ONLY IN GREECE YOU CAN GET THIS KIND OF RESULTS AND TO USE PACLITAXEL AS FIRST LINE TREATMENT FOR SMALL CELL LUNG CANCER

NEW YORK (Reuters Health) Nov 24 - Combining antineoplastic agents with a long-acting somatostatin analogue has benefits in patients with somatostatin-receptor-positive small cell lung cancer (SCLC), particularly those with limited disease, a study from Greece suggests.
As a neuroendocrine cancer, small cell lung tumors often posses high densities of somatostatin receptors. Long-acting somatostatin analogues combined with platinum analogues have demonstrated an anti-proliferative effect on growth of human SCLC xenographs.
"Many scientists have characterized somatostatin as the universal endocrine off switch," the authors note in a paper in Lung Cancer, published online October 22.
To investigate further, Dr. Kostantinos Zarogoulidis from Aristotle University Pulmonary Clinic in Thessaloniki and colleagues enrolled 130 previously untreated patients with SCLC in a phase 2/3 randomized clinical study. All of the patients were treated with paclitaxel plus carboplatin for up to six cycles.
By random allocation, 47 patients received no other therapy (Group A; control group); 43 patients received 30 mg lanreotide (Somatulin) by subcutaneous injection 48 hours after each chemotherapy cycle to stimulate somatostatin receptors for two weeks (Group B); and the remaining 40 patients received 60 mg sustained release lanreotide for four weeks (Group C).
Patients on subcutaneous lanreotide fared best. They had median survival of 476 days, which was significantly longer than that of Group A and Group C (300 and 347 days, respectively; p=0.029).
Patients with limited disease in Group B lived 565 days compared to 320 days and 347 days for their peers with limited disease in group A and C, respectively (p=0.012).
The median time to progression was also significantly longer in Group B relative to Group A and C (350 days vs. 224 days and 294 days; p=0.034). Patients with limited disease in Group B had a median time to progression of 371 days compared with 231 and 217 days for limited disease patients in groups A and C, respectively.
Hematological and non-hematological toxicities were "mild and well manageable" with hematopoietic growth factors, the investigators say.
The current study suggests that long-acting somatostatin analogues could be used as "an additive therapy" in combination with antineoplastic agents in patients positive for somatostatin receptors, they conclude.
However, the researchers say, "many unresolved questions still exist especially for the optimal duration of somatostatin administration."
The current study supports a 30 mg dose of lanreotide, especially in limited disease patients, given 48 hours after chemotherapy administration to stimulate receptors for no more than 2 weeks.
The researchers point out, however, that a reduction in the density of somatostatin receptors was observed in only 28 of 130 patients and was not correlated with extensiveness of disease therapy response or with survival, "thus leaving a gap in our understanding of the role of somatostatin receptors and their stimulation during chemotherapy."
SOURCE: http://bit.ly/us1x09
Lung Cancer 2011.

PROBABLY NO USE OF PREOPERATIVE TREATMENT FOR RESECTABLE LIVER METASTASES FROM COLORECTAL CANCER

NEW YORK (Reuters Health) Nov 30 - When colorectal cancer spreads to the liver, chemotherapy can help shrink inoperable tumors -- but if the liver lesions can be resected, then neoadjuvant chemo adds no benefit, a new review article shows.
This month in Annals of Surgery, Dr. Pierre-Alain Clavien and colleagues at University Hospital Zurich, Switzerland say the value of chemotherapy before hepatic resection of colorectal metastases should be analyzed for two distinct indications: reducing unresectable lesions to resectable status, and as neoadjuvant therapy in patients presenting with resectable tumors.
To assess the risks and benefits of chemo in these scenarios, the authors reviewed clinical articles in English on the topic.
For downsizing, based on a selection of 20 relevant articles, the team concludes that chemotherapy can result in a resectability rate of about 30%, although many regimens are associated with numerous side effects.
In the case of clearly resectable lesions, the authors argue that the only justification for neoadjuvant chemotherapy should be a significant improvement in disease-free and overall survival. They failed to find that in their review of 14 studies.
For example, in the only randomized trial addressing the issue, an increase in progression-free survival at three years with neoadjuvant therapy did not lead to increased overall survival, and rates of steatohepatitis or obstruction syndrome were higher in patients receiving neoadjuvant therapy.
Also, in retrospective studies analyzed, adjuvant therapy after surgery was linked with improved survival but neoadjuvant chemotherapy was not.
Summing up, Dr. Clavien and colleagues conclude: "Taken together, the data indicate that for unresectable liver metastases, downsizing chemotherapy may offer a chance for secondary resection in about a third of patients ... In contrast, routine neoadjuvant chemotherapy cannot be recommended due to the increased risk of complications without clear benefit on survival."

CANADA RECOMMENDS FEWER MAMMOGRAMS

November 28, 2011 — Canadian women will now have to wait as long as 3 years between breast-screening mammograms, according to a new set of breast cancer guidelines released by the Canadian Task Force on Preventive Health Care (CTFOPHC).
They have also been told not to do breast self-exams, and their doctors have been told not to perform breast examinations in the office.
The CTFOPHC reasons that regular screening for breast cancer with mammography, breast self-exam, and clinical examinations — all practices that have been widely recommended to reduce breast cancer mortality — causes women too much anxiety, results in too many false positives, and is too costly.
Currently, women in Canada have yearly mammograms, and primary care physicians do manual breast exams, usually during a woman's annual physical examination.
The restrictive new recommendations were published in the November 22 issue of CMAJ.
Thousands of Women Will Die, Says ACR
These breast cancer screening guidelines will cost the lives of Canadian women, according to the American College of Radiology (ACR).
They "ignore the results of landmark randomized controlled trials, which show that regular screening significantly reduces breast cancer deaths in these women. While implementation of the CTFOPH guidelines may save money each year on screening costs, the result will be thousands of unnecessary breast cancer deaths," the ACR says.
Barbara Monsees, MD, a diagnostic radiologist from St. Louis, Missouri, who chairs the ACR's Breast Imaging Commission, said in a statement that "panels without profound expertise in breast cancer screening should not be issuing guidelines. These recommendations are derived from flawed analyses and they defy common sense. Women and providers who are looking for guidance are getting bad advice from both task forces."
In 2009, the United States Preventative Services Task Force (USPSTF) issued similar guidelines, which created a furor among breast cancer prevention advocates.
Canadian Task Force Should Be Congratulated
In an editorial accompanying the release of the new guidelines, Peter C. Gøtzsche, MD, from the Nordic Cochrane Centre, Copenhagen, Denmark, lauds the CTFOPHC for its recommendations.
He writes that the Canadian recommendations on mammography screening "are even more conservative" than those introduced 2 years ago in the United States, "which created an uproar...from people interested in maintaining the status quo."
Dr. Gøtzsche maintains that screening with mammography does not reduce the occurrence of advanced cancers. He also states that "rigorous observational studies" in Europe have failed to find an effect of mammography screening, and that mammography screening produces patients with breast cancer from among healthy women and increases the number of mastectomies.
"The best method we have to reduce the risk of breast cancer is to stop the screening program. This could reduce the risk by one third in the screened age group, as the level of overdiagnosis in countries with organized screening programs is about 50%," he writes.
"If screening had been a drug, it would have been withdrawn from the market. Which country will be first to stop mammography screening?" he asks.
Dr. Gøtzsche is well known for his outspoken views against mammography, and the Nordic Cochrane Group, of which is a member, was recently accused of orchestrating "an active antiscreening campaign" by an international group of breast screening experts in a letter to the Lancet.
Women in Their 40s Get Breast Cancer
The Canadian guidelines are even more negative than the American guidelines, noted radiologist Stamatia Destounis, MD, from Elizabeth Wende Breast Care, LLC, in Rochester, New York.
"The USPSTF said that for women 40 to 49, it should be a decision made with your doctor; they didn't come out and say don't do it. The Canadians even say no to breast self-exam and clinical breast exam. I don't know. We have patients coming in who have found lumps in their breasts that are significant lumps. We have doctors finding lumps in their patients that are significant lumps. It's very hard to know what to do when you have these kind of recommendations," Dr. Destounis told Medscape Medical News.
She recently did a retrospective review of patients who came to her center over a 10-year period and found that almost 20% of the breast cancers that were diagnosed were in women 40 to 49 years of age. About half of these were diagnosed in women with no known risk factors for breast cancer.
"These task forces say going through screening is stressful for women. But what woman is going to say: 'No, this is too stressful. I am not happy having extra views. I'm not going to have an ultrasound?' Most of us would say: 'I have family, I have kids, I have responsibilities. I want to make sure I'm ok and I'm a productive member of society at any age.' We women tend to be the care providers whatever our age, and we have a lot of things to do. So what woman is going to say: 'No, I'm too stressed to have this needle biopsy; it is just too much for me to handle'?" Dr. Destounis asked.
"Instead, I am going to say: 'Do whatever you need to do to make sure I'm ok.' Yes, it is stressful to go through these tests, but it's our lot as women. Saying don't do screening because it is stressful just doesn't make any sense."
Dr. Monsees is the chair of the American College of Radiology Breast Imaging Commission. Dr. Gøtzsche and Dr. Destounis have disclosed no relevant financial relationships.
CMAJ. 2011;183:1991-2001, 1957-1958. Abstract, Editorial

DWI-MRI CAN DETECT METASTATIC LYMPH NODES

November 29, 2011 (Chicago, IL) – Diffusion-weighted magnetic resonance imaging (DWI) can be used to detect pelvic lymph node metastases even in normal-sized lymph nodes. DWI is noninvasive, has a high negative predictive value, and might improve the staging of bladder and prostate cancer.
The research was presented during a prostate imaging session here at the Radiological Society of North America 97th Scientific Assembly and Annual Meeting.
Evis Sala, MD, PhD, from the University of Cambridge, United Kingdom, who moderated the session, described the work on pelvic lymph nodes as "the best talk of the session."

Harriet C. Thoeny, MD, from the University Hospital Inselspital in Bern, Switzerland, presented the results of the prospective study and discussed the implications with Medscape Medical News. She explained that if bladder lymph nodes are larger than 1 cm and prostate lymph nodes are larger than 8 cm, they are typically flagged for biopsy. However, her team found that approximately 25% of patients with normal-sized lymph nodes have micrometastases.
The study involved 87 patients who underwent conventional magnetic resonance imaging and DWI. Forty lymph nodes were removed from each patient, for a total of 3533 lymph nodes. As Dr. Thoeny explained, "that is the really huge and really the sexy part of this presentation.... Our surgeons took out all lymph nodes."
Image analysis was performed prospectively by 3 independent readers, and the results of the DWI analysis were compared with biopsy results. On a per-patient basis, the 3 readers yielded sensitivities of 64%, 80%, and 84% and specificities of 80.6%, 91.9%, and 90.3%. This resulted in positive predictive values of 57.1%, 80%, and 77.8% and negative predictive values of 84.7%, 91.9%, and 93.3%.
Diagnostic accuracies were 75.9%, 88.5%, and 88.5% for the 3 independent readers. The kappa value between readers 1 and 2 was 0.54, between readers 1 and 3 was 0.65, and between readers 2 and 3 was 0.67.
DWI has been used for many years to image the brain, particularly for the detection of acute stroke. Only recently have investigators directed the technique at the more movement-prone torso.
DWI can be quantified using apparent diffusion coefficient (ADC) values. Previous studies have shown that tumors have low ADC values, but only recently have ADC values been used to identify lymph node metastases. Studies to date have focused on enlarged lymph nodes, and have found that they have low ADC values when they have metastatic cancer. This is the first study to show that some normal-sized lymph nodes have low ADC values and are positive for metastases.
All of the metastatic lymph nodes identified in this study were smaller than 5 mm, and many were smaller than 3 mm, suggesting that they would have been missed with conventional techniques.
Dr. Thoeny and Dr. Sala have disclosed no relevant financial relationships.
Radiological Society of North America (RSNA) 97th Scientific Assembly and Annual Meeting: Abstract SSC06-06. Presented November 28, 2011.

SKIN CANCER HIGHER IN RADON AREAS

NEW YORK (Reuters Health) Nov 30 - Rates of squamous cell carcinoma may be elevated in areas with naturally high levels of the radioactive gas radon, a UK study suggests.
Radon, produced from the decay of naturally occurring uranium in soil and water, is already considered a risk factor for lung cancer. The U.S. Environmental Protection Agency (EPA) estimates that radon contributes to about 21,000 lung cancer deaths each year -- although smoking is also involved in the majority of those cases.
For the new study, reported online November 10th in Epidemiology, UK researchers looked at skin cancer rates across 287 postal codes in southwest England.
They found that the rates of squamous cell carcinoma varied by postal code. In some areas, the yearly rate per 100,000 people was about 35 cases; in others, it was as high as 182 cases.
There was an association between an area's average household radon level and its rate of squamous cell skin cancer. Where the radon level topped 230 Bq/m3, rates were 76% higher than in areas with the lowest average radon levels.
In the UK, radon levels above 200 Bq/m3 are considered "action" levels -- that is, people are advised to take steps to cut their home's radon concentration, such as sealing off cracks in basements and floors, and installing ventilation systems.
In the U.S., the EPA suggests taking those steps if home radon levels are around 150 Bq/m3. (The agency uses a different unit, giving the threshold as 4 pCi/L.)
The current study did not measure actual exposure to radon, which would vary by household even within a postal code with a high radon level, according to lead researcher Dr. Benedict W. Wheeler of the University of Exeter.
"This type of study is at the population/area level, so we only know that areas with high average household radon tend to also have high population rates of squamous cell carcinoma," Dr. Wheeler told Reuters Health in an email.
"It is possible that this relationship does not exist at the individual level," he added.
The researchers also had no information on people's individual behavior -- including how much time they spent in the sun. But if people in high-radon areas tended to spend more time in the sun, you'd expect to see higher rates of basal cell carcinoma as well, Dr. Wheeler noted. Yet in this study, radon levels were unrelated to rates of basal cell cancer or melanoma.
Wheeler said it is plausible that radon could specifically raise the risk of squamous cell cancers. Those tumors form in the more superficial layers of skin, while basal cell cancers arise in deeper layers. And radioactive particles from radon would not be expected to penetrate that deeply into the skin; the particles, Wheeler said, can be stopped by a sheet of paper.
A radon expert not involved in the study agreed.
"Radon decay products deposit on skin in a similar manner to how they plate out on surfaces in a home," said Dr. R. William Field, a professor at the University of Iowa College of Public Health who studies the health effects of radon.
Some researchers have suggested that radon exposure could be behind 2% of non-melanoma skin cancers, he told Reuters Health in an email.
Now, Dr. Field said, more rigorous studies are needed to see whether people's individual exposure to radon is related to their skin cancer risk. Dr. Wheeler agrees.
The EPA suggests that all homes be tested for radon, due to the lung cancer risk. Some state programs offer free or low-cost test kits; the agency has information on state radon contacts at http://www.epa.gov/radon/radontest.html.

WHATS HOT AT ASH

December 2, 2011 — This year's annual meeting of the American Society of Hematology (ASH), which starts next week in San Diego, California, will feature some new drugs, some findings that might breathe new life into an old drug, and also some long-term data that might end a fierce debate.
"We are really building on the foundation of high-throughput genomic sequencing and the discovery of new targets for the development of new drugs," said ASH president J. Evan Sadler, MD, PhD, professor of medicine in the division of hematology at Washington University, in St. Louis, Missouri. "We have, on the one hand, new targeted therapies; on the other hand, we have so much information about individual patients that we can say which targeted therapies may be specifically useful for them."
Speaking at a premeeting conference call with journalists, Dr. Sadler highlighted several abstracts as being particularly newsworthy.
One of the new targeted therapies that holds great promise, although the research is still in the early stages, is the first drug that has been designed to home in on Bruton's tyrosine kinase, he noted. This enzyme plays a central role in B cell development, and has been implicated in chronic lymphocytic leukemia. The new drug, currently known as PCI-32765 (Pharmacyclics), is an oral irreversible inhibitor of the enzyme. The results of a phase 2 study of 61 patients suggest efficacy, and will be presented at the meeting (abstract 983). A larger phase 3 study is now planned.
"I don't want to hype this, but we are hoping for a repeat of the success that was enjoyed by the poster child of targeted therapy, imatanib (Gleevec), for the treatment of chronic myeloid leukemia," Dr. Sadler said. Subsequent tyrosine kinase inhibitors have not shown such spectacular results, he noted, "but this one looks encouraging. There have been some striking responses described."
"This is the way of the future, where scientists first understand the molecular defect of the disease, and then drugs are designed to specifically target those diseases," explained ASH secretary and coordinator of the abstracts review, Charles Abrams, MD, associate chief of the division of hematology/oncology at the University of Pennsylvania in Philadelphia. The defect of Bruton's tyrosine kinase was first identified in children with an inherited blood disorder, X-gammaglobulinemia; this story goes "all the way from the patient to the laboratory bench and then back to the patient," he said.
Another example of how observations in patients have resulted in new therapies is that of thalidomide and related drugs, said Dr. Sadler. Studies of how thalidomide produced birth defects led to its use in the treatment of multiple myeloma, and resulted in the development of related next-generation agents, such as lenalidomide (Revlimid, Celgene) and the investigational agent pomalidomide (under development by Celgene). Exactly how these drugs exert their antitumor effects has been unclear. New research to be presented at the meeting (abstract 127) outlines the central role played by the recently identified protein cereblon. It appears to be "absolutely required" for a response to these drugs, say the authors, and preliminary data suggest that low levels of cereblon in a patient with multiple myeloma predicts a poor response to these drugs.
Breathing New Life Into an Old Drug
Featured in the plenary session will be research that could breathe fresh life into an old drug — gemtuzumab (Mylotarg, Wyeth) (abstract 6). This product was voluntarily withdrawn from the American market last year. It had been available for a decade, after the US Food and Drug Administration (FDA) granted it accelerated approval in 2000 for the treatment of relapsed acute myeloid leukemia (AML). However, subsequent clinical trials and years of postmarketing experience did not show evidence of clinical benefit in patients with AML, according to the FDA, and revealed toxicity that was highlighted in a black box warning.
Gemtuzumab is a monoclonal antibody directed against CD33 on white blood cells; it was used to supplement the treatment of AML, particularly in older patients, Dr. Abrams explained. It was then tested in the initial treatment of AML, but the results were inconclusive and some alarming toxicities emerged, he said. "In one trial in younger patients, mortality actually increased in patients who received the drug," he explained, so the drug was withdrawn.
In the study to be presented, gemtuzumab was used upfront in older patients, around 60 to 70 years of age, who were newly diagnosed with AML. The results show that "not only was there a benefit in the initial treatment of the disease, there was also a survival benefit," Dr. Abrams explained. "This study is really quite tantalizing," he said. There will now be a resurgence of interest in gemtuzumab, he predicted, adding that "this is a drug that wasn't studied fully enough."
Novel Cell-Based Approach
A novel cell-based approach to therapy is highlighted in a study in which genetic engineering was used to program some lymphocytes to attack other lymphocytes (abstract 167), noted Dr. Sadler. "This is instructing the T cells in what they should attack, rather than leaving it up to our immune system," he added. In this research, T cells were genetically engineered to express chimeric antigen receptors that specifically recognize the B cell antigen CD19, and were tested in patients with B cell malignancies. The clinical trial has so far enrolled 4 patients with chronic lymphocytic leukemia and 4 with B cell lymphoma.
Stem-cell transplantation offers a curative therapy for some hematologic malignancies, and a whole press conference at the meeting will focus on developments in this approach. One abstract describes an emerging methodology for preventing chronic graft-vs-host disease (GvHD) (abstract 817); another reports an increased incidence of chronic GvHD and no survival advantage with peripheral blood stem cells, compared with bone marrow transplantation (abstract 1). In addition, there are now long-term data (10+ years) on survivors of hematopoietic cell transplantation (abstract 841).
Answer to Longstanding Question?
An answer to a longstanding question about how best to treat patients with limited-stage Hodgkin's lymphoma comes from a final analysis of a trial now with a median follow-up of 11.3 years (abstract 590). There has been fierce debate about whether the initial treatment of these patients should include radiotherapy or whether they should be treated with chemotherapy alone; proponents of chemotherapy alone argue that adding radiation increases the risk for late toxicities without providing any clear benefit.
However, when radiotherapy was added to chemotherapy, the short-term results do look better, said Dr. Sadler. "Now, looking at the very long-term data, the morbidity and mortality associated with late complications from radiotherapy may well trump this short-term effectiveness," he added.
"I interpret this study as evidence that the long-term complications of radiotherapy are not necessarily worth the short-term efficacy," Dr. Sadler said. It appears that treating initially with chemotherapy alone will give sufficient benefit; if the patient relapses, they can be given radiotherapy, he explained. This approach would spare a number of people the toxicity of radiation, he noted. Dr. Abrams added that this is a very well-designed study with very long-term follow-up. In answer to the question of whether this is a final answer, he said: "I doubt that there will be another trial like this."
Other Hematology News
In addition to news on the hematologic malignancies front, which we will be focusing on here at Medscape Medical News, other newsworthy abstracts to be presented include a new gene therapy for hemophilia B (abstract 5), and research on the use of antiplatelet agents to decrease the recurrence of venous thromboembolism (abstract 543).
Several presentations will focus on sickle-cell disease, which is a fairly common and at times a morbid condition, said Dr. Abrams. It has long been known that these patients have a mutation in hemoglobin, but although they all have the same mutation, some patients have relatively mild disease and others have severe forms and die in childhood. "It has always been extremely perplexing as to why," he said. Metabolomic studies that have looked beyond hemoglobin are starting to provide some answers for the variability in this disease (abstract LBA-3).
Hydroxyurea is a standard treatment for sickle cell disease, but there has always been some discomfort about using such chemotherapy, particularly in children, Dr. Abrams noted. However, a large trial of children provides reassuring data on the safety and efficacy of hydroxyurea in the pediatric population (abstract 7 and abstract 8), which is "good news for our patients," he said. Another trial highlighted in the press program explores the use of preoperative blood transfusions to prevent complications in patients with sickle cell disease who undergo low- or moderate-risk surgery (abstract 9).

CHEMOTHERAPY FOR METASTATIC PARAGAGLIOMAS

NEW YORK (Reuters Health) Nov 29 - Chemotherapy shrinks lesions, relieves symptoms, and prolongs survival in patients with metastatic pheochromocytoma or sympathetic extra-adrenal paraganglioma, according to a report online October 17th in Cancer.
"Chemotherapy could be offered to patients with progressive disease, in particular to patients with rapidly progressive disease," said senior author Dr. Camilo Jimenez in email to Reuters Health.
"In addition, chemotherapy should be considered in patients with unresectable tumors and overwhelming symptoms related to tumor burden and hormone excess," added Dr. Jimenez, from The University of Texas MD Anderson Cancer Center in Houston.
These rare neuroendocrine tumors together have an estimated incidence of roughly one per 10,000 person-years in the U.S. About 17% become metastatic.
Dr. Jimenez and colleagues evaluated the clinical benefits of systemic chemotherapy in a retrospective study of 52 patients with metastatic pheochromocytoma or sympathetic extra-adrenal paraganglioma.
Seventeen patients, or one third, responded to treatment (i.e., with any objective reduction in tumor size on cross-sectional imaging studies during the first chemotherapy regimen).
All 17 responders had received cyclophosphamide and dacarbazine. Twelve had also received doxorubicin, and 14 of 17 also received vincristine.
Thirty-one patients had catecholamine excess, adrenergic symptoms, and hypertension at baseline. Six who responded had their antihypertensive medication doses reduced by more than 50%, and three of these six had complete responses and were able to stop all their antihypertensive medications.
Overall survival at five years was 51%, and median overall survival was longer (albeit nonsignificantly) in responders vs. nonresponders (6.4 vs. 3.7 years).
Patients had significantly longer overall survival if they had metachronous rather than synchronous metastatic disease (median 9.9 vs. 5.1 years) and if they had surgery and chemotherapy rather than chemotherapy alone (6.5 vs. 3.0 years).
In a multivariate model, the favorable impact of chemotherapy on overall survival at one year was significant among patients with synchronous metastatic disease after adjustment for tumor size.
"Because these tumors are scarce, it is imperative to involve expert centers and international networks in order to achieve both expertise and statistical power" in clinical trials, Dr. Jimenez said.
But, Dr. Jimenez added, "Many patients may have indolent and asymptomatic disease and may not need systemic treatment. Appropriate multidisciplinary consultations between physicians familiar with this disease are important before embarking on a treatment plan."
SOURCE: http://bit.ly/tdEiSJ

SURVEILLANCE MAY BE SUFFICIENT FOR SOME PATIENTS WITH MOLAR PREGNANCY

November 30, 2011 — Surveillance instead of chemotherapy might be sufficient for women after a molar pregnancy, and would prevent unnecessary exposure to the toxic effects of agents such as methotrexate. According to a study published online November 29 in the Lancet, high levels of human chorionic gonadotropin (hCG) will spontaneously decline in most cases, negating the need to actively intervene with chemotherapeutic agents.
"Chemotherapy should only be considered in patients whose hCG concentrations are greater than 345 IU/L, and when radiological evidence of disease is present or when hCG levels are consistently plateaued or rising," write the authors, led by Michael J. Seckl, MBBS, PhD, FRCP, from the Department of Medical Oncology, Charing Cross Hospital Campus, London, United Kingdom.
A hydatidiform mole, or molar pregnancy, is an abnormal form of pregnancy in which a nonviable fertilized egg implants in the uterus. Partial and complete hydatidiform moles overexpress paternal genes, the authors note. Complete moles are diploid and androgenetic in origin, and partial moles are triploid and have 1 maternal set and 2 paternal sets of chromosomes.
Molar pregnancies are more common in east Asia than in most western regions. In the United Kingdom, it is estimated that 1 to 3 per 1000 pregnancies are either complete or partial moles.
In all cases, serum or urine hCG concentrations are elevated (5 IU/L or more on the Charing Cross hCG assay). Residual tissue regression occurs spontaneously in most patients, and a corresponding normalization of hCG concentrations is observed in about 92% of patients. However, in a minority of women, progression to malignancy occurs. Progression to gestational trophoblastic neoplasia occurs in about 15% of cases after a complete hydatidiform mole and in about 0.5% to 1.0% of cases after a partial hydatidiform mole.
In the United Kingdom, approximately 8% of patients with hydatidiform moles undergo chemotherapy, generally with methotrexate or dactinomycin monotherapy. Current indications for chemotherapy in gestational trophoblastic disease include elevated hCG concentrations 6 months after uterine evacuation of the hydatidiform mole, even when levels are declining.
No Significant Difference Seen
Dr. Seckl and colleagues sought to establish whether chemotherapy is always necessary in this population.
They retrospectively identified 13,960 women who were registered at Charing Cross Hospital from January 1993 too May 2008 and who had persistently high hCG concentrations 6 months after the evacuation of a hydatidiform mole. The authors examined the rates of normalization of hCG concentration, relapse, and death in patients who were under surveillance and in those who received chemotherapy.
Dr. Seckl and his team hypothesized that a surveillance policy would be clinically acceptable if hCG values returned to normal in 75% of patients or more within 12 months of evacuation and if less than 25% of them developed gestational trophoblastic neoplasia and required chemotherapy.
In the study cohort, 974 patients (7%) required chemotherapy and 12,910 (92%) had their hCG return to normal levels spontaneously within 6 months of evacuation; the remaining 76 (<1%) had high hCG levels that persisted 6 months after evacuation.
Of these 76 remaining patients, 46 (61%) had complete moles, 25 (33%) had partial moles, and 5 (7%) were unclassified. At registration, median plasma hCG concentration was 1343.5 IU/L, peak hCG was 1386 IU/L, hCG at 6 months was 13.5 IU/L, and time to hCG normalization was 7.5 months. The authors note that, overall, hCG concentration at 6 months modestly correlated with time to normalization.
The majority of the patients (n = 66; 87%) continued under surveillance. In all except 1 patient, hCG values spontaneously returned to normal without chemotherapy. The levels in that patient did not normalize because of chronic renal failure.
Of the 10 patients who received chemotherapy, hCG concentrations returned to normal in 8 (80%). In 2 of these patients, values remained slightly high (6 to 11 IU/L), although they had no associated clinical problems once they finished treatment.
There were no significant differences in the return of hCG concentrations between the surveillance and chemotherapy groups (P = .044). The only difference seen was lower median hCG concentrations 6 months after evacuation in surveillance group.
The authors acknowledge that the study is limited by small patient numbers and retrospective data, and that a "further prospective study in a multicenter setting would be useful."
In the absence of these data, they write, "we recommend that women with persistently high hCG concentrations 6 months after evacuation should continue regular hCG monitoring rather than begin chemotherapy."
The study was funded by National Commissioning Group, the Imperial Experimental Cancer Medicine Centre, the Imperial Biomedical Research Centre, and Cancer Research UK. The authors have disclosed no relevant financial relationships.
Lancet. Published online November 29, 2011. Abstract

TOP ONCOLOGY ADVANCES IN 2011

Counting Down: Game Changers 10 Through 6

In 2011, great progress was made in the science and management of a variety of cancers. Our Medscape commentators selected and ranked the top 10 game changers in oncology for 2011. Here are their selections.

10. New Regimen Improves Outcomes in Neuroblastoma

A provocative European study^[1] showed improved outcomes in high-risk neuroblastoma using a high-dose myeloablative regimen. Until now, the best outcome in neuroblastoma has hovered around the 50% survival threshold, but the new regimen tested has pushed this up to 60%. European investigators say this regimen should be the new standard of care. "This is an incredible success and a great achievement for pediatric oncology," said Julie Park, MD, from Seattle Children's Hospital in Washington, who acted as discussant for the study.
The results are important for patients with this extremely difficult-to-treat disease," said principal investigator Ruth Ladenstein, MD, MBA, Associate Professor of Pediatrics at the University of Vienna, Austria.
Treatment for neuroblastoma comprises several steps. It begins with intense upfront chemotherapy to induce remission (induction) and is followed by surgery and radiation, myeloablative therapy with stem cell transplantation, and then consolidation therapy with 13-cis-retinoic acid and immunotherapy, if available.
The European trial used an induction regimen known as rapid COJEC, which consists of both cisplatin and carboplatin, and then compared a high-dose myeloablative regimen known as BuMel (busulphan plus melphalan) with carboplatin, etoposide, and melphalan (control group).
The BuMel group led to significantly improved survival at 3 years compared with the control group (60% vs 48%). "The superiority was based on a lower relapse rate," noted Dr. Ladenstein.
Read the complete Medscape News article on this trial, which was presented during the plenary sessions of the 2011 American Society for Clinical Oncology (ASCO®) annual meeting.

9. A Shooting Gallery of Targets in Lung Cancer

The treatment of non-small cell lung cancer (NSCLC) is undergoing a revolution driven by a greater understanding of the genetic factors fueling this disease. In personalized therapy, drugs are chosen according to the mutations found in the patient's tumor rather than chemotherapy chosen for the organ where the tumor is located.
Contributing to the growing knowledge of genetic targets is a landmark study by the Lung Cancer Mutation Consortium (LCMC),^[2] which involves 14 centers across the United States. The LCMC conducted a prospective study in which lung cancer tissue was assessed using a multiplex assay that identified 10 known driver mutations. In addition to EGFR and ALK, they are testing for KRAS, HER2, BRAF, PIK3CA, AKTI, MEKI, NRAS, and MET. Many of these mutations have targeted agents under development or, in the case of HER2, have targeted drugs already on the market (trastuzumab and lapatinib, which are used in breast cancer). The results so far show that 54% of the tested tumor samples have single-driver mutations. This information is now being used to select patients for first-line therapy with erlotinib or to place these patients into clinical trials with experimental targeted therapies specifically directed at their tumor mutation.
"Although an individual driver mutation may have a single-digit percentage incidence, when you look at all of the possible mutations that exist in lung cancer, you are likely to find a mutation," said Mark G. Kris, MD, lead author and Chief of Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York City, in a Medscape commentary. "Even in individuals who did not have a mutation that would suggest a certain clinical trial, we knew what treatments not to give those patients." This study, Dr. Kris added, "brings us one step closer to our goal of personalized medicine."
View the complete commentary by Mark G. Kris, MD, and read the original Medscape News story on this trial, which was reported at the 2011 ASCO® annual meeting.

8. Strongest Data Ever for ER-Positive Breast Cancer

The combination of everolimus plus exemestane produced "the strongest data ever seen in estrogen receptor [ER]-positive breast cancer," principal investigator José Baselga, MD, from the Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News. The pivotal phase 3 study, known as BOLERO-2,^[3] was stopped early because of the benefit observed. Results were unveiled at the 2011 European Multidisciplinary Cancer Congress (EMCC).
"Everolimus is the most important advance in breast cancer since trastuzumab," said Fabrice André, MD, PhD, from the Institut Gustave Roussy, Paris, France, who acted as discussant. "The data are robust and are clinically relevant," he said, adding that "the efficacy is in the range of the most important recent advances in the field of medical oncology."
Everolimus is an mTOR inhibitor that has already been approved in the United States for the treatment of progressive neuroendocrine tumors of pancreatic origin and advanced renal cell carcinoma in certain patients. Exemestane is an aromatase inhibitor that is already widely used as adjuvant therapy for ER-positive breast cancer. Both drugs are taken orally.
Read the complete Medscape News story on this trial.

7. Extended Adjuvant Treatment Improves Survival in GIST

Extended adjuvant treatment with imatinib improves survival in patients with high-risk gastrointestinal stromal tumors (GIST). Imatinib administered for 3 years improved both relapse-free survival and overall survival in patients after surgery, compared with 1 year of adjuvant treatment.^[4]
Previous data showed that initiating adjuvant imatinib therapy reduces the risk for GIST recurrence compared with placebo. "But the effect of imatinib on overall survival is not known," said lead author Heikki Joensuu, MD, Professor of Oncology at Helsinki University Central Hospital in Finland, who presented the findings during the plenary session here at the ASCO® 2011 annual meeting.
The 5-year relapse-free survival in patients was higher in those who received 3 years of treatment than in those who received 1 year (65.6% vs 47.9%; hazard ratio [HR], 0.46; P < .0001). The 5-year overall survival was also better in patients who received 3 years of therapy (92.0% vs 81.7%; HR. 0.45; P = .019).
Kathy Miller, MD, Chair of the scientific program for the 2011 ASCO® annual meeting, said in a Medscape commentary, "There had been a lot of debate in the GIST community that perhaps the drug was so effective in people with metastatic disease that you didn't really need to give adjuvant therapy for a longer time or maybe you didn't need to give it at all. You could just catch up and treat these folks when they recurred, and that was definitely not true. A longer duration of therapy, 3 years instead of 1, improved survival."
"We are looking at 92% in the 3-year group, and that is very high," said Dr. Joensuu. "We are making substantial improvement here."
View the complete commentary by Kathy D. Miller, MD, and read the original Medscape News story on this trial.

6. New Hope for Patients With Refractory Lymphoma

The experimental agent brentuximab vedotin, which has shown strong responses in patients with resistant and refractory Hodgkin lymphoma, was the first drug approved for lymphoma in 30 years. The results were reported at the 52nd annual meeting of the American Society of Hematology by Robert Chen, MD, Assistant Professor at the City of Hope National Medical Center in Duarte, California.^[5] The data come from a single-group multicenter study of 102 patients, all of whom had failed autologous stem cell transplantation and a median of 4 chemotherapy regimens (range, 1-13). The median age of patients was 31 years (range, 15-77 years).
Brentuximab 1.8 mg/kg was administered as a 30-minute outpatient intravenous infusion once every 3 weeks for up to 16 cycles of therapy (median, 9 cycles).
Responses were "dramatic," Dr. Chen said. The objective response rate was 75%, and tumor reduction was demonstrated in 94 patients (96%). Around one third of patients (34%) achieved complete remission.
In August, the US Food and Drug Administration (FDA) granted accelerated approval of brentuximab vedotin infusion for the treatment of relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, as reported at the time by Medscape.
"Why are we so excited about this?" asked Bruce D. Cheson, MD, Professor of Medicine, Georgetown University, Washington, DC, in a Medscape commentary. "Not only is this a great drug, it is also a proof of concept. We now have demonstrated that you can take an antibody and link it strongly to a poison. It will get in the cells and kill them, without doing much damage to the rest of the body. This will be one of many to follow in its footsteps."

5. Improved Survival in Metastatic Pancreatic Cancer

A chemotherapy combination provided the best survival time ever reported in metastatic pancreatic cancer, according to a study from French researchers, but the combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) was considerably more toxic than gemcitabine. Data from the study, which were first presented at the 2010 annual meeting of ASCO® and reported by Medscape Medical News at that time, were published in May in The New England Journal of Medicine.^[6] Although the data are largely the same, the published paper includes new information on quality-of-life measures, said lead author Thierry Conroy, MD, from the Centre Alexis Vautrin, Vandoeurve les Nancy, France.
Gemcitabine, used alone or in combination with other agents, has been the "reference regimen" for advanced pancreatic cancer treatment for an extended period of time, according to Dr. Conroy and colleagues from 48 centers in France. However, the study authors propose that FOLFIRINOX is now a first-line option for patients with metastatic pancreatic cancer "who are younger than 76 years, and who have a good performance status (Eastern Cooperative Oncology Group score [ECOG] 0 or 1), no cardiac ischemia, and normal or nearly normal bilirubin levels."
"This is the first study to show substantial improvements in survival in advanced pancreatic cancer," said Alok A. Khorana, MD, Associate Professor and Vice-Chief of Hematology-Oncology at the University of Rochester, Rochester, New York, in a Medscape viewpoint. "It is unfortunate, however, that this gain occurs with an aggressive multichemotherapy regimen rather than with the addition of targeted therapy as many had hoped for. Although the efficacy of the regimen is clear and substantial, concerns about toxicity and tolerability are ongoing."

4. New Standard of Care for High-Risk ALL

A regimen of high-dose methotrexate was found to be superior to the standard protocol of escalating methotrexate in children and young adults with high-risk B-precursor acute lymphoblastic leukemia. The results of a phase 3 trial,^[7] which were presented at the 2011 ASCO® annual meeting, established a new standard of treatment for this population.
In a planned interim analysis, 5-year event-free survival for patients who received the high-dose regimen was 82% compared with 75% for those receiving the escalation protocol.
"We feel that it is the standard of care to receive high-dose methotrexate in this population," said lead author Eric C. Larsen, MD, Director of the Maine Children's Cancer Program and the division of pediatric hematology/oncology at the Barbara Bush Children's Hospital at Maine Medical Center in Portland, adding that "high-dose methotrexate will be incorporated in current and future Children's Oncology Group trials for children and young adults."

3. Increased Survival in Metastatic HER2-Positive Breast Cancer

The first randomized trial to compare the novel agent trastuzumab emtansine (T-DM1) with standard therapy shows that it significantly increased progression-free survival in women with metastatic breast cancer.^[8] The study was presented at the 2011 EMCC in Stockholm, Sweden.
"First-line treatment with T-DM1 was associated with a statistically significant improvement in progression-free survival and was also associated with a reduction in the risk for toxicity," said lead author Sara Hurvitz, MD, Director of the Breast Oncology Program, Division of Hematology/Oncology, University of California, Los Angeles.
Median progression-free survival was 14.2 months for women who received T-DM1 and 9.2 months for those who received standard therapy with trastuzumab plus docetaxel. The hazard ratio was 0.59, indicating that treatment with T-DM1 reduced the probability of disease progression or death by 41% compared with standard therapy, noted Dr. Hurvitz.
"These results validate the hypothesis that the unique targeted delivery of chemotherapy through T-DM1 may lead to an improved therapeutic index," she said.
Fabrice André, MD, PhD, Associate Professor at the Institut Gustave Roussy, Villejuif, France, as reported in a Medscape commentary, finds T-DM1 interesting for 3 distinct reasons. "The first is conceptual -- This is the first time that an immunoconjugate (a combination of a monoclonal antibody and a cytotoxic agent) has shown efficacy in cancer. It's a new concept, and we have the proof of concept. The second reason is the finding that immunoconjugate is safer compared with conventional chemotherapy. We had the presentation today, during which we heard that the frequency of grade 3 adverse events was lower in patients treated with T-DM1. The third reason it is so important is that these drugs can be delivered for a long time. Because of this prolongation of the treatment, we had a better progression-free survival, specifically in HER2-positive breast cancer."
Because T-DM1 is not toxic, it can be administered for a long period of time, which leads to long-term progression-free survival.
"We are entering in a new era with this trial," said Dr. André. "At the very beginning, to obtain a response the drug is not better. Once we have a response and once the drug is working, we can administer the drug for a longer time period and know that the patient is not going to present with progressive disease, but at the opposite end -- in patients treated with trastuzumab and docetaxel -- we have to stop both the chemotherapy agents. Then the patient is going to have a progressive disease. In terms of induction of the response, there is not any major difference between T-DM1 and a combination of trastuzumab and docetaxel, but then duration of the response is very long. We are going through a scenario where we have induction with T-DM1, and once the patient has a response, then the response can be long lasting."

2. Lung Cancer Screening Comes of Age

The landmark National Lung Screening Trial,^[9] which enrolled 53,000 persons,showed that screening with low-dose spiral CT reduced mortality from lung cancer by 20%. CT screening was compared with chest radiographs, which have not shown any mortality reduction in previous trials.
The study was accompanied by expressions of enthusiasm from the American oncology community. "It's gratifying. We've been looking for this kind of good news in lung cancer for a long time," Otis Brawley, MD, Chief Medical Officer at the American Cancer Society, told Medscape Medical News. "It's simply an amazing result with an immediate impact on this disease," Mark G. Kris, MD, Chief of Thoracic Oncology at Memorial Sloan-Kettering Cancer Center, reported in a Medscape commentary.
"Finally we have a screening test that meets that gold standard and has a substantial opportunity to decrease the death rate for lung cancer," said Dr. Kris. "In the group that was screened, all patients had smoked 30 pack-years, which is the equivalent of 1 pack per day for 30 years, 2 packs per day for 15 years, and so on. Based on these data, it makes sense to recommend screening with a low-dose helical CT for any person who has smoked 30 pack-years."
In November, the National Comprehensive Cancer Network in an updated set of guidelines came out in favor of lung cancer screening, recommending the use of low-dose CT screening for select patients at high risk for disease.
 

1. The Top Game Changer for 2011 in Oncology

Unprecedented Advances in Melanoma

In 2011, 2 studies and 2 drug approvals revolutionized therapy for patients with metastatic melanoma. Vemurafenib and ipilimumab quickly became household names after studies on their efficacies in metastatic melanoma were highlighted in the plenary session of the 2011 ASCO® annual meeting.
In a phase 3 study^[10] that was accompanied by much praise and grand declarations, the targeted therapy vemurafenib was shown to dramatically improve progression-free and overall survival, compared with standard chemotherapy, in patients with advanced melanoma with no previous treatment.
Vemurafenib targets the V600E mutations in the BRAF gene, and an estimated 40%-60% of melanoma patients have this type of BRAF mutation.
The progression-free survival data constitute "an unprecedented level of difference," said lead author Paul Chapman, MD, from Memorial Sloan-Kettering Cancer Center.
This study is "practice changing," said Lynn Schuchter, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. Responses with the new oral therapy can be dramatic -- patients can have improvement within 72 hours of treatment, she said.
In August, vemurafenib was approved by the FDA for the first-line treatment of both metastatic and unresectable melanomas, as reported at the time by Medscape News. The drug is specifically indicated for patients with melanoma whose tumors have V600E mutations in the BRAF gene.
A phase 3, international, multicenter study showed ipilimumab, a human monoclonal antibody, to be effective as first-line therapy in melanoma,^[11] increasing the number of patients who can benefit from the drug, which has just been approved for use as second-line therapy.
The data on first-line use were presented at the 2011 ASCO® annual meeting and published online in The New England Journal of Medicine to coincide with the presentation.
Ipilimumab in combination with dacarbazine improved overall survival in patients with previously untreated metastatic melanoma, compared with dacarbazine plus placebo, said senior author Jedd Wolchok, MD, from Memorial Sloan-Kettering Cancer Center. The drug was approved in March by the FDA as second-line therapy for patients with advanced melanoma, based on a study of previously treated patients. At the time of its approval, ipilimumab was the first agent ever proven to improve survival in advanced melanoma, as reported at the time by Medscape.
Overall survival in the study was significantly longer in the ipilimumab group than in the placebo group (11.2 vs 9.1 months; hazard ratio [HR] for death, 0.72; P < .001), Dr. Wolchok and his coauthors reported. The ipilimumab group had higher survival rates than the placebo group at 1 year (47.3% vs 36.3%), 2 years (28.5% vs 17.9%), and 3 years (20.8% vs 12.2%). The 3-year results are "very mature," commented Dr. Wolchok.
"Today we are in the very fortunate position of having 2 medicines approved for metastatic melanoma, the first time in 13 years that any medicine has been approved by the FDA for melanoma," said Dr. Wolchok. "Importantly, both of these medicines were approved on the basis of the gold standard endpoint -- namely, improvement of overall survival. We believe these newly approved treatments are a source of great hope to patients, their families, and their physicians."

COST OF LUNG CANCER SCREENING

November 28, 2011 — A series of letters to the New England Journal of Medicine has raised questions about the results of the National Lung Screening Trial (NLST).
The NSLT results were published several months ago (N Engl J Med. 2011;365:395-409), but were initially released to the public in October 2010 when the trial was halted early because of the survival benefit seen with computed tomography (CT) scanning. At a median follow-up of 6.5 years, the 53,000-person trial found a 20% reduction in deaths from lung cancer in current and former heavy smokers screened with low-dose helical CT, compared with those screened with chest x-ray (P = .004).
"This was a large randomized clinical trial and it provides the strongest level of evidence that can be obtained," said Arnold J. Rotter, MD, from the City of Hope Hospital in Duarte, California, in a recent interview with Medscape Medical News. Dr. Rotter is one of the authors of the new guidelines from the National Comprehensive Cancer Network that "strongly recommend" screening the high-risk group of heavy smokers.
Debate about lung cancer screening has raged on for several years now, sparked by results from the International Early Lung Cancer Action Program (I-ELCAP) study. The main criticism of I-ELCAP was that it was not a randomized trial, and experts urged all concerned to wait for results from randomized studies.
Now that the NLST results are in and are overwhelmingly positive for lung cancer screening with low-dose CT in high-risk individuals, there should be an end to these debates, Dr. Rotter said. But the debate continues, as recently reported by Medscape Medical News.
The debate in the series of letters includes questions about the benefits and harms of lung cancer screening.
"It seems to us that the balance between the benefits and harms of screening is tipped toward the latter," write Bruno Heleno, MD, and Jakob Rasmussen, MD, from the Research Unit for General Practice, Copenhagen, Denmark.
According to the NSLT, in a hypothetical population of 1000 healthy heavy smokers (current or former), screening with low-dose CT, as opposed to chest x-ray, would avert 5 deaths, 3 of which would be due to lung cancer, they note.
However, CT screening would also result in 231 people with at least 1 positive result, 22 additional invasive procedures, 18 additional surgeries, and 6 nonfatal complications resulting from these procedures. Plus, the extent of psychosocial harm as a consequence of false-positive results is still unaccounted for, they write.
Other letters highlight the problem of overdiagnosis, which Peter Bach, MD, MAPP, from the Memorial Sloan-Kettering Cancer Center in New York City, says is greater than was reported. The NSLT researchers calculated the rate of overdiagnosis to be 13%, and described this as "not large," but they did not use the appropriate denominator, he asserts. He says the rate is nearly twice that — 25% — and notes that several other studies have pegged the overdiagnosis rate at about 20% to 25%.
The NSLT researchers reply that they did not report formal estimates of overdiagnosis. Longer follow-up is needed, as is a discussion of how to estimate overdiagnosis with CT screening, compared with chest x-ray, which also has a potential for overdiagnosis, write NSLT researchers Christine Berg, MD, from the National Cancer Institute, Bethesda, Maryland, and Denise Aberle, MD, from the University of California at Los Angeles.
The issue of cost effectiveness is raised in a letter from Michael Kohn, MD, MPP, from the University of California at San Francisco. Using a "back of an envelope" analysis, he calculates that according to the NSLT results, the number needed to screen to prevent 1 death from lung cancer is 300.
However, to prevent that 1 death from lung cancer, these 300 people would have to undergo 900 screening CT scans (at a total cost of around $300,000) and about 85 additional positive screening tests (around $425,000), he explains. This gives an approximate total cost of $725,000, which does not include any cost of treatment or distress caused by false-positive results.
The NSTL researchers say that these such calculations are "of interest," and add that because "the average duration of life lost to lung cancer is about 15 years, Kohn's estimate is equivalent to about $48,000 per year of life gained."
Drs. Berg and Aberle note that these issues of overdiagnosis and cost effectiveness, as well as that of interval cancers — which are mentioned in another letter — are all "important issues for further interpretation of our primary result, a reduction in lung-cancer-specific mortality after low-dose CT screening." They add that, in collaboration with other researchers, they are currently involved in modeling studies that will allow the evaluation of benefits/risk ratios.
N Engl J Med. 2011;365:2035-2038. Abstract

 

PRADAXA AND TRAUMA-A DANGEROUS COMBINATION

November 24, 2011 (Boston, Massachusetts) — Very little can be done for a patient taking dabigatran (Pradaxa, Boehringer Ingelheim) who suffers a traumatic injury, and this new, potentially catastrophic predicament--less of an issue in the warfarin era--underscores the need for routine surveillance of new oral anticoagulants to include hemorrhagic complications and trauma deaths.
So say two trauma surgeons and an emergency room physician who authored a research letter appearing in the November 24, 2011 New England Journal of Medicine. They write that they've recently cared for several patients taking dabigatran at the time of their injury, all of whom died [1].
First author on the letter Dr Bryan A Cotton (Center for Translational Injury Research, Houston, TX) spoke with heartwire late Friday, saying he knows that his views, as a trauma surgeon, "are a little bit skewed."
"We don't see anything but complications with these patients, we don't see the people with wonderful interactions with dabigatran. All we see is the bad, but when you do, it's a horrible feeling."
Cotton says "you kind of roll your eyes when you hear that an [incoming trauma] patient is on Coumadin, thinking 'this is going to increase their risk,' but at least you know there are some things you can do. . . . Now, with dabigatran, if I hear a patient is on Pradaxa, I get chest pain myself when I hear it. All of us do."
Cotton and colleagues point out that trauma is the fourth-leading cause of death in the US, reaching 40 000 deaths per year among men and women over age 65. While hemorrhagic complications can also be catastrophic in people taking warfarin, patients on the older drug have the edge over those taking newer oral anticoagulants in a number of ways.
First, the degree of warfarin anticoagulation can be easily assessed, whereas no such tests exist for dabigatran. Second, there are strategies to rapidly reverse the anticoagulant effect of warfarin using vitamin K, plasma factor VIIa, and factor concentrates, Cotton et al note. By contrast, coagulopathy is mostly "irreversible" in patients taking dabigatran.
"Currently, the only reversal option for dabigatran is emergency dialysis (as suggested in a single line in the package insert)," Cotton et al write. "The ability to perform rapid dialysis in patients with bleeding whose condition is unstable or in those with large intracranial hemorrhages will present an incredible challenge, even at level one trauma centers."
Among patients taking dabigatran seen by Cotton et al, all appeared to have normal coagulation on conventional tests, but were grossly abnormal using rapid thromboelastography (rTEG). One patient who suffered a fall and developed neurological deficits died shortly after emergency craniotomy. "Unfortunately, even with the aid of rTEG, supportive care is all that is available in the emergency setting," they write.
In their letter, Cotton and colleagues urge the FDA to consider the "generalizability" of study findings for new, upcoming oral anticoagulants, and to require more pragmatic trials. "We strongly urge that hemorrhagic complications and death resulting from trauma be included as part of the routine surveillance of all newly approved oral anticoagulants," they conclude.
Cotton said he in no way expects the RE-LY investigators to go back and redo their trial, but he believes real-world trauma events should be captured in trials of other anticoagulants that are still ongoing. He also wants trauma deaths, which are not typically captured in postmarketing surveillance, to be included.
In fact, Cotton says he was surprised and pleased to get a call from Boehringer-Ingelheim after his letter was published, asking for details on the three patients, suggesting they are "taking this very seriously." They also told him that the company is actively working on an antidote to reverse dabigatran's effects.
"But until I have that in my back pocket, this is a bad problem," Cotton said, although he acknowledged a traumatic injury, itself, represents a "small risk."
Cotton hopes his letter will spur physicians to discuss the risks in the case of trauma with their patients as part of the discussion of whether to start the drug in the first place or switch from warfarin--something he thinks is not happening enough. "The harm when this happens is real and irreversible, and there ought to be a more balanced discussion between patients and physicians."
Cotton had no conflicts of interest. Disclosures for coauthors are available in the published manuscript .

ANNUAL MAMMOGRAPHY FOR WOMEN ON THEIR 40s

November 30, 2011 (Chicago, Illinois) — Women in their 40s with no family history of breast cancer are just as likely to develop invasive breast cancer as women with a family history, according to research presented here at the Radiological Society of North America 97th Scientific Assembly and Annual Meeting.
The finding offers conclusive evidence that women 40 to 49 years of age should be screened yearly with mammography, Stamatia V. Destounis, MD, from Elizabeth Wende Breast Care, Rochester, New York, told reporters at a press briefing.
This flies in the face of the 2009 recommendation by the US Preventive Services Task Force that came out against screening for women in their 40s.
In fact, just last week, a Canadian task force issued new guidelines recommending against screening women in this age group, and extending the interval between mammography screening in women 50 to 74 years to as much as 3 years.
"All these task forces are coming out saying don't screen, don't do breast self-exam, don't do clinical breast exam. It's just ridiculous," Dr. Destounis told Medscape Medical News.
She and her team performed a retrospective review of all patients who underwent screening mammography at their center from 2000 to 2010. During that period, 6154 cancers were found in 5813 women.
Of these cancers, 1116 (18.1%) were found in women 40 to 49 years of age, and 373 were diagnosed as a result of mammography screening. The remainder were diagnosed because the women presented with symptoms such as pain, a lump, nipple discharge, and skin changes.
When the researchers focused on the women who had their cancers detected on screening mammography, they found that 144 (39%) had a family history of breast cancer and 228 (61%) did not; in the case of 1 woman, family history was unknown.
All but 1 of the patients went on to have surgery. In the women with no family history, the percentage of invasive breast cancer was 64%; in the women with a family history, the percentage was 63.2%.
The researchers also found that 31% of the women with a family history and 29% without a family history had positive lymph nodes.
"Our conclusion is that family history really doesn't seem to impact the rate of invasive disease or metastatic rate in this patient cohort," Dr. Destounis noted.
"Obviously, we know that the risk of getting breast cancer increases per decade. We get that. But 40- to 49-year-old women get breast cancer, too. They get diagnosed with screening mammography, and a considerable number of these are invasive cancers. The groups against screening say we do not have to screen them, but we do have to screen them. These women have a considerable percentage of cancers that are invasive and a considerable number of lymph nodes that are positive," she said.
Breast Cancer Risk in Younger Women Higher Than Previously Thought
Nina A. Mayr, MD, a radiation oncologist from Ohio State University, Columbus, told Medscape Medical News that the study confirms what many people have suspected.
"Many of us believe that the breast cancer risk of younger women in their 40s is much higher than we probably thought, and the recurrence rate is also higher," she said.
"I see these young women. They didn't have a mammogram and then they come in with a cancer that is very large. Many of these women still have children at home, so the socioeconomic cost of breast cancer is very high,...much higher than for in a woman in her 70s. I think these aspects are very important and they tend to be overlooked," Dr. Mayr said.
Critics who oppose screening mammography say that those who are in favor of it have a vested interest in doing mammograms, but Dr. Mayr denied that this is the case.
"If we were talking about a very expensive nuclear medicine test or an expensive surgical procedure that makes a lot of money, they might have a point. But mammograms do not make much money," she said.
In fact, academic centers and private practices find it extremely difficult to find people who want to do mammography, she noted.
"The cost of a mammogram is about $75. It is a procedure that incurs a lot of liability, so the financial yield is low and the liability is high.... If you want to derive a lot of financial benefit, you do not want to do mammography."
Dr. Destounis reports financial relationships with Siemens, Fujifilm Holdings Corporation, Hologic, Koning Corporation, Koninklijke Philips Electronics NV, and Matakina International Limited. Dr. Mayr has disclosed no relevant financial relationships.
Radiological Society of North America (RSNA) 97th Scientific Assembly and Annual Meeting: Abstract SST01-01. Presented November 29, 2011.

WHATS HOT AT SAN ANTONIO BREAST CANCER SYMPOSIUM

November 28, 2011 — Results from a number of high-profile clinical trials of bisphosphonates in breast cancer will be among the headlining news from the 34th Annual San Antonio Breast Cancer Symposium (SABCS), being held December 6 to 10 in Texas.
Vying for attention at the meeting will be the Institute of Medicine's report on environmental factors and breast cancer as well as new results from major clinical trials in advanced breast cancer.
Additionally, there will be a report on the first-ever genomic profiling study of ductal carcinoma in situ (DCIS), an analysis of the overdiagnosis of breast cancer from mammography screening, and the results from an international study of axillary lymph node dissection in patients with clinically node-negative breast cancer and micrometastases in the sentinel node.
Overall, the 2011 meeting looks especially exciting, said Peter Ravdin, MD, PhD, a co-director of the symposium. "We have a lot of outstanding presentations this year, even more so than usual," he told Medscape Medical News. Dr. Ravdin is director of the Comprehensive Breast Health Clinic at the Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio.
There will be presentations of new data from 4 separate clinical trials of bisphosphonates in patients with breast cancer.
The presentations include new, long-term data from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial, which examines the effect of zoledronic acid (Zometa, Novartis) on outcomes in premenopausal women with estrogen-responsive early breast cancer. "This trial caused a sensation 3 years ago," said Dr. Ravdin, referring to the fact that this was one of the first studies to show that zoledronic acid, a bisphosphonate used for osteoporosis and bone metastases, also had a benefit in breast cancer.
The results were impressive; zoledronic acid reduced the risk for breast cancer recurrence and breast cancer death by 33%, said Dr. Ravdin, but the results require interpretation. The patient population in the Austrian trial was very specific (premenopausal women treated with goserelin), and goserelin is not widely used in the United States, he commented in the past.
The new presentation this year will report on the continued follow-up in the ABCSG-12 trial.
The usefulness of bisphosphonates in the treatment of breast cancer may be further clarified by another presentation at SABCS this year — on the final results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-34.
This trial compares adjuvant clodronate (Bonefos, Berlex) versus placebo in patients with early-stage breast cancer who are also treated with systemic chemotherapy and/or tamoxifen or no therapy. "This is the final analysis of the trial that asks the question: does the bisphosphonate clodronate have any impact on survival?" said C. Kent Osborne, MD, a co-director of the meeting, in an interview with Medscape Medical News. He is director of the Dan L. Duncan Cancer Center, Baylor College of Medicine, in Houston.
Clodronate is an oral bisphosphonate, which has the advantage of not causing osteonecrosis of the jaw (an adverse event associated with intravenous bisphosphonates), pointed out Dr. Ravdin.
In yet another bisphosphonate trial, new long-term results from the industry-sponsored ZO-FAST study will be presented. The presentation will cover survival outcomes among postmenopausal women with hormone receptor–positive early breast cancer who received adjuvant letrozole and zoledronic acid.
The studies presented to date suggest that the effect of zoledronic acid on breast cancer is complicated.
In 2010, one of the biggest stories at SABCS was the AZURE trial. The trial results showed no effect from zoledronic acid on the recurrence of breast cancer or overall survival. However, a subset analysis showed a significant effect on both recurrence and survival in postmenopausal women (more than 5 years after menopause), but no effect on premenopausal women.
Zoledronic acid does not appear to have a direct anticancer effect. The drug is administered by injection once every 6 months but is cleared from the system in about 24 hours. However, it persists in the bone and changes the bone marrow environment in such a way that the breast cancer cells are less likely to escape and cause a recurrence, an expert has previously told Medscape Medical News.
IOM, CLEOPATRA, and BOLERO-2
The new report from the Institute of Medicine is entitled "Breast Cancer and the Environment: A Life Course Approach" and assesses the breast cancer risk posed by various environmental factors. The report also identifies actions that might reduce women's risk for the disease and recommends targets for future research. The report is sponsored by Susan G. Komen for the Cure.
A new trial in patients with previously untreated HER2-positive metastatic or locally recurrent, unresectable breast cancer examines the potential benefit of treating patients with 2 targeted therapies instead of just 1. The results from the CLEOPATRA study are "long awaited," said Dr. Osborne.
The trial compares the safety and efficacy of the combination of pertuzumab (Roche) and trastuzumab (Herceptin, Roche) vs trastuzumab alone in these patients, all of whom also received docetaxel. Last year at SABCS, another study, known as NeoSphere, looked at this combination in the neoadjuvant setting and found that pertuzumab improved the activity of trastuzumab and docetaxel.
Another important trial in advanced breast cancer looks at the use of everolimus (Afinitor, Novartis). The drug is indicated for use in renal cell carcinoma and is also used to help prevent rejection in organ transplantation, said Dr. Ravdin. The results from this phase 3 trial, known as BOLERO-2, were presented at the recent European Multidisciplinary Cancer Congress. At that meeting, an expert said that "everolimus is the most important advance in breast cancer since trastuzumab." The results will be updated in San Antonio.
In BOLERO-2, investigators are comparing everolimus plus exemestane with exemestane alone in patients with estrogen-receptor-positive advanced breast cancer that is refractory to letrozole or anastrozole.
DCIS Study
In the treatment of DCIS, clinicians must advise patients about their possible need for radiation in addition to surgery; part of that conversation involves their risk for recurrence, said Dr. Ravdin. "Radiation strongly reduces the risk of local recurrence," he said, adding that the modality also had unwanted adverse effects. Thus, a tool that could help identify which patients have a low risk for recurrence and do not need radiation therapy could have a "huge and immediate impact," said Dr. Ravdin.
A new study to be presented this year at SABCS will provide some insight into one such potential tool, a multigene assay for DCIS from the makers of the Oncotype DX (Genomic Health), the multigene assay used to predict risk for recurrence in estrogen receptor–positive invasive disease.
The study is "really interesting" said Dr. Ravdin, and looks at patients with DCIS treated with surgery but not radiation. The study's primary objective is to determine whether there was a significant association between the risk for an ipsilateral breast event and the continuous DCIS score assessed by the gene assay.
34th Annual San Antonio Breast Cancer Symposium; December 6-10, 2011.

4 DRUGS CAUSE MOST SERIOUS ADVERSE EVENTS

November 23, 2011 — Adverse drug events (ADEs) cause an estimated 100,000 emergency hospitalizations for seniors each year, yet two thirds involve just a handful of anticoagulants and diabetes medications, according to a study published in the November 24 issue of the New England Journal of Medicine.
The study, by researchers from the US Centers for Disease Control and Prevention (CDC), singles out 4 drugs and drug classes — warfarin, oral antiplatelet medications, insulins, and oral hypoglycemic agents. Alone or together, they account for 67% of emergency ADE hospitalizations of adults 65 years and older. Warfarin was implicated in 33%, lead author Daniel Budnitz, MD, MPH, director of the CDC's Medication Safety Program, and coauthors write.
In contrast, medications red-flagged as high risk or inappropriate by health authorities explained only 1.2% and 6.6%, respectively, of such hospital admissions.
For clinicians, the take-home message of the study is clear: Improved management of antithrombotic and antidiabetes drugs can keep thousands of seniors out of the hospital.
"These data suggest that focusing safety initiatives on a few medicines that commonly cause serious, measurable harms can improve care for many older Americans," Dr. Budnitz said in a press release. "Blood thinners and diabetes medicines often require blood testing and dosing changes, but these are critical medicines for older adults with certain medical conditions."
"Doctors and patients should continue to use these medications but remember to work together to safely manage them."
Dr. Budnitz and coauthors analyzed data collected from 2007 to 2009 from 58 hospitals participating in an ADE surveillance project to come up with national estimates for that time frame. Nearly two thirds of the estimated 100,000 emergency ADE hospitalizations of seniors each year stemmed from unintentional overdoses, they write. In 48% of the cases, the patient was 80 years or older.
Hospitalizations arising from ADEs promise to increase "as Americans live longer, have greater numbers of chronic conditions, and take more medications," the authors note. Lowering the number of such hospitalizations, they write, is a major priority of a federal initiative called Partnership for Patients, which was launched in April.
The program aims, among other things, to reduce the number of preventable hospital readmissions by 20% by the end of 2013.
The authors have disclosed no relevant financial relationships.
N Engl J Med. 2011;365:2002-2012. Abstract

AUTOIMMUNE DISEASE INCREASE RISK OF PULMONARY EMBOLISM

November 28, 2011 — A long-term, large-scale investigation supports the hypothesis that autoimmune disorders elevate the risk for pulmonary embolism (PE), according to a report published online November 26 in the Lancet.
Bengt Zöller, MD, from Lund University in Malmö, Sweden, and colleagues used the MigMed2 database to calculate standardized incidence ratios for subsequent PE in patients admitted to the hospital for autoimmune disorders from January 1, 1964, to December 31, 2008. The analysis considered the time from the admission for the autoimmune disorder to the PE, and excluded patients with preexisting venous thromboembolism. The reference population was the entire general Swedish population, which is included in the database.
The inflammation that is part of autoimmunity could drive venous thrombosis. Previous studies have linked increased risk for venous thrombosis to celiac disease, type 1 diabetes mellitus, systemic lupus erythematosus, hyperthyroidism, rheumatoid arthritis, inflammatory bowel disease, Behçet's disease, and Wegener's granulomatosis. The study greatly extends the number of autoimmune disorders evaluated for PE risk.
The analysis revealed a strong association between hospital admission for an autoimmune disorder and PE during the subsequent year. For the 535,538 patients admitted for an autoimmune disorder, the overall risk for PE in the first year after admission was 6.38 (95% confidence interval [CI], 6.19 - 6.57). Both sexes and all ages had the elevated risk, which held up for all 33 autoimmune disorders considered, but 4 demonstrated a particularly strong association: immune thrombocytopenic purpura (standardized incidence ratio [SIR] adjusted for age, sex, time, and comorbidity was 10.79; 95% CI, 7.98 - 14.28), polyarteritis nodosa (SIR, 13.26; 95% CI, 9.33 - 18.29), polymyositis or dermatomyositis (SIR, 16.44, 95% CI, 11.57 - 22.69), and systemic lupus erythematosus (SIR, 10.23; 95% CI, 8.31 - 12.45). Two common autoimmune diseases also had high associations: rheumatoid arthritis (SIR, 5.99; 95% CI, 5.59 - 6.41) and type 1 diabetes mellitus (SIR, 6.38; 95% CI, 3.28 - 11.18).
The elevated overall risk for PE fell over time, from 1.53 (95% CI, 1.48 - 1.57) at 1 and5 years, to 1.15 (95% CI, 1.11 - 1.20) at 5 to 10 years, and 1.04 (95% CI, 1.00 - 1.07) at 10 years and later. The researchers conclude that 33 autoimmune diseases "were associated with significantly increased risks of pulmonary embolism during the first year after admission. Our findings suggest that hypercoagulability is a general feature of most autoimmune disorders."
A study limitation is that considering only hospital admissions might exclude less severe cases of the autoimmune disorders. The database did not include general cardiovascular risk factors, but the investigators adjusted for 10 comorbid conditions. Still, the researchers conclude that the associations are strong enough to warrant consideration of autoimmune disorders as hypercoagulation disorders.
In an accompanying comment, Carani B. Sanjeevi, MD, PhD, from the Karolinska Institute in Stockholm, Sweden, recommends that prospective studies investigate the use of inflammatory markers to identify patients with autoimmune disorders who might benefit from prophylactic use of antiinflammatory agents, perhaps with antithrombolytic agents, to prevent PE.
The study was supported by the Swedish Research Council, the Swedish Council for Working Life and Social Research, the Swedish Research Council Formas, and Region Skåne. The authors and commentator have disclosed no relevant financial relationships.
Lancet. Published online November 26, 2011. Study abstract Editorial extract

AVSTIN IS ALSO OUT AT CANADA BUT NOT EUROPE

November 29, 2011 — Canadian health authorities have revoked the license for bevacizumab (Avastin, Genentech) in metastatic breast cancer, after the US Food and Drug Administration (FDA) recently rescinded approval in the United States.
Health Canada, after consultation with an expert advisory panel, concluded that the drug has not been shown to be safe and effective for this indication, echoing the conclusions reached 10 days ago by the FDA. The panel, which included oncologists scientists and breast cancer advocates, met in March and unanimously concluded that the potential harm of bevacizumab in this indication is "of such magnitude that the risks of the drug far outweigh potential benefits," and that, on the basis of current available evidence, there is no value in leaving the drug available as a treatment option.
Although both the United States and Canada have revoked the license for metastatic breast cancer, bevacizumab remains on the market and approved for other uses, including lung and colorectal cancers and glioblastoma.
However, the metastatic breast cancer indication remains approved in Europe, after the European Medicines Agency (EMA) reviewed exactly the same data that led the United States and Canada to their revoking decisions.
"It is very hard for me to understand how 2 different regulatory authorities — the FDA and the EMA — could come to 2 such very different decisions based on the same data," said Fatima Cardoso, MD, director of the breast cancer unit and breast cancer research program at the Champalimaud Cancer Center in Lisbon, Portugal. Dr. Cardoso was cochair of the committee that authored new guidelines on the treatment of advanced metastatic breast cancer (ABC1), which she said emphasize the need to follow agreed-upon treatment paths.
"This is very disturbing for patients, because it gives the message that anyone can do anything in advanced breast cancer. This is the message we want to change; we all need to apply the same strict rules," Dr. Cardoso told Medscape Medical News.
When the first data on bevacizumab in breast cancer came out, "there was too much hype about what this drug could do. Now, after many more studies, it is clear that there are benefits, but they are much smaller than we initially thought...and the major problem with this drug is the price. The amount of benefit that this drug provides is not worth the amount it costs. If it was less expensive, we could use it more often," Dr. Cardoso explained.
The new ABC1 guidelines recommend that bevacizumab be used only in cases where there is rapidly progressive disease that is very aggressive and symptomatic, she noted.
This is a small select group of patients, she noted. For patients who are not symptomatic, adding bevacizumab can decrease quality of life by adding adverse effects without prolonging survival.
Dr. Cardoso emphasized the need for more research into biomarkers to identify patients who could benefit from bevacizumab. "Some patients benefit from this drug — we just don't know who," she said.
The manufacturer has pledged to continue research into biomarkers.
After the FDA announcement, Genentech said in a press release that it plans to launch a new phase 3 clinical trial of the drug in combination with paclitaxel in patients with previously untreated metastatic breast cancer, and evaluate a potential biomarker that "may help identify which people might derive a more substantial benefit from [bevacizumab]." In response, the FDA said it would welcome a new application from Genentech with data showing that bevacizumab clearly benefits a subset of patients with metastatic breast cancer.