·95; p=0·0002 for non-inferiority; p=0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p=0·09).
INTERPRETATION: Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer.

ASCO GUIDELINESS FOR BONE MODIFYING DRUGS IN METASTATIC BREAST CANCER

March 2, 2011 — An updated guideline on the use of bone-modifying agents in patients with metastatic breast cancer have been issued by the American Society of Clinical Oncology (ASCO). The guideline now includes the novel drug denosumab (Xgeva, Amgen), which was approved late last year, in addition to the bisphosphonates zoledronic acid and pamidronate.
The update was published online February 22 in the Journal of Clinical Oncology.
Previous versions of this guideline (which was last updated in 2003) referred specifically to the use of bisphosphonates in breast cancer, which were the only bone-active drugs indicated in this patient population. Now that denosumab, an anti-RANKL monoclonal antibody, is also available, the guideline refers to "bone-modifying agents."
In addition, the scope of the guideline has been narrowed to consider only metastatic breast cancer, the authors explain. A separate update will cover the use of bone-modifying agents as adjuvant treatment for breast cancer and in managing treatment-associated bone loss.
Start Therapy When There is Bone Destruction
The updated guideline recommends that bone-modifying agents be used in patients with metastatic breast cancer who have evidence of bone destruction on plain radiographs.
In cases where the plain radiographs are normal but there is an abnormal bone scan, and bone destruction can be seen on an abnormal computed tomography or magnetic resonance imaging scan, the panel consensus is that "starting bisphosphonates is considered reasonable."
Once initiated, the panel recommends that bone-modifying agents be continued "until evidence of substantial decline in a patient's general performance status." However, the panel emphasizes that clinical judgement must be used to decide what constitutes a "general decline," and notes that there is no evidence that addresses the consequences of stopping bone-modifying agents after 1 or more skeletal-related events have occurred.
Three Drugs to Choose From
Three choices of therapies is outlined: denosumab 120 mg subcutaneously every 4 weeks; pamidronate 90 mg intravenously over no less than 2 hours every 3 to 4 weeks; and zoledronic acid (Zometa, Novartis) 4 mg intravenously over no less than 15 minutes every 3 to 4 weeks.
"There is insufficient evidence relating to efficacy to support one bone-modifying agent over another," the authors state.
When asked about this in an interview with Medscape Medical News, lead author Catherine Van Poznak, MD, breast medical oncologist at the University of Michigan, Ann Arbor, said that the panel of experts had chosen these words very carefully. She acknowledged that there have been head-to-head clinical trials comparing denosumab and zoledronic acid that have shown some superior outcomes at some end points for denosumab, but when all of the available data were taken into consideration, the panel felt that the evidence was insufficient to recommend any one agent over another, she explained.
For each individual patient, there are a number of factors that should be taken into consideration in addition to efficacy, Dr. Van Poznak emphasized; these include mode of administration, toxicity profile, patients preference, and cost.
Denosumab is administered by subcutaneous injection, whereas zoledronic acid and pamidronate are administered by intravenous infusion, she noted. In addition, the toxicity profiles are different — for example, denosumab is associated with a risk for hypocalcemia, and zoledronic acid and pamidronate are associated with a risk for renal toxicity and require renal function monitoring.
Renal Monitoring With Bisphosphonates
The requirements for renal monitoring with the 2 bisphosphonates are outlined in detail in the updated guideline; although they are new to the guideline, they are not new to physicians.
"Our knowledge of renal toxicity is not really new," because before the updates to the guideline, there were US Food and Drug Administration (FDA) changes to the labeling (in 2005), Dr. Van Poznak explained.
Pamidronate and zoledronic acid are associated with renal deterioration, particularly in patients with preexisting renal impairment and in those who receive multiple cycles of bisphosphonate therapy, the authors write.
The 2 drugs can be used without dosage modification in patients with a calculated serum creatinine clearance above 60 mL/min, but lower levels require dosage modification (details are outlined in the product labels). In addition, serum creatinine levels should be monitored before each dose of pamidronate or zolendronic acid, in accordance with FDA-approved labeling, the panel writes.
Renal monitoring is not required with denosumab, which offers a clear advantage over the bisphosphonates, clinicians reporting the comparative clinical trials have emphasized.
Osteonecrosis of the Jaw
Another new item in the update, but again not new to clinicians, is the association of these drugs with "the uncommon but potentially serious" condition of osteonecrosis of the jaw (ONJ).
The first reports of ONJ associated with intravenous bisphosphonates appeared in 2003; since then, a body of data has built up on this adverse event, with recent reports linking it to oral bisphosphonates and denosumab.
Dr. Van Poznak noted that the risk for ONJ in cancer patients treated with denosumab appears to be comparable to that with zolendronic acid. A meta-analysis of 3 pivotal clinical trials that compared denosumab with zolendronic acid head to head for the treatment of bone metastases in advanced myeloma patients found that ONJ occurred as an adverse event with both drugs at a rate that was not statistically significantly different. The rates were 1.8% with denosumab and 1.3% with zolendronic acid (P = .13), according to data reported last year at the Cancer and Bone Society 10th International Conference (Brown JE, et al. Abstract OC-9).
The update committee concurs with the FDA labeling, which recommends that all cancer patients in whom the use of bone-modifying agents are being considered should receive a dental examination and undergo necessary preventive dentistry prior to initiating therapy. While taking these drugs, patients should maintain optimal oral hygiene and, if possible, avoid invasive dental procedures that involve manipulation of the jaw bone or periosteum.
Other Modalities Needed For Bone Pain
The update also has a change in the timing of the management of bone pain; the new recommendation is that treatment of bone pain should be initiated at the onset of pain, and this should be done in concert with the use of bone-modifying agents. "This is required by good clinical practice," the experts write.
Bone-modifying agents have been shown to reduce pain scores and analgesic use in clinical trials. They are helpful in controlling bone pain, "but they should not supplant established practices in managing bone pain," Dr. Van Poznak emphasized.
The standard of care for pain management includes the use of nonsteroidal anti-inflammatory drugs, opioid and nonopioid analgesics, corticosteroids, adjuvant agents, interventional procedures, systemic radiopharmaceuticals, local radiation therapy, and surgery, the panel notes.
"Bone-modifying agents are an adjunctive therapy for cancer-related bone pain control and are not recommended as first-line treatment for cancer-related pain," the panel concludes.
Dr. Van Poznak reports acting as a consultant to Amgen, and receiving research funding from Amgen and Novartis. Coauthor Gary Yee, PharmD, FCCP, BCOP, from the University of Nebraska Medical Center in Omaha, reports acting as a consultant to Amgen and Roche. Coauthor Linda Bosserman, MD, from Rancho Cucamonga, California, reports acting as a consultant to Amgen and Roche, and receiving honoraria from Abraxis BioScience, Amgen, and Roche.
J Clin Oncol. Published online February 22, 2011. Abstract

RISK FACTORS FOR TRIPLE NEGATIVE BREAST CANCER

March 4, 2011 — Two of the largest studies to date looking at triple-negative breast cancer have found that reproductive factors — specifically, pregnancy and multiple childbirth — and obesity and lack of physical activity increase the risk for the disease. This subtype of breast cancer, which is negative for estrogen receptor, progesterone receptor, and HER2, accounts for 10% to 20% of all breast cancers.
Both studies used data from more than 155,000 women enrolled in the Women Health's Initiative. In that cohort, 307 women were diagnosed with triple-negative breast cancer after a follow-up of 8 years, and 2610 were diagnosed estrogen-receptor (ER)-positive breast cancer.
One study, looking at body size and physical activity, was published online March 1 in Cancer Epidemiology, Biomarkers & Prevention; the other, looking at reproductive history, was published online February 23 in the Journal of the National Cancer Institute.
In the first study, the researchers found that obese women had a 35% higher risk for triple-negative breast cancer than women with the lowest body mass index (BMI); in the second study, women who had never given birth had a 40% lower risk for the disease than those who had experienced a full-term pregnancy. Surprisingly, the number of births affected the risk for triple-negative breast cancer; women who had given birth to 3 or more children were at higher risk than women who had given birth to 1 child (hazard ratio [HR], 1.46; 95% confidence interval [CI], 0.82 to 2.63).
"We found that there were very similar associations between obesity and physical inactivity and both triple-negative and ER-positive disease," said Amanda Phipps, PhD, the lead researcher for both studies and a postdoctoral fellow in the public health sciences division of the Fred Hutchinson Cancer Research Center, in Seattle, Washington, in an interview with Medscape Medical News.
"Our finding that there was a 40% decreased risk for triple-negative breast cancer among women who had never given birth is inconsistent with the existing literature, but not many people have looked at risk factors for this disease, because it's so rare," Dr. Phipps said. Previous research has found either a modest or no association between childbirth and risk for triple-negative breast cancer, she noted.
Different From Other Subtypes
"Our results suggest that triple-negative breast cancer can be a very different disease from other subtypes, and studies that look at risk factors really need to take that into account," Dr. Phipps said. The results suggest that although the hormonal changes of pregnancy make the breast less susceptible to ER-positive cancer, these mechanisms do not affect the risk for triple-negative disease, she noted. And the association between obesity and physical activity and triple-negative disease suggests that mechanisms other than hormonal levels influence the risk for this subtype of breast cancer, she added.
The study of obesity and physical activity found that women in the highest BMI quartile had a 1.35-fold increased risk for triple-negative breast cancer, compared with women in the lowest quartile (95% CI, 0.92 to 1.99); in contrast, women in the lowest quartile had a 1.39-fold increased risk for ER-positive breast cancer, compared with women in the highest quartile (95% CI, 1.22-1.58). Women in the highest physical activity tertile had a lower risk for both triple-negative (HR, 0.77; 95% CI, 0.51 to 1.1.3) and ER-positive (HR, 0.85; 95% CI 0.74 to 0.98) disease.
In the study on reproductive factors, nulliparity was linked to a decreased risk for triple-negative breast cancer (HR, 0.61; 95% CI, 0.37 to 0.97) but an increased risk for ER-positive breast cancer (HR, 1.35; 95% CI, 1.20 to 1.52). Although number of births was associated with an increased risk for triple-negative breast cancer in the study that looked at reproductive risk factors, it was inversely associated with the risk for ER-positive disease (HR for 3 or more births vs 1 birth, 0.88; 95% CI, 0.74 to 1.04).
The small number of women who developed triple-negative breast cancer was a limitation for both studies, and is most likely the reason that the findings on obesity and physical inactivity and risk for triple-negative breast cancer were not statistically significant, Dr. Phipps acknowledged.
Although both studies are among the largest studies ever done on triple-negative breast cancer, more research needs to be done to confirm the findings, Dr. Phipps said. "We'd also like to study the association between these risk factors and younger women," she added.
Dr. Phipps speculated that the findings on the association between pregnancy and an increased risk for triple-negative breast cancer might be due to an abnormal response of the breast to pregnancy. The researchers suggest that obesity and physical inactivity might increase the risk for triple-negative breast cancer by affecting insulin-like growth factors or inflammatory changes in the breast.
Other Mechanisms Involved?
"Obesity and physical inactivity are thought to affect estrogen levels, but this Women's Health Initiative study indicates that other mechanisms may be more important for triple-negative breast cancer," said Leena Hilakivi-Clarke, PhD, professor of oncology at the Georgetown Lombardi Comprehensive Cancer Center, in Washington, DC. She said that inflammatory changes to the breast are the most likely explanation for the findings on obesity and exercise, since they might promote or even initiate the cancer process.
Dr. Hilakivi-Clarke was not involved in these studies, but has conducted research into risk factors for breast cancer, and was approached for comment by Medscape Medical News.
Dr. Hilakivi-Clarke noted that the population of women with triple-negative breast cancer in both studies was too small to really advance our understanding of the disease. "But it does reinforce the fact that there are even more reasons for women to maintain a normal weight and to be physically active," she said.
Dr. Hilakivi-Clarke found the findings on reproduction and triple-negative breast cancer to be particularly interesting. "Future research might look at animal models to see what happens if a tumor that was ER-positive to begin with is exposed to pregnancy," she said. If women already have a malignancy, the hormonal load of pregnancy might cause them to turn the estrogen receptors off," she added.
Dr. Phipps and Dr. Hilakivi-Clarke have disclosed no relevant financial relationships.
Cancer Epidemiol Biomarkers Prev. Published online March 1, 2011. Abstract
J Natl Cancer Inst. Published online February 23, 2011. Abstract

ANAL CANCER RISK INCREASE WITH HPV RELATED GYNECOLOGICAL CANCERS

NEW YORK (Reuters Health) Mar 01 - Gynecologic neoplasms due to human papilloma virus (HPV) can significantly increase a woman's risk of anal cancer, according to a report in the March issue of Obstetrics & Gynecology.
For example, the risk of anal cancer was 17-fold higher for women with vulvar cancer and 16-fold higher with in situ cervical cancer.
Dr. Rocco Ricciardi from Tufts University Medical School, Burlington, Massachusetts, and colleagues used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry to measure the incidence of secondary anal cancers in 189,206 women diagnosed with gynecologic cancers between 1973 and 2007.
There were 255 cases of anal cancer during close to 139 million person-years of follow-up, including 58 cases among 56,876 women with invasive primary gynecologic neoplasm and 197 cases among 132,330 women with in situ gynecologic neoplasm.
The standard incidence ratios for anal cancer were 6.2, 17.4, and 1.8 for women with invasive cervical, vulvar, and vaginal cancer, respectively, and even higher for women with in situ cervical, vulvar, and vaginal cancer: 16.4, 22.2, and 7.6, respectively.
Results were similar when the authors used a restrictive analysis method that removed the potential of confounding from other cancer treatment.
The mean interval between the primary gynecologic malignancy and the primary anal cancer ranged from 7.1 years for invasive vulvar neoplasm to 15.7 years for in situ cervical neoplasm.
The risk of anal cancer among women with a previous cervical cancer was similar whether or not they received radiotherapy for their primary cancer, whereas the data were inconclusive for vulvar and vaginal cancer.
"These data indicate that women with both in situ and invasive cancers of the cervix and vulva are at higher risk for developing anal cancer than the general population and may benefit from close observation and anal cancer screening," the researchers conclude.
As for surveillance, Dr. Ricciardi said, "There are no definitive guidelines to date. More data are needed that demonstrate a health benefit to screening before guidelines can be developed."
"Further studies are needed to identify the highest risk patients," Dr. Ricciardi said. "Some of these women may benefit solely from a simple rectal exam. A comparison of anal Pap smear versus simple rectal exam would be a good first step."
"According to our data, those treated with irradiation are not protected from the development of incident anal cancer and should still be considered high risk," the investigators said.
Obstet Gynecol. 2011;117:643-649. Abstract

DENOSUMAB MAY BE SUPERIOR THAN ZOLEDRONIC ACID BUT AT HIGH COST

Xgeva, Amgen) is superior to zoledronic acid in preventing skeletal-related events (SREs) in cancer patients with bone metastases.
These new data come from 2 of 3 trials funded by the manufacturer that led to the approval of denosumab for this indication late last year. The third trial has already been published (J Clin Oncol. 2010;28:5132-5139).
Data from these 3 studies were widely publicized when they were reported at meetings last year, and the principal investigators of these trials have spoken enthusiastically about denosumab replacing zoledronic acid in this setting.
However, an editorial commentary published online February 22 in the Journal of Clinical Oncology, which accompanies the publication of one of these trials, adds a qualifier to such proposals.
Howard West, MD, from the Swedish Cancer institute in Seattle, Washington, sees denosumab as "a strong option to displace" zoledronic acid in this setting, but adds that the need to balance cost and benefits means that "it falls short of a mandate for a new standard of care."
Dr. West says denosumab offers "incremental benefit" but "debatable value."
It costs nearly twice as much as zoledronic acid, he points out, and generic versions of zole
dronic acid are due out in early 2013. These will offer "a far less expensive but still comparative alternative," he writes.
Superiority Not Recognized in Update
In addition, the superiority emphasized by the clinical trialists was not recognized in the just-published updated guideline from the American Society of Clinical Oncology on the use of bone-modifying drugs in metastatic breast cancer patients.
This update adds denosumab to the drugs that are recommended for use in this setting, alongside zoledronic acid and pamidronate, but it states that "there is insufficient evidence relating to efficacy to support one bone-modifying agent over another."
When asked about this in an interview with Medscape Medical News, lead author Catherine Van Poznak, MD, breast medical oncologist at the University of Michigan, Ann Arbor, said that the panel of experts who wrote the update chose these words very carefully. She acknowledged that there have been head-to-head clinical trials comparing denosumab and zoledronic acid that have shown some superior outcomes at some end points for denosumab, but when all of the available data were taken into consideration, the panel felt that the evidence was insufficient to recommend any one agent over another, she explained.
For each individual patient, there are a number of factors that should be taken into consideration in addition to efficacy, she emphasized; these include mode of administration, toxicity profile, patients preference, and cost.
New Clinical Trial Data
The newly published clinical data come from 2 pivotal head-to-head comparator trials.
One of the new trials, published online February 25 in the Lancet, was conducted in 1904 patients with advanced castration-resistant prostate cancer, and showed that denosumab significantly reduced the median time to the first on-study SRE, compared with zoledronic acid (20.7 vs 17.1 months; P = .008 for superiority).
The other, published online February 22 in the Journal of Clinical Oncology, was conducted in 1776 patients with advanced cancer (excluding prostate and breast cancer) and bone metastases or with myeloma. This study showed that denosumab was noninferior to zoledronic acid in delaying time to first on-study SRE, but in this study it was not statistically superior.
The third pivotal head-to-head study was published last year. That trial involved 2046 patients with advanced breast cancer, and like the prostate cancer study, it showed that denosumab was significantly superior to zoledronic acid in reducing the time to first on-study SRE.
When that breast cancer study was published, an accompanying editorial in the Journal of Clinical Oncology (2010;28:5127-5131), authored by Monica Fornier, MD, from the Memorial Sloan-Kettering Cancer Center at Weill Cornell Medical College in New York City, suggested that "denosumab might indeed provide a new clinical standard."
However, the editorial by Dr. West is more circumspect.
Provides "Incremental Gains"
"Bisphosphonate therapy, most commonly zoledronic acid, has been the cornerstone stone of secondary prevention of SREs in patients with solid tumors during approximately the last decade," Dr. West writes.
However, these drugs have several downsides: they are administered by intravenous infusion, so there is a potential for acute-phase reactions; there is a risk for renal toxicity, so there is a need to monitor creatinine function with each administration of the drug; and there is a "small but worrisome risk of osteonecrosis of the jaw, hypocalcemia, and other adverse effects," Dr. West writes.
In addition, enthusiasm "may remain muted by the recognition that the efficacy of these agents is still relatively modest."
Denosumab provides "incremental gains," Dr. West suggests. It delays the time to SRE, but this is a secondary clinical end point, he points out. The trial data so far have shown no effect on progression-free survival or overall survival, although there was a hint of improved overall survival with denosumab in a subset of patients with nonsmall-cell lung cancer in a post hoc analysis.
"This is not to say that a decrease in SREs is not a laudable goal and a clinically significant end point," he notes, but it is "no longer tenable" to compare efficacy and toxicity without also considering cost differentials.
Denosumab offers a clear advantage over zoledronic acid, in that there is no need for renal monitoring, and it offers the convenience to patients of subcutaneous administration, with a lower risk for acute-phase reactions than is seen with intravenous administration. However, denosumab presents its own toxicity concerns, Dr. West points out, including an increased risk for hypocalcemia. It is also associated with osteonecrosis of the jaw (to the same extent as zoledronic acid), when data from all of the 3 comparator trials are considered, Dr. Van Poznak told Medscape Medical News.
Cost is the real sticking point. Denosumab, with its novel mechanism of action, is a first-in-class therapeutic and commands a premium price ($1650 monthly).
It costs nearly twice as much as zoledronic acid, and Dr. West believes that it is appropriate to question "whether the modest incremental gains provided by the newest therapy justify a disproportionate increase in cost."
"It is only fair that oncologists step back and ask whether the heady cost of the newest agents that offer relatively subtle care advantages in bone health, pain control, reduction of nausea/vomiting, or need for blood product support provide such a clear advantage over far less expensive options," he writes.
"The economic reality is that American oncologists simply cannot reflexively recommend the latest and almost invariably most expensive new option for managing clinical end points that are, at best, secondary to the primary goals of cancer treatment if the costs escalate at a rate disproportionate with the benefits that these agents confer," Dr. West concludes.
All 3 clinical trials comparing denosumab with zoledronic acid were funded by Amgen, and some of the coauthors of these papers are Amgen employees. Dr. West, who writes the Blowing Smoke blog on Medscape Medical News, has disclosed no relevant financial relationships.
J Clin Oncol. Published online February 22, 2011. Abstract, Abstract
Lancet. Published online February 25, 2011. Abstract

ADRENALECTOMY CAN BE AVOIDED EVEN FOR LARGE RENAL TUMORS

NEW YORK (Reuters Health) Mar 02 - Adrenal involvement is rare in cases of renal cell carcinoma, even when the tumor is large or in the upper pole. Therefore, concurrent adrenalectomy is not usually necessary, researchers report.
Writing in the April issue of the Journal of Urology published online February 22, lead author Dr. Alexander Kutikov and colleagues at the Fox Chase Cancer Center in Philadelphia, Pennsylvania, note that concurrent adrenalectomy during surgery for renal cell carcinoma was once routine.
"Over the recent decades, however, the necessity of adrenalectomy at the time of nephrectomy has been questioned," Dr. Kutikov told Reuters Health via email.
Recent recommendations indicate that adrenalectomy should be reserved for large tumors of 7 cm or more located in the upper pole. "We felt that this recommendation stemmed largely from historical 'inertia,'" said Dr. Kutikov. "In this study we examined whether the recommendation is in fact valid."
The team evaluated adrenal involvement in 179 patients in the center's kidney cancer registry who had surgery for renal tumors 7 cm in size or larger. In this group, 91 underwent concurrent adrenalectomy at renal surgery.
The investigators report that pathological adrenal involvement was confirmed in only four of the 91 (4.4%). Furthermore, preoperative adrenal imaging had 100% sensitivity and 92% specificity in detecting adrenal involvement, with 100% negative predictive value.
Upper pole location didn't predict adrenal involvement, and there was no survival advantage among the patients who underwent adrenalectomy compared to those who did not, whether the disease was localized or had metastasized.
"Routine adrenalectomy even in patients with large and/or upper pole renal tumors does not appear to be required," Dr. Kutikov and colleagues conclude. "Modern radiographic imaging is extremely sensitive to detect adrenal pathology and should guide management decisions regarding the need for concurrent adrenalectomy."
Dr. Kutikov added: "Regardless of size and location of the renal tumor, the adrenal gland can be safely spared if preoperative imaging definitively rules out an abnormality in the adrenal gland in question."
J Urol. Posted online February 22, 2011. Abstract

LONG TERM PPI USE ASSOCIATED WITH LOW MAGNESIUM LEVELS

March 2, 2011 — Long-term use of prescription proton-pump inhibitors (PPIs) can be associated with hypomagnesemia, which can in turn cause serious muscle spasms (tetany), arrhythmias, and seizures, but may instead be asymptomatic, the US Food and Drug Administration (FDA) cautioned today.
The FDA recommends that clinicians consider checking serum magnesium levels before starting patients on PPIs for long-term therapy (generally 1 year or longer) and when the drugs will be coadministered with other agents that can cause low magnesium levels, such as diuretics or digoxin. For patients on digoxin, "this is especially important because low magnesium can increase the likelihood of serious side effects," the advisory says.
In addition, periodic monitoring of serum magnesium levels in at-risk patients is recommended.
In about 25% of cases reported to and reviewed by the FDA, magnesium supplementation alone was insufficient for correcting hypomagnesemia, and PPI therapy had to be discontinued.
The alert does not specify whether over-the-counter (OTC) formulations of PPIs have been associated with hypomagnesemia, but it does include a list of the products.
The drugs in question include esomeprazole magnesium (Nexium, AstraZeneca), dexlansoprazole (Dexilant, Takeda), omeprazole (Prilosec, Astra-Zeneca; also available OTC), omeprazole/sodium bicarbonate (Zergerid, AstraZeneca; also available OTC), lansoprazole (Prevacid, Novartis; also available OTC) pantoprazole soidum (Protonix, Wyeth/Pfizer; and generics) rabeprazole sodium (AcipHex, Eisai and Ortho-MacNeil), and esomeprazole magnesium/naproxen (Vimovo, AstraZeneca).
More information about today's announcement is available on the FDA Web site.
To report adverse events related to abacavir, contact MedWatch, the FDA's safety information and adverse event reporting program, 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 MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

NCCN 2011 CONFERENCE

March 3, 2011 — The practicalities of molecular testing, the "revamped" treatment of castration-resistant metastatic prostate cancer, and negotiating the goals of advanced cancer care are among the notable topics at the National Comprehensive Cancer Network (NCCN) 16th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care, being held March 9 to 13 in Hollywood, Florida.
The meeting also includes sessions that will update NCCN guidelines for the following cancers: breast, head and neck, nonsmall-cell lung cancer, multiple myeloma, non-Hodgkin's lymphoma, chronic myelogenous leukemia G, melanoma, sarcoma, prostate, and ovarian.
Other sessions include presentations on newer techniques in radiation oncology and hepatitis B screening and chemotherapy.
The meeting will feature, for the sixth consecutive year, a roundtable discussion led by veteran ABC News journalist Sam Donaldson, who is a cancer survivor. This year's topic is "The Many Faces and Challenges of Caregivers."
The roundtable kicks off the conference and is one of the hallmarks of the annual event, as it brings together an eclectic group of people to discuss a cancer topic, often in a highly personal way. The session always features celebrities, whose public lives seem to provide a unifying sense of collective experience.
This year's roundtable panelists are:

• Bill Cowher, former coach of the Pittsburgh Steelers, whose wife Kaye recently died from melanoma
• Suzanne Daulerio, daughter of the late Pat Daulerio, a longtime NCCN staff member
• Jai Pausch, wife of the late Randy Pausch, an academic perhaps best known for his iconic "last lecture," written when he was terminally ill with pancreatic cancer
• Charlie "Chaz" Ebert, wife of Roger Ebert, who has been treated for salivary gland cancer
• Priscilla Mack, breast cancer survivor and wife of Sen. Connie Mack
• Mary Beth Reardon, RN, MS, from the H. Lee Moffitt Cancer Center & Research Institute in Tampa Bay, Florida
• Liz Scott, mother of the late Alex Scott, creator of Alex's Lemonade Stand Foundation, who died from neuroblastoma
• Samuel M. Silver, MD, PhD, from the University of Michigan Comprehensive Cancer Center in Ann Arbor
• Jill Ellen Snow, wife of the late Tony Snow, former White House press secretary who died from colon cancer.

Molecular Testing: Promise vs Practicality
In one of the meeting's roundtable discussions, a group of experts will discuss molecular testing in oncology.
"The intent of the session is to discuss how we are moving further along the path of individualized medicine," said panel member Michael Kolodziej, MD, from Innovent Oncology, a division of US Oncology in Woodlands, Texas.
Dr. Kolodziej reported that he will play the role of the skeptic in the discussion. "The value of molecular testing has yet to proven," he told Medscape Medical News.
Dr. Kolodziej is also a community-based clinician at New York Hematology-Oncology in Albany, and will bring that perspective to the table.
He believes that the promise of molecular testing currently does not jive with its practicalities for community-based clinicians.
He offered the example of one of his patients — a female nonsmoker diagnosed with nonsmall-cell lung cancer. Because she fit the profile of patients who have tumors that might have a rearrangement of the ALK gene, and therefore might benefit from the investigational drug crizotinib (Pfizer), the woman was a candidate for genotyping of her lung tumor tissue.
The patient could not go to Memorial Sloan-Kettering Cancer Center in New York City for the genotyping process, so Dr. Kolodziej needed a commercial lab for the job. "There are only 1 or 2 commercial labs in the whole country that do the test," he said.
There were also "regulatory hurdles" (the state of New York restricts the types of medical tests that can be done) and insurance problems (insurance companies do not recognize some tests, especially ones related to investigational agents), Dr. Kolodziej noted.
"It took weeks to get this sorted out," he said. In the end, the patient did not have the genotype suited for treatment with crizotinib.
Similar problems with timing exist for a gene test in lung cancer that looks for a mutation of the epidermal growth-factor receptor (EGFR), which indicates potential benefit from targeted therapy with an EGFR inhibitor — a problem that Medscape Medical News has previously reported.
Prostate Cancer Notes
"We have completely revamped systemic therapy for castration-resistant metastatic prostate cancer," said James Mohler, MD, chair of the NCCN prostate cancer panel. The revamping includes 2 new treatments and a new agent for the prevention of skeletal-related events, said Dr. Mohler, who is from Roswell Park Cancer Institute in Buffalo, New York.
One of the new treatments is an immunotherapy — sipuleucel-T (Provenge, Dendreon) — which, according to the NCCN, should be considered for asymptomatic men with castration-resistant metastatic prostate cancer.
These men should have a good performance status, an estimated life expectancy of more than 6 months, and no visceral disease.
Sipuleucel-T has been shown in a phase 3 trial to extend survival; mean survival was 21.7 months in the control group and 25.8 months in the treatment group (a 22% reduction in mortality risk).
Symptomatic men in this setting should still first be considered for chemotherapy (docetaxel and prednisone every 3 weeks), according to the guideline.
For a man who fails docetaxel, there is a new second-line option — cabazitaxel (Jevtana, Sanofi-Aventis).
Cabazitaxel has been shown in a phase 3 trial to prolong overall survival; median survival was 15.1 months in the cabazitaxel group and 12.7 months in the mitoxantrone group.
There are limitations to who can be prescribed cabazitaxel, according to the NCCN; patients selected for treatment should be without severe neuropathy and have adequate liver, kidney, and bone marrow function, "given the high risk of neutropenia and other side effects in this population."
Finally, for men with castration-resistant metastatic prostate cancer, the NCCN panel now recommends denosumab as an alternative to zoledronic acid for the prevention of skeletal-related events. A phase 3 study showed denosumab to be the superior agent in some regards, said Dr. Mohler. However, all patients on denosumab should be treated with vitamin D and calcium and undergo periodic monitoring of serum calcium levels because of the risk for hypocalcemia.
Last year, the NCCN made news by recommending, for the first time, active surveillance as the sole initial treatment for men with low-risk and very-low-risk prostate cancer. The guideline was "ahead of its time," said Dr. Mohler at the 2010 meeting.
This year, there is a major change to the active surveillance section of the guideline, Dr. Mohler told Medscape Medical News. "Active surveillance monitoring has been made more rigorous," he explained.
The tightening of monitoring includes a number of new recommendations.
The guideline now advises clinicians that, when the initial biopsy is more than 10 cores, repeat biopsy should be performed within 18 months. When the initial biopsy is fewer than 10 cores, a repeat biopsy should be performed within 6 months of diagnosis. However, for all patients, physicians should "consider" a repeat prostate biopsy as often as 12 months as part of ongoing active surveillance, according to the guideline. The guideline also suggests that a prostate-specific antigen test be performed as often as every 3 months, but at least every 6 months. Also, a digital rectal exam should be performed as often as every 6 months, and at least every 12 months.
Dr. Mohler noted that this guidance contains "consensus recommendations" — in other words, they are not based on evidence from trials.
"It's very hard to provide concrete guidance because of the lack of evidence," he admitted. As it currently stands, the guidance for active surveillance has a long way to go, Dr. Mohler said.
"We hope to do more for patients and urologists to establish the best possible schedule to detect prostate cancer progression," he said. Some such evidence will eventually come from the Surveillance Therapy Against Radical Treatment (START) trial, the first-ever North American phase 3 trial comparing active surveillance with mainstay treatments. The trial is still enrolling patients, but the enrolment is going "horribly," said Dr. Mohler, because of patient apprehensions about active surveillance.
For a variety of reasons, active surveillance is not catching on in the United States as well as it is in other countries. For instance, the conversion rate from surveillance to treatment because of patient anxiety is only about 10% among Canadians in a Toronto-based cohort. In the United States, the conversion rate in 2 different programs — in Baltimore, Maryland and San Francisco, California — is roughly 33%, said Dr. Mohler.

ERIBULIN FOR BREAST CANCER-2,5 MONTHS SURVIVAL BENEFIT

March 3, 2011 — For the first time, a single agent has shown a significant improvement in survival in women with heavily pretreated metastatic breast cancer. That finding for eribulin (Halaven, Eisai) comes from the pivotal phase 3 EMBRACE trial.
These data were reported at last year's annual meeting of the American Society of Clinical Oncology (ASCO), where they stirred up quite a bit of excitement among breast cancer specialists, and they led to the approval of eribulin by the US Food and Drug Administration in November 2010.
The EMBRACE results were published online today in the Lancet. The researchers, headed by Javier Cortes, MD, from the Vall d'Hebron University Hospital, in Barcelona, Spain, conclude that "eribulin showed a significant and clinically meaningful improvement in overall survival compared with treatment of physicians' choice [TPC] in women with heavily pretreated metastatic breast cancer."
"Our demonstration of improved overall survival as the primary end point in women with metastatic breast cancer treated with cytotoxic therapy seems unique, and challenges the idea that such an expectation is unreasonable," they write.
"This global phase 3 study establishes a new standard treatment for women with heavily pretreated metastatic breast cancer, for whom there was previously no chemotherapy treatment with proven survival benefit," they add.
Real-World Comparison
Participants in this study had already received 2 to 5 chemotherapy regimens (median, 4; range, 1 to 7), including an anthracycline and a taxane.
They were randomized in a 2:1 ratio to receive either eribulin (1.4 mg/m² intravenously for 2 to 5 minutes on days 1 to 8 of a 21-day cycle) or TPC. This was defined as any single-agent treatment (chemotherapy, hormonal or biological) or radiotherapy or symptomatic therapy alone. Many physicians chose to use vinorelbine, gemcitabine, or capecitabine, and none chose best supportive care, even though this was an option, said coauthor Christopher Twelves, MD, from the University of Leeds, United Kingdom, when he presented this trial at the ASCO meeting last year.
This represents "a real-life situation," he noted, because there are no guidelines on which chemotherapy to use after third-line therapy.
At the time, the discussant of the paper, Harold Burstein, MD, PhD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, agreed with that description. He makes the same point in an editorial accompanying the study, which he coauthored with his Dana-Farber colleague Nancy Lin, MD.
"Ultimately, the EMBRACE study invited a real-world comparison of best clinical guess versus eribulin," the editorialists write.
The use of TPC is an important strength of this study, say the trialists. Because the results reflect real-life choices made by oncologists and their patients, the benefits of eribulin seen in this trial are "arguably more likely to be generalizable to clinical practice than if the control treatment had been artificially constrained," they write in the paper.
Is Survival Benefit Clinically Meaningful?
The difference between overall survival in the 2 treatment groups was statistically significant; median overall survival was 13.1 months with eribulin and 10.6 months with TPC (hazard ratio, 0.81; P = .041).
This survival benefit is "clinically meaningful," say the trialists, because the median survival benefit of 2.5 months represents an increase of 23% for these women.
This is similar to what has been reported for docetaxel vs mitomycin plus vinblastine (31%), and for capecitabine plus docetaxel vs docetaxel alone (26%).
In addition, they point out that the survival benefit with eribulin was achieved "with a manageable profile of toxic effects." The most common adverse events were asthenia and fatigue (reported by 54% of patients in the eribulin group and 40% in the TPC group) and neutropenia (52% vs 30%). The most common adverse event leading to the discontinuation of eribulin was peripheral neuropathy, occurring in 5% of patients.
However, the editorialists point out that the survival benefit can be measured in weeks, and say that "it is fair to ask whether there is clinical significance."
The outcomes for the TPC group provide "a sobering reminder of the modest results in the nth-line therapy of breast cancer," Dr. Lin and Dr. Burstein note.
Most oncologists participating in a recent survey (Eur J Cancer. 2010;8:77 [abstract 63]) said that they consider prolongation of life by 2 to 6 months to be a "meaningful incremental gain." However, the same survey found that most patients believe that a threshold of 10 months or more is needed to warrant treatment, the editorialists note.
"But surely some survival benefit is better than none at all," they add.
The data from the EMBRACE trial provide "much needed high-level evidence for chemotherapy use in patients with heavily pretreated breast cancer," the editorialists write. "And that evidence suggests that the methods to treat advanced breast cancer are growing, the treatment challenge in refractory disease is a little bit less daunting, and the treatment results are a little bit better than they were before."
The EMBRACE study was funded by Eisai. Several of the study authors report receiving consultancy fees, honoraria, and/or grants from Eisai, as well as from several other pharmaceutical companies; full details are given in the paper. Dr. Lin and Dr. Burstein have disclosed no relevant financial relationships.
Lancet. Published online March 3, 2011.

IT HAPPENS EVERYWHERE

March 4, 2011 — Four cancer genomics papers from researcher Anil Potti, MD, and colleagues have been retracted from prestigious medical journals.
The latest retraction is of a paper on lung cancer genomics published in the New England Journal of Medicine in 2006. In a letter to the journal, Dr. Potti and his coauthors ask that their paper be retracted, and say they "deeply regret" the effect that this action has on the work of other researchers.
This is the fourth retraction by Dr. Potti, who resigned from his positions at the Duke University School of Medicine and the Duke Institute for Genome Science & Policy, both in Durham, North Carolina, last November. He had been suspended by Duke amid concerns about his research and whether or not he had lied on a grant application.
The much cited and now retracted 2006 study, entitled A Genomic Strategy to Refine Prognosis in Early-Stage Non–Small-Cell Lung Cancer (N Engl J Med. 2006;355:570-580), reported on novel gene-expression profiles that predicted the risk for recurrence of nonsmall-cell lung cancer. At that time, Dr. Potti told Medscape Medical News that this was a "huge deal."
"We are moving away from treating cancer patients as a population and are beginning to focus instead on single patients with individual characteristics," he said.
In their retraction published online March 2, the authors write: "Using a sample set from a study by the American College of Surgeons Oncology Group (ACOSOG) and a collection of samples from a study by the Cancer and Leukemia Group B (CALGB), we have tried and failed to reproduce results supporting the validation of the lung metagene model described in the article."
The study has been cited 290 times, according to Thomson Scientific's Web of Knowledge, and a correction to the article was issued in 2007 (N Engl J Med. 2007;356:201-202).
Continuing Saga
The saga of Dr. Potti has been long and tumultuous, involving not only concerns about the validity of his research, but allegations of misconduct. In July 2010, Dr. Potti was suspended by Duke after the publication of an article in The Cancer Letter, which reported that he overstated his academic achievements by claiming to be a Rhodes scholar.
As reported by the New York Times last year, a spokesperson from the Rhodes House at Oxford University in the United Kingdom confirmed that Dr. Potti had never been the recipient of a Rhodes scholarship.
When questions about Dr. Potti's credentials became public, the American Cancer Society (ACS) suspended payment of a $729,000 grant that it had awarded to him to study lung cancer genetics. The grant was given to him on the basis of his resume, which included mention of the Rhodes scholarship, Otis W. Brawley, MD, the chief medical officer of ACS, told the New York Times.
In addition to his suspension, patient enrolment was halted in 3 ongoing trials funded by the National Cancer Institute after a number of biostatisticians and cancer researchers at academic institutions, including Harvard, Princeton, and Johns Hopkins, began questioning the methodology behind the 3 clinical trials in question (2 in lung cancer and 1 in breast cancer).
In a letter sent to the director of the National Cancer Institute, a group of 31 scientists called for the suspension of ongoing trials because of concerns about the prediction models that were being used. The models were developed on the basis of research reported by Dr. Potti and Joseph Nevins, PhD, also from Duke University, but the validity of those models was called into question after peer-reviewed reanalyses of their work.
About the same time, the Lancet Oncology issued an expression of concern over a paper published in the journal in 2007, which described the validation of gene signatures to predict the response of breast cancer to neoadjuvant chemotherapy (Lancet Oncol. 2007;8:1071-1078). This was issued after the journal was contacted by senior author Richard Iggo, PhD, from the Swiss Institute for Experimental Cancer Research in Epalinges, Switzerland, and first author Hervé Bonnefoi, MD, from the Institut Bergonié, University of Bordeaux, France, who "expressed grave concerns about the validity of their report in light of evolving events."
They said that they had repeatedly tried to contact their coauthors at Duke University (including Dr. Potti) who had been responsible for the statistical analyses in the report, but were ignored.
The Lancet Oncology recently issued a retraction of that study (2011;12:116).
In January 2011, Nature Medicine published a retraction of a 2006 article that had been corrected on 4 separate occasions (Nat Med. 2006;12:1294-1300). First author Dr. Potti and his coauthors wrote that they had "been unable to reproduce certain crucial experiments showing validation of signatures for predicting response to chemotherapies, including docetaxel and topotecan." Even though they believed that their underlying approach to developing predictive signatures is valid, "a corruption of several validation datasets precludes conclusions regarding these signatures" (Nat Med. 2011;17:135).
Last November, the Journal of Clinical Oncology retracted a 2007 paper that was coauthored by Dr. Potti (J Clin Oncol. 2007;25:4350-4357). The retraction was reportedly initiated by Dr. Nevins, and stated that the authors "have been unable to reproduce the experiments demonstrating a capacity of a cisplatin response signature to validate in either a collection of ovarian cancer cell lines or ovarian tumor samples" (J Clin Oncol. 2010;28:5229).
N Engl J Med. Published online March 2, 2011. Abstract

ALIMTA-AVASTIN COMBINATION FOR HEAD-NECK CANCER?

NEW YORK (Reuters Health) Feb 24 - The addition of bevacizumab to pemetrexed improves outcomes in patients with recurrent or metastatic head and neck cancer, according to findings published in the February 22nd online Journal of Clinical Oncology.
"Novel regimens are highly warranted for the treatment of patients with head and neck cancer," Dr. Athanassios Argiris from University of Pittsburgh School of Medicine told Reuters Health by email.
"Although cisplatin is widely accepted as the backbone of chemotherapy for head and neck cancer, this phase II study shows that a non-platinum doublet that contains bevacizumab can be at least as efficacious in recurrent or metastatic head and neck cancer."
Dr. Argiris and colleagues tested the hypothesis that bevacizumab can potentiate pemetrexed in a study of 40 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). The primary end point was time to progression. Secondary efficacy end points included objective response rate and overall survival.
The median time to progression was 5 months, which was significantly greater than the 3.9 months reported in a recent phase II trial of pemetrexed.
The median overall survival was 11.3 months. In 37 evaluable patients, the objective response rate was 30% (including 9 partial and 2 complete responses). The disease control rate was 86%.
Grade 3 to 5 toxicities included bleeding events in 6 patients, infection in 5 patients, neutropenia in 4 patients, and anemia, fatigue, hypokalemia, and hyponatremia in 2 patients each. One patient died from tracheal bleeding.
Overall survival was superior in patients with the AC/CC genotype of MTHFR A1298C single nucleotide polymorphism (32 months) compared with the AA genotype (11 months), and one patient with VEGF G634C GG genotype had significantly better survival than patients with the GC and CC genotypes.
"Patient selection on the basis of gene polymorphisms appears promising and should be explored in future clinical trials in head and neck cancer," Dr. Argiris said.
"The Eastern Cooperative Oncology Group is currently conducting a phase III study of cisplatin-based chemotherapy with or without bevacizumab in patients with recurrent or metastatic head and neck cancer (E1305)," Dr. Argiris noted.
"At the University of Pittsburgh, we have moved the combination of pemetrexed and bevacizumab to the combined modality treatment of locally advanced disease. In an ongoing phase II randomized trial, we evaluate the combination of radiotherapy, pemetrexed and cetuximab with or without bevacizumab in patients with locally advanced head and neck cancer. This is a promising multi-agent regimen that does not contain platinum. Study results are eagerly anticipated."
The study was supported in part by Lilly Oncology and Genentech, which also provided honoraria and/or research funding to 3 of the 8 authors.
J Clin Oncol. Posted February 2011. Abstract