BEGIN WITH AI FOR EVERY POSTMENOPAUSAL WOMAN?

Femara 1st Aromatase Inhibitor To Indicate Overall Survival Benefit Versus Tamoxifen When Taken For Five Years After Breast Cancer Surgery

Femara showed reduced risk of death by 13% (P=0.08) versus tamoxifen, despite inclusion of patients who had switched over from tamoxifen to Femara during the study period, following the study's unblinding

- In a separate censored analysis excluding patients after they crossed over to Femara, reduction in risk of death was 19% (HR= 0.81, 95% CI: 0.69-0.94)

- Long-term follow-up from major independent BIG 1-98 trial adds further evidence that starting with Femara may be the optimal treatment strategy versus tamoxifen

New long-term data from a major international breast cancer study reports that postmenopausal woman with hormone receptor-positive early-stage breast cancer who took Femara(R) (letrozole) for five years following surgery had a 13% (P=0.08) reduced risk of death, when compared with tamoxifen(1).

These results are from a protocol-defined Intent-to-Treat (ITT) analysis (median follow-up of 76 months) of the Femara and tamoxifen monotherapy arms in the Breast International Group (BIG) 1-98 study. The suggested survival benefit from the ITT analysis is important considering that approximately 25% of patients in the tamoxifen arm selectively crossed over to Femara therapy after the tamoxifen arm was unblinded in 2005. While not statistically significant, these are the first data to suggest a survival benefit for an aromatase inhibitor versus tamoxifen in the monotherapy setting immediately following surgery.

To explore the impact of the selective crossover, an additional analysis was conducted censoring follow-up times at the date of crossover to letrozole for 25% of the patients in the tamoxifen arm. In this analysis, a 19% reduction in risk of death (HR=0.81, 95% CI: 0.69-0.94) was observed in favour of Femara.

The International Breast Cancer Study Group (IBCSG) today presented these results from the BIG 1-98 trial at the 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS), an international scientific symposium for scientists and clinicians in breast cancer.

"These data represent an important milestone in the treatment of women with breast cancer. For the first time we are seeing suggested survival benefit with upfront aromatase inhibitor (letrozole) therapy for five years compared with tamoxifen for the same time period," said Professor Nigel Bundred, Professor of Surgical Oncology, University Hospital of South Manchester NHS Foundation Trust.

Also commenting on the study, PhD, Henning T. Mouridsen, MD, Professor of Oncology, Copenhagen University Hospital and one of the investigators of the BIG 1-98 trial said; "The potential reduction in the risk of death that we are seeing with letrozole in the adjuvant setting may be a positive result of letrozole's early and sustained reduction in the risk of recurrence and distant metastases."

BIG 1-98 is the only clinical trial designed to explore both a head-to-head comparison of an aromatase inhibitor with tamoxifen during the first five years following breast cancer surgery and the sequencing of both agents to determine the most effective approach to minimizing the risk of recurrence. In the initial adjuvant setting, Femara is the only aromatase inhibitor to have demonstrated an early significant reduction in distant metastases versus tamoxifen, at a median duration of follow-up of 26 months.

Beyond the potential survival benefit of 13% (P=0.08, HR=0.87, 95% CI: 0.75-1.02) reduction in risk of death for Femara patients seen in the ITT analysis, Femara demonstrated significant long-term benefit in reducing the risk of disease free survival events by 12% (P=0.03, HR=0.88, 95% CI: 0.78-0.99) and reducing the risk of distant metastases by 15% (P=0.05, HR=0.85, 95% CI: 0.72-1.00) compared with tamoxifen.

"Femara has consistently demonstrated remarkable results and these data reaffirm the benefit of Femara for postmenopausal women with early-stage breast cancer," said Alessandro Riva, MD, Executive Vice President, Head of Global Development at Novartis Oncology. "The survival data shown may offer new promise for breast cancer patients."

Also presented at the meeting were results from the Sequential Treatment Analysis (STA) of BIG 1-98 which revealed that sequencing hormone therapy following surgery is not superior to five years of Femara alone.

The five-year disease-free survival rates for the three groups of patients in the STA were 87.9% for those patients receiving Femara only, 86.2% for those patients receiving two years of tamoxifen followed by three years of Femara and 87.6% for those patients receiving two years of Femara followed by three years of tamoxifen. The study investigators conclude that sequential treatment does not improve disease free survival compared with Femara alone.

Study details

This Phase III, randomized, double-blind, controlled clinical trial enrolled postmenopausal women with early breast cancer, in 27 countries1.

Patients were randomly assigned one of four treatment regimens: (1) five years of tamoxifen only; (2) five years of Femara only; (3) two years of tamoxifen followed by three years of Femara; (4) two years of Femara followed by three years of tamoxifen. In 1998 the first cohort began enrolling patients to receive either Femara or tamoxifen alone. In 1999, the second cohort (solely contributing to the Sequential Treatment Analysis) began enrolling patients to receive Femara or tamoxifen alone, tamoxifen followed by Femara or Femara followed by tamoxifen (n=6,182 patients). Combined, the monotherapy arms of the trial included 4,922 patients who were randomly assigned either Femara or tamoxifen treatment1. The Primary Core Analysis, reported in 2005, included all 8,010 patients enrolled in the trial.

The primary study endpoint of the study was disease-free survival (DFS), defined as the time from randomization to the first of one of the following events: recurrence at local, regional, or distant sites; a new invasive cancer in the contralateral breast; any second, non-breast cancer; or death without a prior cancer event, which is similar but not identical to the endpoint definitions used in other AI adjuvant trials. Other endpoints included time to breast cancer recurrence [including invasive contralateral breast cancer, ignoring second (non breast) malignancies, and censoring deaths prior to cancer event], time to distant breast cancer recurrence (time to breast cancer recurrence but ignoring local, regional and contralateral breast events), and overall survival.

In 2005, following initial results showing superiority of Femara monotherapy over tamoxifen monotherapy in improving disease-free survival and reducing the risk of recurrence, the tamoxifen-only treatment arm was unblinded and approximately one quarter of those patients selectively crossed over to Femara treatment. The other three treatment arms remained blinded. Subsequent analyses were designed to estimate the extent to which the crossover affected the comparative benefit of Femara1.

With the long-term follow-up in the analysis conducted more than 10 years after the start of the study, adverse events for Femara and tamoxifen were found to be consistent with the known safety profiles of both drugs. Patients will be monitored for the rest of their lives to track disease status, safety and overall survival(2).

ZOMETA HAS SYNERGISTIC EFFECTS WITH CHEMOTHERAPY

SABCS 2008: Zoledronic Acid Has Direct Effect on Breast Cancer

December 12, 2008 (San Antonio, Texas) — New data suggest that zoledronic acid (Zometa, Novartis) has a direct effect on breast cancer. The bisphosphonate is currently marketed for osteoporosis and bone metastasis, but there is growing evidence to suggest that it might also have a role to play in breast cancer.

Preliminary results from a clinical-trial subset presented here at the 31st Annual San Antonio Breast Cancer Symposium show that when zoledronic acid was used with chemotherapy in the neoadjuvant setting, the combination led to a significantly greater shrinkage of the primary tumor than was seen with chemotherapy alone.

Also, data from molecular studies presented here show that the combination produces a change in the expression of a number of genes and proteins associated with cell-cycle regulation and apoptosis, but neither produced these changes when used alone. "Zoledronic acid on its own had no appreciable effect, but together with chemotherapy, you get this exquisite synergy," commented coauthor Robert Coleman, MD, FRCP, professor of medical oncology at the University of Sheffield, United Kingdom.

These new results are the second time this year that zoledronic acid has shown an effect on breast cancer. When added to adjuvant chemotherapy, it significantly reduced the relapse rate in early breast cancer in the Austrian Breast and Colorectal Cancer Study Group trial 12. These results were presented at this year's American Society of Clinical Oncology meeting, and reported by Medscape Oncology at that time.

Neoadjuvant Use Increased Tumor Shrinkage

The latest data come from the AZURE (Neo-Adjuvant Zoledronic Acid to Reduce Recurrence) trial, conducted in 3360 patients with stage 2 or 3 breast cancer. Patients received standard neoadjuvant chemotherapy with or without the addition of zoledronic acid before surgery, and then standard adjuvant chemotherapy with or without zoledronic acid after surgery. The study was funded by the manufacturer.

The overall results of this trial are still being evaluated, but at the San Antonio meeting, Dr. Coleman presented preliminary results for a subgroup of 205 patients for whom a retrospective pathology analysis had been performed.

The results from this subgroup suggest that the addition of zoledronic acid leads to a greater shrinkage of the primary tumor. After surgery, the median residual tumor size was significantly smaller in women receiving both chemotherapy and zoledronic acid (20.5 mm vs 30.0 mm) than in those receiving chemotherapy alone (P = .002). In addition, a complete pathologic response was seen in 10.8% of women in the combination group vs 5.8% of those in the chemotherapy-alone group (P = .02).

Fewer Women Had a Mastectomy

In this neoadjuvant setting, the goal is to reduce the size of the tumor, and in doing so to potentially improve breast conservation rates and longer-term outcomes, explained coauthor Matthew Winter, MBChB, MSc, clinical research fellow at the University of Sheffield. In this analysis, fewer women in the combination group required a mastectomy (65.3% compared with 77.9% in the chemotherapy-alone group).

"The results support a potential antitumor benefit of combining zoledronic acid with chemotherapy in the neoadjuvant treatment of breast cancer," Dr. Winter commented in a statement.

Dr. Coleman emphasized that these results come from a retrospective and exploratory analysis and, hence, they should be regarded as hypothesis generating. But if the results from the overall AZURE trial confirm these findings, they could be practice changing, he suggested.

The final results from AZURE are expected in the next 2 or 3 years, according to a Novartis spokesperson, who said Novartis is "committed to further exploring zoledronic acid as an anticancer treatment."

OLDER PEOPLE COULD BENEFIT FROM ALLOGENIC STEM CELL TRANSPLANT

ASH 2008: Older Age Doesn't Affect Survival After Allogeneic Stem-Cell Transplant

December 11, 2008 (San Francisco, California) — Older patients with acute myeloid leukemia (AML) and myelodysplastic syndromes should not be prevented from proceeding to allogeneic hematopoietic cell transplantation (HCT) on the basis of age alone. Study results, presented here at the American Society of Hematology 50th Annual Meeting and Exposition, showed that outcomes for older patients undergoing allogeneic HCT were not significantly different from those of younger patients, even after adjustment for multiple comorbidities.

"The main impetus for the introduction of reduced-intensity conditioning was to allow for allogeneic transplants in older patients," said senior author Sergio A. Giralt, MD, professor in the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center, in Houston.

Dr. Giralt and colleagues at MD Anderson pioneered the use of reduced-intensity conditioning, and nonmyeloablative preparation has allowed patients who were not previously considered to be suitable candidates to receive transplants.

Up until that time, older patients were not considered to be candidates for transplantation because the of high doses of radiation and chemotherapy that were needed for engraftment, Dr. Giralt explained. Today, about 30% to 40% of all stem-cell transplants are performed using a low-intensity regimen.

Both AML and myelodysplastic syndromes primarily affect older adults, and although myelodysplastic syndromes are not malignancies themselves, about 30% of the time the syndromes are a precursor to leukemias, such as AML and chrome myelomonocytic leukemia. Transplantation is the best-established curative therapy, but it is usually not made available to older patients because of concerns about toxicity and poor outcomes. Reduced-intensity-conditioning regimens have been developed to allow allografting in older patients, but there are limited data to support their use in patients older than 65 years.

"It is important to recognize that one of the impetuses to do this study [was the fact that] currently in the United States, the Centers for Medicaid and Medicare Services do not consider myelodysplastic syndromes a 'covered' benefit," said Dr. Giralt. "So for many of these patients, an allogeneic transplant is not being covered."

Age Not a Factor for Survival

Dr. Giralt and colleagues retrospectively analyzed data reported to the Center for International Blood and Marrow Transplant Research on 565 patients with AML and 551 patients with myelodysplastic syndromes for transplant-related mortality, engraftment, incidence of acute and chronic graft-vs-host disease, leukemia-free survival, and overall survival. The patients included in the analysis all received reduced-intensity HCT and achieved a first complete remission. The goal was to evaluate the influence of age as a predictor of outcome after allogeneic HCT.

Using multivariate analysis, the researchers did not find statistically significant differences in transplant-related mortality across age groups for either AML or myelodysplastic syndromes patients, and no overall difference in the occurrence of acute graft-vs-host disease (31% to 35% at 100 days) or chronic graft-vs-host disease (36% to 53% at 2 years). Rates of relapse at 3 years were 29% to 30%, and were similar across all age groups. There was also no statistically significant impact of age on transplant-related mortality, leukemia-free survival, or overall survival.

Survival and Relapse Rates for Acute Myeloid Leukemia Patients

	40–54 years, n=220 (range)	55–60 years, n=150 (range)	60–65 years, n=132 (range)	≥65 years, n=63 (range)
Transplant-related mortality
- 100 days, %	11 (7 - 16)	6 (3 - 10)	13 (8 - 20)	10 (4 - 18)
- 1 year, %	20 (15 - 26)	18 (12 - 24)	24 (17 - 33)	30 (19 - 42)
Relapse
- 1 year, %	27 (21 - 33)	34 (26 - 42)	31 (23 - 40)	22 (12 - 33)
- 3 years, %	32 (26 - 39)	35 (27 - 43)	39 (30 - 49)	33 (21 - 46)
Leukemia-free survival
- 1 year, %	53 (46 - 60)	49 (41 - 58)	44 (35 - 53)	48 (36 - 61)
- 3 years, %	43 (36 - 51)	41 (32 - 50)	27 (19 - 37)	34 (22 - 47)
Overall survival
- 100 days, %	84 (78 - 88)	92 (87 - 96)	83 (76 - 89)	89 (80 - 95)
- 1 year, %	59 (52 - 65)	60 (52 - 68)	51 (42 - 60)	51 (39 - 64)
- 3 years, %	45 (40 - 54)	47 (42 - 59)	30 (25 - 43)	36(24 - 49)
Follow-up (months)	37 (2 - 110)	25 (1 - 87)	36 (3 - 96)	29 (3 - 59)

Only disease stage and status at transplantation were significant risk factors for overall survival and leukemia-free survival at 1 year and influenced transplant-related mortality at 2 years.

Clinical characteristics were well matched across all age cohorts, but most AML patients presented with de novo disease and received their allograft from a matched related donor. Half (51%) of patients 65 years and older had a matched related donor. Conversely, myelodysplastic syndromes patients more often had unrelated donors, and this was particularly prevalent in the older cohorts (73% for ≥65 years); but donor type was not significantly different between groups. Most of the patients in the entire cohort received peripheral blood allografts (76% to 97%), fludarabine-containing regimens for conditioning, and cyclosporine-containing regimens for graft-vs-host disease prophylaxis.

"These results allow us to conclude that, for older patients, an allogeneic transplant with a reduced-intensity regimen will result in long-term disease control and should be considered a valid therapeutic strategy, and age should no longer be considered a contraindication," Dr. Giralt said. "Our data should further support the coverage of allogeneic transplant for patients with myelodysplastic syndromes."

Physicians Still Hesitant

In countries where coverage is not an issue, noted Armand Keating, MD, director of the Division of Hematology and professor of medicine at the University of Toronto, in Ontario, physician hesitancy may still limit the use of allogeneic HCT in older patients.

"If you set aside resource availability and payment issues, the reluctance is based on physician acceptance," said Dr. Keating, who was not involved in the study. "One of the reasons that study is important is that it dispels the idea that older patients aren't suitable."

CANCER TO BECOME THE LEADING CAUSE OF DEATH

Cancer to Become Leading Cause of Death Worldwide by 2010

December 10, 2008 — Cancer is projected to become the leading cause of death worldwide in the year 2010, according to a new edition of the World Cancer Report from the International Agency for Research on Cancer.

Low- and middle-income countries will experience the impact of higher cancer incidence and death rates more sharply than industrialized countries, according to the report. This news is in contrast with another recent report that shows that cancer incidence and death rates for men and women in the United States continue to decline, as reported by Medscape Oncology.

The new report was discussed at an event in Atlanta, Georgia called Conquering Cancer: A Global Effort.

Cases of cancer doubled globally between 1975 and 2000, will double again by 2020, and will nearly triple by 2030, says the report. There were an estimated 12 million new cancer diagnoses and more than 7 million deaths worldwide this year. The projected numbers for 2030 are 20 to 26 million new diagnoses and 13 to 17 million deaths.

The global community can expect increases of incidence of about 1% each year, with larger increases in China, Russia, and India. According to the report, reasons for the increased rates include adoption of tobacco use and higher-fat diets in less-developed countries, and demographic changes, including a projected population increase of 38% in less-developed countries between 2008 and 2030.

"The rapid increase in the global cancer burden represents a real challenge for health systems worldwide. However, there is a clear message of hope: Although cancer is a devastating disease, it is largely preventable. We know that preventive measures, such as tobacco control, reduction in alcohol consumption, increased physical activity, vaccinations for hepatitis B and human papillomavirus, and screening and awareness, could have a great impact on reducing the global cancer burden," said Peter Boyle, PhD, DSc, director of the International Agency for Research on Cancer in a statement.

"We recognize that cancer strikes without regard to borders or socioeconomic status," said John R. Seffrin, PhD, chief executive officer of the American Cancer Society, which was one of the groups that organized and sponsored the Atlanta event.

"Even in a challenging economy, people realize that with cancer there is progress to be made and prevention measures to be taken," said Lance Armstrong, founder and chair of the Lance Armstrong Foundation, another of the event organizers, which also included Susan G. Komen for the Cure.

Additional challenges in cancer care, especially in Africa, include pain management and palliative care, which are limited by restrictions and prohibitions on narcotics in several countries.

The event organizers called for action steps, such as making vaccines that prevent cancer-causing infections more widely available to low-income nations, including the HPV vaccine. Other action step is committing to a comprehensive tobacco-control approach in the United States, which includes having Congress grant the US Food and Drug Administration authority to regulate tobacco.

A NEW DRUG FOR ITP

ASH 2008: Eltrombopag Offers "Important New Option" in ITP

December 10, 2008 (San Francisco, California) — Patients with chronic idiopathic thrombocytopenia purpura (ITP) now have another treatment option, which works in some patients when all other therapy has failed.

Results presented here at the American Society of Hematology (ASH) 50th Annual Meeting and Exposition show that eltrombopag (Promacta, GlaxoSmithKline) produced a response in 77% of patients who were refractory to all other treatments, and a response in 84% of patients who were heavily pretreated but not refractory. Patients had previously been treated with corticosteroids, immunoglobulin, anti-D, and rituximab (MabThera, Roche).

The responses were similar in patients who had received a splenectomy and those who had not, reported lead investigator Mansoor Saleh, MD, from Georgia Cancer Specialists, in Atlanta. These data come from the EXTEND study, an open-label extension study that followed up patients for 40 weeks after they had taken part in 6-week placebo-controlled studies.

Also presented at the meeting were data from the pivotal phase 3 study known as RAISE (Randomized Placebo-Controlled ITP Study With Eltrombopag), which were part of the package that secured approval from the US Food and Drug Administration for the drug on November 20.

Eltrombopag offers "an important new option in treating ITP," commented J. Evans Sadler, MD, PhD, from the Division of Hematology at Washington University, in St. Louis, Missouri. It can reduce the need for steroids and might save some patients from undergoing a splenectomy, he commented to Medscape Oncology.

"It's an enormous boon to the management of these patients," commented Sherrill Slichter, MD, from the Puget Sound Blood Center, in Seattle, Washington. "It is of enormous benefit to some patients," she said, "although you have to continue to give the drug, so it is a treatment, not a cure."

First Oral Drug, Injectable Already Available

Eltrombopag is the first oral nonpeptide thrombopoietin-receptor agonist that stimulates the bone marrow into producing megakaryocytes, the precursors to platelets. Another drug with this novel mechanism of action, romiplostim (Nplate, Amgen), was approved for ITP in August 2008, but that drug is a peptide and is administered subcutaneously once weekly.

The fact that these drugs work in ITP confirms the fact that there is an underlying problem with the production of platelets, at least in some patients, commented Dr. Slichter. "This represents a huge change in the thinking of this disorder," she said, because it was thought for years that the main pathology involved an increased destruction of platelets. In fact, her group "got a lot of grief" in the 1980s when they tried to publish data suggesting that a decreased production of platelets was involved, she told Medscape Oncology, so "we are ecstatic now that this mechanism is accepted."

Gregory Chang, MD, from the Chinese University of Hong Kong, who presented the RAISE data at the meeting, said that as many as 50% of patients with chronic ITP could have a problem with the production of platelets.

Pivotal data for romiplostim were presented at last year's ASH meeting. This year, David Kuter, MD, DPhil, from the Massachusetts General Hospital, in Boston, presented long-term data from an open-label extension study out to 3 years. Platelet counts remained stable, and the incidence of severe bleeding events (≥ grade 3) declined over time, he reported. There was no evidence to suggest that the drug's stimulation of platelet production leads to an "exhaustion of the bone marrow," he commented in answer to a question from the audience.

Experts Urge Restraint While Experience Grows

However, some experts urged restraint in the use of these new drugs until more data are available and clinical experience grows. At a press conference that highlighted the new data on eltrombopag, current ASH president Kenneth Kaushansky, MD, professor of medicine at the University of California, San Diego, said: "I would be hesitant to use this new drug." Physicians are conservative in their approach to patient care, he commented, so "I would first use standard therapy with corticosteroids, then go to rituximab and splenectomy, and only then go to these new drugs," he said.

Alan Michelson, MD, from the University of Massachusetts Medical School, in Worcester, who chaired the session at which the eltrombopag data were presented, also urged caution. "These drugs should be used only by experienced hematologists and in patients who are refractory to other treatments," he told Medscape Oncology. He pointed out that both drugs were available only on a restricted program. "The safety data are good so far, but these drugs are very new, and not enough patients have been treated," he said. Nevertheless, the new data are "very exciting and these drugs represent a major breakthrough," he added.

A RAPID INCREASING CANCER

Rapid Increase in Esophageal Cancer Incidence Seen in UK

NEW YORK (Reuters Health) Dec 08 - The incidence of esophageal adenocarcinoma has increased markedly over the past few decades in England and Wales, according to findings published in the November issue of the American Journal of Gastroenterology.

"International variation in the incidence of esophageal cancer is wide," Dr. Come Lepage, of INSERM U 866, Dijon, France, and colleagues write. "The epidemiology of esophageal cancer has changed substantially over the last 30 years."

The researchers examined trends in incidence of esophageal adenocarcinoma in England and Wales from 1971 to 2001. The incidence rates of the disease were calculated by age, sex, and socioeconomic category, by 5-year period, and by birth cohort.

A total of 43,753 esophageal adenocarcinomas were included in the analysis. The authors report that there was a rapid and consistent increase in the incidence of esophageal adenocarcinoma in both men and women. The incidence increased by an average of 39.6% every 5 years in men, and 37.5% every 5 years in women. Since 1971, the incidence of the disease has increased about three-fold in both sexes.

The incidence has increased in all socioeconomic categories since 1986, including the most affluent groups.

"The cumulative risk of developing esophageal adenocarcinoma over the age range 15 to 74 years has increased strikingly in successive birth cohorts," Dr. Lepage's team reports. "It rose from 0.1% for men born around 1900 to 1.1% for those born around 1940, an increase of more than 10-fold," they note. "The corresponding values in women were 0.03% and 0.14%, a nearly five-fold increase."

The investigators suggest that the increase in incidence of esophageal adenocarcinoma may be partly explained by the increasing prevalence of obesity. Apart from that, "etiological studies are required to explain the rapid increase of this lethal cancer."

DO NOT TRUST NEW DRUGS TOO EARLY

Thiazolidinedione Use Further Linked to Fractures in Women

NEW YORK (Reuters Health) Dec 10 - The results of a meta-analysis provide further evidence that use of rosiglitazone and pioglitazone increases the risk of fractures in women with type 2 diabetes. In men, by contrast, no elevated risk is seen.

To assess the risk of fracture with these agents, Dr. Yoon K. Loke from the University of East Anglia, Norwich, UK, and colleagues searched MEDLINE, EMBASE, and other sources to identify relevant studies. Included in the team's analysis were 10 randomized trials that included 13,715 subjects, and two observational studies involving 31,679 subjects.

In the full analysis of the trial data, use of thiazolidinediones for a year or longer increased the odds of fracture by 45%, according to the report in the January 6th issue of the Canadian Medical Association Journal. The results from the observational studies also indicated a link between use of these agents and fractures.

Analysis of data from five trials showed that thiazolidinedione use more than doubled the fracture risk in women, but had no significant effect in men.

Data from two randomized trials indicated that thiazolidinedione-exposed women had significantly reduced bone mineral density at the lumbar spine and hip than did their non-exposed peers.

In a related editorial, Dr. Lorraine L. Lipscombe, from the University of Toronto, comments that "the ongoing accumulation of evidence of harm for thiazolidinediones is unsettling to clinicians and patients and threatens to undermine patient confidence."

She adds that the present study "highlights the need for routine and standardized postmarketing surveillance strategies to be implemented for new drugs, so that both patients and clinicians can be assured that unexpected adverse effects are monitored and reported on a regular basis."

RESTRICTIONS FOR 2 ASTHMA DRUGS

FDA Panel Urges Restrictions on 2 Asthma Drugs

December 11, 2008 — An expert panel said Thursday that the benefits of two inhaler drugs are not worth the risks and should no longer be used to treat asthma.

The vote does not mean the two drugs, Serevent and Foradil, will be pulled from the market. Instead, the panel strongly urged the FDA to tell doctors not to prescribe the drugs to children or adults as a standalone asthma treatment.

The drugs are also widely prescribed for chronic obstructive pulmonary disease. That use was not affected by Thursday's deliberations of a 27-member FDA advisory committee.

At the same time, the experts backed two other popular asthma drugs, saying their benefits outweigh their risks.

Serevent and Foradil are in a class of drugs known as beta-agonists. They help control and prevent airway spasms during asthma attacks. But the drugs have also been associated with a small but significant increase in the risk of hospitalization and death from asthma.

Medical guidelines and the drugs' labeling recommend that beta-agonists only be used in combination with inhaled steroids that cut down on airway inflammation leading to attacks. The combination lowers the risks to a level most experts believed is justified by their benefits.

But studies show that many patients do not use inhaled steroids as directed when taking them separately from beta-agonists. At the same time, patients often feel physical relief from labored breathing when they use their beta-agonist inhaler. The difference can lead to many patients using the beta-agonist alone (called monotherapy), which raises the risk of dangerous side effects, according to FDA analyses presented this week.

"I think the label should be greatly strengthened to say that monotherapy for asthma should basically be contraindicated" for Serevent and Foradil, said Daniel Notterman, MD, a member of the advisory panel from the department of molecular biology at Princeton University.

The rest of the advisors agreed. In a 17-to-10 vote, the panel said the risks of long-term Serevent and Foradil use outweigh the benefits when used alone. The panel cast a similar vote for adolescents with asthma and voted unanimously that the drugs are not worth the risk in children 4 to 11 years old.

"The data is that single use is dangerous," said David Schoenfeld, PhD, a panelist and professor of medicine from Massachusetts General Hospital.

The panel gave broad backing to two other asthma drugs, Advair and Symbicort, in adults. Those products contain a combination of beta-agonist and steroid drugs, thus guaranteeing that patients get both drugs each time they take a puff.

The group was split on whether Advair should be used in children. Thirteen panelists said Advair's benefits outweigh its risks in children, while 11 said they did not. Three abstained.

Experts said they were uneasy with how few studies had been performed showing Advair's safety and efficacy in children.

"I think there's a paucity of data," Notterman said.

Symbicort is generally not used in children.

John Jenkins, MD, who heads FDA's Office of New Drugs, said the agency would consider ordering manufacturers to conduct more safety studies in children, which it can do under new authority granted by Congress.

Ellen Strahlman, MD, the chief medical officer of GlaxoSmithKline, which makes both Advair and Serevent, said the company was pleased with the committee's backing of Advair. But she also said the company was "concerned" that the panel's vote to restrict Serevent could "deny patients needed treatment for optimal care of their asthma."

A statement from Novartis and Schering-Plough said the companies "strongly disagree" with the panel's rejection of Foradil, which they market in a joint venture.

"We believe this opinion is inconsistent with clinical evidence supporting the benefit/risk profile of Foradil in patients not adequately controlled on other asthma-controller treatments," the statement read.

The FDA now has to go back and consider whether to change product labeling or indicated uses for Serevent and Foradil. It will also consider ordering new safety studies, Jenkins said.

Jenkins emphasized that patients currently taking Serevent or Foradil "should not stop taking your asthma medications without talking to your physician."

ARTHRITIS PATIENTS HAVE 40% HIGHER RISK OF CVD DEATH

Arthritis Patients Remain at 50% Higher Risk of CVD Death

December 11, 2008 — A new meta-analysis has shown that patients with rheumatoid arthritis (RA) have a 50% higher risk of death from cardiovascular disease (CVD) than does the general public and that the improvement in CVD mortality seen over time in the wider population has not been mirrored in arthritis sufferers [1]. Dr J Antonio Aviña-Zubieta (University of British Columbia and Arthritis Research Center of Canada, Vancouver) and colleagues report their findings in the December 15, 2008, issue of Arthritis Care & Research.

"Previously, not all studies have consistently found this increased risk," Aviña-Zubieta told heartwire. "We firmly establish that CVD is increased in RA. And it's evident from our study that the argument about the extent of increased risk that has gone on in the past is mainly due to study design," he added.

"We still need to close the gap between CVD death in RA patients and the general population," he stresses. "The rheumatology community, as well as those treating patients with RA, needs to know that this gap still exists and needs to be tackled."

Almost 60% increased mortality risk from MI, 50% increased risk from stroke

In their meta-analysis, Aviña-Zubieta and colleagues searched a number of databases to July 2005 and included 24 observational studies comprising 111,758 patients with 22,927 cardiovascular events.

Overall, there was a 50% increased risk of CVD death in patients with RA. When looking at cause-specific deaths, patients with RA had a 59% increased risk of dying from ischemic heart disease (myocardial infarction [MI]) compared with the general population and a 52% increased risk of death due to stroke.

"Our findings show that the estimated risk varies depending on study design," Aviña-Zubieta explained. "Patients seen in community-based settings have a lower risk when compared with hospital-based clinics (35% vs 53%, respectively). The explanation for these differences in risk among studies is duration of follow-up. Studies that have more than 10 years of follow-up had the highest risk vs those with less than 10 years."

And importantly, he adds, "Changes in treatment strategies over time have not shown improvement in CVD mortality among RA patients — there is a similar risk between patients enrolled before 1987 and after 1987.

"This is very relevant, since it seems that the improvement in CVD mortality that has been demonstrated in the general population seems not to occur in RA patients."

He points out, however, that different RA classification criteria between these two periods could also partly explain this lack of improvement.

Studies of mortality with biologic therapy in RA needed

The researchers also note that the majority of studies included in their meta-analysis enrolled patients before the widespread use of biologic therapies for RA; "therefore, the results obtained may not be generalizable to RA patients treated with biologics."

And recent evidence suggests that all-cause and cause-specific mortality are not greater than expected in RA patients treated with biologic therapy, they note.

"The benefit of newer therapies with biologics remains to be determined," says Aviña-Zubieta. "More studies specifically evaluating mortality in RA patients treated with biologics would be valuable. These studies are urgently needed."

Other ongoing research is evaluating the impact that different treatments for RA have on CVD deaths at the population level, he says, and examining whether the increased mortality is due to increased fatality rate, increased number of events, or both.

WOMEN WITH STEMI HAVE WORSE SURVIVAL THAN MEN

Women With STEMI Fare Worse Than Men

December 10, 2008 — A contemporary look at whether there are still differences between men and women in terms of medical care and outcomes after acute myocardial infarction (AMI) has revealed that the situation appears to be improving for women but that there is still some way to go to achieve equality [1].

In their report published online December 8, 2008 in Circulation, Dr Hani Jneid (Baylor College of Medicine and Michael E De Bakey VA Medical Center, Houston, TX) and colleagues analyzed data from the American Heart Association (AHA) Get With the Guidelines program and found no differences between the sexes in terms of in-hospital mortality from AMI. However, women with ST-elevation MI (STEMI) were still more likely than men to die in the hospital.

Our work is still cut out for us

"It's disturbing that there is still a persistent gap in mortality in the highest-risk STEMI group," Jneid told heartwire. "We were able to close the gap between the sexes after adjusting for age and risk factors, but we found a disparity across the board in all treatments between women and men and a disturbing delay in treatment in women compared with men. We have room to improve on the healthcare and outcome of women when they present with this severe type of heart attack."

Dr Nieca Goldberg (Women's Heart Center, New York University, NY), an AHA spokesperson who was not involved in the research but has a special interest in women's health, told heartwire: "I'm disappointed by this research, as there have been a lot of campaigns to increase awareness about cardiovascular disease in women. It seems like we've improved our care in women with non-STEMI, but it's kind of confusing to me why women with a STEMI come in and are more likely to die." She adds that she is reassured that doctors seem to have gotten better at treating the subtler forms of heart attack, "but our work is still cut out for us."

Women less likely to receive adequate therapies

In their study, Jneid et al examined sex differences in care processes and in-hospital deaths among 78,254 patients with AMI in 420 US hospitals from 2001 to 2006. Women, in general, were older, had more comorbidities, less often presented with STEMI, and had higher unadjusted in-hospital death (8.2% vs 5.7% for men; p <>

But after multivariate adjustment, sex differences in in-hospital mortality were no longer apparent in the overall AMI cohort (adjusted odds ratio 1.04), although they persisted among STEMI patients (mortality rate 10.2% among women compared with 5.5% in men; p <>

This excess death seen in women with STEMI was primarily accounted for by an excess of very early deaths among women in the initial 24 hours of hospitalization, the researchers note. Women were less likely to receive early medical treatments, acute reperfusion therapies, timely pharmacological and mechanical reperfusion, and invasive procedures.

"This tells us that there are true disparities," Jneid says.

Adjusted ORs for clinical performance measures, invasive procedures and in-hospital death*

Measure/treatment/outcome	n	Adjusted ORa (women vs men)	p
Early medical therapy
Aspirin within 24 h	70,360	0.86	<0.0001
Beta blocker within 24 h	64,681	0.90	<0.0001
Invasive procedures
Cardiac cath	74,769	0.91	<0.0001
PCI	67,477	0.78	<0.0001
CABG	67,477	0.60	<0.0001
Revascularization	67,477	0.68	<0.0001
Acute reperfusion and timeliness of reperfusionb
DTN ≤ 30 min	2807	0.78	0.004
DTB ≤ 90 min	7673	0.87	0.004
Reperfusion therapy	24,742	0.75	<0.0001
Primary PCI	24,742	0.83	<0.0001
Fibrinolytic therapy	24,742	0.87	<0.0001
In-hospital death
Overall AMI cohort	70,105	1.04	0.1
STEMI subpopulation	23,015	1.12	0.015

* PCI indicates percutaneous coronary intervention; CABG, coronary artery bypass grafting; DTN, door-to-needle; DTB, door-to-balloon; STEMI, ST-segment elevation myocardial infarction
^a. Adjusted for age, race, body-mass index, insurance type, systolic blood pressure (BP), cardiac diagnosis, initial electrocardiogram (ECG) with diagnostic ST-segment elevation or left bundle-branch block, diabetes, hypertension, hyperlipidemia, heart failure, previous MI, peripheral vascular disease, renal insufficiency, stroke, chronic obstructive pulmonary disease, and adult history of smoking
^b. STEMI subpopulation

Reasons for higher STEMI deaths in women multifactorial

Jneid told heartwire: "Our contemporary analysis is very relevant to current clinical practice. In the present study, the mortality-rate gap was no longer observed after a comprehensive multivariable adjustment, which lends support to the notion that sex, by itself, in the current era, does not independently predict early death after AMI among hospitalized patients."

But the excess in very early death among STEMI women was likely related, at least in part, to the treatment differences, he says, "although the reasons are probably multifactorial."

"Women presenting with STEMI appear to be at high risk of dying in the initial 24 hours and to represent a subgroup of patients in whom prompt and aggressive therapies are warranted," he adds.

Focus on the gap in the chain and how to correct it

Goldberg told heartwire: "We have to see where in the chain this has gotten messed up. Is it that women are getting to the hospital later, so there is more heart-muscle damage?" she wonders. "Did they get the ECGs they needed in a timely manner, and were they correctly evaluated? Is it being explained to them that they might benefit from urgent cardiac catheterization? And is the patient being referred for intervention?"

Jneid says these will be the topics of future research. "We need to address prehospital delays and look at all aspects of patient education, the emergency medical services, the emergency room, and consultant care," he notes. "We need to focus on where the gap in the chain is and how to correct it.

"We as doctors have to use this paper as an example of why you need to go to the hospital quickly and why it's important to treat cardiovascular risk factors before anyone has any symptoms at all," Goldberg stresses. "We need to communicate to our patients that they shouldn't become a statistic."

PARKINSON DISEASE AND GAMBLING

Problem Gambling in Parkinson's Patients Linked to Stimulation of Reward Network

NEW YORK (Reuters Health) Dec 10 - Pathological gambling that may occur in patients with Parkinson's disease may be a result of overstimulation by dopamine replacement therapy of a preserved reward-related mesocorticolimbic dopamine pathway, according to findings published in the December issue of the Archives of Neurology.

In a case-control study, Dr. Roberto Cilia, Istituti Clinici di Perfezionamento, Milano, Italy, and colleagues studied 11 Parkinson's disease (PD) outpatients with active pathological gambling (PG), 40 matched PD controls, and 29 age-matched healthy controls. The mean age of the PD patients was 57 years and all were receiving dopamine replacement therapy.

Perfusion single-photon emission computed tomography was performed on all participants. Parkinson's disease patients with PG showed several clusters of increased perfusion in a right hemisphere network that included the orbitofrontal cortex, the hippocampus, and the amygdala. Overactivity was also observed in the insula and the ventral pallidum. The team saw no areas of relative reduced perfusion.

"We found that normal dosages and types of drugs currently used to treat PD may induce PG by abnormal stimulation of a brain network involved in reward-related processes and impulse control," Dr. Cilia summed up in comments to Reuters Health.

"As we did not find any areas of reduced activity versus both control groups we conclude that this problem is not associated with a disease-related dysfunction but rather with an enhanced and pathological response of a relatively preserved neuronal system in vulnerable individuals," he elaborated.

"I believe that our findings give further insights to the mechanisms underlying this uncommon adverse event occurring in PD patients during standard daily dosage medication treatment," Dr. Cilia said. "The possible association with addictive disorders may widen therapeutic options for PG in PD."

He and his colleagues call for larger prospective controlled studies in order to investigate predisposing factors for the development of impulse control disorders in PD patients undergoing dopamine replacement therapy.

DOPPLER SCREENING IN SICKLE CELL DISEASE

Doppler Screening Program Cuts Strokes in Children With Sickle Cell Disease

NEW YORK (Reuters Health) Dec 09 - Transcranial Doppler (TCD) screening of children with sickle cell disease and treatment of those at high risk can markedly reduce the stroke rate in this patient population, according to study findings presented at the American Society of Hematology annual meeting in San Francisco.

"Prior studies have shown that TCD can identify children with sickle cell disease at high risk of stroke, and the STOP-2 study (1998) showed that transfusion therapy reduced stroke risk in children with abnormal TCD," lead author Dr. Henrietta Enninful-Eghan, from Children's Hospital of Philadelphia, told Reuters Health.

"We have applied the results of these earlier studies to develop a TCD screening and treatment protocol (recommend chronic transfusion therapy for abnormal results) for our patient population," she explained.

With the screening protocol, annual TCD follow-up is recommended for patients with a normal result (<170>

In the present study, the stroke rates 8 years before and after the TCD screening program was implemented in October 1998 were compared. A total of 475 children with 3137 person-years of follow-up were seen in the pre-TCD period and 530 with 3578 person-years of follow-up were evaluated in the post-TCD period.

During the pre-TCD period, 21 patients had an overt stroke, 3 had other neurologic events, and 2 had indeterminate findings. In the post-TCD period, 2 patients had overt strokes, 6 had other neurologic events, and 1 had indeterminate findings.

The rate of overt stroke (per 100 person-years) in the post-TCD period was 0.06, much lower than the 0.67 seen in the pre-TCD period (p <>

The two stroke cases in the post-TCD period involved a patient with an abnormal velocity of the anterior cerebral artery, but not of the internal carotid/middle cerebral arteries, and a child who was 1.2-years of age, which is before screening takes place.

"The take-home message is that TCD screening with treatment of children found to be at high risk of stroke (with transfusions) is extremely effective. All children with the SS or S-beta o types of sickle cell disease should be screened with TCD," Dr. Enninful-Eghan emphasized.

SAVE SOME MONEY

J Clin Oncol. 2008 Dec 8. [Epub ahead of print]

Related Articles

Early Prediction of Response to Sunitinib After Imatinib Failure by 18F-Fluorodeoxyglucose Positron Emission Tomography in Patients With Gastrointestinal Stromal Tumor.

Prior JO, Montemurro M, Orcurto MV, Michielin O, Luthi F, Benhattar J, Guillou L, Elsig V, Stupp R, Delaloye AB, Leyvraz S.

Nuclear Medicine, Pathology, and Medical Oncology Departments, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.

PURPOSE: Positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) was used to evaluate treatment response in patients with gastrointestinal stromal tumors (GIST) after administration of sunitinib, a multitargeted tyrosine kinase inhibitor, after imatinib failure. PATIENTS AND METHODS: Tumor metabolism was assessed with FDG-PET before and after the first 4 weeks of sunitinib therapy in 23 patients who received one to 12 cycles of sunitinib therapy (4 weeks of 50 mg/d, 2 weeks off). Treatment response was expressed as the percent change in maximal standardized uptake values (SUV). The primary end point of time to tumor progression was compared with early PET results on the basis of traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Progression-free survival (PFS) was correlated with early FDG-PET metabolic response (P < .0001). Using -25% and +25% thresholds for SUV variations from baseline, early FDG-PET response was stratified in metabolic partial response, metabolically stable disease, or metabolically progressive disease; median PFS rates were 29, 16, and 4 weeks, respectively. Similarly, when a single FDG-PET positive/negative was considered after 4 weeks of sunitinib, the median PFS was 29 weeks for SUVs less than 8 g/mL versus 4 weeks for SUVs of 8 g/mL or greater (P < .0001). None of the patients with metabolically progressive disease subsequently responded according to RECIST criteria. Multivariate analysis showed shorter PFS in patients who had higher residual SUVs (P < .0001), primary resistance to imatinib (P = .024), or nongastric GIST (P = .002), regardless of the mutational status of the KIT and PDGFRA genes. CONCLUSION: Week 4 FDG-PET is useful for early assessment of treatment response and for the prediction of clinical outcome. Thus, it offers opportunities to individualize and optimize patient therapy

GALLSTONES AND COLORECTAL CANCER

Gallstones a Risk Factor for Colorectal Adenoma

NEW YORK (Reuters Health) Dec 04 - Among subjects undergoing colonoscopy screening, cholelithiasis is associated with an increased risk of colorectal adenoma, findings published in the November issue of the American Journal of Gastroenterology indicate.

Many studies "have reported a moderately increased risk of colorectal cancer in patients with cholecystectomies," note Dr. Yutaka Yamaji, of the University of Tokyo, Japan, and colleagues write. "In contrast, few reports have been published regarding colorectal adenoma, a precursor of cancer." Moreover, they note, "Very few studies have investigated the association between cholelithiasis without resection and colorectal adenoma, but data indicate that the two are not related."

The researchers therefore examined the association between cholelithiasis and colorectal adenoma in 4458 subjects (3053 men, 1405 women) who underwent both ultrasonography and colonoscopy, and completed a questionnaire on lifestyle habits.

Overall, 4189 subjects had normal gallbladders while cholelithiasis was detected in 206 subjects and 63 had cholecystectomies.

The prevalence of colorectal adenoma was 29.6% in cholelithiasis patients, significantly higher than the 17.7% prevalence in subjects with normal gallbladders (p <>

Cholelithiasis was an independent risk factor for colorectal adenoma (adjusted odds ratio, 1.57) in a multivariate analysis controlling for sex, age, family history of colorectal cancer, alcohol, smoking, and body mass index.

A strong association was observed between cholelithiasis and the presence of at least 3 lesions (adjusted OR 2.39) and left-sided colorectal adenomas (adjusted OR 1.82).

"We did not detect an association between cholecystectomy and colorectal adenoma, but silent cholelithiasis and colorectal adenoma were related," Dr. Yamaji and colleagues conclude. "Although the mechanism of this association is unclear, it is possible that the carcinogenic properties of bile acid may play a role."

NEOADJUVANT CHEMOTHERAPY IN ADVANCED NASOPHARYNGEAL CARCINOMA

J Clin Oncol. 2008 Dec 8. [Epub ahead of print]

Related Articles

Randomized Phase II Trial of Concurrent Cisplatin-Radiotherapy With or Without Neoadjuvant Docetaxel and Cisplatin in Advanced Nasopharyngeal Carcinoma.

Hui EP, Ma BB, Leung SF, King AD, Mo F, Kam MK, Yu BK, Chiu SK, Kwan WH, Ho R, Chan I, Ahuja AT, Zee BC, Chan AT.

Department of Clinical Oncology; Department of Diagnostic Radiology and Organ Imaging, Prince of Wales Hospital; State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Hong Kong Cancer Institute; Center for Clinical Trials, School of Public Health, The Chinese University of Hong Kong; and Sanofi-aventis Hong Kong, Hong Kong SAR, China.

PURPOSE: To compare the toxicities, tumor control, survival, and quality of life of nasopharyngeal cancer (NPC) patients treated with sequential neoadjuvant chemotherapy followed by concurrent cisplatin-radiotherapy (CRT) or CRT alone. PATIENTS AND METHODS: Previously untreated stage III to IVB NPC were randomly assigned to (1) neoadjuvant docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 3 weeks for two cycles, followed by cisplatin 40 mg/m(2)/wk concurrent with radiotherapy, or (2) CRT alone. Planned accrual was 30 patients per arm to detect 20% difference of toxicities based on 95% CIs. RESULTS: From November 2002 to November 2004, 65 eligible patients were randomly assigned to neoadjuvant chemotherapy followed by CRT (n = 34) or CRT alone (n = 31). There was a high rate of grade 3/4 neutropenia (97%) but not neutropenic fever (12%) during neoadjuvant chemotherapy. No significant differences in rates of acute toxicities were observed between the two arms during CRT. Dose intensities of concurrent cisplatin, late RT toxicities and quality of life scores were comparable in both arms. The 3-year progression-free survival for neoadjuvant versus control arm was 88.2% and 59.5% (hazard ratio = 0.49; 95% CI, 0.20 to 1.19; P = .12). The 3-year overall survival for neoadjuvant versus control arm was 94.1% and 67.7% (hazard ratio = 0.24; 95% CI, 0.078 to 0.73; P = .012). CONCLUSION: Neoadjuvant docetaxel-cisplatin followed by CRT was well tolerated with a manageable toxicity profile that allowed subsequent delivery of full-dose CRT. Preliminary results suggested a positive impact on survival. A phase III study to definitively test this neoadjuvant-concurrent strategy is warranted.

LAPATINIB PLUS LETROZOLE

SABCS 2008: Lapatinib Plus Letrozole Benefit Metastatic Breast Cancer

December 12, 2008 (San Antonio, Texas) — Lapatinib (Tykerb, GlaxoSmithKline) has shown benefit when used as first-line treatment in metastatic breast cancer. A large phase 3 trial, presented here at the 31st Annual San Antonio Breast Cancer Symposium, opens up a potential new use for the drug, which so far has only been approved for use after other drugs have failed.

The results come from a trial of 1286 postmenopausal women with hormone-receptor-positive metastatic breast cancer who had not received any previous treatment. In such patients, endocrine treatment is a standard and accepted first-line therapy, commented lead investigator Stephen Johnston, PhD, from the Royal Marsden NHS Foundation Trusts and Institute of Cancer Research, in London, United Kingdom. In this trial, all the patients were treated with the aromatase inhibitor letrozole (Femara, Novartis), and then half were randomized to also receive lapatinib. The study was funded by GlaxoSmithKline.

In the overall patient population, the addition of lapatinib increased progression-free survival up to 11.9 months, from 10.8 months for letrozole alone (hazard ratio [HR], 0.86; P = .026).

Large Benefit in Subgroup of Patients

The benefit was much larger in a subset of 219 patients whose cancer was also HER2 positive. In this subset of patients, the combination of lapatinib plus letrozole increased progression-free survival to 8.2 months, a 29% increase over the 3 months seen with letrozole alone (HR, 0.71; P = .019).

Also in this subgroup, the overall response rate with the combination was 28%, compared with 15% with letrozole alone (P =.021), and the clinical benefit rate was 48% and 29%, respectively (P = .003). Side effects were manageable, and no new ones emerged, Dr. Johnston commented.

For this particular group of patients — postmenopausal women with metastatic breast cancer that is hormone-receptor positive and HER2 positive, and who have been deemed suitable for endocrine therapy by their physicians — these new results suggest that the addition of lapatinib is beneficial.

"Previously, these women would have been offered an aromatase inhibitor; now the suggestion is that they would do better on an aromatase inhibitor plus lapatinib," Dr. Johnston said.

"There was a much better chance of getting tumor control and holding it for longer," he told Medscape Oncology.

Asked to comment on the finding, Carlos Arteaga, MD, from Vanderbilt University, in Nashville, Tennessee, said the addition of lapatinib to an aromatase inhibitor is a reasonable alternative in these patients. Dr. Arteaga, who moderated the press conference at which these results were highlighted, is the director of the Breast Cancer Research Program and Breast Cancer Specialized Program of Research Excellence (SPORE) of the National Cancer Institute (NCI)-designated Vanderbilt–Ingram Comprehensive Cancer Center.

There have been some previous data in this area from the TANDEM study, in which trastuzumab (Herceptin, Roche) was added to a different aromatase inhibitor, anastrozole (Aromasin, Pfizer). Dr. Johnston said it is unfair to compare the 2 studies, but the results from that study also showed a benefit for the combination over the aromatase inhibitor alone. However, progression-free survival (4.8 months with the combination vs 2.4 months with the aromatase inhibitor alone) was shorter than in the current study, he pointed out.

"My sense is that physicians may be more persuaded" by these latest data on lapatinib plus letrozole, and also by the fact that lapatinib is an oral drug, Dr. Arteaga told Medscape Oncology. Importantly, these data also confirm that HER2 is a mechanism to overcome resistance to hormonal therapy, he said. "There is a pretty significant alteration in the natural history of the disease."

This was the hypothetical basis behind the study. Recent work has shown that interactions between hormone receptors and HER2 receptors are a primary contributor to the development of resistance to hormonal therapy. Both lapatinib and trastuzumab target the HER2-positive receptor, although they interact with it in different ways.

A spokesperson for GlaxoSmithKline said that the company plans to discuss these new data with regulators in the near future. "The encouraging positive results seen in women who are hormone-receptor positive and HER2 positive show that the lapatinib and letrozole combination has the potential to become a first-line oral treatment option for clinicians and patients in this setting in the future," the spokesperson sai

NEW DATA FOR ESAs

ASH 2008: New Data Confirm Increased Mortality With ESAs in Cancer Patients

December 10, 2008 (San Francisco, California) — A large meta-analysis of individual patient data from clinical trials of erythropoietin-stimulating agents (ESAs) in cancer patients has confirmed that there is a significantly increased risk for death associated with these agents. While the finding is not new — it has already led to restrictive labeling and black box warnings for these products — it will reignite concern over the use of ESAs in cancer patients, say experts.

These latest data come from a detailed analysis of 13,933 cancer patients from 53 clinical trials. They show cancer patients who were treated for anemia with ESAs and blood transfusions as needed had a 6% lower overall survival than those treated with blood transfusions alone.

"The increased risk of death must be balanced against the benefits of ESAs, taking into account each patient's clinical circumstances and preferences," commented lead researcher Julia Bohlius MD, MscPH, from the University of Bern. Her presentation at a late-breaking session here at the American Society of Hematology (ASH) 50th Annual Meeting and Exposition elicited many congratulatory comments from the audience, one of whom thanked the researchers for "undertaking this Herculean task."

Dr. Bohlius and colleagues collected individual data for every patient from individual trialists and from the makers (Amgen, Johnson & Johnson, and Roche). She emphasized that the makers had no involvement in the study design or analysis of the data, and that funding for the study came from an independent source (the German Ministry of Education and Research and OncoSuisse).

Impact on Both On-Study Mortality and Overall Survival

Overall, for cancer patients who received ESAs, there was a significant increase in on-study mortality (ie, deaths during the active study phase) and a significant decrease in overall survival (ie, deaths during the longest follow-up available). Both of these values are higher than have been reported previously from individual studies and literature-based meta-analyses, Dr. Bohlius commented.

Table 1. Results for All Cancer Patients Who Received ESAs (N = 13,933)

Outcome	Hazard Ratio (95% Confidence Interval)	P value
On-study mortality	1.17 (1.06 - 130)	.002
Overall survival	1.06 (1.00 - 1.12)	.005

From these results, Dr. Bohlius calculated the number-needed-to-harm (NNH) for cancer patients with various prognoses. For low-risk patients who have a 5% chance of dying within the next 4 months, the NNH was 121 (95% confidence interval [CI], 69 - 343). "You would have to treat 121 patients with ESAs for 1 additional patient to die," she explained. For medium-risk patients who have a 20% risk of dying within months, the NNH was 34 (95% CI, 19 - 94), whereas for high-risk patients with a 70% risk of dying within 4 months, the NNH was 24 (95% CI, 14 - 67).

No Strong Evidence That Any Factor Influences the Effect

The majority of the cancer patients in these clinical trials were receiving chemotherapy (10,441 [75%] of 13,933 patients), and this patient population was analyzed separately. (Chemotherapy-induced anemia is currently the only approved indication for the use of ESAs in cancer patients.) In this patient population, the increase in on-study mortality and decrease in overall survival was not significant. For patients undergoing chemotherapy, the increased risk for death "was less pronounced, but could not be excluded," Dr. Bohlius commented.

Table 2. Results for Cancer Patients Receiving Chemotherapy Who Received ESAs (n = 10,441)

Outcome	Hazard Ratio (95% Confidence Interval)	P value
On-study mortality	1.10 (0.98 - 1.24)	.12
Overall survival	1.04 (0.97 - 1.11)	.26

No significant differences were seen between any of the different cancer treatments that patients received: chemotherapy, radiotherapy, chemoradiotherapy, or no treatment. There were small differences between these groups, but "they can be explained by chance," Dr. Bohlius said.

There was also no evidence that the effect of ESAs was any different in patients with different tumor types, he said.

In total, the researchers investigated 20 factors and found no strong evidence that any factor modified the treatment effect, although there was some evidence for an effect modification by a history of thromboembolic disease, hematocrit at baseline, and the planned frequency of ESA administration.

"Not all patients are affected, but some are affected," Dr. Bohlius commented, adding that "at the moment, we cannot predict whether the drug will be harmful or not." She said further study at the molecular level is needed because so far analysis of clinical factors has not found any answers.

What Is the Mechanism Involved?

Why there is an increase in mortality in cancer patients receiving erythropoietin is not known, commented senior author Andreas Engert, MD, from the University of Cologne, Germany. There has been speculation, and some early data, that erythropoietin receptors are found on tumors, and that the ESA may act via these receptors to stimulate and promote tumor growth. However, there is no evidence to show this, Dr. Engert commented at an ASH press conference. "There is no convincing data to suggest that this is clinically relevant."

Another explanation that has been put forward is that the increase in mortality results from an increase in thromboembolic events. "I think that this may be the case," Dr. Engert commented. "Dialysis patients treated with ESAs who have too high a level of haemoglobin have a higher risk of dying from cardiovascular disease, and this may also be the case in cancer patients."

"I suspect that there has been an under-reporting of thromboembolic events," Dr. Engert commented. He pointed out that in one of the trials — the BEST study in breast cancer, one of the individual studies that found an increase in mortality with ESA use — some of the deaths did not have an autopsy report.

These latest results will reignite concern about the use of ESAs in cancer patients, predicted J. Evan Sadler, MD, PhD, Washington University, St. Louis, Missouri. "The increase in mortality is very worrisome," he told Medscape Oncology, and these products should be used with "appropriate caution."

"There are hazards associated with these drugs, and I think we have to watch the blood cell count very carefully," said Leonard Zon, MD, from the Children's Hospital, Boston, Massachusetts. "There is still a lot of discussion about these agents, and new clinical guidelines are being developed by a number of organizations, including the National Institutes of Health, about exactly how we should prescribe erythropoietin."

"There is no new cause for concern," commented Samuel Silver, MD, PhD, FACP, from the University of Michigan. The recent changes to these products' labeling (black box warnings, restrictions on use, etc) are in line with these findings, and he said that he did not anticipate any new moves soon.

But, the concern persists and "it makes sense to review and discuss the issue once again, and these data are going to be very important going forward," he said. "This reanalysis of the data at the patient level is critically important," he told the attendees at the press conference. "It was a huge amount of work, and the authors should be congratulated."

MOLECULAR AND CYTOGENETIC MARKERS INTO AML

Table 1. AML Prognostic Groupings by Karyotype

Table 2. Molecular Markers in Normal Karyotype AML

PET IN FOLLICULAR LYMPHOMA

Value of [18F]Fluorodeoxyglucose Positron Emission Tomography in the Management of Follicular Lymphoma: The End of a Dilemma?

Background: [¹⁸F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is a powerful tool for the imaging of various lymphomas. Despite its high FDG avidity, there is little data on PET in follicular lymphoma (FL). In this work, we present findings concerning PET at staging and posttreatment evaluation in FL.
Patients and Methods: A total of 181 PET scans were evaluated in 117 patients with FL in a retrospective study. Positron emission tomography-based results were compared with conventional staging in 82 patients. Posttreatment PET evaluation was performed in 99 patients; there were comparable progression-free survivals of PET-positive and PET-negative patients.
Results: Positron emission tomography showed more involvement than computed tomography (CT) with clinical examination in 41 of 82 patients (50%), less in 11 of 82 (13%); the same extension was found in 27 of 82 patients (33%), and 3 patients revealed discordant foci visible on PET only and lymphadenopathy without PET activity (P < .001). Including the results of trephine biopsy, PET finally upstaged FL in 15 of 82 patients (18%), which was projected in change of treatment strategy. There were 73 of 99 negative posttreatment PET scans; 54 of 73 PET-negative patients (74%) remain in complete remission (median follow-up, 27 months); 19 (26%) of them relapsed with median of 12 months. Fourteen of 20 (70%) PET-positive patients relapsed with a median of 4.5 months regardless of findings on CT and subsequent therapy. The difference in relapse rates between PET-positive and PET-negative patients is statistically significant (P < .001).
Conclusion: Positron emission tomography at staging is able to substantially change treatment strategy in an important proportion of patients with FL. Persisting PET positivity after treatment predicts for a high risk of an early relapse and can identify patients with poor prognosis.

Clin Lymphoma Myeloma. 2008;8(5):287-293

IN UTERO DIABETES EXPOSURE

In Utero Diabetes Exposure May Predispose to Type 2 Diabetes at Earlier Age

NEW YORK (Reuters Health) Nov 27 - Exposure to a diabetic intrauterine environment is associated with an earlier age at diagnosis of type 2 diabetes in offspring, according to findings from the SEARCH for Diabetes in Youth Study -- a survey of ethnically diverse people diagnosed with diabetes before age 20 years.

"This study helps explain why other studies have found higher age-specific rates of type 2 diabetes among offspring of women with diabetes," note Dr. David J. Pettitt from the Sansum Diabetes Research Institute, Santa Barbara, California, and colleagues in the November issue of Diabetes Care.

The study sample included 2,342 young patients with type 1 diabetes and 331 with type 2 diabetes. A total of 269 subjects with type 1 diabetes and 174 with type 2 diabetes had a family history of diabetes.

Dr. Pettitt and colleagues observed that individuals with type 2 diabetes were significantly more likely than subjects with type 1 diabetes to have a parent with diabetes (type 1 or type 2).

They also discovered that type 2 diabetes was diagnosed 1.68 years earlier among the 174 young patients exposed to diabetes in utero than among those whose mothers' diabetes was not diagnosed until after the offspring's birth.

"The significance of this finding persisted when analyses were controlled for the age at which the mothers' diabetes was diagnosed," the investigators note.

Among youth with type 1 diabetes, the effect of intrauterine exposure was not significant when controlled for the mother's age at diagnosis. Father's diabetes before birth was not associated with age at diagnosis of type 1 or type 2 diabetes.

These findings, note Dr. Pettitt and colleagues, "suggest that the hyperglycemic intrauterine environment predisposes to an earlier onset of type 2 diabetes, whereas the age of onset of type 1 diabetes is largely familial, is possibly genetic, and is influenced very little by the intrauterine milieu."

As rates of obesity and type 2 diabetes increase, more young women will be exposing their unborn children to hyperglycemia. "Thus, children exposed at this early stage of life to abnormal nutrients from their diabetic mothers need to be followed carefully, and known risk factors, such as obesity, hypertension, and hyperlipidemia, need early treatment," the investigators conclude.

FDA APPROVALS

Eltrombopag (Promacta) for Treatment of Chronic Idiopathic Thrombocytopenic Purpura

On November 20, the FDA granted accelerated approval and orphan drug designation for eltrombopag 25-mg and 50-mg tablets (Promacta; GlaxoSmithKline), allowing their use for the treatment of chronic immune (idiopathic) thrombocytopenic purpura (ITP) in patients who have demonstrated inadequate response to corticosteroids, immunoglobulins, or splenectomy.

Approval of the thrombopoietin receptor agonist was based primarily on data from 2 pivotal short-term studies and supported by a unanimous decision from the FDA's Oncology Drugs Advisory Committee regarding the favorable nature of risk-benefit profile of eltrombopag in short-term therapy.

In the studies, patients who had completed at least 1 previous regimen of ITP therapy and who had a platelet count of less than 30 x 10⁹/L were randomly assigned to either daily placebo or eltrombopag administered for a maximal treatment period of 6 weeks, followed by 6 weeks off therapy. Treatment was discontinued if platelet counts exceeded 200 x 10⁹/L.

Results showed that eltrombopag 50 mg/day was significantly more effective vs placebo to achieve platelet count response, defined as a shift from a baseline of less than 30 x 10⁹/L to a level of 50 x 10⁹/L or more at any time during the treatment period (study 1, 59% vs 16%; study 2, 70% vs 11%; P < .001 for both).

The platelet count response to eltrombopag was similar between patients who had undergone a splenectomy and those who had not; in general, increases in platelet count were detected after 1 week of treatment and were highest after 2 weeks of therapy. Discontinuation of treatment because of increased platelet counts (> 200 x 10⁹/L) occurred in 27% of eltrombopag-treated patients and in 3% of those given placebo.

Eltrombopag therapy should be initiated at a dose of 50 mg once daily, except in patients of East Asian ancestry or in those who have moderate to severe hepatic impairment. For these patients, the recommended starting dose is 25 mg once daily.

Clinical hematologic and liver tests should be monitored regularly throughout therapy. Dosing should be adjusted to achieve and maintain a platelet count of 50 x 10⁹/L as necessary to reduce the risk for bleeding, but should not exceed 75 mg daily.

In the studies, hemorrhage was the most common serious adverse reaction, with most cases occurring after discontinuation of eltrombopag. Other serious events included liver test abnormalities and thrombotic or thromboembolic complications.

Because of these risks, eltrombopag will only be available through a restricted distribution program called Promacta CARES, which has been developed as part of a risk evaluation and mitigation strategy that will also provide patient support and education and assist with safety data collection.

Bendamustine (Treanda) Approved for Refractory Indolent B-Cell NHL

On October 31, the FDA approved a new indication for bendamustine HCl intravenous infusion (Treanda; Cephalon, Inc [under license from Astellas Deutschland GmbH]), allowing its use for the treatment of indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Bendamustine consists of an alkylating group and a benzimidazole component. Although its mechanism of action remains unclear, the agent can cause the death of cancer cells via several pathways including DNA damage (leading to apoptosis) and disruption of normal cell division (mitotic catastrophe).

Approval of the NHL indication was based on a data from a pivotal study (n = 100), showing that the overall response rate to bendamustine therapy was 74% (95% confidence interval [CI], 64.3% - 82.3%); 13% of patients achieved a complete response. Median response duration was 9.2 months (95% CI, 7.1 - 10.8 months).

In the study, the most commonly reported hematologic adverse events (incidence, > 15%) were lymphopenia, leukopenia, anemia, thrombocytopenia, and neutropenia. Nonhematologic events included nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decrease, dyspnea, rash, and stomatitis.

The recommended dose of bendamustine in NHL is 120 mg/m² infused intravenously for 60 minutes on days 1 and 2 of a 21-day cycle, for up to 8 cycles. Dose delays are recommended for grade 4 hematologic toxicity or clinically significant nonhematologic toxicities of grade 2 or higher; dose reductions to 60 mg/m² are recommended for grade 4 hematologic toxicities, or grade 3 or higher nonhematologic toxicities.

Bendamustine previously was approved by the FDA for the treatment of chronic lymphocytic leukemia.

DRUG ELUTING STENTS IN STEMI

Int J Cardiol. 2008 Dec 2. [Epub ahead of print]

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Long-term outcome after drug eluting stenting in patients with ST-segment Elevation Myocardial Infarction Data from the REAL Registry.

Campo G, Saia F, Percoco G, Manari A, Santarelli A, Vignali L, Varani E, Benassi A, Sangiorgio P, Tarantino F, Magnavacchi P, De Palma R, Guastaroba P, Marzocchi A.

Unità Operativa di Cardiologia, Azienda Ospedaliera Universitaria S. Anna, Ferrara, Italy.

BACKGROUND: The long-term safety and efficacy of drug eluting stents (DES) implanted during primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) is unclear. The purpose of this study was to compare the long-term outcome of STEMI patients undergoing primary PCI with DES vs. bare metal stent (BMS) implantation. METHODS: In the present analysis 4764 patients were enrolled (706, 15%, received DES). We assessed the cumulative incidence of major adverse cardiac events (MACE) and stent thrombosis (ST). RESULTS: Overall, no significant difference emerged for the rates of death and reinfarction. DES implantation was associated to a reduction of target vessel revascularization (TVR) (HR 0.65, 95%CI 0.47-0.91; p=0.01), leading to a MACE reduction (HR 0.7, 95%CI 0.56-0.86; p<0.01). p="0.01)." p="0.6).">