HYPOLIPEMIC AND ANTIDIABETIC EFFECTS OF IMATINIB

Leuk Res. 2009 Mar 25. [Epub ahead of print]

Related Articles, Links

Hypolipemiant besides antileukemic effect of imatinib mesylate.

Gologan R, Constantinescu G, Georgescu D, Ostroveanu D, Vasilache D, Dobrea C, Iancu D, Popov V.

Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest, Romania.

The use of imatinib mesylate (IM) (Gleevec, Novartis) in chronic myeloid leukemia (CML) and other neoplastic disorders is in a dramatic increase, inducing long-standing survival. Therefore, the interest in the associated events with this treatment is more and more manifest. We describe a case of CML in which, at the usual antileukemic dose, IM induced a rapid and persistent normalization of the levels of serum cholesterol, triglycerides, low- and high-density lipoproteins and glucose. In the present case report we confirm other observations on the hypolipemiant and antidiabetic effects, concomitant with that antileukemic, of IM.

STATINS NOT GOOD FOR EVERYONE

ACC 2009: Statins Offer No Cardiovascular Protection for Patients With End-Stage Renal Disease on Hemodialysis

March 31, 2009 (Orlando, Florida) — Statin therapy does not prevent cardiovascular events and death in patients with end-stage renal disease (ESRD) who are on hemodialysis, according to A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA), presented here at the American College of Cardiology 2009 Scientific Sessions and published simultaneously online in the New England Journal of Medicine [1].

When they started the trial in 2005, it was the hope of the AURORA investigators, led by Dr Bengt Fellström (Uppsala University Hospital, Sweden), that statin therapy, which reduces cardiovascular events and mortality in patients without renal disease and patients with modest renal failure, would be just as useful in ESRD patients on hemodialysis--a population that has generally been excluded from statin-outcome trials.

Truly International AURORA Done on Every Continent But Africa

AURORA studied 2776 patients on hemodialysis for at least three months prior to study entry to receive rosuvastatin (Crestor, AstraZeneca) 10 mg daily (n=1391) or placebo (n=1385).The study was done in 25 countries and 284 centers. The patients' ages ranged from 50 to 80 years, and they had to be statin-free for six months prior to enrollment. Patients in whom a kidney transplant was likely within one year were excluded, as were patients with creatine kinase more than three times the upper limit of normal (>3xULN), alanine aminotransferase (ALT) >3xULN, and thyroid-stimulating hormone (TSH) >1.5xULN.

The primary end point of the study was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke. Secondary end points included all-cause mortality, cardiovascular event-free survival, cardiovascular and noncardiovascular death, procedures for stenosis or thrombosis of the vascular access for hemodialysis, coronary or peripheral revascularizations, and adverse events. The study also assessed changes in lipids and C-reactive protein (CRP).

No Treatment Effect on Any Trial End Points

Patients tolerated rosuvastatin very well, and there was no difference in adverse events between placebo- and rosuvastatin-treated patients. But, despite a 43% reduction in LDL-cholesterol and an 11% reduction in CRP in the patients in the statin group, there was no beneficial treatment effect on the composite cardiovascular end point or on any of the secondary end points with rosuvastatin, said Fellström.

In an interview with heartwire, Fellström speculated that vascular disease in dialysis patients is probably very different from vascular disease in patients without renal disease or even patients with mild renal disease. As well, the duration of hemodialysis--patients were on dialysis treatment for up to four years--could have produced greater calcification of the coronary arteries, a known side effect of hemodialysis.

"A negative trial can be just as useful as a positive one," he added. "We excluded patients under age 50, but we now want to look at patients below this age who will eventually also get a renal transplant. These patients are probably a group that should be treated with statins, because we know that transplanted patients benefit a lot from statin treatment."

Despite Negative Result, Statins Still Worth a Try

Even though the results of AURORA were negative, dialysis patients should still get a statin if they have other risk factors associated with the coronary arteries or other parts of their vascular tree, Dr Hani Sabbah (Henry Ford Hospital, Detroit, MI) told heartwire.

"I didn't hear anything to say it hurts them to take a statin. The problem is, these patients don't die from a heart attack or stroke, they die from kidney failure from their end-stage renal disease. But if you can save them from dying from coronary disease so that they live to get a transplant, that would be something."

BETA BLOCKERS BLUNT ANTI-INFLAMMATORY EFFECT OF STATINS

Beta Blockers Blunt Anti-Inflammatory Effect of Statins After Acute MI

NEW YORK (Reuters Health) Mar 26 - C reactive protein (CRP) levels are lowered to a greater extent with simvastatin alone after acute MI (AMI) than when metoprolol or propranolol is added, indicating that the beta blockers attenuate the anti-inflammatory effect of the statin.

Those findings come from the Brasilia Heart Study, published in the February 15 issue of the American Journal of Cardiology.

Dr. Andrei C. Sposito and colleagues at the University of Brasilia Medical School, Brazil, divided 189 patients with AMI into those given simvastatin alone, those on metoprolol or propranolol, those given simvastatin plus either metoprolol or propranolol, or patients given neither. The researchers evaluated the effects of the four regimens on CRP levels on days 1 and 5 after AMI.

Baseline median CRP level was 0.4 mg/dL in the simvastatin group and between 0.5 and 0.6 mg/dL in the other three groups.

By day 5, median CRP was 1.3 mg/dL in the simvastatin group, 4.3 mg/dL in the beta-blocker group, 4.6 mg/dl in the beta- blocker plus statin group, and 4.4 mg/dL in patients who received neither.

The difference in CRP between days 1 and 5 was significantly lower in the simvastatin group compared with levels in any of the other three cohorts, who all had similar CRP levels. The significance remained after adjustment for age, gender, and baseline CRP.

"In line with our previous study with atorvastatin, we found that simvastatin treatment attenuated the intense increase in systemic inflammatory activity during the acute phase of MI," Dr. Sposito and colleagues write. "In addition, for the first time, this study indicated that such an anti-inflammatory effect of statins could be attenuated by concomitant treatment with propranolol or metoprolol."

MOURATIDOU SPEAKING

Long-Term Opioid Use May Increase Sensitivity to Pain

April 2, 2009 — Long-term use of opioids to manage chronic pain increases patients' sensitivity to certain types of pain, and similar hyperalgesia develops with methadone-maintained drug abusers, researchers from the University of Adelaide, in Australia, report.

"There is a low ceiling dose for opioids in the treatment of persistent nonmalignant pain. Increasing doses may be causing more pain, not less pain. So use opioids sparingly," coauthor Andrew A. Somogyi, MD, told Medscape Psychiatry.

"If methadone-managed opioid-dependent patients need acute analgesia, the dose of opioid may need to be much higher due to the well-known phenomenon of tolerance and also hyperalgesia," he added.

The observational study by Justin L. Hay, MD, and colleagues is in the March issue of the Journal of Pain.

Growing Body of Evidence

The investigators compared pain sensitivity in patients with noncancer chronic pain taking either methadone (n = 10) or morphine (n = 10) with those maintained on methadone due to opioid dependence (n = 10) and with a control group (n = 10).

The outcome variables were hyperalgesia (enhanced pain in response to a normally painful stimulus) and allodynia (pain due to a stimulus that does not normally cause pain). These were measured using cold-pressor tolerance and electrical stimulation for hyperalgesia and von Frey hairs–stimulation testing for allodynia.

Results showed that the methadone-maintained group and both of the chronic pain groups were hyperalgesic measured by the cold-pressor test but not measured by electrical stimulation. None of the groups had allodynia.

"We did not expect that chronic noncancer pain patients on morphine or methadone would have similar cold-pressor–induced hyperalgesia. Perhaps it will occur in all patients on any opioid," Dr. Somogyi speculated.

"These results add to the growing body of evidence that chronic opioid exposure increases sensitivity to some types of pain. They also demonstrate that in humans, this hyperalgesia is not associated with allodynia," the authors write.

Evidence "Not Terribly Encouraging"

David Clark, MD, from the Palo Alto VA Health Care System, in California, has also studied opioid-induced hyperalgesia. According to Dr. Clark, "[An] important finding in this study was that not only addicts have this type of sensitization. Chronic-pain patients have it as well, so this problem goes beyond the boundaries of what is unique to drug abusers."

Dr. Clark said the finding that long-term use of opioids might sensitize patients to pain itself suggests factors that could both limit the clinical utility of opioids used to control chronic pain and add to pain problems in those being treated for addiction.

"The emerging experience regarding the long-term use of opioids for chronic pain is not terribly encouraging, and opioid-induced hyperalgesia is 1 explanation for why this therapy might have limited success," he said.

The researchers' data on allodynia have both clinical and research implications. "Allodynia is perhaps the most commonly followed feature of opioid-induced hyperalgesia in animal populations," Dr. Clark said.

"The authors very reasonably conclude that particular types of pain might be more altered than others after long-term opioid use. The trouble is that no one knows which of these pain models might be the best index of anything experienced by a human with clinical pain," he added.

Dr. Somogyi said that this study also raises new questions about opioid-related hyperalgesia. "Is it dose related? How quickly might it start? Why does it occur only for cold-pressor pain and not electrical-stimulation–induced pain? What nonneuronal mechanism might be involved?" he said.

MMP8 AS A TUMOR SUPPRESOR?

Suppressor of Melanoma Tumor Growth Identified

April 3, 2009 — A gene that suppresses tumor growth in melanoma has been identified by researchers at the National Institutes of Health (NIH). The gene, known as matrix metalloproteinase-8 (MMP8), could pave the way for new individualized therapies for melanoma, write the authors of a new study that was published online March 29 in Nature Genetics.

The new finding also provides insight into why MMP inhibitors, once considered promising anticancer agents, disappointed clinically.

MMPs are enzymes that degrade components of cells, including the extracellular matrix, explain the study authors, led by Lavanya H. Palavalli, MD, from the National Human Genome Research Institute (NHGRI) at the NIH, in Bethesda, Maryland. The enzymes help the body break down and recycle proteins, and thus play a role in the process of remodeling skin after sunburns, cuts, or other injuries.

MMP8 is 1 of a family of 23 MMP genes. This family of genes has been associated with cancer metastasis, say the study authors.

MMP genes that mutate have been thought to be oncogenes, or promoters of cancer cell growth. Thus, the suppression of MMP activity with MMP inhibitors was the focus of oncologic research and drug development. There have been "decades of research on MMPs," note the authors, but it has proven fruitless. "Clinical trials using these inhibitors showed no effect and, occasionally, accelerated tumor growth," write the authors.

The new NIH research hints at why MMP inhibitors and MMP suppression were problematic and why MMP8 holds promise as a melanoma tumor suppressor.

Through a series of experiments, the NIH investigators discovered that the expression of wild-type, or normal, MMP8 — but not mutant MMP8 — in human melanoma cells inhibited those melanoma cells from growing. Thus, expression of some (the wild-type) MMP8 genes inhibit melanoma cell growth.

The finding is consistent with the molecular understanding of cancer, suggested 1 of the authors.

"We often talk about cancer as though it is 1 disease, and cancers do have many common denominators. But when we look at the DNA level, we see that different cancers have different genetic profiles, and so do different patients who have the same cancer," said the study's senior author, Yardena Samuels, PhD, in a statement. She is an investigator in the Cancer Genetics Branch of the NHGRI's Division of Intramural Research.

The new finding about MMP8 should spur research on the rest of this gene family, suggest the authors. "These findings emphasize the need to test the role of each MMP in an individual manner and to precisely define its functional role in cancer," they write.

Mutational Analysis Yields the Finding

The NIH undertook their new study in an effort to determine whether MMP genes are genetically altered in melanoma. There was good reason for the investigation.

As mentioned above, MMPs had been associated with cancer metastasis. However, in mouse models, there was the suggestion that MMPs had an antitumor effect, note the authors. "In particular, an increase in skin-tumor incidence was seen in MMP8-deficient mice," they write. The conflicting information about MMPs (agents of tumor growth vs producers of an antitumor effect) called for "an indepth analysis of the specific role of individual MMPs in particular cancer types," observe the authors.

Melanomas were chosen as the first cancer type. The study is the first systematic mutational analysis of the MMP family, say the authors.

To study the MMP genes, the researchers used a bank of tumor and blood samples collected from 79 patients with aggressive melanoma by coauthor Steven Rosenberg, MD, PhD, chief of surgery at the National Cancer Institute.

After comparing the sequence of MMP genes in tumors and normal DNA from the same patients, the researchers identified 28 different mutations in 8 MMP genes (from a total of 23 genes) in the melanoma tumors.

These mutations were distributed in different frequencies and patterns among the tumor samples. Of the tumors analyzed, 23% had at least 1 MMP gene mutation. Notably, more than 6% of tumors had mutations in MMP8 and more than 7% had mutations in MMP27, making them the most frequently mutated genes in the samples.

In a series of subsequent in vitro and in vivo (mice) experiments that focused on MMP8, the researchers note that the expression of wild-type but not mutant MMP8 was associated with inhibition of melanoma cell growth.

For example, the researchers found that mice injected with cells expressing wild-type MMP8 did not develop skin ulcers, which are important measures of cancer aggressiveness in melanoma. However, mice injected with cells expressing mutated MMP8 developed ulcerations and metastases in their lungs.

A combination of genetic, biochemical, and cellular data suggests that MMP8 is a tumor suppressor in human melanoma, they summarize. Further research might eventually allow the "development of individualized therapy on the basis of the mutant MMP present in the specific tumors," the authors conclude.

MAMMOGRAPHY BENEFIT AND HARMS

Screening-Mammography Benefits and Harms in Spotlight Again

April 2, 2009 — A new study adds to the debate about how the benefits and harms of screening mammography are presented to the public and provides new estimates of the absolute numbers of breast cancer deaths prevented by the screening.

The authors argue that the public is not currently presented with a balanced view of the screening, with potential benefits overemphasized and potential harms rarely discussed.

The study was published April 2 in the open-access online journal BMC Medical Informatics and Decision-Making.

Repeated screening mammography starting at age 50 saves about 1.8 lives over 15 years for every 1000 women screened, according the study authors.

They calculated that the absolute death risk from breast cancer without any screening is about 1% over those 15 years. "This means the survival percentage among women aged 50 to 60 who are not screened is 99%," said lead author John D. Keen, MD, senior attending radiologist at the John H. Stroger Hospital of Cook County, in Chicago, Illinois.

These statistical facts about mammography are in sharp contrast with what is most publicized about this screening, which is "mammography saves lives," suggested Dr. Keen.

"From a consumer perspective, the screening-mammography discussion in the United States is rather paternalistic and 1-sided," said Dr. Keen in an interview with Medscape Oncology.

What's needed is a balanced presentation of the facts to patients, which should include mention of the absolute benefits associated with screening and a discussion of potential harms, such as false positives, anxiety, unnecessary biopsies, and overdiagnosis, emphasized Dr. Keen. "This is not occurring now," he added.

However, a critic of the study says that its statistical methods are questionable and its findings debatable. Furthermore, the paper "labors an obvious point" about preventive medicine, says the critic.

"One has to apply an intervention to large numbers of healthy subjects in order to benefit the few who are unlucky enough to develop the disease," writes Stephen W. Duffy, MD, from the Cancer Research Center, in London, the United Kingdom, in an editorial that accompanies the study.

Dr. Keen's response to that criticism was that the "public has a right to know what the statistics are regarding mammography screening so that individuals can make informed decisions about participating."

Another cancer-screening expert approached by Medscape Oncology joined the study authors in calling for a better presentation of the facts about screening mammography. "We all have to do a better job to best inform the public about the benefits and harms of screening mammography," said Bob Smith, PhD, director of cancer screening at the American Cancer Society, in Atlanta, Georgia.

The new study appears at a time of increased public scrutiny of screening mammography. The New York Times recently covered the story of a public-health leaflet on screening mammography in the United Kingdom and the public outcry that resulted because the leaflet failed to mention the potential harms of screening. The controversy had been reported a month earlier by Medscape Oncology.

Findings Disputed and Supported

In their new paper, Dr. John Keen and his brother and coauthor James E. Keen, DVM, PhD, associate professor of epidemiology at the University of Nebraska, in Lincoln, analyzed the claim that "mammography saves lives" by calculating the life-saving absolute benefit of screening mammography in reducing breast cancer mortality in women aged 40 to 65.

To make this estimate, the authors used a variety of existing data sources, including randomized trials and SEER data on breast cancer mortality.

Dr. Duffy points out in his editorial that this study is one of modeled results and not empirical observation. "The accuracy of the figures arrived at is questionable," he writes.

Dr. Duffy notes that empirical data from 2 different randomized trials indicate that 3 or 2.1 breast cancer deaths, respectively, are prevented by repeatedly screening 1000 women. So the figure of 1.8 prevented deaths used in the current study is low, he says.

However, in a second editorial that accompanies the new study, Michael Retsky, PhD, from Harvard Medical School, in Boston, Massachusetts, says that the 1.8 deaths prevented by screening are consistent with other results.

"The crux of the problem is that early detection from screening only benefits approximately 1 in 1000 participants. That ratio appears in many trials and in the Keen and Keen paper," he told Medscape Oncology. The numerical results of the new study "are consistent with my knowledge and experience," he writes.

Dr. Duffy also disputes the new study's estimate that only 4.3% of screen-detected breast cancer cases have their lives saved as a result of screening. "This is clearly at odds with the experimental evidence. In the Swedish Two-County Trial, 141 breast cancer deaths were prevented — 15% of the 928 screen-detected cancers," he writes.

However, Dr. Keen countered this criticism by pointing out that a recent review of Swedish screening trials had turned up "multiple problems" and that his study findings predicted the results from the most recent AGE trial in England. He also said that the new study's data are derived from American sources and are "therefore more likely accurate for women in the United States."

Challenging a Popular Perception; A Question About Patient Knowledge

The finding that so few (only 4.3%) screen-detected breast cancer cases have their lives saved as a result of screening seems counterintuitive, write the authors. There is a widely held view that breast cancer is a uniformly progressive disease and that it is rarely curable unless caught early, they write. But in reality, breast cancer is a heterogenous disease, and it may be systemic from the start or it may never metastasize, they say.

In effect, this finding about lives saved by mammography challenges "the popular perception that earlier detection through mammography helps most patients with screen-detected breast cancer," write the authors.

In his editorial, Dr. Retsky agrees that the new study findings "defy" some "well-established viewpoints." He also believes that screening has considerable limitations.

"Personally, I am doubtful that imaging-based early detection will ever make dramatic improvements in breast cancer mortality. Rather, I think improved therapies are needed," Dr. Retsky commented to Medscape Oncology.

The limitations of mammography screening make the discussion of the harms all the more important, suggested Dr. Keen.

"Authorities acknowledge that screening-mammography harms include a 30% increase in overdiagnosis and overtreatment, delayed diagnosis, and radiation-induced cancers," write the authors. They also cite a survey that showed that physicians discuss these potential harms only 7% of the time when talking to women before a baseline mammogram (Health Expect. 2008;11:366-375).

However, the American Cancer Society's Dr. Smith believes that women are not uninformed about most of the potential harms of screening mammography.

"The authors imply that women are naive about these harms. They aren't. A study by Schwartz [et al. BMJ. 2000;320:1635-1640] observed that 90% of women said they were fully aware of false-positive mammograms and biopsies, and this awareness remained just as high when women who had experienced a false positive were compared with those who had not," he told Medscape Oncology.

The new study authors suggest that substantial business concerns influence the likelihood that consumers will receive "professional even-handed advice" about the harms and benefits of mammography. "Fundamentally, cancer testing is a business," they write.

Breast radiologists, equipment manufacturers, and advocacy groups all have conflicts of interest arising from financial incentives. "These incentives create the temptation to exaggerate the benefits and dismiss the harms of screening for breast cancer when advertising to the public," the authors write.

SURVEILLANCE FEASIBLE FOR LOW RISK PROSTATE CANCER PATIENTS

Active Surveillance Safe for Men With Low-Risk Prostate Cancer

NEW YORK (Reuters Health) Mar 31 - For selected patients with prostate cancer, active surveillance appears to be safe and is associated with a low risk of systemic progression, researchers report in the April issue of The Journal of Urology.

Despite the potential survival advantages associated with therapy, senior investigator Dr. Bertrand Guillonneau told Reuters Health, "there is still a large number of patients who are over-treated and who will suffer from prolonged side effects that impair their quality of life."

To study the safety of active monitoring of men with low-risk prostate cancer, Dr. Guillonneau of Memorial Sloan-Kettering Cancer Center, New York, and colleagues studied 268 men younger than 75 years old who had been given multiple treatment options but ultimately chose active surveillance.

They had a prostate specific antigen (PSA) level no higher than 10 ng/mL, clinical stage T1-T2a disease, a Gleason score of 6 or lower, and no more than 3 positive cores at diagnostic biopsy.

The subjects had a restaging biopsy immediately before active surveillance began and no treatment in the following 6 months.

Over a median follow-up of 29 months, 43 patients received treatment; 41 of them have no disease progression at a median of 23 months following treatment.

At 2 years the probability of staying on active surveillance was 91%. At 5 years, it was 75%.

Patients with cancer on the second biopsy and a higher total number of cancerous cores were significantly more likely to undergo treatment. Other factors, including age, PSA and clinical stage, were not associated with outcome.

"Active surveillance, based on strict criteria based on repeat prostate biopsy," continued Dr. Guillonneau, "might be a way to sort out patients with growing tumor that requires treatment from quiescent tumor that will not progress."

"Our study indicates that 75% of the patients who are real candidates for active surveillance will still fulfill the same criteria 5 years later, demonstrating the absence of noticeable progression."

"These patients should still be closely monitored," he concluded, "but it seems likely, for many of them, the prostate cancer will not ultimately develop and will not require any kind of active and therefore morbid treatment."

A NEW HEMODIALYSIS TECHNIQUE FOR MM PATIENTS

Novel Hemodialysis Procedure Helps Restore Renal Function in Multiple Myeloma Patients

April 1, 2009 — Extended hemodialysis using a high-cutoff dialyzer (HCO-HD) appears to improve outcomes in multiple myeloma patients with dialysis-dependent renal failure, according to the results of a pilot study published in the April issue of the Clinical Journal of the American Society Nephrology.

Even though it was a small and uncontrolled trial, the data showed that a combination of chemotherapy and HCO-HD improved renal function and overall survival in this population. Previous studies have shown that among multiple myeloma patients with biopsy-proven cast nephropathy and dialysis-dependent renal failure, less than 25% are able to come off of dialysis. In this study, however, 74% of the cohort became independent of dialysis, and patients who recovered renal function had significantly improved survival.

"Historically, these patients have done very badly, and renal failure in the context of multiple myeloma is associated with a greatly reduced survival," said lead author Colin A. Hutchison, MD, from the Department of Nephrology, University Hospital Birmingham, in the United Kingdom. "However, several groups have demonstrated that if renal failure improves, patients live longer. We would expect they will have a higher quality of life as well, especially if they no longer require dialysis."

"The conclusions drawn from our study are limited by the uncontrolled nature of the small population," he told Medscape Oncology. "But the rates are certainly significantly higher than expected from historic populations."

Extended hemodialysis using a HCO-HD is able to remove large amounts of free light chains (FLCs), which are byproducts of intact immunoglobulin synthesis. Under physiologic circumstances, the researchers explain, they are rapidly removed from circulation by renal clearance. The clonal proliferation of plasma cells can result in serum concentrations of monoclonal FLCs that are several thousand times higher than normal in multiple myeloma patients, and the elevated concentrations can result in cast nephropathy. This complication accounts for approximately 70% of dialysis-dependent renal failure in this population.

The researchers point out that plasma exchange has been studied as a method of removing FLCs, but current data have not demonstrated any real clinical benefit. However, data have also suggested that patients with cast nephropathy are more likely to recover renal function if serum FLC concentrations are decreased by at least 50%. Thus far, plasma exchange has not resulted in sustained reductions in serum FLC concentrations.

In this study, Dr. Hutchison and colleagues investigated whether HCO-HD might be an alternate approach to removing FLC concentrations. Their objective was to determine if chemotherapy in combination with FLC removal by HCO-HD would result in a sustained reduction in serum FLCs in multiple myeloma patients with cast nephropathy, and how it would affect renal recovery.

Uninterrupted Chemotherapy Course Essential to Outcome

The open-label study consisted of 19 people with multiple myeloma and dialysis-dependent acute renal failure who were also receiving standard chemotherapy. Of this group, 6 patients had to interrupt their chemotherapy because of complications; therefore, only 13 participants completed 6 weeks of full treatment.

The authors observed sustained early reductions in serum FLC concentrations (median, 85%; range, 50 to 97) in the 13 patients who received an uninterrupted course of chemotherapy, and they became dialysis-independent at a median of 27 days (range, 13 to 120). Only 1 of the patients who received an interrupted course of chemotherapy was able to recover renal function (at 105 days).

Another observation was that the patients who successfully recovered renal function had significantly improved survival, compared with those who did not. The median survival for the patients who received interrupted chemotherapy was 53 days (range, 21 to 331), whereas those who received uninterrupted chemotherapy were alive at a median follow-up of 360 days (range, 150 to 630; P <0.02).

Multicenter Randomized Trial in the Works

The experience reported in this paper and elsewhere has led to the development of a multicenter randomized control trial, known as EuLITE (European Trial of Free Light Chain Removal by Extended Hemodialysis in Cast Nephropathy). Patients are currently being recruited in the United Kingdom, and will be joined by centers in Germany in the coming months, explained Dr. Hutchison. The goal is to recruit 90 patients, which they anticipate will be reached within 18 months.

"Our multinational randomized controlled trial will provide further evidence of the potential benefit of combining FLC removal by dialysis with effective chemotherapy," said Dr. Hutchison.

He also pointed out that changes in medical practice occur gradually, and it is very likely that if the results of EuLITE are positive, they will be replicated by other studies. "Already, a French myeloma group is seeking funding for a study to further investigate the utility of HCO-HD in this setting using a very similar protocol to ours and, in the longer term, I would expect clinicians in North America to undertake a study as well."

"However, as there are no current effective treatments for these patients, it is therefore very likely that, as is happening already, clinicians will treat the patient before them with what they believe to be a logical and beneficial treatment," he told Medscape Oncology.

Currently, high-cutoff hemodialysis is being used to treat multiple myeloma patients across Europe and Australia on a patient-by-patient basis.

CONSOLIDATION WITH THALIDOMIDE

Thalidomide Improves Myeloma Survival After Stem Cell Transplantation

NEW YORK (Reuters Health) Mar 27 - Consolidation therapy with low-dose thalidomide and prednisolone can improve survival in patients with multiple myeloma who have undergone autologous stem-cell transplantation (ASCT), according to a report in the March 9th issue of the Journal of Clinical Oncology.

The addition of thalidomide to the treatment regimen increased 3-year progression-free survival from 23% to 42% (p <>

Thalidomide has proven useful against newly diagnosed and relapsed/refractory multiple myeloma, but its efficacy, if any, in treating patients after ASCT has been unclear, the researchers explain.

To investigate, the authors assessed the survival of 269 patients who received high-dose melphalan conditioned ASCT and were randomized to receive prednisolone maintenance therapy alone or in addition to 12 months of thalidomide consolidation.

In addition to progression-free survival, overall survival at 3 years was also higher in the thalidomide group: 86% vs. 75% in controls (p = 0.004).

Moreover, among subjects who experienced a disease relapse, there was no evidence that prior treatment with thalidomide reduced the efficacy of salvage therapy: 12-month survival rates following relapse were comparable in subjects treated with or without thalidomide consolidation, at 79% and 77%, respectively.

Neurologic adverse effects were more common with thalidomide therapy, whereas no difference in thromboembolic event rates was noted between the treatment groups.

"Based on our findings, we recommend that multiple myeloma patients undergoing an initial single high-dose melphalan conditioned ASCT as part of first-line therapy be offered 12 months of thalidomide consolidation in combination with prednisolone maintenance therapy irrespective of the ASCT response achieved," the authors conclude.

BEVACIZUMAB FOR GLIOBLASTOMA

Bevacizumab in Glioblastoma Approval Recommended

April 2, 2009 — Bevacizumab (Avastin, Genentech/Roche) has been recommended for accelerated approval for use in patients with previously treated glioblastoma by the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC). The FDA is expected to make a decision about the approval by May 5.

The vote for recommending approval was unanimous, with all 10 members agreeing, James Vrendenberg, MD, professor of medicine at Duke University, in Durham, North Carolina, told Medscape Oncology. He expects that the FDA will grant this approval. Bevacizumab is already being used by many clinicians in the United States for previously treated glioblastoma, because this is a setting of urgent medical need in which there are no other beneficial therapies, he said.

This will be an additional indication for the product. Bevacizumab, a monoclonal antibody inhibitor of vascular endothelial growth factor (VEGF), is already approved for use in colorectal, lung, and breast cancer

Dr. Vrendenberg was present at the ODAC meeting as 1 of the investigators of the clinical trial that was being discussed and as a consultant for the manufacturers.

The clinical data presented at the meeting came from a phase 2 trial that had no comparator group, but the results were significantly better than have been seen with historic controls, and the response rate was 4 times higher "than has ever been seen," Dr. Vrendenberg noted. Previous studies have investigated irinotecan, lomustine, etoposide, and other drugs, he said. The response rate was defined as a decrease in tumor size by at least 50% on 2 consecutive independent assessments at least 4 weeks apart.

"All the data went in the same direction of benefit," he continued. The results for 6-month progression-free survival, overall survival, and discontinuation of steroids were all significantly better than historic controls, so there was a "clear story of benefit," he added.

The study, known as BRAIN, was conducted in 167 patients with previously treated glioblastoma and, "when it was being designed, we felt it was immoral to have a comparator arm that would be ineffective," Dr. Vrendenberg said. That group would have been irinotecan alone, but there had already been several studies suggesting that bevacizumab is effective in this patient population. Hence, the study offered patients either bevacizumab alone (n = 85 patients) or bevacizumab in combination with irinotecan.

These patients had previously been treated with radiation and temozolomide (Temodar, Schering-Plough), which is the established standard therapy for newly diagnosed glioblastoma. This is the setting in which 2 new trials are exploring whether the addition of bevacizumab can improve outcomes. Both are phase 3 trials, with results expected in about 2014.

"Bevacizumab is a major step for the brain tumor community, and takes advantage of glioma biology to treat it more effectively," Dr. Vrendenberg commented.

Gliomas are very dependent on VEGF, he explained. "So this is the 1 tumor — in addition to renal cell carcinoma — in which you would predict that VEGF inhibitors would work well and other treatments would not work well. And that's what we have found; it has just taken a long time to test it."

"I also think this is just the beginning," he added. "There are some very exciting clinical trials and there is hope for better survival for brain tumor patients."

A NEW DRUG APPROVED FOR RENAL CANCER (AFINITOR)-BEWARE OF PNEUMONITIS

Everolimus (Afinitor) Approved for Refractory Renal Cell Carcinoma

On March 30, the FDA approved everolimus 5- and 10-mg tablets (Afinitor, Novartis Pharmaceuticals Corp) for the treatment of advanced renal cell carcinoma after failure of treatment with sunitinib (Sutent, Pfizer, Inc) or sorafenib (Nexavar, Bayer Healthcare AG).

Everolimus potently inhibits the molecular target of rapamycin, a critical downstream effector of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, thereby inhibiting cell cycle progression, cell growth, and proliferation.

"This approval provides a new and useful tool for treating advanced renal cell carcinoma, representing an important step forward in managing this disease," said Robert J. Motzer, MD, in a company news release. "New treatment options are vital to help us continue to offer patients with advanced kidney cancer new ways to battle their difficult-to-treat disease. Based on clinical trial data, this option should be considered when sunitinib or sorafenib fail."

Dr. Motzer is an attending physician at Memorial Sloan-Kettering Cancer Center in New York and principal investigator of the Renal Cell Cancer Treatment With Oral RAD001 Given Daily trial (n = 416), which served as the basis for the FDA's approval.

Results of the study showed that treatment with 10 mg/day everolimus more than doubled the time to tumor growth or to death (4.9 vs 1.9 months) and decreased the risk for disease or death by 67% (hazard ratio = 0.33; 95% confidence interval [CI], 0.25 – 0.43, P < .0001). After 10 months of treatment, about 25% of patients still had no tumor growth.

The most frequently reported adverse events related to treatment with everolimus (incidence ≥ 20%) were stomatitis, asthenia, diarrhea, poor appetite, fluid buildup in the extremities, dyspnea, coughing, nausea, vomiting, rash, and fever.

Laboratory tests of blood samples determined that 50% or more patients experienced anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine levels. Renal function, blood glucose, lipids, and hematological parameters should be evaluated before initiating treatment with everolimus and periodically thereafter.

Potentially serious adverse reactions include noninfectious pneumonitis and infections for which patients should be monitored carefully and treated as needed, the FDA warns, noting that temporary dose reductions and/or interruption or discontinuation of therapy may be warranted. Live vaccinations and close contact with those who have received live vaccines should be avoided during treatment with everolimus.

Concomitant use of strong or moderate CYP3A4 or P-glycoprotein inhibitors should be avoided in patients receiving everolimus therapy; dose increases are recommended for coadministered strong CYP3A4 inducers.

Everolimus, marketed as Certican (Novartis Pharmaceuticals), previously was approved in the European Union for the prevention of organ rejection in heart and kidney transplant recipients. Applications currently under investigation in phase 3 trials include multiple cancer types (neuroendocrine, breast, and gastric), tuberous sclerosis complex, and non-Hodgkin's lymphoma.

Sunitinib and sorafenib are multiple kinase inhibitors indicated for the primary treatment of advanced renal cell carcinoma; sunitinib is also approved to treat gastrointestinal stromal tumors, and sorafenib may be used for unresectable hepatocellular carcinoma.

AVASTIN RESTRICTION REMOVED

Roche Says Avastin Restriction Removed

ZURICH (Reuters) Mar 31 - Swiss drugmaker Roche Holding AG said the European Medicines Agency has removed a restriction on the label that prevented the use of Avastin in some patients whose cancer had spread to their brain.

Roche said the agency made its decision following a review of a number of analyses from clinical trials, as well as a safety database generated through use of Avastin over more than a decade.

Avastin is approved for the treatment of advanced-stage colorectal cancer, breast cancer, lung cancer and renal cell cancer.

NO USE OF GEFITINIB FOR HEAD AND NECK CANCER

Gefitinib of No Benefit in Recurrent Squamous Cell Carcinoma of Head and Neck

NEW YORK (Reuters Health) Mar 27 - Compared with methotrexate, gefitinib does not improve survival in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN), according to a report published online by the Journal of Clinical Oncology on March 16th.

"I was surprised at the lack of a survival advantage of this new agent compared to methotrexate," lead author Dr. J. Simon W. Stewart from Imperial College Healthcare NHS Trust, London, UK told Reuters Health. "I had assumed that gefitinib would have a tumor-static effect as well as a mild response rate."

Dr. Stewart and an international team compared the efficacy and safety of gefitinib (250 or 500 mg/day orally) versus intravenous methotrexate (40 mg/m2 weekly) in 486 patients with recurrent SCCHN.

At a median follow-up of 6.2 months, the authors report, overall mortality was 78.6%, with no significant difference in survival between treatment arms.

In patients with platinum-resistant disease, outcomes appeared superior in the methotrexate treatment group. Among patients not suited for platinum chemotherapy, there was no difference in the results of the treatments.

Tumor response, quality of life improvement rates, and symptom improvement rates did not differ significantly among the treatment groups, the researchers note.

Similarly, results did not differ between treatment groups when patients were analyzed according to the presence of epidermal growth factor receptor (EFGR) gene copy number or protein expression.

Tumor hemorrhage-type events were more common in the gefitinib treatment groups than in the methotrexate group, the investigators say, but interstitial lung disease events occurred with similar frequency in the 3 study arms.

"There is no evidence that gefitinib has a place in the routine treatment of SCCHN," Dr. Stewart stated.

BEWARE OF FOOD SUPPLEMENTS

Long-Term Use of High-Dose Carotenoid Supplements Tied to Lung Cancer Risk

NEW YORK (Reuters Health) Mar 26 - Extended use of individual beta-carotene, retinol, and lutein supplements, at doses higher than in multivitamins, increases lung cancer risk, according to data from the Vitamins and Lifestyle (VITAL) prospective cohort study.

High-dose beta-carotene supplements increase lung cancer rates in high-risk individuals, even though carotenoids from dietary sources tend to lower risk, Dr. Jessie A. Satia and co-researchers note in the April 1 issue of the American Journal of Epidemiology. "Whether effects are similar in the general population is unclear."

The researchers analyzed data from 77,126 subjects ages 50 to 76 who filled out questionnaires in 2000-2002 regarding supplement use over the previous decade. The cohort was predominantly white and generally healthy, the authors note, and while there were few never-smokers among the lung cancer cases, there were fewer current smokers in the overall cohort than in the general population.

By linking to the SEER cancer registry, Dr. Satia, at the University of North Carolina at Chapel Hill, and her team identified 521 incident lung cancer cases. They estimated hazard ratios (HRs) for individual supplements after adjusting for age, gender, and smoking history.

For beta-carotene used for at least 4 years, the HRs for total lung cancer and for small-cell lung cancer were 1.18 (p = NS) and 3.22 (p = 0.01).

For retinol, the HR for total lung cancer was 1.53 (p = 0.02). For non-small-cell lung cancer, it was 1.80 (p = 0.002). For lutein, corresponding HRs were 2.02 (p = 0.006) and 2.48 (p = 0.01).

The researchers speculate that "1) these nutrients from supplements may be more bioavailable than those from dietary sources; 2) large intakes may interfere with absorption, transport, and distribution and/or metabolism of other carotenoids or micronutrients that could have offered significant protection; and 3) too high a dose of an antioxidant vitamin may interfere with generation of reactive oxygen species needed for beneficial processes, such as normal immune response and apoptosis."

They conclude: "Long-term use of individual beta-carotene, retinol, and lutein supplements should not be recommended for lung cancer prevention, particularly among smokers."

PARASKEYOPOULOS SPEAKING

Anticancer Res. 2009 Feb;29(2):667-70.

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A phase II trial of oral vinorelbine and capecitabine in anthracycline pretreated patients with metastatic breast cancer.

Finek J, Holubec L Jr, Svoboda T, Sefrhansova L, Pavlikova I, Votavova M, Sediva M, Filip S, Kozevnikova R, Kormunda S.

University Hospital Pilsen, Czech Republic. finek@fnplzen.cz

BACKGROUND: Optimal chemotherapy (CT) for advanced breast treatment should be effective, well tolerated and convenient. In this study the efficacy and safety of the fully oral combination of oral vinorelbine (Navelbine Oral) plus capecitabine (Xeloda) in metastatic breast cancer (MBC) patients pretreated with anthracycline, was evaluated. PATIENTS AND METHODS: In this phase II multicenter study, this combination CT was given as a first- or second-line therapy for MBC. The treatment schedule was: oral vinorelbine 60 mg/m2 day 1 and day 8 plus capecitabine 1,000 mg/m2 twice daily from day 1 to day 14, every 21 days. RESULTS: One hundred and fifteen patients were included in this trial. The median age was 58 years (range: 40-75). All the patients had received prior anthracycline-based chemotherapy. The combination was well tolerated, with, in particular, only 0.8% of patients presenting with febrile neutropenia. In the intention-to-treat (ITT) population, an objective response was achieved in 65 patients (56.5%). A complete response was achieved in 22 patients (19.1%); partial response in 43 patients (37.4%); stable disease in 36 patients (31.3%), and progressive disease was observed in 14 patients (12.2%). After a median follow-up of 10.0 months, the median progression-free survival (PFS) was 10.5 months and the median survival was 17.5 months. CONCLUSION: Oral vinorelbine-capecitabine shows very promising activity and low toxicity in MBC treatment, with high compliance of the patients.

WHY NOT DCF?

Anticancer Res. 2009 Feb;29(2):529-38.

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Induction chemotherapy with docetaxel and cisplatin followed by concomitant chemoradiotherapy in patients with inoperable non-nasopharyngeal carcinoma of the head and neck.

Fountzilas G, Bamias A, Kalogera-Fountzila A, Karayannopoulou G, Bobos M, Athanassiou E, Kalogeras KT, Tolis C, Tsekeris P, Papakostas P, Vamvouka C, Zaramboukas T, Kosmidis P, Zamboglou N, Misailidou D.

Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. fountzil@med.auth.gr

BACKGROUND: Induction chemotherapy (IC) followed by concomitant chemoradiotherapy (CCRT) has the potential of being an ideal multi-modality approach for improving the prognosis of patients with squamous cell carcinoma of the head and neck (SSCHN). PATIENTS AND METHODS: Thirty-four patients with locally advanced SCCHN were treated with 3 cycles of IC, consisting of docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks, followed 3-4 weeks later by definitive radiotherapy (70 Gy) and concomitant weekly cisplatin 40 mg/m2. RESULTS: After a median follow-up of 27.7 months, 6-month progression-free survival (PFS), the primary study end-point, was 84%. The median PFS was 16.4 months and median overall survival 24.4 months. The majority of the patients completed 3 cycles to moderate toxicity. Anemia, nausea/vomiting and mucositis were the prominent toxicities during CCRT. Retrospective analysis of a panel of biomarkers suggested that excision repair cross-complementation group 1 (ERCC1) protein expression was associated with shorter PFS. CONCLUSION: IC followed by CCRT, as administered in the present study, is a feasible and well-tolerated therapeutic approach. However, its real impact on the prognosis of SCCHN patients has to be demonstrated in a randomized study comparing this treatment to CCRT alone.

PUT EVERYTHING TOGETHER AND YOU GET A NICE SOUP

Anticancer Res. 2009 Feb;29(2):769-75.

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Combination chemotherapy with docetaxel, vinorelbine and estramustine phosphate in metastatic androgen-resistant prostate cancer: a single institution experience.

Pectasides D, Pectasides E, Papaxoinis G, Koumarianou A, Psyrri A, Xiros N, Tountas N, Kamposioras K, Papatsibas G, Floros T, Gouveris P, Karageorgopoulou S, Economopoulos T.

Second Department of Internal Medicine, Propaedeutic, Oncology Section, University of Athens, Attikon University Hospital, Haidari, Athens, Greece. pectasid@otenet.gr

The aim of this study was to evaluate the activity and toxicity of docetaxel, vinorelbine and oral estramustine in androgen-resistant prostate cancer (ARPC). PATIENTS AND METHODS: Fifty-two eligible patients were treated with docetaxel at 30 mg/m2 (day 1 and 8), vinorelbine at 20 mg/m2 (day 1 and 8), and oral estramustine of 280 mg p.o. (daily on days 1 to 7) every 3 weeks for 12 cycles. Patients with osseous metastases received zoledronic acid of 4 mg every 3 weeks. Low molecular weight heparin was administered on a prophylaxis basis to all patients. RESULTS: A prostate-specific antigen (PSA) response > or = 50% from baseline was obtained in 29 (56%; 95% confidence interval [CI], 42-70%) patients. Objective responses among the 25 patients with measurable disease were observed in 48% (95% CI, 27-69%), including 1 patient with complete response (CR) and 11 patients with partial response (PR). Patients with extraosseous only, skeletal only, and extraosseous and skeletal metastases showed different PSA responses (87% vs. 44% vs. 59%, respectively, p = 0.094). Furthermore, patients with soft tissue disease only showed insignificantly better PSA response than those with skeletal metastases (response rate: 87% vs. 50%, p = 0.064). The median progression-free survival was 7.6 months (95% CI, 6.7-8.4 months) and the median overall survival was 18.2 months (95% CI, 15.5-20.8 months). The only parameters which were found to have an impact on survival were the extent of disease and the baseline levels of PSA. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 33% of patients and 6% experienced febrile neutropenia. Anemia and thrombocytopenia grade 3 or 4 were not a problem. Three patients (6%) developed grade 3 sensory neuropathy and 2 patients (4%) developed grade 3 fatigue. Edema grade 3 occurred in 1 (2%) patient and thromboembolism grade 3 occurred in 2 (4%) patients. CONCLUSION: The combination of docetaxel, vinorelbine and oral estramustine is a well-tolerated regimen with high biochemical and objective response rates in patients with ARPC.

BONADONNA LIVES

1: J Clin Oncol. 2009 Mar 30. [Epub ahead of print]

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Phase III Trial Evaluating the Addition of Paclitaxel to Doxorubicin Followed by Cyclophosphamide, Methotrexate, and Fluorouracil, as Adjuvant or Primary Systemic Therapy: European Cooperative Trial in Operable Breast Cancer.

Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G.

Fondazione IRCCS Istituto Nazionale Tumori, Milan; Ospedale Universitario Santa Maria della Misericordia, Udine, Italy; Hospital Vall d'Hebron and Hospital de San Pau, Barcelona; Istituto Valenciano de Oncologia and Hospital Clinico Universitario de Valencia, Valencia, Spain; Frauenklinik vom Roten Kreuz, Munich, Germany; N.N. Petrov Research Institute of Oncology, St Petersburg; and the N.A. Semashko Central Clinical Hospital, Moscow, Russia.

PURPOSE: To evaluate the addition of paclitaxel to an anthracycline-based adjuvant regimen and to compare this combination with the same regimen given as primary systemic (neoadjuvant) therapy. PATIENTS AND METHODS: A total of 1,355 women with operable breast cancer were randomly assigned to one of three treatments: surgery followed by adjuvant doxorubicin (75 mg/m(2)) followed by cyclophosphamide, methotrexate, and fluorouracil (CMF; arm A); surgery followed by adjuvant paclitaxel (200 mg/m(2)) plus doxorubicin (60 mg/m(2)), followed by CMF (arm B); or paclitaxel (200 mg/m(2)) plus doxorubicin (60 mg/m(2)) followed by CMF followed by surgery (arm C). The two coprimary objectives were to assess the effects on relapse-free survival (RFS) of the addition of paclitaxel to postoperative chemotherapy (arm B v arm A) and primary chemotherapy versus adjuvant chemotherapy (arm B v arm C). RESULTS: Doxorubicin plus paclitaxel followed by CMF was well-tolerated as adjuvant or as primary chemotherapy. The addition of paclitaxel to adjuvant doxorubicin followed by CMF significantly improved RFS compared with adjuvant doxorubicin alone followed by CMF (hazard ratio [HR], 0.73; P = .03). Distant RFS was similarly improved (HR, 0.70; P = .027). There was no significant difference in RFS when the paclitaxel/doxorubicin/CMF chemotherapy was given before surgery compared with the same regimen given after surgery (HR, 1.21; P = .18). However, the rate of breast-conserving surgery was significantly higher with preoperative chemotherapy (63% v 34%; P < .001). CONCLUSION: Incorporating paclitaxel into anthracycline-based adjuvant therapy resulted in a significant improvement in RFS and distant RFS. When given as primary systemic therapy, the paclitaxel-containing regimen allowed breast-sparing surgery in a significant percentage of patients.

ΤΗΝ ΕΠΟΜΕΝΗ ΕΒΔΟΜΑΔΑ ΘΑ ΣΤΑΛΕΙ ΚΑΙ Η ΕΓΚΥΚΛΙΟΣ

Παρασκευή, 3 Απρίλιος 2009

Τα νέα μαντάτα από τη συνάντηση ΟΕΝΓΕ - ΥΥΚΑ

Οι απαντήσεις που δόθηκαν

Η ερμηνευτική εγκύκλιος είναι ήδη γραμμένη από τις υπηρεσίες του Υπουργείου και πρόκειται εντός της εβδομάδος να αποσταλεί στα Νοσοκομεία. Η ΟΕΝΓΕ έκανε παρατηρήσεις σε αρκετά σημεία, ώστε να διασφαλίζεται η σαφήνεια. Πχ στο θέμα του ρεπό η τελική διατύπωση είναι «καθιερώνεται 24ωρη ανάπαυση, η οποία δίδεται σε κάθε γιατρό, ειδικευμένο ή ειδικευόμενο, μέσα σε μία εβδομάδα μετά την πραγματοποίηση ενεργού εφημερίας».

Μέσω της εγκυκλίου επιβάλλεται στις Διοικήσεις η άμεση εφαρμογή όλων των διατάξεων του νόμου και στα λογιστήρια των Νοσοκομείων η ενημέρωση των προγραμμάτων μισθοδοσίας με τους νέους Βασικούς Μισθούς και όσα αυτοί συμπαρασύρουν.

Μια δεύτερη εγκύκλιος θα απευθύνεται στις ΥΠΕ, οι οποίες πρέπει να συντάξουν άμεσα καταλόγους ανά ειδικότητα, από τους οποίους θα γίνει η κλήρωση μελών στα Συμβούλια Κρίσεων.

Για το πλαφόν έχουν γίνει συζητήσεις ανάμεσα στα Υπουργεία Υγείας και Οικονομικών και προσανατολίζονται σε ρύθμιση από πλευράς Υπουργείου Οικονομικών η οποία θα ανεβάζει το πλαφόν στα 7854 ευρώ. Από πλευράς μας ζητήθηκε η ρύθμιση να ισχύσει αναδρομικά από 1-1-09. Πάντως είναι άγνωστο πότε θα δημοσιευτεί το νέο πλαφόν.

Για τα κονδύλια εφημεριών ενημερωθήκαμε ότι έχει συνταχθεί Υπουργική Απόφαση από το Υπουργείο Υγείας και βρίσκεται στο Υπουργείο Οικονομικών για προσυπογραφή, ώστε στη συνέχεια να προωθηθεί για δημοσίευση σε ΦΕΚ. Θα χορηγεί κονδύλια για ένα τετράμηνο και αργότερα θα εκδοθεί συμπληρωματική για το υπόλοιπο του έτους. Επίσης ενημερωθήκαμε ότι ζητήθηκαν επιπλέον των 350 εκατ. ευρώ που είναι τα εγγεγραμμένα στον προϋπολογισμό του 2009 ως κονδύλια εφημεριών άλλα 80 εκατ. ευρώ, ώστε να καλυφθούν οι διαφορές που προκύπτουν από το νέο μισθολόγιο.

Στη συγκρότηση της Επιτροπής Προσλήψεων έχουν προταθεί 6 μέλη από πλευράς ΟΕΝΓΕ και υπήρξε δέσμευση ότι εντός της εβδομάδος θα συμπληρωθούν τα μέλη που προτείνει το Υπουργείο, ώστε να γίνει η πρώτη συνεδρίαση τη Μεγάλη Εβδομάδα.
Τέλος για το επίδομα τροφής ειπώθηκε ότι στο νομοσχέδιο-σκούπα που πρόκειται να κατατεθεί σύντομα έχει περιληφθεί διάταξη, η οποία αναφέρει ότι το χορηγούμενο επίδομα καλώς εχορηγείτο από το 2003 έως σήμερα και η χορήγησή του θα συνεχιστεί.

INCREASE IN CANCER SURVIVAL IN EUROPE BUT STILL SURVIVAL IS BETTER IN USA

European Data Show Increase in Proportion of "Cured" Cancer Patients

April 1, 2009 — Although large differences in cancer survival remain among individual European countries, the overall data for Europe show that the number of patients who are considered "cured" is rising steadily.

This trend emerges from 1 of the latest analyses carried out by the EUROCARE (European Cancer Registry-Based Study of Cancer Patients' Survival and Care)-4 Working Group, and detailed in a paper appearing in the special April issue of the European Journal of Cancer. In an accompanying commentary, the working group also suggests that cancer care in Europe is comparable to that in the United States, despite statistics showing lower survival rates.

EUROCARE began in the early 1990s, and has published results on cancer survival periodically since 1995. Initially funded by the European Community, the project is now funded by the Italian Compagnia di San Paolo Foundation.

This latest version of the study, EUROCARE-4, is based on records of more than 13,500,000 cancer patients diagnosed from 1978 to 2002. Preliminary cancer survival data were published in 2007, but like the conclusions from the earlier EUROCARE studies, these survival statistics were based on cancer patients who were still alive 5 years after diagnosis.

However, these classic survival indicators do not distinguish between patients who are cured (and thus have a life expectancy close to the rest of the population) and those who will die of their disease, the authors of the new analysis explain. Another shortcoming is that this classic approach does not account for so-called lead-time bias, where there is an earlier diagnosis of the disease but no improvement in life expectancy.

To overcome these drawbacks, the authors performed a new analysis, based on a parametric-cure model. Cancer patients were divided into 2 groups: those who were expected to die from their disease, and those who were considered "cured" and likely to die from another cause.

This new analysis compared data for the periods 1988 to 1990 and 1997 to 1999, and shows increases in the proportion of patients who were considered cured. For lung cancer, this proportion rose from 6% to 8%, for stomach cancer the jump was from 15% to 18%, and for colorectal cancer, the increase was from 42% to 49%.

These increases are "noteworthy," says Richard Capocaccia, MD, from the National Center for Epidemiology, Surveillance and Health Promotion, in Rome, Italy. Dr. Capocaccia was a key member of the EUROCARE-4 working group, and is a guest editor of the special issue of the Journal.

The proportion of patients cured is not affected by the lead time, so "these trends suggest genuine progress in cancer control," he said in a statement.

However, there was a wide variation in the proportion of patients cured in individual European countries. For instance, the figures for 1988 to 1999 show that for lung cancer less than 5% of patients were cured in Denmark, the Czech Republic, and Poland, whereas more than 10% of patients were cured in Spain. For colorectal cancer, the best cure rate (49%) was seen in France, whereas the worst cure rates (<30%)>

The very wide range in the proportion of patients cured in the contributing countries depends, to some extent, on the varying frequencies across Europe of these different cancers, Dr. Capocaccia commented. "This proportion is, therefore, also an indicator of Europe-wide variations in cancer control, because it reflects the progress in diagnosis and treatment, as well as success in the prevention of the most fatal cancers," he said.

Wide Variation Across European Countries

This wide variation across the individual countries of Europe has been a recurring theme of all of the EUROCARE reports, and these statistics have been used as ammunition by critics of healthcare systems.

Such criticism has been particularly fierce in the United Kingdom, which comes out badly in these studies, showing cancer survival rates that are among the worst in Europe. Highly vocal critics, including a leading medical oncologist, have said these statistics show that the UK National Health System is inefficient at managing cancer, and that the National Cancer Plan has not improved matters much, as recently reported by Medscape Oncology.

New data in these latest reports from EUROCARE-4 will add fuel to this fire. In 1 of the new analyses, the authors consider cancer survival rates alongside each country's per capita total national expenditure on health, and found that there was "moderate correlation" between these 2 factors.

However, there were notable exceptions; Denmark and the United Kingdom had lower survival rates than countries with similar spending on healthcare, the authors note. In addition, it is noteworthy that Switzerland has very similar rates to Sweden, but at a much higher cost, suggesting that cost-effectiveness could be improved in Switzerland, the authors note.

Denmark is an anomaly among the Nordic countries. The authors note that Iceland, Norway, Sweden, and Finland are characterized by "excellent overall cancer survival, while Denmark has much worse survival, and the difference can only be partly explained by differences in case mix."

Finland had better survival than expected from its moderate health expenditure, suggesting effective health management, the authors comment. Spain, Italy, and Portugal also had better survival than countries with comparable spending, but the authors caution that the cancer registries in these countries were incomplete, and survival in the areas covered may not reflect those of the whole country. In particular, in Italy, survival is significantly better in the wealthy north than in the poorer south — a finding that was reported by the Italian newspaper L'Espresso as "only miracles can save cancer patients in southern Italy," they note.

Eastern European countries have the lowest healthcare expenditure and also the lowest cancer survival rates. The relative excess risk for death is 28% higher in eastern Europe than in central Europe, the authors note.

New Data Show "Reduction in Disparities"

In an editorial comment, Franco Berrino, MD, from the Istituto Nazionale die Tumori, in Milan Italy, and colleagues from the EUROCARE-4 working group provide some context for the new findings.

The first of the reports, EUROCARE-1 (published in 1995), revealed dramatic between-country differences, with low rates in eastern Europe, intermediate rates in Denmark and the United Kingdom, and high rates in the other western European populations. The 2 subsequent studies broadly confirmed these findings, but also suggested that, across Europe, the survival differences may be widening, the group notes. "However, time-trend analyses presented in the current EUROCARE-4 monograph, which includes cases diagnosed up to 1999, clearly indicate a narrowing of survival differences, with absolute improvements greater for countries with low survival in the past than for countries where survival was already high," they write.

This point was emphasized by Alexander Eggermont, MD, PhD, president of the European Cancer Organization, who commented on the latest report in a statement.

"The good news is that, for most cancers, survival increased during the 1980s and 1990s," Dr. Eggermont said. "Most of the largest increases in survival occurred in countries where survival was low at first, and this has contributed to a reduction in the disparities in survival across Europe."

How Does Europe Compare With United States?

"European patients need to know that there is no particular reason to think that cancer treatment in the United States is better than can be obtained in Europe," say Dr. Berrino and colleagues. Although the statistics show better cancer survival rates in the United States than in Europe, the group analyzes and dissects the data, and suggests that the differences may be smaller than they at first appear.

For all cancers combined, 5-year survival estimates for 2000 to 2002 were much higher for the American patients monitored by the 14 cancer registries in the SEER program than in the 47 cancer registries included in the EUROCARE survival analysis, the group notes. The figures were 66.3% vs 47.3% for men and 62.9% vs 55.8% for women.

However, the huge difference for men was largely due to the lower incidence of rapidly fatal cancers (mainly lung and stomach), and the exceptionally high incidence and survival for prostate cancers in the United States were largely attributable to overdiagnosis, Dr. Berrino and colleagues state. After excluding prostate cancer, the difference between the United States and Europe for men is halved (46.9% vs 38.1%), although the survival rate remains better in the United States.

In addition, the authors note that although breast cancer survival has been reported as being significantly higher in the United States than in Europe, a comparative study found that differences in age, stage at diagnosis, and number of lymph nodes evaluated explained most of the excess risk for European patients, indicating that the problem is later diagnosis, rather than less effective treatments (Cancer. 2004;100:715-722).

When cancer was considered by specific site, nearly all of the sites showed a higher average survival rate in the United States than in Europe, the authors comment. The exceptions were cancers of the stomach and testes, Hodgkin's disease, and acute myeloid leukemia, for which survival rates were better in Europe. Nonetheless, for most cancer sites — but not prostate or colon — American "survival was within the range of European countries," the group comments.

"It is also important to stress than in both Europe and the Untied States, there are large survival differences between the rich and the poor," Dr. Berrino and colleagues note.

EMEA APPROVES ADJUVANT IMATINIB FOR HIGH RISK GIST

New treatment option for imatinib

26.03.09

Category: Scientific News

EMEA approves imatinib for patients at high risk of relapse following GIST resection

At its meeting on 16–19 March 2009, the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use gave a positive opinion on an application to extend the indication of imatinib to include the adjuvant treatment of adult patients who are at significant risk of relapse following resection of Kit (CD117) positive gastrointestinal stromal tumors (GIST). Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.

18% GRADE 3-4 PNEUMONITIS?

A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer.

Department of Internal Medicine, Division of Oncology, The University of Texas Health Medical School, Memorial Hermann Cancer Center, Houston, Texas.

BACKGROUND:: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, affects tumor growth by blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. mTOR inhibitors and agents with primarily antiangiogenic activity have been shown to have efficacy in renal cell cancer (RCC). This phase 2 study assessed the efficacy of daily oral dosing with everolimus in patients with RCC. METHODS:: Patients had confirmed predominantly clear cell RCC; had received