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.

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

PRELOAD WITH STATIN BEFORE PCI

ACC 2009: Studies Support Statin Preloading, Even a Statin Reload, Prior to PCI

April 1, 2009 (Orlando, Florida) — Two new Italian studies presented Monday during the i2 Summit at the American College of Cardiology 2009 Scientific Sessions point to the benefit of pretreating patients undergoing PCI with statin therapy. One study even suggests that patients already receiving the lipid-lowering medications receive cardioprotective benefit with an additional statin boost prior to the procedure.

"The statin-naive patient population is disappearing," said lead investigator Dr Germano Di Sciascio (Campus Bio-Medico University, Rome, Italy) during a press conference announcing the results of the Atorvastatin for Reduction of Myocardial Damage During Angioplasty-Acute Coronary Syndromes (ARMYDA) RECAPTURE study. "They are an endangered species. The large majority of patients who come to the lab are on statins. In our group, about 70% of patients coming to the lab are on statins. We wanted to test the hypothesis that an acute reload of atorvastatin in those patients on chronic therapy would have the same cardioprotective effect during PCI."

In ARYMDA-RECAPTURE, investigators showed that atorvastatin 80 mg given to statin-treated patients 12 hours prior to PCI, followed by 40 mg just before the procedure, reduced the risk of major adverse coronary events, specifically the risk of MI at 30 days.

Similarly, in the Novel Approaches for Preventing or Limiting Events (NAPLES) II study, investigators, led by Dr Carlo Briguori (Clinica Mediterranea, Naples, Italy), showed that atorvastatin 80 mg loaded 24 hours prior to PCI in statin-naive patients reduced the incidence of periprocedural MI.

Results in Line With Previous ARMYDA Studies

Presenting the results during a morning press conference, Di Sciascio pointed out that the ARMYDA investigators have conducted two prior studies, both reported by heartwire, showing the benefit of statin therapy in patients undergoing PCI.

In ARMYDA-ACS, statin-naive patients with non-ST-segment-elevation acute coronary syndrome were randomized to pretreatment with atorvastatin, and this treatment reduced the risk of adverse events, primarily postprocedural MI at 30 days. An earlier study showed that pretreatment could reduce the risk of myocardial damage after PCI in unstable patients.

In ARMYDA-RECAPTURE, investigators randomized 352 patients with stable angina and non-ST-segment-elevation acute coronary syndrome to the atorvastatin "reload" arm or to placebo. All patients were pretreated with statin therapy, but the reload patients received 80 mg of atorvastatin 12 hours prior to PCI, followed by an additional 40 mg before the procedure. All patients were treated with atorvastatin 40 mg after PCI.

At 30 days, the rate of major adverse cardiac events, a composite of cardiac death, MI, and target vessel revascularization, was significantly lower among patients reloaded with atorvastatin prior to PCI. This benefit was primarily driven by a significant reduction in the incidence of periprocedural MI (3.4% vs 8.6%).

ARMYDA-RECAPTURE: Primary End Point and Secondary End Points at 30 Days

End point	Atorvastatin (n=177)	Placebo (n=175)	p
Major adverse cardiac events	3.4	9.1	0.045
Creatinine kinase-MB (% of patients with elevations 3xULN)	13	23	0.023
Troponin I (% of patients with elevations 3xULN	36	47	0.032

ULN=upper limit of normal

Discussing the results with the media, Di Sciascio said that patients with acute coronary syndrome on admission, and not patients with stable angina, were the primary benefactors of statin therapy. There was only a trend toward reduced major adverse events among those with stable angina, whereas the incidence of adverse events declined to 2.4% among those with acute coronary syndrome, which translated into a relative risk reduction of 87% compared with placebo.

As far as mechanisms are concerned, we can discuss these until we are blue in the face.

"As far as mechanisms are concerned, we can discuss these until we are blue in the face," said Di Sciascio, adding that he believes the mechanism to be independent of LDL lowering. Regardless of how the drugs work, Di Sciascio said, the data, if confirmed in other, larger studies, has the potential to change clinical practice. Specifically, statins might even be administered on first medical contact, not unlike aspirin or clopidogrel.

"I believe in moving very upstream with statin therapy," he said.

Commenting on the results of the study during the late-breaking clinical-trials session, Dr Robert Harrington (Duke Clinical Research Institute, Durham, NC) said the trial is small but important, as it addresses the clinical problem that when clinicians intervene in the coronary artery, they unleash an inflammatory cascade that has the potential to turn into downstream events. However, confirmation of the benefits in larger trials is needed before clinicians start initiating the statin boost prior to PCI. Harrington noted, however, there is a relationship between long-term mortality and myocardial necrosis.

NAPLES II

In NAPLES II, researchers studied whether a high loading dose of atorvastatin given in the 24 hours before an intervention would provide protection against periprocedural MI. In total, 668 statin-naive patients scheduled for elective PCI were randomized to atorvastatin 80 mg or placebo. At 30 days, treatment with atorvastatin significantly reduced the risk of periprocedural MI as defined by elevations of creatine kinase myocardial enzyme (CK-MB) and cardiac troponin I.

NAPLES II: Primary End Point 30 Days

End point	Atorvastatin (n=338)	Placebo (n=330)	p
Creatine kinase-MB (% of patients with elevations 3xULN)	9.5	15.8	0.014
Troponin-I (% of patients with elevations 3xULN)	26.6	39.1	<0.001>

ULN=upper limit of normal

Discussing the results of NAPLES II during the late-breaking clinical trials session, Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA) said that one of the surprises of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study was the early separation of event curves, as early as 14 days, which suggested that high-dose atorvastatin might be beneficial in ACS patients beyond LDL lowering. ACC 2009: Studies Support Statin Preloading, Even a Statin Reload, Prior to PCI

Later studies, including the most recent JUPITER analysis, have suggested that pleiotropic effects, specifically anti-inflammatory effects, are responsible for some of the drug's benefit.

"I think we have now seen a shift where this is probably ready for prime time in our practice, such that the early benefit observed in PROVE-IT, linked to the anti-inflammatory effects of statins, now is shifting into the cath lab," said Cannon. "We're now talking about statin pretreatment as something that will possibly influence the outcomes of PCI."

In practice, said Cannon, clinicians should start intensive statin therapy in acute coronary syndrome patients on hospital admission and potentially the night prior to the procedure in elective PCI. During a discussion of the results following the late-breaking clinical-trials session, others were more cautious and focused on the definition of periprocedural MI and whether these enzyme elevations translate into clinical significance, particularly elevations in troponin I, which is considered a sensitive marker.

AN INTERESTING NON-TOXIC REGIMEN!!!

Lung Cancer. 2009 Mar 23. [Epub ahead of print]

Related Articles, LinkOut

Topotecan-carboplatin-etoposide combination as 1st line treatment in patients with small cell lung cancer.

Zarogoulidis K, Mylonaki E, Kakavelas P, Zarogoulidis P, Tsiouda T, Rapti E, Lithoxopoulou H, Zarogoulidou V, Kontakiotis T; Hellenic Pulmonary Oncology Study Group (HE.P.O.G.).

Lung Tumour Research Section, University Pulmonary Clinic, Aristotle Univ. of Thessaloniki, G. Papanicolaou Hospital, Greece.

PURPOSE: To test toxicity, tolerability, time to progression, survival and response rate in the 3-day administration of topotecan (T) followed by carboplatin (C), and then etoposide (E) in a study for small cell lung cancer (SCLC) treatment. PATIENTS: 44 chemotherapy-naive patients with SCLC (median age 63.5, PS 0-1). ED was present in 28 patients. METHODS: Each treatment cycle consisted of T (0.8mg/m(2) on days 1-3), C (AUC=5, day 3) and a standard oral dose of E (100mg on days 15-17). Cycles were repeated every 32 days and up to eight were performed. Responders received radiotherapy to the primary site (50Gy) after the 4th cycle and complete responders also received PCI. RESULTS: Complete response (CR) was achieved in 4 patients, partial response (PR) in 18, stable disease in 10 and PD in 12. Median survival was 280 (+/-36.7) days and median time to progression 137 days. 11 patients developed grade 3/4 neutropenia and 3 patients grade 3/4 anaemia. Non-haematological toxicity was mild. CONCLUSION: In contrast to ORR, PFS and survival were quite similar to those of SCLC patients suffering from ED treated by a platinum-etoposide regimen. The T/C/E combination was well tolerated and with low toxicity, but without improvement in the ORR and survival in comparison to platinum analogue regimes.

A NEW MARKER FOR SEMINOMA?

EAU 2009: New Marker May Predict Clinical Course of Testicular Seminoma

March 27, 2009 (Stockholm, Sweden) — The free subunit of human chorionic gonadotropin (hCG)ß, known to be associated with aggressive renal cancers, might provide clinically valuable information about testicular seminoma, according to a small Finnish study presented here at the European Association of Urology (EAU) 24th Annual Congress.

About a decade ago, it was found that 30% to 40% of seminomas have elevated serum levels of hCGß. Lead investigator Anna Lempiäinen, MD, of Helsinki University, in Finland, and colleagues studied whether separate measurement of hCGß in the serum of seminoma patients could offer information in addition to the determination of intact hCG.

"We know that hCG is a marker for testicular cancer, but it is seldom possible to detect it in seminomas, and since seminomas are, by definition, alphafetoprotein negative, there is no perfect marker for seminoma," Dr. Lempiäinen said. "The treatment of seminoma is changing, there is increasing use of adjuvant therapy; as a result, relapses can be more common. So there is a need for a good marker. There have been reports that the free ß subunit of hCG could be a useful marker in seminomas, so we wanted to evaluate this further."

Using their own "ultrasensitive and ultraspecific" immunofluourometric assay, the investigators studied preoperative serum samples for the presence of intact hCG, free hCGß, and glycosylated hCG from 42 seminoma and 51 nonseminoma testicular cancer patients, and from 22 relapsed seminoma patients.

They found that 40% of seminoma patients had an isolated elevation of the free hCGß subunit, whereas hCG was negative in all of the seminoma patients. In contrast, the free hCGß subunit was elevated in 8% of the nonseminoma patients. Both markers were elevated in 12% of seminoma and 71% of nonseminoma patients, and both were normal in 43% of seminoma and 20% of nonseminoma patients. In samples from relapsed seminoma patients, separate determination of the free hCGß subunit increased the amount of marker-positive seminomas that were found, from 32% to 59%.

In an interview with Medscape Urology, Dr. Lempiäinen said that "the main clinical significance of our finding is that patients who have a negative hCG might still have elevated levels of hCGß, and this is of value in the diagnosis and especially in the follow-up of cancer, since rising marker levels are a strong indicator of relapse. Determining both hCG and hCGß reveals more marker-positive seminomas and marker-positive relapses than determining hCG alone."

Jack Baniel, MD, head of urology at Beilinson Medical Center, in Petach Tikva, Israel, and Pilar Laguna, MD, professor of urology at AMC University Hospital, in Amsterdam, the Netherlands, who chaired the session on testicular cancer at the EAU, offered their comments on the Finnish study, which was awarded one of the 2 Best Poster awards of the session.

"They showed that in a small number of patients with seminoma, the free ß subunit of hCG goes up. This is very important for seminoma, where we don't actually have markers. Right now all we really have is [lactate dehydrogenase]. If we have another significant marker, like they showed in 40% of patients, it could help our management of seminoma patients."

Dr. Laguna cautioned that all the patients in the study were low-stage seminoma patients and that more work needs to be done to show whether this new potential marker does, indeed, have value. "Irrespective of all the markers, we know at this moment that the prognosis is excellent for seminoma. More patients are needed and the data have to be confirmed with clinical results, because if the marker is not adding anything to what we already know, then it's not a marker."

NHL RITUXIMAB AND PET

High Incidence of False-Positive PET Scans in Patients With Aggressive Non-Hodgkin's Lymphoma Treated With Rituximab-Containing Regimens

H. S. Han; M. P. Escalón; B. Hsiao; A. Serafini; I. S. LossosAnn Oncol. 2009;20(2):309-318. ©2009 Oxford University Press
Copyright 2008 European Society for Medical Oncology. Published by Oxford University Press. All rights reserved.

Posted 03/23/2009

Abstract and Introduction

Abstract

Background: Positron emission tomography (PET) is a powerful predictor of relapse and survival in non-Hodgkin's lymphomas (NHLs) based on studies carried out in the prerituximab era. Little is known about the predictive power of PET in rituximab-treated patients.
Patients and Methods: Patients with aggressive B-cell NHL with baseline and follow-up PET studies were included. Clinical characteristics, PET and computed tomography scans, biopsy results, and outcomes were reviewed. PET was defined as positive if higher than mediastinal or background activity was observed.
Results: In all, 51 patients (diffuse large B cell—38; mantle cell lymphoma—13) treated with rituximab-containing regimens were included. For 13 of 40 patients (32.5%), mid-therapy PET studies were positive and 9 of 48 patients (18.7%) had positive posttherapy PET. The positive predictive value (PPV), negative predictive value (NPV), sensitivity (Se), and specificity (Sp) of the mid-therapy PET for predicting relapse were 33% [95% confidence interval (CI) 19% to 49%], 68% (95% CI 51% to 81%), 33% (95% CI 6% to 76%), and 68% (95% CI 49% to 82%), respectively. For posttherapy PET, the relapse PPV, NPV, Se and Sp were 19% (95% CI 9% to 33%), 81% (95% CI 67% to 91%), 13% (95% CI 0.6% to 53%), and 80%(95% CI 64% to 90%), respectively.
Conclusions: Compared with previous reports in prerituximab era, addition of rituximab resulted in reduced PPV and sensitivity of mid- and posttherapy PET in patients with aggressive B-cell NHL.

JEWS KNOW BETTER

Circumcision May Reduce Incidence of HIV, HSV-2, HPV Infection

March 25, 2009 — Male circumcision significantly reduced the incidence of HIV and herpes simplex virus type 2 (HSV-2) infection and the prevalence of human papillomavirus (HPV) infection, suggesting potential public health benefits, according to the results of a randomized controlled trial reported in the March 26 issue of the New England Journal of Medicine.

"Male circumcision significantly reduced the incidence of...HIV infection among men in three clinical trials," write Aaron A.R. Tobian, MD, PhD, from Bloomberg School of Public Health, Johns Hopkins University in Baltimore, Maryland, and colleagues. "We assessed the efficacy of male circumcision for the prevention of...HSV-2 and...HPV infections and syphilis in HIV-negative adolescent boys and men."

Two trials of male circumcision to prevent HIV and other sexually transmitted infections in a rural Ugandan population enrolled a total of 5534 HIV-negative, uncircumcised male subjects aged 15 to 49 years. Of 3393 subjects (61.3%) who were HSV-2 seronegative at enrollment, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision after 24 months (control group). Subjects were tested for HSV-2 and HIV infection and syphilis and underwent physical examinations and interviews at baseline and at 6, 12, and 24 months. A subgroup of subjects was also evaluated for HPV infection at baseline and at 24 months.

The cumulative probability of HSV-2 seroconversion by 24 months was 7.8% in the intervention group vs 10.3% in the control group (adjusted hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.56 - 0.92; P = .008). High-risk HPV genotypes were present at 24 months in 18.0% of the intervention group vs 27.9% of the control group (adjusted risk ratio, 0.65; 95% CI, 0.46 - 0.90; P = .009). The incidence of syphilis was not significantly different between groups (adjusted HR, 1.10; 95% CI, 0.75 - 1.65; P = .44).

"In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure," the study authors write. "These findings, in conjunction with those of previous trials, indicate that circumcision should now be accepted as an efficacious intervention for reducing heterosexually acquired infections with HSV-2, HPV, and HIV in adolescent boys and men. However, it must be emphasized that protection was only partial, and it is critical to promote the practice of safe sex."

Limitations of this study include evaluation of the use of circumcision to prevent HPV infection only in a subgroup of subjects observed both at enrollment and at 24 months.

"Male circumcision has now been shown to decrease the rates of HIV, HSV-2, and HPV infections in men and of trichomoniasis and bacterial vaginosis in their female partners," the study authors conclude. "Circumcision also reduces symptomatic ulceration in HIV-negative men and women and HIV-positive men. Thus, male circumcision reduces the risk of several sexually transmitted infections in both sexes, and these benefits should guide public health policies for neonatal, adolescent, and adult male circumcision programs."

In an accompanying editorial, Matthew R. Golden, MD, MPH, and Judith N. Wasserheit, MD, MPH, from the University of Washington, Public Health–Seattle, note that this study contributes strong evidence that circumcision offers an important prevention opportunity and should be widely available.

"Professional organizations have a leadership role to play in ensuring that medical providers actively educate all parents or guardians of newborn sons about the benefits and risks of circumcision," Drs. Golden and Wasserheit write. "The American Academy of Pediatrics, which previously concluded that evidence was insufficient to recommend routine neonatal circumcision, is reviewing its position in collaboration with other professional organizations. This process should optimally lead to a multidisciplinary consensus statement involving providers such as obstetricians, midwives, pediatricians, urologists, and family doctors and to the development and dissemination of educational materials for medical professionals and families."

NEWER ANTIEPILEPTIC DRUGS ARE SAFER

Newer Antiepileptic Drugs Cause Less Cardiovascular Risk Than Older Agents

March 19, 2009 — Switching patients with epilepsy from older antiepileptic drugs that induce cytochrome P450 to 1 of the newer drugs that do not affect this enzyme system can dramatically reduce cardiovascular risk.

Investigators at Thomas Jefferson University, in Philadelphia, Pennsylvania, report these findings online March 18 in the Annals of Neurology in 34 epilepsy patients switched from phenytoin or carbamazepine to either lamotrigine (Lamictal, GlaxoSmithKline) or levetiracetam (Keppra, UCB).

Within 6 weeks of the switch, patients had significant decreases in total cholesterol, non–high-density-lipoprotein (atherogenic) cholesterol, triglycerides, and C-reactive protein (CRP). All 4 markers are associated with elevated risk for atherosclerosis, cardiovascular disease, and stroke.

"The most important point that clinicians should take from this study is that carbamazepine and phenytoin cause a panoply of serologic changes that would be expected to increase myocardial infarction and stroke risk significantly.

"In the epilepsy field, that means that it is highly questionable whether or not these drugs should be first-line agents. In psychiatry, this has to be balanced against the potential risks and benefits of alternative treatments," principal investigator Scott Mintzer, MD, told Medscape Psychiatry.

Unexpected Reduction in Lipoprotein(a)

This repeated-measures, within-patient study is also notable because it is 1 of the few vascular risk studies done in adults with epilepsy. Most previous studies are either conducted in children or are cross-sectional.

After changing to lamotrigine or levetiracetam, subjects had average declines of 24.8 mg/dL in total cholesterol, 19.9 mg/dL in atherogenic cholesterol, and 47.1 mg/dL in triglycerides (all P < .0001). Average CRP levels fell by 31.4% (P = .027).

One unexpected finding was that patients who stopped taking carbamazepine also had a 31.2% decline in lipoprotein(a) (Lp[a]) levels (P = .0004), while those who stopped phenytoin had a 1.7 mmol/L decrease in homocysteine (P = .005).

"Many of the findings were expected, but 2 findings surprised me — first, that carbamazepine and phenytoin appear to have such sharply different effects on Lp(a); and second, that CRP appears to be markedly affected by these drugs. No one has ever examined CRP in epilepsy patients or in any patients who take these drugs, to my knowledge," said Dr. Mintzer.

More data are needed to establish that patients who were seizure-free on the older drugs will remain seizure-free on the newer drugs. However, said Dr. Mintzer, in his opinion, all epilepsy patients are potential candidates for this switch.

Reduction in Health Costs?

Cost questions typically arise when clinicians begin pressing for switching from older, usually cheaper agents, to newer, usually more expensive, drugs. Dr. Mintzer's data are expected to be helpful to clinicians arguing this point with third-party payers, national health agencies, or formulary committees.

He predicts that changing patients to the newer drugs will actually save healthcare dollars by reducing the current high rate of cardiovascular problems in these patients. “In any case, most of the newer drugs have just come off patent, so their prices will drop substantially in the not-too-distant future,” he added.

John O. Elliott, clinical research data manager at Ohio State University, in Columbus, told Medscape Psychiatry that the study design "was the correct one to use, and this paper certain adds much to the literature."

However, Mr. Elliott noted, there is still some question about whether cardiovascular disease is more prevalent in people with epilepsy.

"Based on my own research, I believe that poorer health habits (lack of exercise, smoking, and poor diet) in people with epilepsy put them at greater risk for comorbid conditions. Patients with chronic epilepsy also have significant economic challenges (unemployment and lower education) that are significantly related to poorer health outcomes.

"In a recent project that will be coming out in the journal Epilepsy Research we examine the effects that social determinants of health, including poverty, have on people with epilepsy. Practitioners recognize the effect that these factors have on treatment and health outcomes. However, there are also no quick and easy solutions to such social problems," Mr. Elliott said.

Exposure to radiation from CT scans may increase cancer risk

Study suggests cumulative exposure to radiation from CT scans may increase cancer risk

HealthDay (3/31, Reinberg) reported, "Cumulative exposure to radiation from CT scans can increase the risk for cancer by as much as 12 percent," according to research published in the April issue of Radiology. Dr. Aaron Sodickson, assistant director of emergency radiology at Brigham and Women's Hospital in Boston, and colleagues, examined medical records for "31,462 people who had undergone a total of 190,712 CT scans over 22 years." The records showed that "about 33 percent had five or more scans, five percent had more than 22, and one percent had more than 38." Overall, "15 percent of the people in the study had received cumulative radiation doses of more than 100 millisieverts (mSv), the same level of radiation as 1,000 chest X-rays." 
  WebMD (3/31, Boyles) reported that "four percent of patients had lifetime exposures equivalent to 2,500 conventional chest X-rays." Based on "a cancer risk assessment model," the researchers discovered that "7.3 percent of the study participants had an elevated risk of cancer because of radiation from CT scans." And, although "the risk was very small for most patients, totaling just one percent over the average lifetime risk of 42 percent," an estimated one percent "of the patients in the study had CT-related elevations in risk of between 2.7 percent and 12 percent." 
  The researchers found that with the size of the study's cohort, "baseline cancer rates predict 13,214 cancers, including 6,292 fatal cancers," MedPage Today (3/31, Fiore) reported. But, "CT imaging will produce 98 additional radiation-induced cancers, including 62 fatal cancers" in the cohort, based on "lifetime attributable risk calculations," the study showed. Notably, "40 percent of the subgroup with a risk estimate one percent above baseline have no history of malignancy or a cancer history with no evidence of active disease." The researchers concluded that "a risk-benefit decision must be made at the level of the individual patient," taking into account "patient-specific cumulative risks." 

AVASTIN's MECHANISM OF ACTION IS NOT CLEAR

Study suggests Avastin, similar drugs may not halt tumor growth in patients with deadly form of brain cancer.
Bloomberg News (3/31, Larkin) reports that "Avastin [bevacizumab] and similar drugs being tested on the most deadly form of brain cancer may not halt tumor growth," according to a study appearing in the Journal of Clinical Oncology. Researchers at Harvard Medical School "induced brain tumors in mice and treated them with an experimental AstraZeneca Plc drug," cediranib, "that works the same way as Avastin." They found that "while the therapy prolongs survival by reducing swelling in the brain...it doesn't usually shrink tumors," and "cancer progression didn't slow." Meanwhile, Roche's Genentech unit is expected to "ask a US panel tomorrow to expand approval of Avastin based on preliminary data supporting a benefit for some people with glioblastoma." But, FDA regulators "questioned last week whether brain scans used for Genentech's analysis were sufficient to support approval before a large, randomized study is conducted." 

PANCREATIC CANCER RESPONSE TO GEMCITABINE

Clin Cancer Res. 2009 Mar 24. [Epub ahead of print]

Related Articles, LinkOut

Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma.

Maréchal R, Mackey JR, Lai R, Demetter P, Peeters M, Polus M, Cass CE, Young J, Salmon I, Devière J, Van Laethem JL.

Authors' Affiliations: Department of Gastroenterology and Hepato-Pancreatology, Gastrointestinal Cancer Unit, and Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium; Departments of Oncology and Physiology, University of Alberta, Cross Cancer Institute; Department of Pathology and Laboratory Medicine, University of Alberta, Edmonton, Alberta, Canada; Department of Hepato-Gastroenterology, Digestive Oncology Unit, University Hospital Ghent, Gent, Belgium; and Department of Medical Oncology, Centre Hospitalier Universitaire Sart-Tilman, Liège, Belgium.

PURPOSE: Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic adenocarcinoma and its use in combination with radiotherapy is under exploration. Human equilibrative nucleoside transporter 1 (hENT1) and human concentrative nucleoside transporter (hCNT) 1 and 3 are the major transporters responsible for 2',2'-difluoro-2-deoxycytidine (gemcitabine) uptake into cells. The aim of this study was to determine patients' outcome according to the expression of hENT1 and hCNT3 in tumoral cells after postoperative gemcitabine-based chemoradiation regimen.EXPERIMENTAL DESIGN: We studied tumor blocks from 45 pancreatic adenocarcinoma patients treated with gemcitabine-based chemoradiation after curative resection and assessed hENT1 and hCNT3 expression using immunohistochemistry.RESULTS: When adjusted for the effects of lymph node ratio and tumor diameter, patients with high hENT1 expression had significantly longer disease-free survival and overall survival (OS) than patients with low expression, whereas high hCNT3 expression was only associated with longer OS. In a combined analysis, patients with two favorable prognostic factors (hENT1(high)/hCNT3(high) expression) had a longer survival (median OS, 94.8 months) than those having one (median OS, 18.7 months) or no (median OS, 12.2 months) favorable prognostic factor.CONCLUSIONS: Pancreatic adenocarcinoma patients with a high expression of hENT1 and hCNT3 immunostaining have a significantly longer survival after adjuvant gemcitabine-based chemoradiation. These biomarkers deserve prospective evaluation in patients receiving gemcitabine-based adjuvant therapy.

TAKE A BIOPSY FROM METASTASES

Discordance Between Primary and Metastatic Tumors Seen in Breast Cancer

March 24, 2009 — There appears to be a substantial rate of discordance in pathology and molecular markers between primary and suspected metastatic lesions in women with breast cancer. This discordance is prevalent enough to alter treatment decisions in 20% of cases, according to a report published online March 18 in the Annals of Oncology.

These changes in molecular markers between primary lesions and metastatic disease are increasingly important because of the growing use of targeted therapies, the researchers note, and confirmation of tissue should be considered the standard of care in patients with clinical and/or radiologic suspicion of metastatic recurrence and lesions amenable to biopsy.

"It is not standard of care anywhere, but I think it is being increasingly done, given the results of retrospective and now this prospective trial," lead investigator Mark Clemons, MD, head of the Breast Medical Oncology Group at Princess Margaret Hospital, in Toronto, Ontario, told Medscape Oncology. "I think it would be prudent to talk about it with a patient."

But Dr. Clemons added that it is difficult to imagine that this will ever be a standard of care, because doing biopsies requires incredible interdisciplinary support. "We could not have done this study without our colleagues in interventional radiology and pathology," he said, adding that they had funding support as well.

Other studies have suggested that there can be changes in molecular phenotype between the primary and relapsed breast cancer, which can significantly alter response to treatment. As reported by Medscape Oncology at that time, a study presented at the 2008 annual meeting of the American Society of Clinical Oncology found that 28% of relapsed tumors had changes in either estrogen-receptor (ER)/progesterone-receptor (PR) or HER2-receptor status, and suggested that biopsies of relapsed sites should routinely be performed to determine optimal treatment options.

In the current study, Dr. Clemons and colleagues prospectively examined concordance in receptor status between primary tumor and distant metastases, and then evaluated the impact of discordance on treatment decisions.

Management Changes Needed in 20% of Cohort

Of 40 breast cancer patients enrolled in the study, 35 underwent biopsies of their metastatic lesions, from which 29 analyzable samples were obtained. Within this group, 61% had received adjuvant chemotherapy, 53% had received endocrine therapy, 2% had received trastuzumab, and 26% were still receiving endocrine therapy when metastases were diagnosed. The median time between the diagnosis of the primary breast cancer and metastasis was 2.4 years.

Upon analysis, 3 biopsy samples were diagnosed with benign disease and 1 sample was diagnosed as low-grade follicular lymphoma. The remaining 25 specimens confirmed the presence of metastatic breast cancer.

The original biopsy results from the primary tumor showed that 16 of 25 patients were ER-positive, 9 were PR-positive, and 4 were HER2-positive. The researchers noted that when these 25 samples from primary and metastatic lesions were paired together, 10 were discordant for ER/PR status, and 2 showed discordance for HER2, with a complete change in receptor status. The result was an overall discordance rate for ER and PR status of 40%, and an 8% discordance rate for HER2.

The results of the second biopsy resulted in a complete change in management in 6 (20%) of the 29 patients. The treatment plan changed for the 4 patients who showed no evidence of metastatic disease, as did their prognosis. The remaining 2 patients experienced a gain in HER2 overexpression, which now qualified them for either treatment with trastuzumab or entry into a clinical trial.

Although this study only included breast cancer patients, it is possible that discordance between primary lesions and metastatic disease exists in other types of tumors. "I see no reason at all why it would not be applicable for other cancers," said Dr. Clemons. "However, breast cancer is unique in that many years can pass between diagnosis and development of metastatic disease."

The researchers conclude that this study also "has implications for the design of clinical trials that evaluate targeted therapies."

"Mandating a biopsy of metastases at study entry would ensure that the target is expressed and would allow for a more efficient study to be carried out," they write.

GEMCITABINE PLUS DOCETAXEL FOLLOWED BY CAPECITABINE PROBABLY THE BETTER COMBINATION

Gemcitabine/Docetaxel After Anthracycline Advised for Advanced Breast Cancer

NEW YORK (Reuters Health) Mar 23 - Although the combination of gemcitabine and docetaxel does not provide better survival than capecitabine and docetaxel for patients with metastatic breast cancer, gemcitabine might still be the better option, based on its nonhematologic toxicity profile and the average time to treatment failure.

These findings, from a multicenter European phase 3 trial, were published online March 9 by the Journal of Clinical Oncology.

All 305 women in the study (median age 55 years) had locally advanced or metastatic breast cancer, and all had been treated with an anthracycline. Forty-eight percent had 3 or more disease sites, and 86% had visceral disease.

Participants were randomly selected to receive intravenous (IV) gemcitabine 1,000 mg/m on days 1 and 8, or oral capecitabine 1,250 mg/m twice daily on days 1 through 14. All patients received IV docetaxel, 75 mg/m on day 1 before gemcitabine or capecitabine. Cycles were repeated every 21 days until disease progression or unacceptable toxicity occurred. Median administration in both arms was 6 cycles.

Neither progression-free survival nor overall survival differed significantly between the treatment arms. Median progression-free survival was 8.05 months in the gemcitabine arm versus 7.98 months in the capecitabine arm, and median overall survival was 19.29 months in the gemcitabine arm versus 21.45 months in the capecitabine arm.

Time to treatment failure, however, was significantly longer in the gemcitabine arm (4.24 months) than in the capecitabine arm (4.07 months). The researchers defined time to failure as the interval between the date of randomization and the date of discontinuation, disease progression, death from any cause, or the start of a new anticancer therapy.

Serious hematologic toxicity was not significantly different between the 2 groups, except for grades 3 or 4 leukopenia, which was more common in the gemcitabine group (78% versus 66%). Serious nonhematologic toxicities, however, including diarrhea, hand-foot syndrome and mucositis, were significantly more frequent in the capecitabine group. In addition, fewer patients in the gemcitabine arm (13% versus 27%) discontinued treatment because of drug-related adverse events.

"My personal view," lead author Dr. Stephen Chan, at Nottingham University Hospital, Nottingham, U.K., told Reuters Health, "is that capecitabine as a monotherapy at the lower dose than recommended, i.e., at 2 gram per m daily rather 2.5 gram per m daily, is well tolerated, and in responsive tumors, this can be maintained for a relatively long period of time, sometimes over 12 months.... One strategy for oncologists advising patients is to use the gemcitabine combination as a first line in metastatic breast cancer followed by single agent capecitabine for relapse."

PROSTATECTOMY INCREASES SURVIVAL

EAU 2009: Radical Prostatectomy Reduces Prostate Cancer Mortality Without Adversely Affecting Quality of Life

March 23, 2009 (Stockholm, Sweden) — Men with localized prostate cancer who were randomly assigned to receive radical prostatectomy in the Scandinavian Prostate Cancer Group (SPCG)-4 trial not only achieved superior survival, compared with men who were randomized to watchful waiting, they did so without sacrificing quality of life.

In fact, they scored slightly better in terms of anxiety, depression, well-being, and overall quality of life than men in the watchful-waiting group, said Lars Holmberg, MD, professor of cancer epidemiology at King's College London School of Medicine, in the United Kingdom, who was one of the SPCG-4 study authors.

Speaking here at the European Association of Urology 24th Annual Congress, Dr. Holmberg told delegates that the SPCG-4 investigators were surprised to find no difference in quality-of-life scores between the 2 study groups. "It is widely accepted that radical prostatectomy is associated with severe morbidity," he said. "But when we assessed quality of life, we found that it was actually slightly higher in the men who got the surgery. So we were wrong in our assumption that we would gain some years of life with radical prostatectomy at the cost of quality of life."

Long-Term Trial

The SPCG-4 trial has been ongoing since 1989, when it was launched to compare the effects of radical prostatectomy and watchful waiting on disease-specific mortality in Scandinavian men with locally advanced prostate cancer. For the next 10 years, until 1999, men from Sweden, Finland, and Iceland were randomly assigned to radical prostatectomy (n = 347) or to watchful waiting (n = 348). In 2005, after a median follow-up of 8.2 years, the investigators reported that men in the surgery group had lower rates of death from prostate cancer than men in the watchful-waiting group.

In August 2008, the investigators reported updated data (J Natl Cancer Inst. 2008;100(16):1144-1154) that showed that men in the surgery group continued to have decreased cancer-related mortality, compared with men in the watchful-waiting group.

The 12-year results showed that 12.5% of the surgery group and 17.9% of the watchful-waiting group had died of prostate cancer, for a relative risk reduction of about 35% and a 5.4% absolute risk reduction in disease-specific survival in favor of radical prostatectomy (P = .03). "This means that we need to operate on 19 patients to gain 1 life," noted Dr. Holmberg.

In addition, 19.3% of men in the surgery group and 26% of men in the watchful-waiting group had been diagnosed with distant metastases, for a 6.7% absolute risk reduction in favor of radical prostatectomy (P = .006).

"We had expected that the absolute difference in cumulative incidence of distant metastasis and prostate cancer death would increase with longer duration of follow-up, but there was no further increase after 7 to 9 years," said Dr. Holmberg.

In the men who were treated surgically, all but 1 of the deaths occurred in patients with extracapsulary extension in the radical-prostatectomy specimen.

Patients with a Gleason score of 2 to 6 had the lowest risk for recurrence.

Radical Prostatectomy Had Large Effect on Reducing Mortality

Radical prostatectomy had a large effect on reducing mortality in men younger than 65 years but had little or no effect in patients older than 65 years. But Dr. Holmberg cautioned against taking this finding as evidence of a lack of effect in elderly patients. "This was a subgroup analysis, which is always unstable. The finding represents a hypothesis that needs further investigation."

Prostate-specific antigen (PSA) kinetics were useless to guide treatment decisions for the watchful-waiting group, he added. "To use only PSA to follow watchful-waiting patients does not seem to be that safe. You would need to combine that with other more sophisticated methods of follow-up. People right now are experimenting with a series of biopsies and other methods."

In an interview with Medscape Oncology after his presentation, Dr. Holmberg said that the data from the quality-of-life analysis are very important.

He pointed out that the patterns of symptoms differ between the 2 groups, because the treatments are associated with vastly different adverse effects. For surgery patients, the adverse effects appear early, right after the surgery. But for watchful-waiting patients, the pattern is reversed. In those patients, symptoms increase as the disease burden increases, he said.

Increase in Symptoms Decreases Quality of Life

"People who have surgery learn to live with their symptoms afterward. They learn to use Viagra, they get support, and the symptoms tend to wear off. In contrast, patients in the watchful-waiting arm do not have many symptoms at the start but, as the disease grows, they get more and more symptoms. They also get many more hormonal treatments, which have side effects," Holmberg said.

Because SPCG-4 was begun before the era of PSA screening, the results may not be entirely generalizeable to the current population of prostate cancer patients. Dr. Holmberg admitted that the trial could not be started today, in the era of PSA testing, noting that the patients in SPCG-4 are not representative of the prostate cancer patients clinicians see today. "The tumors we saw in our study are larger tumors than you would expect to see in today's current screening situation. There were more T2 tumors."

Nevertheless, the study has yielded important and useful information, Dr. Holmberg said.

"I think our trial has actually shown that, even if the tumor is more advanced, it is worthwhile to do an operation, and we have data to show that it actually cures some patients. When we started the study, we doubted whether it was beneficial at all to intervene as early in the disease as this. There were no randomized studies at that time to tell us that, just indirect inferences."

An Important Study

Asked by Medscape Oncology to comment about the SPCG-4 study, Fritz Schröder, MD, from the Erasmus Medical Center, in Rotterdam, the Netherlands, called it an important study. "This is the only study that shows that radical treatment is better than watchful waiting. It shows a significant difference, which in absolute terms amounts to only about 5%, but it is still very relevant. The question is whether this finding will translate from statistical to clinical significance," he said.

The key to that question lies in the number of patients needed to treat in order to save 1 life. Dr. Schröder said that many of his colleagues will doubt whether it is worthwhile treating a patient with surgery when there are other treatments available that might also prolong life. But others will say that the evidence that radical prostatectomy saves lives clearly demonstrated in the study makes the choice for surgery compelling.

"My feeling is that this has to be discussed with the patient. It is not only up to the doctor to determine whether a 1 to 20 relation is adequate or acceptable. It is an ethical issue that has to be discussed with the patient," he said.

Dr. Schröder said that he found the results of the quality of life analysis encouraging. "The finding that there is no big difference between watchful waiting and active treatment reflects the fact that, although there are adverse effects in the sexual and micturition field, these are clearly not experienced as something very bad in the radical-treatment group. This is important."

He agreed with Dr. Holmberg's assertion to be very careful in interpreting the subgroup analysis that found less benefit for radical prostatectomy in patients older than 65 years.

"It is important to take this observation with a grain of salt. If I see a patient who is in excellent shape at 70 years old and I estimate that he could make it to 95 because his family history is very favorable, I would not hesitate to recommend aggressive treatment to the man, in spite of this suggestive subgroup finding."

USE LOWER DOSE OF AZACYTIDINE FOR MDS

Low-Dose Azacitidine Better Tolerated by Myelodysplastic Syndrome Patients

NEW YORK (Reuters Health) Mar 19 - The use of a less intensive azacitidine dosing schedule than the current standard in patients with lower-risk myelodysplastic syndrome is better tolerated, and still provides treatment advantages, researchers report in a March 2nd on-line publication in the Journal of Clinical Oncology.

"This study, done in the community setting, largely in 'lower risk' patients," lead investigator Dr. Roger M. Lyons told Reuters Health, "provides support for a more convenient and cost-effective way to treat patients with the myelodysplastic syndrome."

"We observed the same response with less toxicity with only 5 days of treatment every 28 days as opposed to 7 or 10 days, in all three settings avoiding weekends," he said.

Dr. Lyons of Cancer Care Centers of South Texas and US Oncology, San Antonio, and colleagues randomized 151 patients to three different regimens every 4 weeks for 6 cycles.

The first regimen was azacitidine 75 mg per square meter per day subcutaneously for 5 days followed by 2 days of no treatment and then a further 2 days of treatment at the same dosage. The second was 50 mg per square meter for 5 days, followed by 2 days of no treatment and then the same dosage for 5 days. The last group of patients was given 75 mg per square meter subcutaneously for 5 days.

Hematological improvement was seen in 44% of the first group, 45% of the second and 56% of the last group. Corresponding proportions for RBC transfusion-dependent patients who achieved independence were 50%, 55% and 64%. For transfusion-dependent patients in the lower risk category, the figures were 53%, 50% and 61%.

Overall, one or more grade 3 to 4 adverse events were experienced by 84% of the first group, 77% of the second and 58% of the third group.

The researchers conclude that all three approaches provide hematologic improvement and a reduction in transfusion dependence. They add that the straightforward 5-day regimen "may be better tolerated, with a more convenient dosing schedule than the other two alternative dosing regimens."

A TREATMENT FOR LYMPHEDEMA

Lymphedema Swelling Reduced by One Third with Microsurgery

March 25, 2009 — Microsurgery for lymphedema reduced arm swelling by an average of 39% at 6 months and 35% at 1 year among 20 breast cancer patients.

Nineteen of the patients reported significant clinical improvement after the procedure.

These results are from a new study of a microsurgical technique known as lymphaticovenular bypass. The study was presented at the 88th Annual Meeting of the American Association of Plastic Surgeons, which was held in Rancho Mirage, California.

"This procedure does a lot to help relieve lymphedema by giving the fluid a way out. While it does not totally eliminate the condition, there is very little downside for the patient and we may see significant improvement in its severity," said study lead author David W. Chang, MD, in a statement.

Dr. Chang is director of the plastic surgery clinic at the University of Texas MD Anderson Cancer Center, in Houston, where the study was performed.

Long-term follow-up is needed to determine whether surgery continues to promote lymphatic fluid drainage after 1 year, he added.

The surgery redirects lymphatic fluid to microscopic vessels approximately 0.3 to 0.8 mm in diameter to promote drainage. The fluid accumulates and causes swelling when lymph nodes are removed or blocked.

Dr. Chang believes that the surgery could possibly be used as a preventive measure for lymphedema in the future. "Working toward a definitive technique to cure this encumbering side effect of cancer and improve a patient's quality of life as a cancer survivor is a priority for those of us in this field," he said.

An estimated 25% to 30% of women undergoing breast cancer surgery with lymph-node dissection and radiation therapy develop lymphedema, according to the National Cancer Institute.

The new microsurgery can also be performed on lymphedema of the leg in patients with cancers in the pelvic region, said Dr. Chang.

Patients Had Advanced Lymphedema

The patients in the prospective study presented with stage II and III treatment-related lymphedema of the upper arm, with a mean duration of 4.8 years. All patients had axillary lymph-node dissection and 16 had preoperative radiation therapy.

Prior to the microsurgery, affected arms in the study were an average of 34% larger than unaffected arms.

The mean number of bypasses performed per patient was 3.5 and the mean operative time was 3.3 hours. After surgery, the mean lymphedema volume reduction was 29% at 1 month, 36% at 3 months, 39% at 6 months, and 35% at 1 year.

In 3 of the 19 patients who reported clinical improvement, no significant quantitative improvement was noted, said the MD Anderson researchers. Also, there were no postoperative complications or exacerbation of lymphedema.

Surgical Options Limited

There is no cure or prevention for lymphedema. The goal of treatment is to decrease the excess limb volume as much as possible and to maintain the limb at its smallest size. This reduces the amount of stagnant fluid in the tissues, potentially preventing or eliminating infections, as previously reported by Medscape Oncology

The gold-standard treatment for lymphedema is widely recognized to be complete decongestive therapy, which consists of a treatment and a maintenance phase; the latter is life-long and principally involves self-care, which includes skin care, wearing a compression garment, and exercise .

Surgical approaches to lymphedema include another microsurgery, lymphatic-venous anastomoses. However, there is room for improvement here, suggested Dr. Chang. "Surgical techniques, in particular, have been limited and therefore have been met with skepticism by surgeons, making it extremely important to determine which new techniques promise to bring real benefits to patients," he said.

3 DRUG INDUCTION CHEMOTHERAPY FOR LARYNX CANCER

Three-Drug Induction Chemotherapy Increases Larynx Preservation

March 26, 2009 — Three-drug induction chemotherapy might increase the likelihood of preserving larynx function in patients with larynx and hypopharynx cancers, compared with a commonly used 2-drug regimen.

In a study published online March 24 in the Journal of the National Cancer Institute, French researchers report that patients who received docetaxel, cisplatin, and 5-fluorouracil (TPF) during induction chemotherapy were more likely to retain larynx function than those treated with cisplatin and 5-fluoruracil (PF).

At a median follow-up of 36 months, the estimated larynx preservation rate was 70.3% in the TPF-treated patients and 57.5% in the PF-treated patients.

Induction chemotherapy with cisplatin and 5-fluorouracil, followed by radiation therapy in patients who respond to chemotherapy, is an alternative approach to total laryngectomy for people with advanced malignancies of the larynx and hypopharynx. The researchers note that recent data from clinical trials conducted with a curative intent suggest that the addition of docetaxel increases both the response rate and overall survival.

In this trial, Gilles Calais, MD, from the Centre Hospitalier Régional et Universitaire de Tours, in France, and colleagues randomized 213 patients with advanced larynx and hypopharynx cancer to induction therapy with either TPF (n = 110) or PF (n = 103).

Induction chemotherapy for the TPF group consisted of 75 mg/m² docetaxel on day 1, 75 mg/ m² cisplatin at on day 1, and 750 mg /m² 5-fluorouracil by 24-hour continuous infusion for 5 days; 3 cycles with a 21-day interval were planned.

Patients in the PF group received 100 mg/m² cisplatin on days 1 and 5, and 1000 mg/ m² fluorouracil by 24-hour continuous infusion for 5 days for 3 cycles, with a 21-day interval. All eligible patients received radiotherapy between 3 and 7 weeks after the final cycle of chemotherapy.

Radiation therapy for larynx preservation was performed in 76.4% of patients in the TPF group (all were responders to induction chemotherapy) and in 61.2% of patients in the PF group (57 were responders, 6 refused surgery).

Better Response Seen, But No Survival Difference

The researchers observed that patients in the TPF group had a better overall response rate to chemotherapy than those in the PF group (80% vs 59.2%). Individuals who did not respond to induction chemotherapy underwent total laryngectomy with neck dissection, with surgery being performed 3 to 7 weeks after the last chemotherapy cycle.

They also noted that a greater percentage of patients in the TPF group recovered to normal larynx mobility (42.7% vs 29.1%, respectively; P = .034), and no residual tumor was detected in 64.4% of patients in the TPF group and in 35.8% of patients in the PF group.

Although induction with the TPF regimen achieved a statistically significantly superior 3-year larynx-preservation rate, survival rates were similar between the 2 groups. At 3 years, overall survival was 60% in each group, whereas disease-free survival was 58% for TPF patients and 44% for PF patients. The 14% difference did not reach statistical significance (P = 0.57 and P = 0.11, respectively).

Acute and Late Toxicity Seen in Both Groups

Acute toxicity was observed in both groups. A total of 5 patients died from acute toxicity (3 in the TPF group and 2 in the PF group). Patients in the TPF group also experienced a higher degree of grade 2 alopecia (19.4% vs 2.0%), more grade 4 neutropenia (31.5% vs 17.6%), and more grade 3 infections, such as febrile neutropenia (10.9% vs 5.8%). In comparison, those in the PF group experienced more grade 3 and 4 stomatitis (7.8% vs 4.6%), more grade 3 and 4 thrombocytopenia (7.8% vs 1.8%), and more grade 4 creatinine elevation (2.0% vs 0%).

Late toxicity was seen in both groups, with grade 4 larynx toxicity experienced by 6.2% of patients in the TPF group (2 patients received concurrent chemoradiotherapy following induction) and in 13.6% of patients in the PF group (3 received concurrent chemoradiotherapy after induction). The researchers note that other late toxic effects were comparable between groups, and that long-term follow-up is necessary to further evaluate late toxicities.

As the study was designed for advanced cancers of the larynx and hypopharynx, the findings should not be generalized to all sites of advanced cancers of the head and neck, the authors conclude.

"Future trials should be designed to compare the concomitant schedule with the induction approach using TPF," they write. "Emphasis should be put on the functional results of these approaches."

PLAVIX LOADING DOSE

Source: Coron Artery Dis

Clopidogrel pretreatment before primary percutaneous coronary stenting in patients with acute ST-segment elevation myocardial infarction: comparison of high loading dose (600 mg) versus low loading dose (300 mg); Jung JH, Min PK, Lee SH, Sung CW, Choi S, Cho JR, Lee N, Byun KH; Coronary Artery Disease 20 (2), 150-4 (Mar 2009)

BACKGROUND: Aggressive platelet inhibition is crucial to reduce myocardial injury and early cardiac events after coronary intervention. As compared with the conventional 300-mg dose, pretreatment with a 600-mg loading dose of clopidogrel significantly reduced periprocedural myocardial infarction (MI) in patients undergoing percutaneous coronary intervention (PCI). We investigated that the advantage of the 600-mg dose in inhibiting platelet aggregation more rapidly than the 300-mg dose may actually have special value for acute ST-segment elevation MI patients. METHODS: A total of 171 patients with ST-segment elevation MI underwent primary PCI. A 600-mg (n=73) or 300-mg (n=98) loading regimen of clopidogrel was given before the procedure. We did a follow-up of all patients clinically for 30 days after coronary intervention. The primary endpoint was the 30-day occurrence of death, MI, urgent revascularization, or stroke. RESULTS: The primary endpoint occurred in 1.4% (1 of 73) of patients in the high dose versus 11.2% (11 of 98) of those in the conventional loading dose group (P=0.013). Death, recurrent MI, urgent revascularization, and stroke were lower in patients treated with the high dose of clopidogrel compared with conventional dose. Safety endpoints were similar in the two groups. CONCLUSION: Pretreatment with a 600-mg loading dose of clopidogrel before the procedure is safe and, as compared with the conventional 300-mg dose, significantly reduces recurrent MI and urgent revascularization in patients with primary PCI.

DURATION OF ADJUVANT HORMONAL THERAPY IN PROSTATE CANCER PATIENTS

J Clin Oncol. 2009 Mar 23. [Epub ahead of print]

Related Articles, LinkOut

Impact of the Duration of Adjuvant Hormonal Therapy in Patients With Locally Advanced Prostate Cancer Treated With Radiotherapy: A Secondary Analysis of RTOG 85-31.

Souhami L, Bae K, Pilepich M, Sandler H.

McGill University Health Center, Montreal, Quebec, Canada; Radiation Therapy Oncology Group, Philadelphia, PA; University of California Medical Center, Los Angeles, CA; and University of Michigan, Ann Arbor, MI.

PURPOSE: Radiation Therapy Oncology Group 85-31 was a randomized trial of androgen suppression for life for patients with locally advanced prostate cancer. However, not all patients continued on the protocol-mandated long-term hormonal therapy despite no evidence of recurrence. We correlated duration of adjuvant hormonal therapy and outcomes among patients who prematurely discontinued hormonal therapy. PATIENTS AND METHODS: The protocol mandated pelvic radiotherapy followed by goserelin given indefinitely or until disease progression. There were 189 analyzable patients. Patients were divided in groups based on the tertile of hormonal therapy duration (HTD) as follows:

ENDOMETRIAL CANCER AND COLORECTAL CANCER RISK

Colorectal Cancer Risk Increased With Endometrial Cancer

NEW YORK (Reuters Health) Mar 25 - Endometrial cancer is associated with an elevated risk of colorectal cancer, but not breast cancer, according to study results in the April issue of Obstetrics & Gynecology.

In the study, the age-standardized incidence rate of colorectal cancer in women with endometrial cancer was 0.7% -- low but significantly higher than the 0.2% rate seen in the general population, Dr. Janice S. Kwon, from the University of British Columbia, Canada, and colleagues report.

The results also indicate that screening rates for colorectal cancer, as well as breast cancer, were roughly twice as high in women with endometrial cancer than in other women.

To assess the occurrence of secondary malignancies during follow-up for endometrial cancer, Dr. Kwon's team analyzed data from 3473 women who were diagnosed with the malignancy in Ontario, Canada, from 1996 to 2000. None of the women had a history of breast or colorectal cancer.

The 5-year recurrence and overall survival rates in the cohort were 15.0% and 79.3%, respectively. Follow-up care was typically provided by family physicians.

Although colorectal cancer was more likely to develop in study patients than in the general population, breast cancer was not. The age-adjusted incidence rates of breast cancer in the two groups were identical, 0.5%.

Screening rates for breast and colorectal cancer in the study group were 64.0% and 30.0%, respectively, compared with rates of 31.0% and 15.0% in the general population.

Age over 70 years and low income were both predictive of not receiving secondary cancer screening, the report shows.

"Over 44,000 women will be diagnosed with endometrial cancer this year in Canada and the US, and after 5 years approximately 35,000 of them will still be alive," the authors point out. "These endometrial cancer survivors have specific health risks that need to be addressed during their follow-up to maximize long-term survivorship."

GEMCITABINE AND CISPLATIN IN BREAST CANCER

J Clin Oncol. 2009 Mar 23. [Epub ahead of print]

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Phase II Studies of Gemcitabine and Cisplatin in Heavily and Minimally Pretreated Metastatic Breast Cancer.

Chew HK, Doroshow JH, Frankel P, Margolin KA, Somlo G, Lenz HJ, Gordon M, Zhang W, Yang D, Russell C, Spicer D, Synold T, Bayer R, Hantel A, Stiff PJ, Tetef ML, Gandara DR, Albain KS.

Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis, Sacramento; City of Hope National Medical Center, Duarte; and University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA; Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD; and Loyola University Chicago, Stritch School of Medicine, Department of Medicine, Division of Hematology/Oncology, Maywood, IL.

PURPOSE: Cisplatin and gemcitabine have single-agent activity in metastatic breast cancer, and preclinical data support synergy of the combination. Two parallel, phase II trials were conducted to evaluate the response rate, response duration, and toxicities of the combination. Genetic polymorphisms were analyzed for correlation with outcomes. PATIENTS AND METHODS: Eligible women had measurable disease and heavily or minimally pretreated metastatic breast cancer. The heavily pretreated protocol required prior anthracycline and taxane therapy; cisplatin as part of high-dose therapy was allowed. All patients received cisplatin 25 mg/m(2) on days 1 through 4 and gemcitabine 1,000 mg/m(2) on days 2 and 8 of a 21-day cycle with prophylactic granulocyte colony-stimulating factor in the heavily pretreated group. Sera from a subset of patients were evaluated by polymerase chain reaction restriction fragment length polymorphism for polymorphisms in 10 genes of interest. RESULTS: Of 136 women enrolled, 74 were heavily pretreated. Both protocols accrued to their two-stage design. The response rate for both the heavily and minimally pretreated cohorts was 26%, and the median durations of response were 5.3 and 5.9 months, respectively. In a multivariate analysis, hormone receptor-negative disease was associated with a higher response rate. The most common grades 3 or 4 toxicities were thrombocytopenia (71%), neutropenia (66%), and anemia (38%). In a subset of 55 patients, the xeroderma pigmentosum group D (XPD)-751, x-ray cross-complementing group 3 (XRCC3) and cytidine deaminase polymorphisms were significantly associated with clinical outcomes. CONCLUSION: Combination cisplatin and gemcitabine is active in metastatic breast cancer regardless of prior therapy. Genetic polymorphisms may tailor which patients benefit from this regimen.