FLU PANDEMIC IS HERE

June 11, 2009 — The World Health Organization (WHO) has increased the pandemic level to phase 6, the final alert phase, indicating that a global pandemic of influenza A (H1N1) is under way.

According to the WHO, pandemic alert level phase 6 is characterized by "community level outbreaks in at least one other country in a different WHO region in addition to the criteria defined in Phase 5." Phase 5 is characterized by human-to-human transmission of the virus into at least 2 countries in 1 WHO region.

After holding an emergency meeting with its influenza experts, the WHO said it has raised the pandemic warning level from phase 5 to 6, according to a statement sent to health officials. WHO Director Dr. Margaret Chan made the announcement during a press conference today.

Scientific Criteria Met

"The world is now at the start of the 2009 influenza pandemic," she said. "The scientific criteria for a pandemic has been met."

According to Dr. Chan, further spread is considered inevitable, "but no previous pandemic has been detected so early or watched real time right at the very beginning."

"The virus is stable" and it looks very similar among countries, Dr. Chan said. "We need to continue to check this virus and monitor it. We should never forget...we still have H5N1 in phase 3 pandemic alert status, and this is the first time we have 2 viruses coexisting...it is an extremely unusual situation."

She added that the virus can change the rules without rhyme or reason at any time, and it will be important to see how the virus changes as it returns to the Northern hemisphere in the fall.

The H1N1 virus is of "moderate severity" with most people making a rapid and full recovery often in the absence of treatment, and the number of deaths is small.

She pointed out that pregnant women are at increased risk for complications, and the virus preferentially infects younger age groups, under age 25 years. She added that it is unknown how this virus will behave under conditions in the developing world. The WHO says that it continues to put no restrictions on travel.

Because of the susceptibility of the population, "influenza pandemics are remarkable events," she said, "but we are all in this together."

As of today, the WHO is reporting nearly 30,000 confirmed cases from 74 countries.

Pandemic Level Increase "Not a Surprise"

At a press briefing immediately after the WHO announcement, Thomas R. Frieden, MD, MPH, who assumed the role of US Centers for Disease Control and Prevention (CDC) director on Monday, commented on the WHO's decision, stating that the increase to pandemic level phase 6 was "not a surprise" and that it was "expected based on the data."

According to Dr. Frieden, the WHO waited until they were certain that they had documentation that on multiple continents that the virus was being transmitted from person to person in a sustained way and this "basically meets our definition of a pandemic."

The key goals are to determine where the virus is spreading and to reduce its impact, "particularly on those who are most vulnerable — people with underlying health conditions and infants as well in this case," he said.

Also at the briefing, Anne Schuchat, MD, the interim deputy director for science and public health program and director of the CDC's National Center for Immunization and Respiratory Diseases, noted that there are more than 13,000 confirmed cases reported in the United States.

"There are over 1000 people who have been hospitalized that have been reported to us, and our last update on the counts of death are 27, but we'll be updating that soon and I do, unfortunately, expect that number to rise," she said.

According to Dr. Schuchat, increases in influenza cases above normal levels for this time of year are still being observed in region 1 (New England) and region 2 (New York and New Jersey).

CDC Was Responding as if to Pandemic Already

"People think it is over, but we need to remain vigilant," she said. However, she pointed out that the CDC has been "reacting as though we were in a pandemic already in terms of our intensive efforts to prepare individuals and respond as a nation."

According to Dr. Schuchat, 57% of the cases have occurred in people aged 5 to 24 years, and 41% of hospitalizations were also within that age range. The highest rates of hospitalizations are in children younger than 5 years. Of the hospitalizations, 71% have occurred in people with an underlying condition.

"As we have noted, there's been a disproportionate amount of pregnant women among those who have had infection," she said.

"What this declaration does do is remind the world that flu viruses like H1N1 need to be taken seriously," Health and Human Services Secretary Katherine Sebelius said in a news release today.

"Although we have not seen large numbers of severe cases in this country so far, things could possibly be very different in the fall, especially if things change in the Southern hemisphere, and we need to start preparing now in order to be ready for a possible H1N1 immunization campaign starting in late September," she noted.

ANDROGEN DERPIVATION THERAPY OVERUSED IN PROSTATE CANCER

June 11, 2009 — Androgen-deprivation therapy (ADT) for prostate cancer is overused, according to experts who have written recent editorials in 2 major journals.

"It's becoming increasingly clear that androgen-deprivation therapy is overused in treating prostate cancer," writes William Dale, MD, PhD, in an editorial accompanying a new American study that indicates that ADT contributes to the development of diabetes. The study and editorial were published online June 8 in the Journal of Clinical Oncology. Dr. Dale is from the geriatrics and palliative medicine and hematology/oncology sections at the University of Chicago in Illinois.

"No doubt there is gross overuse of androgen-deprivation therapy in the treatment of prostate cancer," said Peter Albertsen, MD, MS, in an interview with Medscape Oncology. Dr. Albertsen is the author of an editorial published in the June 11 issue of the New England Journal of Medicine that accompanies a new European study on the use of ADT in men with locally advanced prostate cancer. He is professor of surgery and chief of the Division of Urology at the University of Connecticut Health Center in Framingham.

Both Dr. Albertsen and Dr. Dale note that ADT has been shown to improve survival in men with metastatic prostate cancer, but that its survival benefits are mostly uncertain or unproven in other stages of the disease.

What's Driving the Overuse?

The overuse of ADT has been driven, in part, by clinicians in the United States overestimating the effectiveness of ADT, suggests Dr. Albertsen. "If it's good for advanced disease, there's a good chance it will work for localized disease — that's probably been the thinking," he explained.

Money has also been a driver. "Overuse was probably worse a few years ago when clinicians were making a lot of money off of it," Dr. Albertsen said about the administration of ADT and related follow-up care.

The desire to take action is another driver, said Dr. Dale. "There is a propensity to 'do something' about cancer that leads to starting a therapy that is not justified. This is particularly true for older men," he told Medscape Oncology.

Dr. Dale cited 2 "do something" settings in which data don't support the use of ADT. "Starting it early when PSA [prostate-specific antigen] first rises following surgery or radiation — versus waiting until later to start it — has not been shown to extend life. It is also being used increasingly in older men as primary therapy rather than surgery or radiation therapy," he noted.

Dr. Dale, who is trained as a geriatrician and has an appointment in oncology, spent a month in an oncology clinic talking to clinicians and patients about their decisions to start ADT. "I was struck by men who had their PSA rising and were going out of their minds with worry," he noted. In a study coauthored by Dr. Dale (J Clin Oncol 2009; 27:1557-1563), patient anxiety was shown to be the primary reason men with rising PSA counts, or biorecurrence, decided to start ADT .

In their editorials and comments to Medscape Oncology, Drs. Albertsen and Dale encouraged clinicians to limit their use of ADT to appropriate patients.

They also reminded clinicians of the potential deleterious effects of treatment, including osteoporosis, fatigue, weakness, adiposity, worse cholesterol profiles, hot flashes, and now the development of diabetes.

ADT for Some, But Not All, Advanced Localized Disease

In the treatment of prostate cancer, ADT should be "primarily be limited to men with advanced localized disease undergoing radiation therapy and to men with clear signs of systemic disease," writes Dr. Albertsen in his editorial.

"These are the patients most likely to benefit from either symptom relief or increased survival that would justify the compromise in quality of life that is associated with androgen-deprivation therapy," he notes.

Dr. Albertsen reached this conclusion based on the available literature, which now includes the European study of men with advanced localized disease published in the New England Journal of Medicine.

In the study, the definition of locally advanced disease was either tumor stages T1c to T2a–b and nodal stage N1 or N2, or tumor stages T2c to T4 and clinical nodal stages N0 to N2. Patients with clinical evidence of metastatic spread were excluded.

The study indicates that, following external-beam radiation for locally advanced prostate cancer, 6 months of ADT does not provide survival superior to 3 years of treatment; the now-published results were originally presented at the ASCO annual meeting in 2007 and reported on by Medscape Oncology at the time.

In short, the study says that 3 years of ADT, which is the standard in this setting, should remain the standard.

The results are not generalizeable to men with other stages of prostate cancer, emphasized Dr. Albertsen. He added that the results might not be very helpful when considering American men with advanced localized disease.

"In Europe, more men have T3 disease," Dr. Albertsen said, referring to roughly 70% of the men in the study. European countries do not screen for prostate cancer as aggressively as the United States, he said. As a consequence, Europe has more cancers detected clinically and thus a different pool of patients with locally advanced prostate cancer.

In the United States, many men with advanced local disease will have T1c disease, which is characteristic of screen-detected cancers, Dr. Albertsen continued. These men typically have prostate cancers of much smaller volume and lower grade than the men in the European study, he explained.

It is "unclear" whether the European findings apply to men who receive radiation and ADT and have smaller volume and lower grade tumors characteristic of so much of screen-detected T1c disease, writes Dr. Albertsen.

Thus, the term locally advanced disease might need some qualification when considering ADT in the United States, suggested Dr. Albertsen.

Balancing the Risks for Therapy and Disease

According to Dr. Dale, the best candidates for early use of ADT are, in addition to patients with overt metastasis, younger patients (under 65) with "high-risk" disease (high-grade prostate cancer, local spread of disease into lymph nodes) receiving external-beam radiation. His comments, in effect, echoed Dr. Albertsen's

Dr. Dale also suggested that otherwise healthy men with very high-risk features (Gleason grade of 8–10, PSA doubling times of less than 3 months, short time between primary therapy and rising PSA) could be started early.

However, older patients with moderate-grade or lower disease and long PSA doubling times should definitely not be started on it right away, he emphasized.

"We have to balance the risk of the prostate cancer with the risks of the therapy when making these decisions," said Dr. Dale, adding that mixed information exists about the role ADT plays in worsening cardiovascular disease or diabetes.

However, the new American study "convincingly supports the conclusion that ADT contributes to the development of [diabetes mellitus]," writes Dr. Dale in his editorial.

In the retrospective study of more than 19,000 patients, the investigators found an adjusted hazard ratio of 1.26 (95% confidence interval, 1.16 - 1.36) for the development of diabetes mellitus among men undergoing ADT, said Dr. Dale. The number needed to harm due to the use of ADT was 91, he added.

Dr. Dale and Dr. Albertsen have disclosed no relevant financial relationships.

J Clin Oncol. 2009. Published online ahead of print June 8, 2009.
N Engl J Med. 2009;360:2516-2525 and 2572-2574.

ASCO 2009-SENTINEL NODE BIOPSY FOR EARLY STAGE CERVICAL CANCER?

June 10, 2009 (Orlando, Florida) — New research suggests that the majority of women with early-stage cervical cancer can safely undergo sentinel node biopsy to detect the spread of cancer instead of the conventional pelvic lymph node removal.

The results of the study, presented here at the at the American Society of Clinical Oncology 45th Annual Meeting, show that sentinel node biopsy was useful in providing information about lymphatic drainage that occurred through unusual pathways and detecting micrometastases and isolated tumor cells.

Lead author Fabrice Lécuru, MD, PhD, from Hôpital Européen Georges Pompido in Paris, France, explained that full pelvic lymph node removal and its associated complications might have been avoided in 81% of patients in the study if sentinel node biopsy had been used instead. "Targeted node sampling may be more relevant than full node dissection," said Dr. Lécuru.

However, an expert discussing this paper said that the technique needs to be explored further in clinical trials, and that it is not yet ready for clinical use.

Sentinel node biopsy has been used and validated for cancers of the breast and penis and malignant melanoma. It is also currently being evaluated for several other malignancies, including cancers of the vulva, cervix, head and neck, and colon. Previous studies of cervical cancer have shown that sentinel node biopsy can be used to assess cancer spread in usual areas of the pelvis, said Dr. Lécuru. The current study adds strength to the research by showing that sentinel node sampling is effective for identifying metastatic disease in unexpected or unusual regions.

An estimated 10% to 15% of patients with pN0 early cervical cancer will experience a recurrence, which could be related either to nodes missed by the dissection or located outside the dissection field, or to the failure to diagnose node metastases. Among patients with early-stage disease who undergo surgery, metastasis to the lymph nodes is detected in 10% to 20% of cases using lymphadenectomy, but the procedure can potentially cause complications.

"Sentinel node biopsy is a good option for women with cervical cancer because it enables us to remove fewer lymph nodes to get information about cancer spread, and could decrease the risk of complications from surgery, such as lymphedema," said Dr. Lécuru.

Effective for Identifying Cancer Spread to Atypical Areas

The primary objective of the study was to determine the sensitivity and negative predictive value of sentinel node dissection for evaluating local and regional node status in early cervical cancer. Secondary objectives, explained Dr. Lécuru, were to determine the rate of sentinel node micrometastasis and the frequency of unexpected lymphatic drainage patterns.

The study cohort consisted of 128 patients with stage Ia1 or Ib1 epidermoid cancer or adenocarcinoma or adenosquamous cancer, and was conducted at 7 centers in France from January 2005 to June 2007.

All of the patients had undergone a routine pelvic lymphadenectomy, with or without para-aortic lymphadenectomy. Selective sentinel node identification and dissection was performed using a combined approach of radioactive technetium tracing and blue-dye labeling to identify sentinel nodes in pelvic and para-aortic territories. Detection in an unusual territory was defined as sentinel nodes outside the ilio-obturator region.

One or more sentinel nodes were detected in 98.4% of the cohort and, in 48 women (37.5%), at least 1 node was detected in an unusual territory. The researchers identified 26 positive sentinel nodes in 21 patients (16.4%), of whom 8 (38%) had macrometastases, 7 (33%) had micrometastases, and 6 (29%) had isolated tumor cells. Of the 26 nodes, 7 (27%) were detected only by immunohistochemistry. There were no false negatives in the cohort, and node metastasis was not detected in the majority of patients (n = 104; 81.2%).

Overall, sensitivity was 91.3% (95% confidence interval [CI], 71.9% - 99%) and negative predictive value was 98.1% (95% CI, 93.2% - 99.8%).

"Targeted node sampling may be more relevant than full node dissection," said Dr. Lécuru, and could improve nodal staging of early cervical cancer. Sentinel node detection added information in 39.8% of the patients, showing that drainage occurred through unusual pathways or detecting metastasis using immunohistochemistry.

The "sentinel node technique could improve nodal staging of early cervical cancer," he concluded.

Not Ready for Clinical Use

However, Ate van der Zee, MD, from University Hospital Groningen in the Netherlands, who served as a discussant of the paper, felt that there were still too many unanswered questions. He expressed concern about the reproducibility of sentinel node detection in cervical cancer and whether it was safe to omit lymphadenectomy, among other issues.

"There are really some issues about the technique for sentinel detection in cervical cancer," he said. Standard procedures have not yet been established, such as where and how deep to inject, which tracers should be used, and who should perform the procedure.

The study was also underpowered, and the significance of isolated tumor cells and/or micrometastasis remains to be established, he explained.

"At the present time, in patients with early-stage cervical cancer, I think that sentinel node detection should only be performed within the protection of clinical trials," he said.

The study was funded by the French National Institute of Cancer. Dr. Lécuru and Dr. van der Zee have disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract CRA5506. Presented May 31, 2009.

AN INTERESTING REGIMEN

Am J Clin Oncol. 2009 Jun 5. [Epub ahead of print]

Related Articles, Links

Phase I/II Study of a Cisplatin-Taxol-Dacarbazine Regimen in Metastatic Melanoma.

Papadopoulos NE, Bedikian A, Ring S, Kim KB, Hwu WJ, Gerber DL, Homsi J, Hwu P.

From the Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.

OBJECTIVE:: This phase I/II study was done to evaluate the safety and efficacy of a cisplatin-paclitaxel-dacarbazine regimen in patients with metastatic melanoma. PATIENTS AND METHODS:: Chemotherapy-naive patients with surgically unresectable stage III/IV melanoma who had measurable lesions, no brain metastasis, and an Eastern Oncology Cooperative Group performance status of 0 or 1 were enrolled. Cohorts of 4 patients were treated at each dose level. The starting doses of the drugs were as follows: cisplatin 20 mg/m IV on days 1 to 4, paclitaxel 100 mg/m IV on days 1 and 8, and dacarbazine 800 mg/m IV on day 1 only. The doses of cisplatin and paclitaxel were escalated to the next dose level, until the maximum tolerable doses were reached. The dose level without dose-limiting grade 4 toxicity was chosen for phase II part of the study. The primary end point of the phase II study was to determine the antitumor activity in terms of response rate and survival of patients. RESULTS:: The optimum chemotherapy doses for phase II study were as follows: cisplatin 20 mg/m on days 1 to 4, paclitaxel 120 mg/m on days 1 and 8, and dacarbazine 800 mg/m on day 1. Overall, 46 patients were enrolled in the study. Two complete and 17 partial responses were seen for an overall response rate of 41%. The median overall survival time and time to tumor progression were 11.0 and 4.3 months, respectively. Median response duration was 6.2 months. Myelosuppression and neuropathy were the dose-limiting toxicities. CONCLUSION:: Cisplatin-paclitaxel-dacarbazine regimen is effective in patients with advanced melanoma.

ALLOGENIC TRANSPLANT FOR POOR AND INTERMEDIATE RISK AML PATIENTS

June 11, 2009 — The optimal treatment of acute myeloid leukemia (AML) for patients in their first complete remission remains unclear, especially patients with intermediate-risk AML. However, a new meta-analysis shows that allogeneic stem-cell transplantation (SCT) is associated with a significant overall and relapse-free survival benefit among adult patients in first complete remission with intermediate- and poor-risk but not good-risk AML.

The results of the study, published in the June 10 issue of the Journal of the American Medical Association, are consistent with current practice, which recommends myeloablative allogeneic SCT for poor-risk but not for good-risk AML, say the authors. But there has been no consensus or preferred therapy for intermediate-risk AML, which encompasses the largest portion of AML patients. Allogeneic SCT, consolidation chemotherapy, and autologous SCT have been considered to be of equivalent benefit.

"This strengthens the fact that what has been done as the current standard of care for good/poor-risk patients is actually appropriate," said lead author John Koreth, MBBS, DPhil, from the Dana-Farber Cancer Institute in Boston, Massachusetts. "For good-risk patients, our data show that there is no benefit to donor transplantation up front, and for poor-risk patients, there actually is a benefit, which really wasn't very clear until now."

This changes the recommendations for the intermediate-risk group, explained Dr. Koreth in an interview. "Until now, the guidelines did not clearly define treatment for this group. But now we are able to say that, compared with other therapies, donor transplantation is better."

Potentially Practice Changing

Peter D. Emanuel, MD, director of the University of Arkansas for Medical Sciences Winthrop P. Rockefeller Cancer Institute in Little Rock, agrees that this analysis helps clarify the role of transplantation for the largest group of AML patients. "There has pretty much been agreement across leukemia experts that good-risk patients should not receive an allogeneic transplant, and that poor-risk patients should receive one," he told Medscape Oncology.

"But what hasn't been agreed at all upon is the optimal treatment for the intermediate-risk group," said Dr. Emanuel, who was not involved with the study. "Up until now, there haven't been any reports that gave any indication or hint about how those patients should be treated. It was basically left as an open question."

The current treatment consensus is reflected in the National Comprehensive Cancer Network guidelines, explained Dr. Emmanuel, which are based on the cytogenetic stratification of good-, intermediate-, and poor-risk AML. According to the guidelines, it is recommended that patients in complete remission with good-risk AML undergo consolidation chemotherapy, and that autologous SCT is an acceptable alternative. Allogeneic SCT is recommended for poor-risk patients, but there is no specific recommendation for intermediate-risk patients.

"There aren't any data saying that one therapy is better or worse than another for the intermediate-risk group," Dr. Emanuel pointed out. "This meta-analysis starts to say, in a credible fashion, that these patients should receive allogeneic transplantation. One paper or meta-analysis doesn't change clinical practice, but it certainly sends things down that path."

Dr. Emanuel added that these results are potentially practice changing because it gives clinicians some direction in selecting the most suitable therapy for their intermediate-risk patients.

Benefit Seen for Poor or Intermediate Risk, None for Good Risk

In outlining the aim of the current study, the researchers note that prospective clinical trials, retrospective studies, and systematic reviews have all helped to determine the current treatment consensus for AML patients in first complete remission. However, the results of these studies have not provided definitive evidence to support treatment recommendations.

To quantify relapse-free and overall survival benefit of allogeneic SCT for AML patients in complete remission from the totality of the clinical-trial data available, Dr. Koreth and colleagues conducted a systematic literature review and meta-analysis of all prospective biological assignment clinical trials of allogeneic SCT vs consolidation chemotherapy, autologous SCT, or both for AML in complete remission, on an intention-to- treat donor vs no-donor basis.

A total of 24 trials met the inclusion criteria, which included 6007 patients. Of this group, 5951 patients were included in relapse-free survival analyses, 5606 were included in overall survival analyses, and 3638 were analyzed by cytogenetic risk (547 good, 2499 intermediate, and 592 poor).

The researchers found that, compared with nonallogeneic SCT, the hazard ratio (HR) for relapse or death with allogeneic SCT was 0.80 (95% confidence interval [CI], 0.74 - 0.86). When broken down by cytogenetic risk, a significant relapse-free survival benefit for allogeneic SCT was documented for both poor-risk (HR, 0.69; 95% CI, 0.57 - 0.84) and intermediate-risk (HR, 0.76; 95% CI, 0.68 - 0.85) AML. However, the same benefit was not seen for good-risk AML (HR, 1.06; 95% CI, 0.80 - 1.42).

The overall HR for death with allogeneic SCT in this population was 0.90 (95% CI, 0.82 - 0.97), but significant overall survival benefit with allogeneic SCT was observed only for poor-risk (HR, 0.73; 95%CI, 0.59 - 0.90) and intermediate-risk (HR, 0.83; 95% CI, 0.74 - 0.93) patients. Again, there was no significant benefit noted for good-risk AML (HR, 1.07; 95% CI, 0.83 - 1.38).

"This analysis combined the highest-quality clinical-trial data in a comprehensive way, and therefore would qualify this as one of the highest levels of clinical evidence that one can use to define treatment," said Dr. Koreth. "The emphasis here is that there is a clear benefit in overall survival, and it is clearly based on the patient's chromosomal analysis."

Down the road, there will be newer molecular characterization, he added. "We might be able to further stratify and individualize the risk. But in this analysis, we are setting the foundation for the routine tests that are immediately applicable today."

OFATUMUMAB A NOVEL CD20 MONOCLONAL ANTIBODY FOR CLL

June 11, 2009 (Berlin, Germany) — The novel CD20 monoclonal antibody ofatumumab (Arzerra) has demonstrated superior response rates in 2 challenging groups of chronic lymphocytic leukemia (CLL) patients: those refractory to fludarabine and alemtuzumab; and those refractory to fludarabine and considered inappropriate candidates for alemtuzumab because of bulky tumor masses in their lymph nodes. Updated results in both patient groups were presented here at the 14th Congress of the European Hematology Association.

Ofatumumab is not marketed yet, but could be soon. Recently, on the basis of these results, the drug received a favorable recommendation from the US Food and Drug Administration's Oncologic Drugs Advisory Committee (ODAC) for use in CLL patients refractory to other therapies.

The data come from an interim analysis of 59 patients who were refractory to fludarabine and alemtuzumab and 79 patients who were refractory to fludarabine and considered inappropriate candidates for alemtuzumab because of bulky tumor masses in their lymph nodes. Over the 24 months of the study, patients received 8 weekly intravenous infusions of ofatumumab, followed by 4 monthly infusions. Patients received 300 mg of ofatumumab at the first infusion and 2000 mg at each subsequent infusion. Disease status was assessed every 4 weeks until week 28, and every 3 months thereafter until disease progression or month 24.

Responses were assessed by the ODAC according to the National Cancer Institute Working Group guidelines. An overall response rate of 58% was achieved in the double-refractory group and of 47% in the group refractory to fludarabine with bulky tumor masses (>5 cm). Responses lasted for a median of 6 months in both groups.

In the double-refractory group, median progression-free survival was 5.7 months and overall survival was 13.7 months; in the group refractory to fludarabine with bulky tumor masses, median progression-free survival was 5.9 months and median overall survival was 15.4 months.

"With our data from MD Anderson Cancer Center, we found that a variety of salvage therapies in similar patients gave an overall response rate of 23%, with average patient survival of 9 months," said lead investigator William Wierda, MD, associate professor of medicine at the University of Texas MD Anderson Cancer Center in Houston. Thus, with ofatumumab, "survival is improved in responders by a landmark analysis," he said.

Adverse effects seen with ofatumumab were not beyond the range expected for this patient population. Infusion reactions occurred in 38% of patients and were more common at the first 3 treatments. Infections and neutropenia were the most common grade 3 or 4 adverse events. Dr. Wierda noted that these patients experienced infections because they had previously received 2 lines of immunosuppressive standard therapy. "They had very little immunity when they entered the study and, by virtue of them being refractory, they were at very high risk of infection."

Different Binding Site to Rituximab

Ofatumumab is an investigational monoclonal antibody that is fully human-derived. It binds to a specific part of the CD20 protein on the surface of B cells, known as the small loop epitope, and then recruits complement to aid in cell destruction. Because this binding site is different than that used by rituximab, another CD20 monoclonal antibody used to treat CLL patients, the investigators looked at response to ofatumumab in patients who had previously received rituximab.

This second analysis was based on the premise that previous rituximab therapy might affect response to later treatment with another CD20 monoclonal antibody. "We found that patients treated with rituximab and then ofatumumab showed no statistical difference in response rate to those patients who had not had prior rituximab," said Dr. Wierda.

He added that direct in vitro comparisons showed that ofatumumab might be more effective at killing leukemia cells than rituximab, but this is difficult to show in patients. "This is a major question in people's minds. They both bind to CD20, but which is the better or more effective?"

Paolo Ghia, MD, assistant professor of internal medicine at the Università Vita-Salute San Raffaele in Milan, Italy, told Medscape Oncology that refractory CLL patients desperately need novel treatments to extend life expectancy. "This drug belongs to an interesting new category of anti-CD20 compounds, which should demonstrate good results in patients in the next few years, especially in combination. Older agents such as rituximab are ineffective as monotherapy, but these new ones prove efficacious when used alone and may be even more promising in combination with chemotherapy. It would be good to use this first-line in all CLL patients."

The study was funded by GlaxoSmithKline and Genmab. Dr. Wierda and Dr. Ghia have disclosed no relevant financial relationships.

ASCO 2009-ANOTHER "ME-TOO" DRUG FOR KIDNEY CANCER

June 11, 2009 (Orlando, Florida) —The investigational drug pazopanib showed significant activity against advanced renal cell cancer in a placebo-controlled phase 3 trial presented here at the American Society of Clinical Oncology 45th Annual Meeting. But in a discussion session, one expert suggested that it needs to show more because there are already similar drugs approved for this indication.

Pazopanib is not marketed yet. The study was funded by the manufacturer, GlaxoSmithKline, and the company has submitted these data for approval for this indication to both the US Food and Drug Administration and the European Medicines Evaluation Agency.

The results from the study showed "not surprisingly" that pazopanib was better than placebo, said Primo Lara, MD, professor of medicine at the University of California at Davis, speaking at a Highlights of the Day session. The hazard ratio (0.46) was similar to those seen in previous phase 3 trials in this setting, he noted, such as with sunitinib vs interferon and sorafenib vs placebo.

However, sunitinib (Sutent, Pfizer) and sorafenib (Nevaxar, Bayer) are already approved for use in kidney cancer, and pazopanib has a very similar mechanism of action to these drugs — acting as an inhibitor of vascular endothelial growth-factor receptor, platelet-derived growth-factor receptor, and c-Kit. In addition, all of these drugs are oral. This makes pazopanib a "me-too" drug in this indication and, as such, it needs to show something more, Dr. Lara commented.

"The threshold for me-too drug success, compared with available in-class agents, should be higher, much higher," he said. These need to demonstrate better efficacy or have less toxicity, or they should be less expensive, he suggested. The current phase 3 trial of pazopanib has not met any of these criteria, he added.

"Does pazopanib's win against placebo fulfill an unmet medical need? Not yet," he said. In fact, he questioned the use of a placebo control, saying that this is a "pure scientific design" but it would be impossible to carry out in countries where active targeted agents are available, such as in the United States and some parts of Western Europe. A trial comparing pazopanib with sunitinib is now ongoing, he noted.

The pazopanib results were presented at the meeting by Cora Sternberg, MD, from the San Camillo and Forlanini Hospitals in Rome, Italy. Her coauthors were from Poland, Slovakia, Chile, Korea, Australia, and the United Kingdom, and some were employees of GlaxoSmithKline.

The trial was conducted in 435 patients with advanced kidney cancer who had not received any previous therapy or had only received 1 cytokine-based therapy. Patients were randomized 2:1 to receive pazopanib (800 mg orally once daily) or placebo, and those in the placebo group were given pazopanib on disease progression.

The results showed an overall response rate of 30% for pazopanib, compared with 3% for placebo, and a median progression-free survival of 9.2 months with pazopanib and 4.2 months with placebo (hazard ratio, 0.46; P < .0000001).

Pazopanib was well tolerated, Dr. Sternberg noted, with the majority of adverse events being mild to moderate. The most common adverse events were diarrhea (in 52% patients, but grade 4 diarrhea was seen in only 4%), hypertension (40%, but grade 3/4 in only 4%), hair color change (38%; but grade 3/4 in less than 1%), nausea (26%, but grade 3/4 in less than 1%), anorexia (22%, but grade 3/4 in 2%), and vomiting (21%, but grade 3/4 in 2%). The most common laboratory abnormality was alanine aminotransferase elevation (53%, but grade 3 in 10% and grade 4 in 2%).

INFLAMMATION MARKERS AND BREAST CANCER SURVIVAL

NEW YORK (Reuters Health) Jun 08 - Systemic C-reactive protein (CRP) and serum amyloid A (SAA), measures of low-grade chronic inflammation, are inversely associated with survival in patients with breast cancer, researchers report in a May 26th online publication in the Journal of Clinical Oncology.

"C-reactive protein is available as a clinical test for heart disease and now it looks like this may also be useful for monitoring breast-cancer patients' well being," lead investigator Dr. Cornelia M. Ulrich told Reuters Health. "In addition, the lowering of CRP through exercise, weight loss or medications, may be helpful to reduce risk of recurrence."

Dr. Ulrich of the Fred Hutchinson Cancer Research Center, Seattle, Washington, and colleagues studied data on 734 women treated successfully for early stage breast cancer. The researchers examined circulating levels of CRP and SAA about 31 months after diagnosis.

After follow-up of almost 7 years, the team found that elevated levels of the biomarkers were associated with reduced overall survival. This persisted despite adjustment for age, tumor stage, race, and body mass index. For the highest versus the lowest levels of CRP, the hazard ratio form reduced survival was 2.27. For SAA, the corresponding value was 3.15.

Elevated CRP and SAA were also associated with reduced disease-free survival, but the significance was borderline.

In an accompanying editorial, Dr. Steven W. Cole, of the University of California Los Angeles School of Medicine, observes that the study provides "some of the most persuasive evidence yet that chronic inflammation might increase the risk of breast cancer recurrence."

He concludes that if the findings are replicated in larger studies, post-treatment monitoring of circulating acute phase proteins "could provide a new strategy for assessing the risk of breast cancer recurrence in seemingly cured patients."

J Clin Oncol 2009;27.

GENETIC MUTATION FOR GRANULOSA CELL OVARIAN TUMORS DIAGNOSIS

June 12, 2009 — Granulosa-cell tumors (GCTs) are relatively rare, accounting for less than 5% of all ovarian cancers. Traditional chemotherapeutic approaches have limited efficacy in treating patients with advanced-stage or recurrent disease, indicating the need for more effective treatment regimens. However, in a study published online June 10 in the New England Journal of Medicine, researchers report having identified a single mutation in the genetic code of GCTs.

The whole-transcriptome sequencing of 4 GCTs identified a single recurrent somatic mutation (402C→G) in FOXL2, a gene encoding a transcription factor known to be critical for the development of granulosa cells. The mutation was present in almost all morphologically identified adult-type GCTs, but absent from 49 other ovarian sex-cord stromal tumors (SCSTs) and 329 unrelated ovarian or breast tumors.

"GCTs are sometimes problematic to diagnose," said senior author David G. Huntsman, MD, a genetic pathologist at the British Columbia Cancer Agency and Vancouver General Hospital and associate professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia. "This finding will assist in making an accurate diagnosis."

In this study, Dr. Huntsman told Medscape Oncology, a mutation was identified that appears to be common in all GCT tumors. "There are currently no effective treatments beyond primary surgery," he said. "We think the mutation is the driver of the tumor, and now we have the first clue to developing a treatment."

Methods for rapidly sequencing whole cancer genomes have recently been developed. "A suite of new technologies has emerged that allow sequencing of whole genomes," said Dr. Huntsman. "We can undertake genomic research in ways that we never could have considered doing even just a few years ago."

Mutation Common in GCTs, Rare in Other Tumors

Initial studies suggested that hundreds of samples of any type of malignancy would have to be sequenced to derive clinically useful information or make any clinically useful discoveries, but Dr. Huntsman and colleagues hypothesized that knowledge could be gained from much smaller studies if the cancers were carefully selected and represented clinically homogenous diseases.

Since GCTs are genomically stable, the researchers speculated that common GCT-specific molecular abnormalities in the transcriptomes of GCTs could be identified through the analysis of a limited number of samples. They analyzed 4 ovarian adult-type GCTs (1 primary and 3 recurrent tumors), 10 ovarian carcinomas, and 1 cell line derived from a serous borderline tumor. Frozen tissue samples from 149 epithelial ovarian tumors and 180 breast carcinomas were also analyzed.

In addition, the researchers analyzed a second series of formalin-fixed paraffin-embedded ovarian SCSTs that consisted of 95 tumor samples: 27 adult-type GCTs, 8 juvenile-type GCTs, 23 fibromas, 14 Sertoli–Leydig cell tumors, 13 thecomas, and 10 steroid-cell tumors.

Dr. Huntsman and his team found that all 4 index GCTs had a missense point mutation, 402C→G (C134W), in FOXL2. The FOXL2 mutation was also detected in 86 of 89 additional adult-type GCTs (97%), in 3 of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%).

However, the mutation was not observed in 49 of the other types of SCSTs or in 329 unrelated ovarian or breast tumors.

"This is the first example of the way new technology will enhance our understanding of cancer and provide the knowledge to really allow the personalization of cancer care," said Dr. Huntsman. "This is a really exciting taste of what's to come. The technology is going to change they way we look at these diseases."

May Improve Diagnostic Accuracy

Although there are limitations to the study, the researchers successfully applied transcriptome sequencing to identify a consistently occurring somatic mutation in GCTs, according to an accompanying editorial.

"This demonstrates that transcriptome sequencing has strong potential as an efficient and cost-effective alternative to whole-genome sequencing," writes Jay Shendure, MD, PhD, from the University of Washington in Seattle, and Colin J. Stewart, MB, ChB, from King Edward Memorial Hospital and Bendat Cancer Centre at St. John of God Hospital in Perth, Australia.

Although immunohistochemical techniques that have been developed during the past decade have proved to be very helpful in diagnosing GCTs, they note, none of the currently available markers are completely reliable. "Thus, as with other tumors that show characteristic genetic alterations, an adjunct molecular test involving FOXL2 analysis offers the possibility of improving diagnostic accuracy in patients with GCTs."

NAPROSYN BEST NSAID FOR HEART DISEASE PATIENTS

June 4, 2009 (Nashville, Tennessee) — One of the first large studies to look at the safety of different nonsteroidal anti-inflammatory drugs (NSAIDs) specifically in patients with heart disease has found that naproxen appears to have better cardiovascular safety than diclofenac, ibuprofen, and higher doses of rofecoxib (Vioxx, Merck) and celecoxib (Celebrex, Pfizer) [1].

The study, published in the May 2009 issue of Circulation: Cardiovascular Quality and Outcomes, was conducted by a group led by Dr Wayne Ray (Vanderbilt University School of Medicine, Nashville, TN).

They explain that the cardiovascular safety of NSAIDs is highly controversial, with several studies suggesting increased cardiovascular risk associated with the new COX-2 inhibitors and also some older traditional NSAIDs, and that this issue is particularly important for patients with existing serious coronary heart disease, whose baseline risk of adverse cardiovascular events is increased. In addition, many of these patients take low-dose aspirin, which may interact with the NSAID.

But they note that data on the cardiovascular safety of these drugs in heart-disease patients is limited. They therefore conducted the current retrospective cohort study in which they examined the cardiovascular safety of individual NSAIDs in 48 566 patients with a hospitalization for MI, revascularization, or unstable angina that had been recorded in one of three large databases-- Tennessee's expanded Medicaid program, Saskatchewan Health databases in Canada, and the United Kingdom's General Practice Research Database--between 1999 and 2004. Medications given outside the hospital were identified from pharmacy and physician records. The primary study end point was serious coronary heart disease, defined as MI or out-of-hospital death from CHD. A secondary end point was the composite of serious cardiovascular disease (MI or stroke) and death from any cause. Preplanned analyses were conducted for the most frequently prescribed NSAIDs, which were naproxen, ibuprofen diclofenac, celecoxib, and rofecoxib.

Results showed that cardiovascular safety was best for naproxen, which had a lower incidence rate ratio (IRR) for serious cardiovascular disease than non-NSAID users. In contrast, there was evidence that cardiovascular risk was increased for users of the other study NSAIDs.

Incidence Rate Ratios (IRRs) for Serious CV Disease or Serious CV Disease and Death for Users of Various Nsaids vs Non-NSAID Users

Drug	IRR (serious CV disease)	IRR (serious CV disease/death)
Naproxen	0.88	0.91
Ibuprofen	1.18	1.14
Diclofenac	1.27	1.38
Celecoxib	1.03	0.99
Rofecoxib	1.19	1.07

Other results showed that individuals who took diclofenac had a 50% increased risk of MI, stroke, or death from any cause compared with naproxen users. The authors point out that diclofenac is widely used outside the US and has been the reference drug in several COX-2-inhibitor outcome trials, and this excess risk was present for low and moderate doses (<150>200 mg/day) and rofecoxib (>25 mg/day) had increased risk of serious coronary heart disease.

Relative to NSAID nonusers, serious coronary heart disease risk increased with short-term (less than 90 days) use for ibuprofen, diclofenac, celecoxib, and rofecoxib, but not for naproxen. The authors note that this is in contrast to a widely publicized post hoc analysis of the APPROVE trial data, interpreted by some as suggesting no risk for use of less than 18 months. But they point out that observational studies of rofecoxib have reported increased risk within the first month of therapy, and in the VICTOR trial, rofecoxib patients had increased risk after a mean duration of 7.4 months. "Thus, our findings add to the evidence that at least one of the mechanisms for increased cardiovascular risk is acute," they say.

They comment that their current findings are generally consistent with previous studies, most of which were not restricted to patients with serious coronary heart disease. They caution that the follow-up in this study began 45 days after the qualifying hospitalization admission for coronary heart disease, so these results do not apply to the early postdischarge period, during which NSAID use may be particularly hazardous.

Breaking New Ground

In an accompanying editorial [2], Dr Daniel Solomon (Brigham and Women's Hospital, Boston, MA) says that this study breaks new ground in focusing on patients with known cardiovascular disease. As arthritis and cardiovascular disease commonly coexist, studying the cardiovascular safety of NSAIDs in this subgroup is of great public-health value, he comments.

Noting that the relative risks for rofecoxib were consistently lower when death from any cause was also included in the end point, Solomon suggests that this raises the possibility that death from gastrointestinal bleeds may have been reduced in persons using rofecoxib. He says this leads to questions about how to measure the overall safety of a drug. "Cardiovascular safety in patients with known cardiovascular disease is tremendously important, but clinicians and patients should focus on 'net' safety," he writes. But he adds that this is difficult concept to understand and even harder to measure.

Solomon continues that the use of NSAIDs in patients with cardiovascular disease is concerning because of the cardiovascular and gastrointestinal toxicities associated with these agents, but until newer analgesics are developed, these agents will continue to be used in this patient group.

While more information will come from the PRECISION trial, a large randomized comparison of celecoxib, naproxen, and ibuprofen in patients at moderate cardiovascular risk, these results will not be available until 2011 or later, and thus, until then, doctors will continue to rely on well-done pharmacoepidemiology to help answer questions about the relative safety of various analgesic strategies in important subgroups of patients, Solomon says.

He concludes that the current study "gives us new and useful information from an observational study focusing on an important subgroup with known cardiovascular disease" and that "diclofenac use should be limited in this group and naproxen appears relatively safe, but non-NSAID analgesic strategies might also be considered."

METOCLOPRAMIDE SAFE IN FIRST TRIMESTER OF PREGNANCY

Although metoclopramide is a popular antiemetic drug for pregnant women, data regarding its safety are lacking, Dr. Rafael Gorodischer, from Soroka Medical Center, Beer-Sheva, Israel, and colleagues note. The few studies that have examined this topic have been small and, therefore, have been unable to reach definitive conclusions.

The present study, reported in The New England Journal of Medicine for June 11, analyzed data on 81,703 singleton births that occurred among women registered in the Clalit Health Services, southern district of Israel, from January 1998 to March 2007.

Overall, 4.2% of the infants were exposed to metoclopramide during the first trimester of pregnancy, the researchers report.

Exposure to metoclopramide, relative to non-exposure to the drug, did not significantly affect the risks of major congenital malformations (5.3% vs. 4.9%), low birth weight (8.5% vs. 8.3%), preterm delivery (6.3% vs. 5.9%), or perinatal death (1.5% vs. 2.2%).

The null findings were still apparent even when therapeutic abortions of exposed and unexposed fetuses were included in the analysis, the researchers note.

"In this large, population-based cohort, we found no significant association between metoclopramide treatment in the first trimester and adverse outcomes for the fetus, including congenital malformations, perinatal death, low birth weight, and low Apgar scores," the authors conclude.

N Engl J Med 2009;360:2528-2535.

HIGH COLA CONSUMPTION AND HYPOKALEMIC MYOPATHY

NEW YORK (Reuters Health) Jun 05 - Drinking several liters of cola-containing soft drinks per day can cause chronic hypokalemia leading to muscle weakness and even paralysis, according to a review article in the International Journal of Clinical Practice for June.

While one might argue that "excessive soft drink consumption at this level is so rare that it is not a public health issue," the author of an accompanying editorial writes, "the problem is that we have every reason to think that it is not rare."

In a search of PubMed, Dr. Moses Elisaf and associates at the University of Ioannina, Greece, identified six reports of cola-induced hypokalemia published since 1994. Quantities of cola consumed ranged from 2 to 9 liters/day. Muscle complaints ranged from mild weakness to profound paralysis, and all patients had abnormally low serum potassium levels.

"Fortunately," Dr. Elisaf and colleagues write, "all patients had a rapid and complete recovery after the discontinuation of cola ingestion and the oral or intravenous supplementation of potassium."

The authors suggest that one component with the potential to alter potassium metabolism is high-fructose corn syrup, which can cause chronic osmotic diarrhea and potassium depletion. Glucose -- by inducing osmotic diuresis and hyperinsulinemia - or caffeine - by causing potassium redistribution into cells and/or increased renal potassium excretion - may also be responsible.

Dr. Elisaf's team cautions that "the cola-induced chronic hypokalemia clearly predisposes to the development of potentially fatal complications such as cardiac arrhythmias."

In his editorial, Dr. Clifford D. Packer at the Louis Stokes Cleveland VA Medical Center in Cleveland, Ohio, comments that "with aggressive mass marketing, super-sizing of soft drinks, and the effects of caffeine tolerance and dependence, there is very little doubt that tens of millions of people in industrialized countries drink at least 2-3 L of cola per day."

The resulting drop in serum potassium levels increases the risk of cardiac ischemia, heart failure, or left ventricular hypertrophy. He also notes that sugar-sweetened soft drinks have been linked to osteoporosis, gout, GERD, chronic kidney disease, secondary hyperparathyroidism, esophageal perforation, hematuria, tongue erosions, and gastritis.

Dr. Packer advises physicians to start asking their patients about soft drink consumption, and stresses that "the soft drink industry needs to promote safe and moderate use of its products for all age groups, reduce serving sizes, and pay heed to the rising call for healthier drinks."

Int J Clin Pract 2009;63:833-835,900-902.

WHO IS GETTING CLOSER TO DECLARING H1N1 FLU PANDEMIC

GENEVA (Reuters) Jun 09 - The World Health Organization is getting close to declaring a full H1N1 influenza pandemic but wants to make sure countries are well prepared for such a move to prevent a panic, its top flu expert said Tuesday.

Keiji Fukuda, acting WHO assistant director-general, voiced concern at the sustained spread of the new strain in countries, including more than 1,000 cases in Australia, following major outbreaks in North America where it was first detected.

The disease, widely known as swine flu, which has infected over 26,500 people in 73 countries, with 140 deaths, has also spread widely in Britain, Spain and Japan.

Confirmed community spread in a second region beyond North America would trigger moving to phase 6 from the current phase 5 on the WHO's 6-level pandemic alert scale.

Asked whether there was any doubt that a pandemic was under way, Fukuda told a weekly teleconference: "We are really getting very close to that."

Fukuda said a decision to declare a pandemic involved more than simply making an announcement. The United Nations agency had to ensure that countries were able to deal with the new situation and also handle any public reaction.

"One of the critical issues is that we do not want people to 'over-panic' if they hear that we are in a pandemic situation," Fukuda said.

A very real danger was that hospitals could be overwhelmed by people seeking help when they did not really need it.

Since the new flu strain first appeared, many people have stopped eating pork, pigs have been culled in some countries, trade bans on meat imposed, travelers quarantined and some countries have discussed closing borders.

"These are the kinds of potential adverse effects that you can have if you go out without making sure people understand the situation as well as possible," Fukuda said.

5-FU AS EFFECTIVE AS GEMCITABINE FOR PANCREATIC CANCER IN ADJUVANT SETTING?

June 10, 2009 (Orlando, Florida) — Don't dismiss the value of 5-fluorouracil (5-FU) in the treatment of pancreatic cancer, say experts.
In the adjuvant setting, 5-FU provided overall survival — about 23 months — similar to that of gemcitabine (Gemzar), according to the results of a new randomized trial presented here at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting.

"It's a fantastic result," said lead author John P. Neoptolemos, MD, adding that of the 1088 resected patients, 35% had positive resection margins and 72% had metastases to the lymph nodes.

"Keep in mind that, in the past, many of these patients would have died within 12 months," said Dr. Neoptolemos, who is head of the Division of Surgery and Oncology at the University of Liverpool in the United Kingdom. He addressed reporters at a meeting press conference

The study was an affirmation of the effectiveness of 5-FU, said Dr. Neoptolemos.

"Gemzar arrived in 1996 and changed the treatment landscape for advanced pancreatic cancer. It acquired a mythical status," Dr. Neoptolemos told Medscape Oncology, suggesting that the reputation of 5-FU suffered as a consequence, in the United States at least.

"It's been previously thought by [American] clinicians that 5-FU might not be as effective," Dr. Neoptolemos continued. Gemcitabine combined with radiation has been the treatment of choice in the United States; however, 5-FU remains the preferred treatment in many parts of the world, including Europe, he said

The new study addressed an information gap in pancreatic cancer, suggested Jennifer Obel, MD, who moderated the press conference. "We've never had a large study comparing these 2 therapies," she told Medscape Oncology. Dr. Obel is a gastrointestinal oncologist at the NorthShore University HealthSystem in Evanston, Illinois. She also is a member of the ASCO Communications Committee.

Dr. Obel also suggested that 5-FU might be even better, at least in terms of adverse events, than the study reported.

"This study shows that 5-FU, even when given in an outdated fashion, which is more toxic, is equivalent to gemcitabine. Perhaps 5-FU in an updated fashion — namely, oral capecitabine — will be even more effective. It will certainly be less toxic," she told Medscape Oncology.

Combination Chemotherapy Now Makes Sense

The new study, known as the European Study Group for Pancreatic Cancer-3 trial (ESPAC-3), is the largest adjuvant trial ever conducted in pancreatic cancer, said Dr. Neoptolemos

The results should "harmonize treatment worldwide," he said, explaining that they "open up the opportunity to give both drugs at the same time" because the drugs work equally well and have different mechanisms of action.

Dr. Neoptolemos also offered clinicians worldwide some advice. "The [United States] should drop chemoradiation, which is very expensive and lacks good evidence, and adopt 5-FU, and the Europeans should adopt gemcitabine," he said.

In addition to being a cheerleader for gemcitabine–5-FU combination therapy, Dr. Neoptolemos is also part of a new clinical trial (ESPAC-4) that aims to find out if it's effective.

"It's exciting that there's a potential for combination therapy," said Dr. Obel. Oral capecitabine (Xeloda) is the form of 5-FU being used in ESPAC-4, she added.

There is a great need to improve chemotherapy in this setting, Dr. Obel continued. "The main problem with the treatment of early-stage pancreatic cancer is that there is only a 20% cure rate at 5 years postsurgery," she said, even though more than 200 drugs have been tested in pancreatic cancer.

Gemcitabine Has Better Safety Profile in Current Study

For clinicians who want to choose either 5-FU or gemcitabine, the new data show that gemcitabine is likely to be the preferred adjuvant therapy because of a better safety profile, said Dr. Neoptolemos.

In the study, patients who received 5-FU reported more toxicities than those treated with gemcitabine, including grade 3/4 toxicity stomatitis (10% vs 0%, respectively), diarrhea (13% vs 2%), and treatment-related hospitalizations (10% vs 3.5%).

All patients taking part in the 16-country phase 3 study had either an R0 or R1 resection for pancreatic ductal adenocarcinoma and were randomized (stratified for resection margin status and country) within 8 weeks of surgery to receive either 5-FUl/folinic acid (FA) or gemcitabine.

The 5FU/FA regimen consisted of an IV bolus injection of FA 20 mg/m², followed by an IV bolus injection of 5-FU 425 mg/m² given on days 1 to 5 every 28 days. The gemcitabine regimen consisted of an IV infusion of gemcitabine 1000 mg/m² on days 1, 8, and 15 every 4 weeks for 6 months.

Dr. Neoptolemos is a consultant to Pfizer and has received research funding from Pharmexa, Oxford Biomedica, and Cytimmune. Dr. Obel is a consultant to Onyx.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract LBA4505. Presented May 31, 2009.

NATURAL HISTORY OF VAGINAL CANCER

June 9, 2009 — Stage, tumor size, histologic features, and treatment modality are associated with an increased risk for mortality from vaginal cancer, according to the results of a study reported in the May issue of Obstetrics & Gynecology.

"Recognized factors that increase a woman's lifetime risk of vaginal cancer include younger age at coitarche, greater number of lifetime sexual partners, smoking, in utero diethylstilbestrol exposure, and human papillomavirus (HPV) infection," write Chirag A. Shah, MD, MPH, from the University of Washington in Seattle, and colleagues. "The cause of vaginal cancer is closely linked to cervical cancer, and HPV infection seems to be a necessary cofactor in most cases."

The goal of this study was to assess the current effect on mortality of demographic factors, pathologic characteristics of the tumor, and choice of treatment in women with vaginal cancer. The investigators identified 2149 women diagnosed with primary vaginal cancer between 1990 and 2004, using data from 17 population-based cancer registries participating in the Surveillance, Epidemiology, and End Results program. Cox proportional hazards modeling was used to determine the association between various demographic factors, tumor characteristics, and treatments and risk for vaginal cancer mortality.

At diagnosis, mean age was 65.7 ± 14.3 years, and approximately two thirds were non-Hispanic whites. However, African American women had the highest incidence of vaginal cancer (1.24 per 100,000 person-years). Higher stage predicted lower 5-year disease-specific survival duration, which was 84% for stage I, 75% for stage II, and 57% for stage III/IV. The risks for mortality were increased for tumor size greater than 4 cm (hazard ratio [HR], 1.71) and for advanced disease (HR, 4.67), as determined in a multivariate adjusted model.

Women with vaginal melanoma had a 1.51-fold increased risk for mortality vs those who had squamous cell carcinomas (95% confidence interval, 1.07 - 2.41). In treatment modality, surgery alone had the lowest risk for mortality. Compared with women diagnosed from 1990 to 1994, those diagnosed after 2000 had an adjusted 17% decrease in their risk for death, suggesting a decrease in risk of mortality with time.

"Stage, tumor size, histology, and treatment modality significantly affect a woman's risk of mortality from vaginal cancer," the study authors write. "There seems to be a survival advantage that is temporally related to the advent of chemoradiation."

Limitations of this study include observational design, use of data that had already been collected, missing data on tumor size for more than half of cases, lack of data on chemotherapy, and possible residual confounding by unmeasured predictors.

"When possible in early stage disease, surgery seems to confer a survival advantage," the study authors conclude. "The decision on treatment modality must still be made in the context of the individual patient, because it is unlikely that prospective trials will be undertaken to answer this specific question. In the future we may be able to see if the trend of decreased mortality with modern treatment continues; but presently, it seems there may be an ongoing reduction in the risk of mortality associated with the use of chemoradiation in women with vaginal cancer."

• 2694 women with primary vaginal cancer were identified from 17 population-based US cancer registries in the Surveillance, Epidemiology, and End Results program.
• 2531 patients diagnosed between January 1990 and November 2004 without a history of in situ or invasive cancer were eligible for analysis.
• The final multivariate analysis included 2149 cases of invasive vaginal cancer.
• Exclusion criteria were age younger than 20 years or older than 89 years and vaginal carcinoma in situ.
• Follow-up period started with the date of diagnosis and ended with the date of death, last known date of living, or end of study.
• The primary outcome measure was death from vaginal cancer.
• Factors evaluated for a relationship with mortality risk included age at diagnosis, year of diagnosis, ethnicity, socioeconomic status, histologic tumor type, American Joint Committee on Cancer stage, grade, tumor size, lymph node status, and treatment method.
• Multivariate analysis adjusted for age, year of diagnosis, stage, and treatment.
• Mean age at diagnosis was 65.7 years (SD, 14.3 years).
• Most women were non-Hispanic whites (66%), with the remainder being African Americans (14%), Hispanic whites (12%), Asian or Pacific Islanders (7%), and others (1%).
• Stage I was the most common, occurring in 36%.
• Most women (65%) had squamous-type histologic features.
• The incidence rate of vaginal cancer per 100,000 person-years increased with age (4.43 in ages 80 - 89 years vs 0.03 in ages 20 - 29 years).
• The vaginal cancer incidence rate per 100,000 person-years was highest in African Americans and lowest in Asians or Pacific Islanders (1.24 vs 0.64).
• The vaginal cancer incidence rate per 100,000 person-years was highest in metropolitan Detroit and lowest in Utah (1.32 vs 0.56).
• Kaplan-Meier curves showed the 5-year disease-specific survival rate was 84% for stage I tumors, 75% for stage II tumors, and 57% for stage III or IV tumors.
• 5-year survival rate was worse if tumor size was more than 4 cm vs less than 4 cm.
• 5-year survival rate was similar for various histologic types: 78% for squamous cell carcinomas, 78% for adenocarcinoma, 70% for melanoma, and 73% for other rarer types.
• Multivariate analysis showed increased vaginal cancer mortality rate was associated with:
  • Stage II (HR, 2.35; P < .001) and stage III/IV (HR, 4.67; P < .001) vs stage I
  • Age at diagnosis 70 to 79 years (HR, 1.56; P < .05) and 80 to 89 years (HR, 2.12; P < .001) vs age 50 to 59 years
  • Tumor size more than 4 cm vs less than 4 cm (HR, 1.71; P < .001)
  • Presence vs absence of positive lymph nodes (HR, 2.90; P < .05)
  • Melanoma (HR, 1.51; P < .05) or rarer other type (HR, 1.33; P < .05) vs squamous cell carcinoma
• Vaginal cancer mortality rate was not linked with year of diagnosis, ethnicity, socioeconomic status, grade of tumor, or adenocarcinoma vs squamous cell carcinoma.
• Treatment with surgery or radiation or both was not related to mortality risk, but no treatment vs surgery was linked with increased mortality risk (HR, 2.07; P < .05).
• Analysis of treatment methods stratified by stage showed mortality risk was significantly increased only for no treatment vs surgery in women with stage I or stage III/IV disease.
• Limitations of the study included retrospective design, missing tumor size data in 52% of cases, missing tumor grade data in 33% of cases, no database information on chemotherapy, and no data on potential

NILOTINIB SUPERIOR THAN IMATINIB FOR CML?

June 9, 2009 (Berlin, Germany) — New results from a phase 2 trial with nilotinib (Tasigna) used first-line in patients with early chronic-phase chronic myeloid leukemia (CML) showed responses that were superior and faster than those seen historically with the current standard of care, imatinib (Gleevec).

"These early results are very encouraging," said lead investigator Gianantonio Rosti, MD, from St. Orsola-Malpighi University Hospital in Bologna, Italy, who presented the findings here at the 14th Congress of the European Hematology Association.

Currently, nilotinib is approved only for second-line use in patients who have become resistant or intolerant to imatinib. But in the long term, only 70% of CML patients taking imatinib maintain a perfect response, so other therapies are needed, Dr. Rosti explained.

The new results come from a multicenter study, conducted by the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) CML working party, investigating the use of nilotinib 400 mg twice daily as a first-line treatment for early chronic-phase CML for 1 year.

Blood counts and differential and serum chemistry were assessed at baseline, every 15 days for 3 months, and then every 30 days for 9 months. A bone-marrow aspirate was taken after 3 and 6 months for cytology and cytogenetics, and after 12 months for cytology, cytogenetics, quantitative molecular biology, and mutational analysis. After the end of the study, data were collected every 6 months.

Nilotinib showed a complete cytogenetic response (CCgR) of 96% at 6 months. The achievement of the first major molecular response, after 1, 2, 3, 6, 9, and 12 months, was 3%, 21%, 52%, 66%, 73%, and 85%, respectively.

Results from this uncontrolled intervention study were compared with data for imatinib. For reference, the 400 mg imatinib group of a study known as the IRIS trial showed cumulative rates of CCgR of 51%, 69%, and 87% at 6, 12, and 60 months, respectively. However, one quarter of all imatinib-treated patients fail to acheive or maintain a stable CCgR because of upfront resistance, refractoriness, or intolerance.

"Clearly, the results with nilotinib in CML show that the response is superior to imatinib in terms of rapidity and molecular quality. It is difficult to do better than imatinib, with which we see 60% to 80% CCgR after 1 year of treatment or more, but these results show that improvement is very clear. This study only had 73 patients . . . from 18 centers, but these early results are very encouraging," Dr. Rosti emphasized.

CML is characterized by a chromosomal marker called the Philadelphia chromosome. This carries the BCR-ABL gene, which codes for a specific leukemic BCR-ABL protein. Imatinib selectively inhibits the action of the BCR-ABL protein, but nilotinib has a higher binding affinity and selectivity for the oncoprotein than imatinib, and is highly effective in imatinib-resistant patients across all 3 disease phases. Furthermore, nilotinib inhibits nearly all the imatinib-resistant BCR-ABL mutants.

"At the moment, we aim to have most patients alive with minimal or no trace of the disease at a molecular level. Ultimately, we want a proportion of patients to stop treatment altogether. Even with new drugs, nothing acts in such a way as to eliminate the last leukemia stem cell. As yet it is unknown, but a combination of [tyrosine kinase inhibitor] with interferon, for example, might help cure the disease or at least enable a patient to remain without treatment for 4 or 5 years," explained Dr. Rosti.

Dr. Rosti pointed out that nilotinib is well tolerated and adverse effects are manageable. "From a biochemical point of view, we see increased bilirubin, a transitory increase in liver enzymes, and some hyperglycemia, but most side effects are short lived and nearly all patients continue treatment." One patient discontinued treatment because of an increase in the pancreatic enzymes amylase and lipase without pancreatitis. A second patient progressed to the blastic phase after 6 months on nilotinib.

Commenting on the results, John Goldman, MD, senior research investigator at Imperial College London in the United Kingdom, told to Medscape Oncology that imatinib was facing competition from 2 promising new tyrosine kinase inhibitors. "Nilotinib is a chemical modification of imatinib. It fits into the binding pocket [of the BCR-ABL protein] with less extraneous material than imatinib. In vitro studies show it is more powerful than imatinib and it is 1 of the 2 or 3 second-generation [tyrosine kinase inhibitors] that, in my view, will replace imatinib in the next couple of years as primary therapy. Dasatinib is [as] effective as nilotinib against leukemia, so for a new patient who can afford either of these new drugs, I expect they will become the treatment of choice."

PET-CT CAN CHARACTERIZE ACCURATELY ADRENAL MASSES IN CANCER PATIENTS

A recent report examined the prevalence and nature of adrenal masses that were identified incidentally on computed tomography (CT) in patients with no known malignancy.^[1] A computer search of the abdominal CT reports in 65,231 consecutive patients over a 3-year period at a single institution resulted in identification of an adrenal mass in 3307 (5%) of patients; 973 of whom (1.5% of all patients and 29% of patients with adrenal mass) had 1049 adrenal masses had no known malignancy or suspicion for a hyperfunctioning adrenal mass. With the use of histopathology, further imaging follow-up, and characterization and clinical follow-up serving as validation criteria, the following types of adrenal lesions were identified: 75% adenomas, 6% myelolipomas, 4% hamartomas, 1% cysts, 0.3% pheochromocytomas, and 0.1% cortisol-producing adenoma, and no malignancy. The focus of the following complementary study was to assess the ability of positron-emission tomographic CT (PET-CT) in characterizing adrenal masses in patients with known cancer.

PET/CT for the Characterization of Adrenal Masses in Patients With Cancer: Quantitative Versus Qualitative Accuracy in 150 Consecutive Patients

Boland GWL, Blake MA, Holalkere NS, et al
AJR. 2009;192:956-962

Summary

The study cohort included 150 consecutive patients with a wide variety of known underlying malignancies, with lung cancer, lymphoma, and colorectal cancer as the most common etiologies -- comprising about two thirds of all cancers in the group. Patients were referred to 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG) PET-CT for evaluation of extent of disease. Validation for the detected adrenal lesions was by histology and all relevant prior and follow-up CT scans (unenhanced, contrast-enhanced, and delayed contrast-enhanced washout studies). Qualitative analysis was performed by comparing the level of FDG uptake in the adrenal gland with that of the liver using the following scoring scheme:

• 0 -- adrenal activity less than liver activity;
  
  
• 1 -- equal to liver;
  
  
• 2 -- moderately higher than liver; and
  
  
• 3 -- markedly higher than liver.

Semiquantitative analysis was performed by using the typical mean standardized uptake value formulation with the region of interest drawn over two thirds of the adrenal lesion on fused PET-CT image.

A total of 165 adrenal lesions were found, with 139 lesions (84%) ultimately determined as benign and 26 lesions (16%) as malignant. The analysis of the unenhanced CT demonstrated a mean diameter of 2.6 cm (range, 1.2-6.9 cm) for malignant adrenal lesions and 1.8 cm (range, 1-4.3 cm) for the benign lesions. The mean CT density was 36 Hounsfield units (HU) (range, 22-67 HU) for the malignant lesions and 1.1 HU (range, -66 to 35 HU) for the benign lesions. All malignant lesions showed CT density greater than 10 HU. Using 10 HU as the unenhanced CT density threshold, the sensitivity and specificity for detection of adrenal malignancy were 100% and 66%, respectively. The analysis of FDG PET showed a standardized uptake value range of 2.3 to 26.1 for malignant lesions and 0.5 to 3.3 for benign lesions. Using the lowest malignant standardized uptake value value of 2.3 as threshold, the sensitivity and specificity for detection of adrenal malignancy were 100% and 94%, respectively. For the qualitative PET analysis, using a score of 2 as the threshold yielded a sensitivity of 100% and a specificity of 97% for detection of adrenal malignancy. The authors concluded that PET-CT is highly accurate in differentiating benign from malignant adrenal masses in patients with known cancer.

Viewpoint

Based on their study, the authors offer a recommendation for a stepwise diagnostic procedure for the characterization of adrenal masses in patients with known cancer. In the first step, if there is no evidence for benign disease with unenhanced CT (<>

Ki67 EXPRESSION AND DOCETAXEL EFFICACY IN RECEPTOR POSITIVE PATIENTS

Ki67 Expression and Docetaxel Efficacy in Patients With Estrogen Receptor–Positive Breast Cancer

Frédérique Penault-Llorca, Fabrice André, Christine Sagan, Magali Lacroix-Triki, Yves Denoux, Veronique Verriele, Jocelyne Jacquemier, Marie Christine Baranzelli, Frederic Bibeau, Martine Antoine, Nicole Lagarde, Anne-Laure Martin, Bernard Asselain, Henri Roché

From the Department of Pathology, Centre Jean Perrin, Clermont-Ferrand; Department of Medicine and Translational Research Unit, Institut Gustave Roussy, Villejuif; Department of Pathology, Centre Hospitalier Universitaire, Nantes; Departments of Pathology and Medical Oncology, Institut Claudius Regaud, Toulouse; Department of Pathology, Centre François Baclesse, Caen; Department of Pathology, Centre Paul Papin, Angers; Department of Pathology, Institut Paoli-Calmettes, Marseille; Department of Pathology, Centre Oscar Lambret, Lille; Department of Pathology, Centre Val d'Aurelle, Montpellier; Department of Pathology, Centre Hospitalier Universitaire Tenon; Fédération Nationale des Centres de Lutte Contre le Cancer; Department of Biostatistics, Institut Curie, Paris; and Department of Pathology, Centre Hospitalier Universitaire Brest, Brest, France.

Corresponding author: Frédérique Penault-Llorca, MD, Department of Pathology, Centre Jean Perrin, EA 4233, Université d'Allvergne Clermont 1, 63000 Clermont-Ferrand, France; e-mail: frederique.penault-llorca@cjp.fr.

Purpose The indications of adjuvant chemotherapy for patients with estrogen receptor (ER) –positive breast cancer are controversial. We analyzed the predictive value of Ki67, HER2, and progesterone receptor (PR) expression for the efficacy of docetaxel in patients with ER-positive, node-positive breast cancer.

Patients and Methods Expression of Ki67, HER2, and PR was measured by immunohistochemistry in tumor samples from 798 patients with ER-positive breast cancer who participated in PACS01, a randomized trial that evaluated the efficacy of docetaxel. Risk reduction was evaluated using a Cox model adjusted for age, tumor size, nodal involvement, treatment arm, and biomarkers. The predictive value of biomarkers was assessed by an interaction test. Disease-free survival (DFS) was the primary end point.

Results Ki67, HER2, and PR were expressed in 21%, 9%, and 62% of samples, respectively. Hazard ratios for relapse associated with docetaxel were 0.51 (95% CI, 0.26 to 1.01) in ER-positive/Ki67-positive tumors and 1.03 (95% CI, 0.69 to 1.55) in ER-positive/Ki67-negative tumors (ratio for interaction: 0.53; 95% CI, 0.24 to 1.16; P = .11). Five-year DFS rates were 81% (95% CI, 76% to 86%) and 84% (95% CI, 75% to 93%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with docetaxel and 81% (95% CI, 76% to 86%) and 62% (95% CI, 52% to 72%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with fluorouracil, epirubicin, and cisplatin. No trend for interaction was observed between docetaxel and HER2 (ratio for interaction: 0.83; 95% CI, 0.35 to 1.94; P = .66), nor between docetaxel and PR (ratio for interaction: 0.89; 95% CI, 0.47 to 1.66; P = .71).

Conclusion Ki67 expression identifies a subset of patients with ER-positive breast cancer who could be sensitive to docetaxel treatment in the adjuvant setting.

IRINOTECAN NOT INFERIOR TO OXLIPLATIN

Phase III Noninferiority Trial Comparing Irinotecan With Oxaliplatin, Fluorouracil, and Leucovorin in Patients With Advanced Colorectal Carcinoma Previously Treated With Fluorouracil: N9841

George P. Kim, Daniel J. Sargent, Michelle R. Mahoney, Kendrith M. Rowland, Jr, Philip A. Philip, Edith Mitchell, Abraham P. Mathews, Tom R. Fitch, Richard M. Goldberg, Steven R. Alberts, Henry C. Pitot

Mayo Clinic Jacksonville, Jacksonville, FL; Mayo Clinic Rochester, Rochester, MN; Carle Cancer Center Community Clinical Oncology Program, Urbana, IL; Southwest Oncology Group Operations Office, San Antonio, TX; Eastern Cooperative Oncology Group Data Management Office, Brookline, MA; Missouri Valley Cancer Consortium, Omaha, NE; Mayo Clinic Arizona, Scottsdale, AZ; and University of North Carolina at Chapel Hill, Chapel Hill, NC.

Corresponding author: George P. Kim, MD, Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: kim.george@mayo.edu.

Purpose The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated.

Patients and Methods Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m² every 3 weeks) or arm B (FOLFOX4).

Results A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias.

Conclusion In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.

A PREDICTIVE FACTOR OF GEFITINIB RESPONSE

Epidermal Growth Factor Receptor Mutations in Plasma DNA Samples Predict Tumor Response in Chinese Patients With Stages IIIB to IV Non–Small-Cell Lung Cancer

Hua Bai, Li Mao, hang Shu Wang, Jun Zhao, Lu Yang, tong Tong An, Xin Wang, chun Jian Duan, na Mei Wu, zhi Qing Guo, yi Xu Liu, hong Ning Liu, ye Yu Wang, Jie Wang

From the Department of Thoracic Medical Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China; and the Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.

Corresponding author: Jie Wang, MD, PhD, Department of Thoracic Medical Oncology Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing 100036, China; e-mail: wangjie_cc@yahoo.com.

Purpose Mutations in the epidermal growth factor receptor (EGFR) kinase domain can predict tumor response to tyrosine kinase inhibitors (TKIs) in non–small-cell lung cancer (NSCLC). However, obtaining tumor tissues for mutation analysis is challenging. We hypothesized that plasma-based EGFR mutation analysis is feasible and has value in predicting tumor response in patients with NSCLC.

Patients and Methods Plasma DNA samples and matched tumors from 230 patients with stages IIIB to IV NSCLC were analyzed for EGFR mutations in exons 19 and 21 by using denaturing high-performance liquid chromatography. We compared the mutations in the plasma samples and the matched tumors and determined an association between EGFR mutation status and the patients' clinical outcomes prospectively.

Results In 230 patients, we detected 81 EGFR mutations in 79 (34.3%) of the patients' plasma samples. We detected the same mutations in 63 (79.7%) of the matched tumors. Sixteen plasma (7.0%) and fourteen tumor (6.1%) samples showed unique mutations. The mutation frequencies were significantly higher in never-smokers and in patients with adenocarcinomas (P = .012 and P = .009, respectively). In the 102 patients who failed platinum-based treatment and who were treated with gefitinib, 22 (59.5%) of the 37 with EGFR mutations in the plasma samples, whereas only 15 (23.1%) of the 65 without EGFR mutations, achieved an objective response (P = .002). Patients with EGFR mutations had a significantly longer progression-free survival time than those without mutations (P = .044) in plasma.

Conclusion EGFR mutations can be reliably detected in plasma DNA of patients with stages IIIB to IV NSCLC and can be used as a biomarker to predict tumor response to TKIs.

Supported by Grants No. 863 Program 2006AA02A401 from the National High Technology Research and Development Program of China, No. 30772472 from the Capital Development Foundation, and No. 2-013-39 from Peking University Program 985.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article

EVEROLIMUS AND SIDE EFFECTS

Phase II Randomized Study of Neoadjuvant Everolimus Plus Letrozole Compared With Placebo Plus Letrozole in Patients With Estrogen Receptor–Positive Breast Cancer

José Baselga, Vladimir Semiglazov, Peter van Dam, Alexey Manikhas, Meritxell Bellet, José Mayordomo, Mario Campone, Ernst Kubista, Richard Greil, Giulia Bianchi, Jutta Steinseifer, Betty Molloy, Erika Tokaji, Humphrey Gardner, Penny Phillips, Michael Stumm, Heidi A. Lane, J. Michael Dixon, Walter Jonat, Hope S. Rugo

From the Vall d'Hebron University Hospital, Barcelona; Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain; NN Petrov Research Institute of Oncology; and City Oncological Dispensary, St Petersburg, Russian Federation; Onc Centrum St Augustinus, Wilrijk, Belgium; Centre Rene Gauducheau, Nantes, France; Department of Special Gynecology, Medical University of Vienna/Austria; University Hospital, Salzburg, Austria; Istituto Nazionale Tumori, Milan, Italy; Novartis Pharma AG, Basel, Switzerland; Novartis Institutes for Biomedical Research, Cambridge, MA; Novartis Pharmaceuticals, East Hanover, NJ; Western General Hospital, Edinburgh, United Kingdom; Univ-Frauenklinik, Kiel, Germany; and University of California, San Francisco, CA.

Corresponding author: José Baselga, MD, Medical Oncology Department, Vall d'Hebron University Hospital, P Vall d'Hebron, 119-129, 08035 Barcelona, Spain; e-mail: jbaselga@vhebron.net.

Purpose Cross-talk between the estrogen receptor (ER) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways is a mechanism of resistance to endocrine therapy, and blockade of both pathways enhances antitumor activity in preclinical models. This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor, everolimus (RAD001).

Patients and Methods Two hundred seventy postmenopausal women with operable ER-positive breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole (2.5 mg/day) and either everolimus (10 mg/day) or placebo. The primary end point was clinical response by palpation. Mandatory biopsies were obtained at baseline and after 2 weeks of treatment (ie, day 15). Samples were assessed for PI3K mutation status (PIK3CA) and for pharmacodynamic changes of Ki67, phospho-S6, cyclin D1, and progesterone receptor (PgR) by immunohistochemistry.

Results Response rate by clinical palpation in the everolimus arm was higher than that with letrozole alone (ie, placebo; 68.1% v 59.1%), which was statistically significant at the preplanned, one-sided, = 0.1 level (P = .062). Marked reductions in progesterone receptor and cyclin D1 expression occurred in both treatment arms, and dramatic downregulation of phospho-S6 occurred only in the everolimus arm. An antiproliferative response, as defined by a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15, occurred in 52 (57%) of 91 patients in the everolimus arm and in 25 (30%) of 82 patients in the placebo arm (P < .01). The safety profile was consistent with historical results of everolimus monotherapy; grades 3 to 4 adverse events occurred in 22.6% of patients who received everolimus and in 3.8% of patients who received placebo.

Conclusion Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer.