ONCE DAILY ORAL DRUG COMBINATION FOR DIABETES APPROVED BY FDA

February 3, 2012 — Merck announced on February 2 that the US Food and Drug Administration (FDA) has approved sitagliptin and metformin hydrochloride (HCl) extended-release tablets (Janumet XR) for treatment of type 2 diabetes.The new formulation, meant to be used as an adjunct to diet and exercise to improve glycemic control, combines sitagliptin (the active component of Januvia [Merck]), with extended-release metformin.

According to a company news release, "Janumet XR should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Janumet XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Janumet XR."

FDA approval was based on a clinical bioequivalence study showing that the new tablets were equivalent to coadministration of corresponding doses of the 2 individual medications, sitagliptin and metformin HCl extended release.

"Janumet XR is a new treatment that adds once-daily convenience to the powerful efficacy of Janumet for patients with type 2 diabetes," said Barry J. Goldstein, MD, PhD, vice president, diabetes and endocrinology, Merck, in the news release. "This is important because many patients with type 2 diabetes require treatment with multiple drugs to maintain blood sugar control, and Janumet XR is a new option to help more patients get to their glucose goals."

The labeling for the combination drug contains a boxed warning for lactic acidosis, a rare but serious complication caused by metformin accumulation. According to a Merck statement, the reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, but when lactic acidosis occurs, it is fatal in approximately 50% of cases. Reported cases have occurred primarily in patients with diabetes who have significant renal impairment.

"There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with Janumet XR and at least annually thereafter, renal function should be assessed and verified as normal," the company advised in the release.

"In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Janumet XR treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, Janumet XR should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis."

Increased risk for lactic acidosis is also associated with excess alcohol intake, hepatic impairment, and acute congestive heart failure. "If acidosis is suspected, Janumet XR should be discontinued and the patient hospitalized immediately," the company added.

The manufacturer advises physicians to maintain the same total daily dose of sitagliptin and metformin when changing between Janumet and Janumet XR, and to titrate the dose up gradually to the maximum recommended dose to reduce gastrointestinal adverse effects.

The new extended-release tablets should be taken once daily with food (preferably in the evening) to reduce the gastrointestinal adverse effects associated with the metformin component. Patients should be warned that the tablets must not be split, broken, crushed, or chewed before swallowing, the company said.

VACCINATION COVERAGE REMAIN LOW IN USA

February 4, 2012 — Adult vaccination coverage remains low in the United States, with little improvement in rates from 2009 to 2010, researchers at the US Centers for Disease Control and Prevention reported in an article published in the February 3 issue of theMorbidity and Mortality Weekly Report.

Walter W. Williams, MD, from the Immunization Services Division, National Center for Immunization and Respiratory Diseases, and colleagues analyzed data from the 2010 National Health Interview Survey, an annual household survey by the National Center for Health Statistics and the US Census Bureau that has been conducted since 1957.

The current report covers pneumococcal, hepatitis A and B, herpes zoster (shingles), human papillomavirus (HPV), and tetanus, diphtheria, and acellular pertussis (Tdap) vaccines. A previous report covered influenza vaccinations.

"Substantial improvement in adult vaccination is needed to reduce the health consequences of vaccine-preventable diseases among adults," the researchers write. Adult vaccination coverage remains far below the recommendations of Healthy People 2020, the government program that issues science-based health goals in 10-year cycles.

Only limited increases in coverage for 3 types of vaccines occurred during the year, according to the researchers. Vaccination coverage rose 1.6 percentage points to 8.2% coverage for Tdap for adults 19 to 64 years old, 4.4 percentage points to 14.4% coverage in adults aged 60 years and older for herpes zoster vaccine for shingles, and 3.6 percentage points to 20.7% coverage for 1 or more doses of HPV vaccination in women aged 19 to 26 years.

For high-risk adults aged 19 to 64 years, pneumococcal vaccination coverage amounted to18.5%, and for adults 65 and older coverage came to 59.7%. People are considered at high risk if they have been diagnosed with diabetes, emphysema, heart disease, cancer, or some other disorders.

Although Tdap vaccinations increased, the percentage of adults receiving any tetanus toxoid-containing vaccination remained unchanged, at 64.0% for ages 19 to 49 years, 63.4% for ages 50 to 64 years, and 53.4% for adults aged 65 years and older.

The researchers characterized coverage of hepatitis A vaccine in 2010 as "similar" to that seen in 2009. Coverage amounted to 10.7% for adults aged 19 to 49 years in 2010 compared with 9.8% in 2009. However, for adults who had travelled since 1995 to countries other than the United States, Europe, Japan, Australia, New Zealand, and Canada, hepatitis A vaccine coverage was higher, at 16.6%, in 2010 compared with in 2009, when it was 7.5%.

Hepatitis B coverage stood at 42.0% for high-risk adults aged 19 to 49 years, which is essentially unchanged from 2009. People with assisted blood glucose monitoring through instruments used in different people without appropriate infection control are at risk for hepatitis B. Diabetes will be included in risk factors for hepatitis B in future assessments, the researchers note.

Healthy People 2020 goals for vaccination coverage are:

• pneumococcal: 90% of those older than 65 years, 60% of those aged 18 to 64 years;
• herpes zoster: 30%; and
• hepatitis A and B: 90%.

The authors have disclosed no relevant financial relationships.

Morb Mortal Wkly Rep. 2012;61;66-72. Full text

MULTIDRUG RESISTANT TB IS SPREADING

February 6, 2012 — Cases of multidrug-resistant tuberculosis (MDR-TB) hit an all-time high worldwide in 2009 and 2010, with 1 country reporting multidrug resistance in 65.1% of all previously treated TB cases, according to the latest World Health Organization (WHO) study, published in the February Bulletin of the World Health Organization.

Matteo Zignol, MD, MPH, from the Stop TB Department, WHO, Geneva, Switzerland, and colleagues analyzed data collected from 2007 to 2010 from 80 countries and 8 territories. The analysis showed that Eastern Europe and central Asia continue to record the world's highest proportion of MDR-TB. Still, there are no data on drug-resistant TB from much of Russia, India, and Africa, and from large portions of Eastern Europe and central Asia, the authors report.

"Surveillance of resistance to drugs is the cornerstone of TB control," Dr. Zignol said in a news release. "Following 15 years of intensive effort, we now have high quality data for two-thirds of countries in the world. At the same time, we don't know the full extent of the problem because we lack data from many countries, in particular India and most of Africa where the TB burden is high."

One bright spot in new surveillance efforts, the authors points out, is China, which conducted its first nationwide survey in 2007. Dr. Zignol and colleagues call China's efforts "a critical step towards addressing MDR-TB in one of the largest TB control programmes in the world." China, India, and Russia are home to more than half of the world's MDR-TB cases, the report states.

Worldwide, 3.4% (95% confidence interval [CI], 1.9% - 5.0%) of all new TB cases are multidrug-resistant, meaning Mycobacterium tuberculosis resists treatment with at least rifampicin and isoniazid. Among previously treated TB cases worldwide, 19.8% (95% CI, 14.4% - 25.1%) of TB cases are multidrug resistant, according to the report.

Some MDR-TB cases are considered extensively drug resistant (XDR), meaning they not only meet the criteria for multidrug resistance but also fail to respond adequately to fluoroquinolone and at least 1 second-line injectable agent, such as amikacin, kanamycin, or capreomycin. Worldwide, some 9.4% (95% CI, 7.4% - 11.6%) of MDR-TB cases are XDR cases. The number of MDR-TB cases considered to be XDR cases rose to more than 10% in South Africa (10.5%) and 3 former Soviet Union countries: Estonia (19.7%), Latvia (15.1%), and Tajikistan (Dushanbe city and Rudaki district, 21.0%).

However, only 38 countries and 3 territories reported surveillance data for XDR-TB. Among those, only 6 had more than 10 cases of XDR.

The Russian oblast of Murmansk, on the Kola Peninsula near Finland, had the highest level of newly diagnosed MDR-TB, at 28.9%. The Republic of Moldova, a landlocked country between Ukraine and Romania, had the highest rate of MDR-TB among previously treated TB cases, at 65.1%.

TB cases resistant to several treatment regimens require longer and more treatment regimens and are less likely to be cured. Despite the rising number of resistant cases, in 2010, only 16% of the world's patients with MDR-TB received appropriate treatment, the WHO report reveals.

In the United States, MDR-TB cases are in decline, falling even more quickly than new TB cases, the authors report. US TB cases have dropped 5.1% per year since 1996, and MDR-TB diagnoses declined 5.4% per year in the same period. Surveillance showed that 1.1% of new TB cases diagnosed in the United States were multidrug resistant in 2010, and 4.4% of previously treated cases were multidrug resistant.

Despite high MDR-TB rates in Latvia and Estonia, both those countries, along with the United States, have seen a decline in new TB cases and in MDR-TB cases during the last decade.

MDR-TB is increasing most rapidly in Botswana, at 10.9% per year; Peru, at 19.4% per year; and the Republic of Korea, with an increase of 4.3% per year. The Republic of Korea is also recording a 7.4% annual increase in new TB cases. Despite increases in MDR-TB rates, Botswana's overall new case rate is nearly stable, increasing at 0.3% per year, and Peru's rate of new cases is declining by 3.3% per year.

WHO began gathering drug resistance data from 127 countries in 1994 with the launch of the Global Project on Anti-tuberculosis Drug Resistance Surveillance. Today, 64 countries have continuous surveillance based on routine susceptibly testing of all patients with TB. The rest of the countries rely on special surveys of representative patient samples.

Among the report's other findings:

• Countries with new cases of MDR-TB at more than 12% include Belarus, at 25.7%; Estonia, at 18.3%; several oblasts of the Russian Federation, with Murmansk having the highest at 28.9%; and Tajikistan, with Dushanbe city and Rudaki district at 16.5%.
• Countries with MDR-TB in previously treated cases above 50% included Belarus, at 60.2%; Lithuania, at 51.5%; the Republic of Moldova, at 65.1%, 5 oblasts of the Russian Federation; and Tajikistan (Dushanbe city and Rudaki district), at 61.6%.
• Patients with TB who have HIV were no more likely to have a drug-resistant form of TB than those without HIV. In the 17 countries and 1 territory that looked at HIV status, odds of having MDR-TB among HIV-positive cases was 40% higher than among those without HIV (pooled odds ratio [OR], 1.4; 95% CI, 0.7 - 3.0; OR consistent across countries, I² = 23.2%; P = .19), but the difference was not significant.
• The sex of the patients with TB was not a factor in resistance. Among the 58 countries and 2 special territories that collected data on the sex of patients with MDR-TB, odds of MDR-TB were 10% higher among women (OR, 1.1; 95% CI, 0.8 - 1.4; OR heterogeneous across countries, I² = 32.9%; P = .009), which is not statistically significant.

The authors have disclosed no relevant financial relationships.

Bull World Health Org. 2012;90:111-119D. Full text

DENOSUMAB FOR DELAYING BONE METASTASES NOT RECOMMENDED

February 9, 2012 — An additional indication for the novel bone drug denosumab (Xgeva, Amgen) — that of delaying bone metastases in men with castration-resistant prostate cancer (CRPC) — has not been recommended for approval by the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee that met yesterday.

The FDA is expected to make a ruling on this indication by April 26; the agency usually follows the committee's recommendation, but not always.

Denosumab was approved for use in cancer patients who have bone metastases because data showed that it prevents skeletal-related events, such as pathological fracture, spinal cord compression, and radiotherapy or surgery for the bone metastases.

The indication under consideration is use of the drug to delay the onset of bone metastases in patients with CRPC who are at high risk of developing this complication. The data supporting this indication come from a phase 3 clinical trial of 1432 men with CRPC, and show that denosumab significantly delayed the time to a first bone metastasis or death from any cause by about 4 months, compared with placebo (29.5 vs 25.2 months; P = .03). These results were presented last year at the European Multidisciplinary Cancer Congress (EMCC), and were later published in the Lancet.

When the study was presented at the EMCC meeting, prostate cancer experts were enthusiastic about the results, pointing out that this was the first drug shown to delay the onset of bone metastasis and that it represented a "paradigm shift."

There was less enthusiasm at the committee meeting yesterday, however. The panel voted 12 to 1 against recommending the indication for approval, saying that the benefit was not outweighed by the potential risks of treatment (which include jaw osteonecrosis, seen in about 5% of trial participants). The committee also noted that there was no effect on overall survival or on the overall course of the disease in general.

Committee chair Wyndham Wilson, MD, chief of the lymphoma therapeutics section at the National Institutes of Health, explained that the magnitude of the benefit that was seen (delaying the onset of bone metastasis by 4 months) was "quite low." In addition, there was discussion about whether this benefit is clinically meaningful, in light of the lack of effect on overall survival.

Amgen said that it believes that the drug offers a clinically meaningful benefit. "The development of bone metastasis is an irreversible life-changing event for men living with castration-resistant prostate cancer, and is associated with significant and progressive morbidity," said Sean Harper, MD, chief medical officer at Amgen. Denosumab is the first agent shown to prolong the time to this event, and it addresses an important unmet medical need, he said.

Analysts have forecast sales of denosumab of $3 to $4 billion by 2015, and they estimate that this new indication would be worth about $1 billion of that.

 

NEOADJUVANT TREATMENT OF BREAST CANCER

Recommendations From an International Consensus Conference on the Current Status and Future of Neoadjuvant Systemic Therapy in Primary Breast Cancer

Kaufmann M, von Minckwitz G, Mamounas EP, et al
Ann Surg Oncol. 2011 Dec 23. [Epub ahead of print]

Study Summary

This article summarizes the recommendations from a panel of experts that met in Biedenkopf, Germany, in September 2010. This was the fourth meeting of this group, which comprised experts in medical oncology, breast surgery, diagnostics, radiology, radiation oncology, pathology, and genomics -- 6 of whom were from the United States and 13 from Europe. Panel members were charged with reviewing all available data from published prospective clinical trials of neoadjuvant therapy as well as unpublished presentations made at major scientific meetings.

The major recommendations concerned 5 management issues.

Goals and indications of neoadjuvant therapy. The most important clinical goals remain to improve disease-free and overall survival and enable more limited surgery. Neoadjuvant therapy increases the rates of conservation for patients with locally advanced disease. There is still controversy about proper management in patients whose response to neoadjuvant therapy is suboptimal, as well as the extent of axillary surgery in patients who had involved nodes at presentation. Any patient who is a candidate for adjuvant systemic therapy can be considered for neoadjuvant treatment. However, neoadjuvant therapy should not be recommended if there is any uncertainty about the appropriateness of or need for systemic therapy.

Assessing response to therapy. Pathologic complete response (pCR) should be defined as the absence of invasive cancer in both breast and lymph nodes. The presence, extent, and classification of ductal carcinoma in situ should be reported separately. pCR has been consistently shown to be associated with excellent long-term survival. That said, 60%-85% of patients treated with neoadjuvant therapy do not achieve pCR. It is important to bear in mind that the differences between treatment arms in clinical trials may not translate into survival differences. To monitor response to therapy, physical examination and standard pathologic, staging, and receptor studies should be performed.

The group recommended imaging studies of axillary nodes and diagnostic fine-needle aspiration biopsy for patients in whom incomplete response is suspected. Sentinel node biopsy should be considered for patients with a clinically negative axilla. For those with an initially uninvolved axilla, the group recommends sentinel lymph node biopsy after neoadjuvant therapy. No data support the use of imaging modalities during neoadjuvant therapy, and practices vary.

Treatment options. In practice, the same regimens should be used for neoadjuvant therapy as for adjuvant therapy. All chemotherapy should be provided before surgery, not split into preoperative and postoperative phases. Trastuzumab-based chemotherapy is indicated for patients with human epidermal growth factor receptor-positive (HER+) disease. Given recent studies showing the efficacy of anti-HER2 therapy alone without chemotherapy, this could be considered in the future. Neoajduvant endocrine therapy with aromatase inhibition is effective for postmenopausal woman with estrogen receptor-positive (ER+) disease.

Role of surgery and radiation therapy. Surgery is necessary in every patient. In cases of clinical complete remission, resection is still required. After breast-conserving therapy, radiation is indicated to decrease the risk for local recurrence. In general, radiation is guided by the initial clinical stage and pathologic findings at the time of surgery.

Follow-up care. In cases of a switch in receptors (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2) between the initial biopsy and the biopsy obtained at the time of surgery, patients with at least 1 ER+ biopsy should be given adjuvant endocrine therapy. For HER2+ disease, 1 year of trastuzumab therapy is also considered the standard of care.

Viewpoint

This article is a helpful review of state-of-the-art neoadjuvant therapy for breast cancer. We are well aware of the benefits for research, but this focus on treatment of patients in a nonresearch setting is clear and sets the standards we should use routinely.

These experts remind us of areas of ongoing controversy. Axillary staging needs to be personalized: Fine-needle aspiration biopsy of suspicious axillary nodes is a useful resource, but sentinel node biopsy remains essential for patients with a clinically negative axilla. Practices vary considerably in terms of the frequency and type of imaging studies that are used during neoadjuvant therapy.

Perhaps the most valuable reminder for medical oncologists is to choose regimens with a proven track record in the adjuvant setting and to make judicious recommendations for additional treatment after a suboptimal response to neoadjuvant chemotherapy. These situations remain challenging, and we hope that future trials will provide direction and guidance.

FATAL ADVERSE EVENTS WITH TKIs

February 9, 2001 — New details on the risk for fatal adverse events associated with several targeted cancer drugs have come from a large meta-analysis of clinical trials, which was published onlineFebruary 6 in the Journal of Clinical Oncology.

The drugs investigated were pazopanib (Votrient, GlaxoSmithKline), which is approved for use in renal cell carcinoma; sorafenib (Nexavar, Bayer & Onyx), which is approved for use in renal cell carcinoma and hepatocellular cancer; and sunitinib (Sutent, Pfizer), which is approved for use in hepatocellular cancer and gastrointestinal stromal tumors. All 3 products are vascular endothelial growth-factor (VEGF) receptor tyrosine kinase inhibitors.

The meta-analysis, which examined data on 4679 patients from 10 clinical trials, found that these 3 drugs were associated with fatal adverse events at a rate that was about twice that seen in the placebo groups. The crude incidence of fatal adverse events was 1.5% in patients taking these drugs, compared with 0.7% in patients in the placebo or control groups (relative risk [RR], 2.23; P = .023).

The most common cause of death was hemorrhage; the second most common was myocardial ischemia. Liver failure and congestive heart failure were also reported.

Senior author Toni Choueiri, MD, from the Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, said that clinicians need to be aware of the risks associated with these drugs.

"There is no doubt that for the average patient, these drugs have benefits," Dr. Choueiri said in a statement. In fact, these drugs represent a major step forward in the treatment of several malignancies, and they have led to significant improvements in patient outcomes.

However, they are associated with a significant increase in the risk of developing fatal drug-related events, and "practitioners must be aware of the risks associated with their use and must provide rigorous monitoring to continue to improve patient outcomes," the researchers note.

"While the absolute incidence of these fatal side effects is very small, the relative risks are higher," Dr. Choueiri noted. In addition, the patients in this meta-analysis were participating in clinical trials and all had adequate organ function at study entry, so the overall incidence and risk for unreported fatal adverse events could be higher in common medical practice.

Similar Data on Bevacizumab

An increase in the risk for fatal adverse events has also been reported for bevacizumab (Avastin, Genentech/Roche), which inhibits VEGF but by another mechanism; it is a monoclonal antibody that binds to VEGF. The data on bevacizumab, reported last year, came from a meta-analysis of clinical trials involving 10,217 patients, which found a significantly higher rate of fatal adverse events associated with bevacizumab than with chemotherapy alone (2.5% vs 1.7%; RR, 1.46; P = .01).

This increased risk and incidence of fatal adverse events reported for bevacizumab "are on the same scale" as those described in this meta-analysis looking at pazopanib, sorafenib, and sunitinib, note Dr. Choueiri and colleagues. In both cases, hemorrhage was the cause of death in the majority of patients.

When the bevacizumab data were published (JAMA. 2011;305;487-494), an accompanying editorial questioned the overall benefit of adding bevacizumab to chemotherapy (JAMA. 2011;305:506-508). Editorialist Daniel Hayes, MD, from the University of Michigan Comprehensive Cancer Center in Ann Arbor, speculated that the increased rate of fatal adverse events "might negate any survival benefit."

Medscape Medical News asked Dr. Hayes to comment on the findings of an increased rate of fatal adverse events with pazopanib, sorafenib, and sunitinib.

"I really don't have much to add. The data are as they are," he said. "All drugs have benefits and risks, and it is up to caregivers, patients, and society to decide if the benefits outweigh the risks."

"It seems like we sometimes throw out one or the other side of this equation when reviewing therapeutic strategies," Dr. Hayes explained. "Regardless, certainly one cannot determine the benefit/risk ratio if we don't have a legitimate estimate of the latter, so this is an important paper."

Breakdown of the New Findings

Of the 4679 patients in this meta-analysis, 2856 were involved in sorafenib clinical trials, 1388 were involved in sunitinib trials, and 435 were involved in pazopanib trials.

Although there were more fatal adverse events reported for sorafenib than for the other 2 drugs, there was no statistically significant difference in the RR for the 3 drugs, the researchers note. All 3 products have a similar mechanism of action (antagonizing the intracellular domain of VEGF and blocking downstream signaling), and all 3 drugs have similar class-effect toxicity profiles, they add.

Half of the 19 study deaths (47.5%) that occurred in patients taking pazopanib, sorafenib, or sunitinib were due to hemorrhage. The majority of these deaths from hemorrhage (79%) occurred in patients with nonsmall-cell lung cancer (NSCLC). This is not surprising, the researchers note, because NSCLC lesions are known to be highly necrotic and have a propensity to bleed, even without the inhibition of the VEGF pathway.

The second most common reason for death was myocardial ischemia (n = 6), the researchers note. Other causes were abnormal hepatic function or failure (n = 40), sepsis (n = 3), congestive heart failure (n = 2), ischemic stroke (n = 1), pulmonary embolism (n = 1), dehydration (n = 1), and sudden death (n = 1).

The findings of myocardial infraction and other cardiovascular events is consistent with previous analyses, the researchers note. Dr. Choueiri and colleagues have previously reported a significant increase in the risk forarterial thromboembolic events and in the risk for bleeding associated with sorafenib and sunitinib. They have also reported an increase in the risk for congestive heart failure with bevacizumab.

Dr. Choueiri previously told Medscape Medical News that the adverse events are a result of these drugs inhibiting VEGF, which is a class effect. In a tumor, blocking VEGF inhibits angiogenesis and an anticancer effect, but in the body, the inhibitory effects of VEGF can disrupt the hemostatic balance, he explained. 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.

Dr. Choueiri reports serving as a consultant for Pfizer, Bayer/Onyx, Novartis, GlaxoSmithKline, Abbott, Genentech, AVEO Pharmaceuticals, and Agennix. Dr. Hayes reports stock ownership in Oncimmune LLC and Halcyon Diagnostics Inc; and receiving honoraria for consulting from Compendia Bioscience, Chugai Pharmaceuticals, and Biomarker Strategies.

J Clin Oncol. Published online February 6, 2012. Abstract

BIOPSY OF BREAST CANCER METASTASES CHANGE TREATMENT IN 14% OF PATIENTS

February 9, 2012 — Taking a biopsy of metastatic cancer that has spread beyond the breast can lead to a change in systemic therapy, and thus management, in some patients, according to a prospective study published online November 28, 2011, in the Journal of Clinical Oncology.

Canadian researchers biopsied metastases to see if the receptor status was "discordant" with the original status of the primary breast tumor.

Specifically, the status of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth-factor receptor 2 (HER2) were determined in both the breast tumor and a metastatic site in 121 women.

The discordance in ER, PR, and HER2 between the primary tumor and the metastasis was 16%, 40%, and 10%, respectively, write the study authors, led by Eitan Amir, MD, from the University of Toronto in Ontario, Canada.

Biopsy led to a reported change of management in 14% of women (95% confidence interval, 8.4% to 21.5%).

Dr. Amir described one such a change in management.

A postmenopausal patient in the study, who had an initial breast tumor that was ER-positive, PR-positive, and HER2-negative, was diagnosed with a liver metastasis 18 months later. "The rebiopsy showed ER-positive, PR-positive, and HER2-positive disease. Therefore, the planned treatment was changed from letrozole to paclitaxel and trastuzumab," he told Medscape Medical News in an email.

Rebiopsies of metastases represent a substantial change in practice, Dr. Amir and colleagues suggest.

"The receptor status of metastatic disease is usually assumed to be the same as that of the primary tumor," they write, adding that the primary tumor's receptor status dictates the choice of systemic therapy.

This study challenges those assumptions and dictates and suggests that biopsy of metastases, which the researchers call "technically feasible," be performed in this setting.

"Tissue confirmation should be considered in women with breast cancer and suspected metastatic recurrence," the researchers conclude.

The call to biopsy breast cancer metastases has been made by other investigators, as has been previously reported by Medscape Medical News.

Need Proof of Benefit, Says Expert

But an expert not involved with the study expressed skepticism about such testing.

In an editorial related to the study, published online January 30, Stephen Chia, MD, from the British Columbia Cancer Agency in Vancouver, Canada, writes that various retrospective studies have repeatedly demonstrated that discordance is a fairly common phenomenon — occurring in 20% to 30% of breast cancer metastases.

However, Dr. Chia emphasizes that prospective studies are needed to demonstrate that any changes in treatment based on biopsies actually result in improved outcomes.

He points out that, in retrospective studies, the majority of the discordance seen was in a loss of receptor expression. In practice, this means that clinicians will "struggle with whether to withhold the associated targeted therapy." Such drugs have the potential for "significant efficacy," he writes.

Dr. Chia also says there is another reason that clinicians should be cautious about the idea of routinely biopsying metastases: the results are not entirely reliable. In other words, different labs and techniques come up with different results sometimes.

A recent round-robin review of HER2 testing in 3 central laboratories involved in large adjuvant trials demonstrated that 8% of HER2 immunohistochemistry and fluorescent in situ hybridization test results differed, Dr. Chia explains. This highlights the role that testing variables "may play in the observed discordance in biomarker testing."

Another Study in HER2-Positive Disease

Another study, also published online November 28, 2012, in the Journal of Clinical Oncology, suggests that a discordant metastasis influences prognosis — for the worse.

Having a discordant metastasis was associated with worse survival in 182 women with HER2-positive primary breast cancers, according to a single-center study conducted at the University of Texas M.D. Anderson Cancer Center in Houston.

The investigators, led by Naoki Niikura, MD, retrospectively found that 24% of the women (n = 43) had a HER2-negative metastatic lesion on review. The team demonstrated that the patients with a discordant HER2 result (HER2-positive primary disease but HER2-negative metastases) had worse survival than patients with a concordant HER2 result (hazard ratio, 0.43; P = .003).

Dr. Chia explains that the survival difference presumably occurred because the patients with HER2-positive metastases benefited from anti-HER2 therapy, whereas those without this receptor expression did not.

The researchers and Dr. Chia have disclosed no relevant financial relationships.

J Clin Oncol. Published online November 28, 2011, and January 30, 2012. Abstract, Abstract, Editorial

EXAMESTANE WEAKENS BONE

February 6, 2012 — New data from a subset of postmenopausal women participating in a landmark trial that established exemestane for the prevention of breast cancer show that the drug significantly worsens age-related bone loss.

When the exemestane results from the Mammary Prevention 3 (MAP.3) trial were reported last year, experts welcomed a new option for the chemoprevention of breast cancer, and several called for its widespread use in women who are at high risk for breast cancer. They noted that exemestane, an aromatase inhibitor, appeared to be safer and more effective than the selective estrogen-receptor modulators found to be effective in this setting — tamoxifen and raloxifene.

However, new data from a subset of patients taking part in that trial, published online on February 7 in the Lancet Oncology, show that exemestane weakens bones.

The subset data were collected from 351 women, representing 7.6% of the MAP.3 cohort (n = 4569). The subset study specifically examined bone effects of the drug; it measured bone mineral density (BMD) at baseline and after 2 years of therapy using high-resolution peripheral quantitative computed tomography (CT) screening and the more usual method of dual-energy x-ray absorptiometry (DXA).

The extra CT screening provided information on bone infrastructure and showed large decreases in cortical bone. These changes cannot be seen on DXA, the researchers explain.

"Exemestane worsens age-related decreases in bone mineral density by about 3 times, even in the setting of adequate calcium and vitamin D intake," noted lead author Angela Cheung, MD, from the University Health Network in Toronto, Ontario, Canada.

In an interview with Medscape Medical News, Dr. Cheung explained that each women will have to weigh the benefits of taking the drug — substantially reducing the risk for invasive breast cancer — against the deleterious effects of the drug on bone seen in this new study. The clinical significance of these bone effects is not yet clear, she said, noting that longer-term studies are needed.

In the 2-year period of this subset study, there was no increase in fractures in the exemestane group, but the numbers are small and the time period is short, she emphasized.

"Results of this study are important," writes Jane Cauley, DrPH, professor of epidemiology at the University of Pittsburg, Pennsylvania, in an accompanying editorial.

"The bone changes that we saw on CT were real," Dr. Cheung said, "but whether they will increase the risk of fracture — time will tell."

This is the first study of the bone effects of an aromatase inhibitor that has used high-resolution peripheral quantitative CT. It sheds light on how bone is affected by these agents.

These results show that exemestane substantially affects the loss of cortical bone, compared with trabecular bone, Dr. Cauley notes. "This finding is important because 80% of our bone mass is cortical, and 80% of all fractures occur in nonvertebral sites that are mainly cortical."

"Cortical bone is not solid, but is riddled with pores that are active sites of bone remodeling," she explains. Cortical porosity increases with age, and most of the bone loss that is seen after 65 years of age occurs in this cortical component.

"If aromatase inhibitors increase cortical porosity, this effect could be a key cause of loss of bone strength and nonvertebral fractures associated with their use," Dr. Cauley notes. "Thus, one might not be too reassured about the use of exemestane in the prevention setting."

Study Underpowered for Fracture Outcome

The MAP.3 study was conducted in healthy postmenopausal women who were at moderately high risk of developing breast cancer, and showed that exemestane more than halved the risk for invasive breast cancer (65% reduction).

As reported at the time by Medscape Medical News, these results were presented at the 2011 annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine(2011;364:2381-2391). In that paper, the MAP.3 researchers note that the "absence of excess clinical fractures in patients treated with exemestane in this study is reassuring."

However, in her editorial, Dr. Cauley argues that the study was underpowered for a clinical fracture outcome, in part because of the underlying high risk for breast cancer in the participants. "Women with higher BMD have a higher risk of breast cancer than do women with lower BMD," she notes.

Closer Look at Bone Effects

In the MAP.3 subset study, Dr. Cheung and colleagues specifically set out examine the effects of exemestane on the skeleton.

The substudy involved 3 participating centers in Canada, and focused on 351 healthy postmenopausal women with an average age of 61 years. This is about a year younger than the main MAP.3 trial cohort, but otherwise the subset participants had similar characteristics, the researchers note. As with all the participants in the MAP.3 trial, those in the subset were taking calcium and vitamin D supplements.

The women in the subset study were not osteoporotic at baseline (BMD T score above –2.0 at the lumbar spine, total hip, and femoral neck).

The DXA results showed a small but significant decrease in areal BMD at the lumbar spine and at the total hip and femoral neck in women taking exemestane for 2 years, compared with those taking placebo. The magnitude of this loss of BMD is similar to that reported with exemestane in other trials, including other studies conducted in healthy postmenopausal women and studies conducted in women with breast cancer, the researchers note.

However, the results from the CT screening showed much larger decreases in BMD than those seen on DXA, the researchers note, demonstrating large and significant decreases in total volumetric BMD at the distal radius and distal tibia. More specifically, these CT scans showed decreases in cortical volumetric BMD and cortical thickness in women who were taking exemestane, which "implicate the loss of cortical bone," the researchers explain.

The loss of bone in women taking exemestane was about 3 times greater than in those taking placebo. Dr. Cheung noted that the loss measured with DXA was about 2.4% in the exemestane group and 0.8% in the placebo group; the loss measured with CT screening was about 6.1% in the exemestane group and 1.8% in the placebo group.

However, not all women showed bone loss. The deleterious effects of exemestane on bone were seen in about 65% of those on the drug, Dr. Cheung noted, but the extent of bone loss varied from woman to woman.

Thus, the risk for this deleterious effect on bone will be different for each individual woman. The impact of these changes will depend on the state of the bones before therapy begins, which needs to be taken into consideration when this treatment is being contemplated, she said. It also reinforces the need for monitoring of bone health, so that the women who are experiencing bone loss can be identified, she added.

Funding for this subset study came from the Canadian Breast Cancer Research Alliance. Dr. Cheung's coauthor, P.E. Goss, reports serving as a consultant for Pfizer. The remaining researchers and Dr. Cauley have disclosed no relevant financial relationships.

Lancet Oncol. Published online February 7, 2012. Abstract, Editorial

CLOSE INR MONITORING WHEN YOU ADD ANTIBIOTICS TO WARFARIN

NEW YORK (Reuters Health) Feb 03 - An analysis of Medicare data has shown that adults taking warfarin had a twofold increased risk of serious bleeding when an antibiotic was introduced.

Consistent with prior studies, the highest risks were seen with azole antifungals (greater than fourfold increased risk) and cotrimoxazole (nearly threefold increased risk), according to Dr. Jacques Baillargeon of the Department of Preventive Medicine & Community Health, University of Texas Medical Branch at Galveston and colleagues.

Dr. David N. Juurlink, from the Sunnybrook Health Sciences Center in Toronto, Ontario, Canada, who was not involved in the study, told Reuters Health the findings provide "more evidence of interactions between warfarin and antibiotics and a good reminder for clinicians to be aware of this interaction."

Dr. Baillargeon told Reuters Health, "Bleeding risks among continuous warfarin users may be reduced by using antibiotics with low-risk profiles, if appropriate, based on a patient's clinical situation." He said if therapeutic substitution isn't possible, close monitoring of the International Normalized Ratio (INR) "is imperative to reduce the risk of bleeding."

In a report this month in the American Journal of Medicine, he and his colleagues say a "prudent strategy" would be to monitor INR one week after an antibiotic is started and consider more frequent monitoring in patients at higher risk of bleeding.

Using newly available Medicare Part D prescription drug data, the researchers conducted a case-control study nested within a cohort of 38,762 Medicare beneficiaries aged 65 and older who were continuous warfarin users.

Cases were 798 individuals hospitalized for a primary diagnosis of bleeding at any time during 2008. Each case patient was matched to three control subjects on age, sex, race and indication for warfarin (2,394 controls).

Warfarin users exposed to any of the six antibiotic drug classes studied were twice as likely to experience a bleeding event that required hospital admission as those who were not exposed (adjusted odds ratio 2.01), the researchers found.

Antibiotic use was associated with a 2.49 adjusted OR for non-gastrointestinal (GI) bleeding and a 1.68 adjusted OR for GI bleeding.

Individuals whose antibiotic prescriptions started up to 15 days or 16-60 days before the event/index date were more likely to have been hospitalized for bleeding compared with the reference group, patients who were not current antibiotic users (adjusted OR 2.37 and 2.11, respectively).

In contrast, antibiotic-exposed individuals whose antibiotic prescription started more than 60 days before the event/index date did not have a statistically significant increased of bleeding compared with nonusers.

Adjusted ORs for bleeding requiring hospitalization by antibiotic class were 4.57 for azole antifungals; 2.70 for cotrimoxazole; 2.45 for cephalosporins; 1.92 for penicillins; 1.86 for macrolides; and 1.69 for quinolones.

The current study, say the authors, joins a number of other studies indicating that concomitant use of antibiotics and warfarin is associated with a high risk of over coagulation.

As with any study, the current one has its share of limitations, including reliance on ICD-9 bleeding codes, which "are not always accurate or complete," the authors point out.

Also, the authors didn't have data on a number of potential confounding factors, such as diet and use of alcohol, herbal supplements, or over-the-counter medications. "Many over-the-counter medications, including aspirin and nonsteroidal anti-inflammatory drugs, interact with warfarin to increase the risk of bleeding," they note.

They also had no information on the intensity of anticoagulation therapy.

SOURCE: http://bit.ly/AqXyQe

ANOTHER FAILURE OF HIGH DOSE SALVAGE CHEMOTHERAPY FOR TESTICULAR CANCER

February 9, 2012 — Testicular cancer is highly curable with chemotherapy, but about 20% to 30% of patients will relapse and require some form of salvage therapy.

Unfortunately, the optimal salvage chemotherapy for patients with first-relapse testicular cancer is "still unknown," according to an American expert commenting on a German phase 3 trial of this study population.

The trial compared 2 approaches to high-dose chemotherapy in men with relapsed and/or refractory germ cell tumors, and was conducted by the German Testicular Cancer Study Group.

"They are to be congratulated for initiating one of the few phase 3 studies in this patient population and for reporting the results with a median follow-up of 7.5 years," writes Lawrence Einhorn, MD, from the Simon Cancer Center at Indiana University in Indianapolis, in an editorial that accompanies the new study, both of which were published online January 30 in the Journal of Clinical Oncology.

However, the 211-patient study found no difference in 5-year progression-free survival between patients randomized to "single" high-dose chemotherapy and those treated with a "sequential" high-dose regimen (45% vs47%; P = .454). All patients also received autologous hemopoietic stem cell rescue after their chemotherapy.

The single high-dose chemotherapy regimen consisted of 3 cycles of etoposide, ifosfamide, and cisplatin (VIP), followed by 1 cycle of high-dose carboplatin, etoposide, and cyclophosphamide.

The sequential regimen consisted of 1 cycle of VIP plus 3 cycles of high-dose carboplatin and etoposide.

Recruitment in the trial was stopped prematurely because of increased treatment-related mortality with the high-dose single cycle that included cyclophosphamide (14% vs 4%; P = .01).

The results are "disappointing," says Dr. Einhorn.

The investigators say that they studied high-dose chemotherapy as a salvage therapy in this setting because it "has become standard treatment for patients with relapsed or refractory germ cell tumors at many centers worldwide."

But Dr. Einhorn says that it is not known whether high-dose salvage treatment regimens are better than standard-dose regimens.

"There are 2 approaches to salvage chemotherapy," writes Dr. Einhorn. One approach is a standard-dose cisplatin-based regimen with drugs not previously used, which may include cisplatin, ifosfamide, and either vinblastine or paclitaxel. The other approach is high-dose chemotherapy with autologous hematopoietic stem cell rescue.

Dr. Einhorn adds that there have been no studies to determine if "one strategy of high-dose chemotherapy is preferred over a different [high-dose] regimen." Thus, the new study addressed just one of the many questions in this setting.

There are silver linings to be found in the cloud of the new results and in salvage chemotherapy in general, Dr. Einhorn explains.

"It is remarkable that salvage chemotherapy can reproducibly cure patients when used as second- or third-line chemotherapy," he writes.

Indeed, with a median follow-up time of more than 7 years, 45% of these salvage patients — the great majority of whom experienced failure on a first-line chemotherapy (86%) — were still alive. "Hopefully, cures remain durable in a substantial proportion of patients," write the German investigators, led by Anja Lorch, MD, from the University of Giessen and Marburg.

Overall Survival Needs Interpretation

In the study, from November 1999 to November 2004, 211 patients with relapsed or refractory testicular cancer were randomly assigned to 1 of 2 treatment regimens, both followed by autologous stem cell reinfusion: the sequential regimen consisted of 1 cycle of cisplatin 100 mg/m², etoposide 375 mg/m², and ifosfamide 6 g/m² (VIP) plus 3 cycles of high-dose carboplatin 1500 mg/m² and etoposide 1500 mg/m²; the single regimen consisted of 3 cycles of VIP plus 1 cycle of high-dose carboplatin 2200 mg/m², etoposide 1800 mg/m², and cyclophosphamide 6400 mg/m².

Overall survival was better with the sequential regimen than with the single regimen (49% vs 39%; P = .057), the investigators report. However, this was not a result of improved therapeutic efficacy. Instead, the difference was due to the abovementioned treatment-related mortality associated with the single regimen.

Two subgroups in the study "deserve to be mentioned in particular," say the investigators. One is a small group of 6 patients who were part of a larger group of patients who relapsed or progressed after high-dose chemotherapy (the majority of whom died from their disease). These 6 patients not only survived, they became "permanently free of tumor with third-line chemotherapy and/or desperation surgery." These men "serve as a reminder that expert treatment might successfully salvage individual patients."

The other group was patients with relapses more than 2 years after their cisplatin-based first-line chemotherapy. Such men are considered "poor candidates" for subsequent chemotherapy, the investigators explain. However, 4 such patients achieved complete remission with high-dose chemotherapy in the trial. "Patients with unresectable late relapses of germ cell tumors should therefore not routinely be excluded from high-dose chemotherapy," they write.

However, Dr. Einhorn is not convinced, and he maintains that it is unclear whether high-dose chemotherapy — as opposed to less toxic standard chemotherapy — should be offered to such men.

The study authors have disclosed no relevant financial relationships. Dr. Einhorn reports owning stock in Amgen.

J Clin Oncol. Published online January 30, 2012. Abstract, Editorial

 

PERTUZUMAB NEAR APPROVAL

(Reuters) Feb 07 - U.S. health regulators granted a priority review for an experimental Roche breast cancer drug that in clinical trials added six months to progression-free survival.

The Food and Drug Administration will make its decision on whether to approve pertuzumab by June 8, for patients with advanced HER2-positive breast cancer who have not received prior treatment or who have suffered a relapse following surgery.

The agency grants priority review to medicines that are considered potentially significant therapeutic advancements over existing therapies.

In the phase III CLEOPATRA trial, patients who received pertuzumab in combination with Herceptin (trastuzumab) and docetaxel lived for an average of 18.5 months without disease progression, compared with 12.4 months for those who got only Herceptin and docetaxel.

The pertuzumab-treated patients also had a 38% reduction in the risk of disease progression or death (HR=0.62, p <0.0001).

Overall survival data from that trial is not expected to be available until 2013, but the FDA apparently found the available progression-free survival data compelling enough to makes its decision prior to that.

"We have been researching HER2-positive breast cancer for more than 30 years, and we hope an expedited review will help us quickly bring another personalized medicine to people battling this aggressive disease," Hal Barron, Roche's chief medical officer, said in a statement.

The statement went on to explain that the drug works by preventing the HER2 receptor from pairing (dimerizing) with other HER receptors (EGFR/HER1, HER3 and HER4), "a process that is believed to play a critical role in the growth and formation of several different cancer types."

Roche has already submitted a Marketing Authorization Application to the European Medicines Agency for pertuzumab for treating previously untreated HER2-positive metastatic breast cancer.