PROGRESS IN HIV VACCINE RESEARCH

September 24, 2009 — A prime-boost HIV vaccine is safe and 31% effective in the prevention of HIV infection in the more than 16,000 adults who participated in the trial, according to the Surgeon General of the US Army, which sponsored the clinical trial of the vaccine.

"These new findings represent an important step forward in HIV vaccine research," Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), announced today in a National Institutes of Health (NIH) release. NIH provided major funding and other support for the study.

"For the first time, an investigational HIV vaccine has demonstrated some ability to prevent HIV infection among vaccinated individuals. Additional research is needed to better understand how this vaccine regimen reduced the risk of HIV infection, but certainly this is an encouraging advance for the HIV vaccine field," Dr. Fauci said.

The phase 3 placebo-controlled RV144 trial was launched in October 2003. It was led by principal investigator Supachai Rerks-Ngarm, MD, from the Thai Ministry of Public Health's Department of Disease Control, and was conducted in the Rayong and Chon Buri provinces of Thailand. It involved 16,402 men and women 18 to 30 years of age who had various levels of risk for HIV infection.

Investigators tested the safety and efficacy of a prime-boost regimen of 2 vaccines. The primer dose consisted of the ALVAC-HIV vaccine, a modified canarypox vaccine developed by Sanofi Pasteur in Lyon, France. The booster dose consisted of the AIDSVAX B/E vaccine, a glycoprotein 120 vaccine developed by VaxGen Inc., and now licensed to Global Solutions for Infectious Diseases, based in South San Francisco, California.

The booster vaccine is based on HIV subtypes B and E, the most common HIV strains in Thailand. Subtype B is also one of the most common strains found in the United States.

Participants received the ALVAC-HIV vaccine or placebo at enrollment and again after 1, 3, and 6 months. The AIDSVAX B/E vaccine or placebo was given to participants at 3 and 6 months. Participants were tested for HIV infection every 6 months for 3 years.

In the final analysis, 51 of 8197 participants who received the vaccine regimen became infected with HIV, compared with 74 of 8198 placebo recipients.

This level of efficacy in preventing HIV infection was found to be statistically significant, said Margaret I. Johnston, PhD, director of NIAID's Vaccine Research Program within the Division of AIDS, in the NIH release. She added that the vaccine regimen had no effect on the amount of virus in the blood of those who acquired HIV infection during the study.

"The Thai study demonstrates why the HIV vaccine field must take a balanced approach to conducting the basic research needed to discover and design new HIV vaccines and, when appropriate, testing candidate vaccines in people," Dr. Johnson said. "Both avenues provide critical information that will continue to help us better understand what is needed to develop a fully protective HIV vaccine."

HIGH DOSE DAUNORUBICIN FOR AML

September 24, 2009 — High-dose daunorubicin produced a higher rate of remission than the standard dose in patients with acute myeloid leukemia (AML), according to results from 2 large trials published in the September 24 issue of the New England Journal of Medicine.

The higher dose did not significantly increase adverse events or delay delivery of consolidation therapy in either study.

The results establish a new standard of care for AML — for some patients, says an accompanying editorial.

Different Ages in the 2 Trials

The patient population in the 2 trials differed widely in age. In the American trial, the median age was 48 years, and in the European trial (conducted in the Netherlands, Belgium, Germany, and Switzerland), the median age was 67 years.

In the American trial, the high-dose induction therapy (daunorubicin 90 mg/m² of body surface) resulted in improved overall survival, compared with the standard therapy of 45 mg/m² (23.7 vs 15.7 months; P =.003).

However, the beneficiaries of improved survival are younger patients (under age 50) and those who do not have adverse cytogenetic profiles, note the authors, led by Hugo F. Fernandez, MD, from the Moffitt Cancer Center and Research Institute in Tampa, Florida.

"The lack of an increase in toxic effects and the benefit in overall survival strongly argue for incorporating high-dose daunorubicin into the initial treatment of younger patients with AML, at least those with favorable- and intermediate-risk cytogenetic profiles," write the editorialists, Hervé Dombret, MD, and Claude Gardin, MD, from Université Paris in France.

The American authors agreed. "In younger patients, a dose of daunorubicin that exceeds the standard 45 mg/m² dose for induction should be considered the new standard of care," they write.

The European researchers did not have such strong words to offer because they did not find a survival benefit in their planned analyses. In post hoc analyses, they did find a survival benefit of high-dose daunorubicin in patients 60 to 65 years old, although they caution that this finding could be due to chance.

As a result, the European authors, headed by Bob Löwenberg, MD, from the Erasmus University Medical Center in Rotterdam, the Netherlands, conclude that the high-dose daunorubicin strategy could be "an alternative therapy" to high-dose cytarabine, which is effective in younger patients but "far too toxic" in those 60 years and older.

Not the First High-Dose Study

For more than 20 years, the standard induction therapy for attaining complete remission in AML has been an anthracycline — daunorubicin mostly — at a daily dose of 45 to 60 mg/m² of body surface area for 3 days, in combination with cytarabine for 7 days, the editorialists explain. Neither adding other drugs during the induction phase nor increasing the dose of cytarabine has led to improved survival, they add.

Previous studies have shown that various high doses of daunorubicin (70 to 95 mg/m² of body surface) improve the rate of remission, compared with the standard dose (45 mg/m²), but none have "definitively" shown an improvement in overall survival with the higher doses, write the American investigators.

In the new studies, this standard induction dose of daunorubicin was doubled. In the American trial, 657 patients with either primary or therapy-related AML were followed for a median of 25.2 months; all patients were 60 years of age or younger. Patients in complete remission continued with a consolidation phase that included either autologous or allogeneic stem cell transplantation.

In the trial conducted by the European collaborative, 813 patients with AML, including some with secondary AML or a high-risk myelodysplastic syndrome, were followed for a median of 40 months. All patients were 60 years of age or older, and a course of cytarabine followed for all those who survived the induction therapy.

Remission, Survival, and an Adverse Cytogenetic Profile

Significantly higher rates of remission were achieved with the higher dose than with the standard dose of daunorubicin in both studies (71% vs 57%, respectively, in American study and 64% vs 54% in the European study).

The rate of complete remission in the American trial was not as high as in some other trials because, the authors explain, the patients included those with an antecedent hematologic disorder (within previous 6 months) and those with multilineage dysplasia.

In addition, in the American study, the high-dose strategy did not significantly improve overall survival among patients with either the FLT3-ITD or MLL-PTD mutation. Other aspects of an unfavorable or adverse cytogenetic profile included MDR1 gene overexpression.

In the European trial, the 2-year rate of overall survival among those 60 to 65 years of age was 38% for the high-dose of group and 23% for the standard-dose group.

In the high-dose groups in both studies, there was no increase in early death rates, no delay in hematologic recovery, no affect on planned postremission therapies, and no increase in cardiac toxicities, observe the editorialists. The latter was "a relief," they suggest.

"On the basis of previous trials, a possible concern of dose intensification was an increase in cardiac toxic effects, which was not seen in either trial," they note.

However, it is still not entirely clear what the best dose of daunorubicin is, note the American authors.

"Whether standard-dose cytarabine with 90 mg of daunorubicin per square meter of body surface area is better than cytarabine with a 60 mg dose of daunorubicin (or idarubicin or mitoxantrone at equivalent doses) remains to be studied in future trials," write the study authors.

SORAFENIB IN BREAST CANCER

September 23, 2009 (Berlin, Germany) — Sorafenib (Nexavar) has shown promise in breast cancer in a phase 2b trial, and further studies are now planned.

The results were presented here at a presidential session of the 15th Congress of the European CanCer Organization and the 34th European Society for Medical Oncology Multidisciplinary Congress.

Sorafenib added to capecitabine (Xeloda) significantly improved progression-free survival, compared with capecitabine alone, in locally advanced or metastatic breast cancer.

The fact that both drugs were administered orally "may represent a unique and convenient treatment option for patients with breast cancer," said principal investigator José Baselga, MD, professor of medicine at the Vall d'Hebron Institute of Oncology in Barcelona, Spain.

Sorafenib is currently indicated for use in renal cell carcinoma and hepatocellular carcinoma. It was tried in breast cancer because a number of recent studies have shown "clear evidence that the role of angiogenesis is critically important," Dr. Baselga explained.

Inhibition of angiogenesis has been shown to be beneficial in breast cancer in studies with bevacizumab (Avastin), which received accelerated approval from the US Food and Drug Administration for this indication.

Sorafenib is another step in this approach, but it is active on many more targets and is also an oral drug, noted Anne-Lisa Børresen-Dale, PhD, from the Norwegian Radium Hospital in Oslo. Bevacizumab is active against the vascular endothelial growth-factor (VEGF) receptor; sorafenib, in addition to inhibiting VEGF, acts on the platelet-derived growth-factor receptor and several other tyrosine kinases.

"This means that sorafenib offers a broader approach," Dr. Børresen-Dale told Medscape Oncology. This does not necessarily mean that it will have a bigger clinical impact, but "it is an interesting idea to test," she said, adding that the results so far have been "very promising."

Increase in Progression-Free Survival

The new study, known as SOLTI-0701, compared sorafenib plus capecitabine with capecitabine alone. Sorafenib 400 mg was given twice daily, and capecitabine1000 mg/m² was given twice daily for 14 of every 21 days, which is the dose that is normally used in clinical practice and slightly lower than the dose that was approved (1250 mg/m²), Dr. Baselga explained.

The study was conducted in 229 patients with unresectable locally advanced or metastatic breast cancer (HER-negative), who had previously undergone only 1 course of or no chemotherapy.

Median progression-free survival was significantly higher in the combination group (6.4 vs 4.1 months for capecitabine alone; P = .0006), with a hazard ratio (HR) of 0.576 (95% confidence interval 0.410 - 0.809).

"This shows a 42% reduction in the risk of disease progression," Dr. Baselga said.

The difference in progression-free survival was statistically significant in patients who had not received any previous chemotherapy (first line HR, 0.498) and in those who had already received 1 previous regimen (second line HR, 0.652), he reported.

However, there was no significant difference in the overall response, and "we are still waiting for data on overall survival," he told meeting attendees.

There was a higher incidence of hand and foot syndrome in patients who were treated with the combination of sorafenib and capecitabine, and 15 patients (13.4%) taking the combination withdrew from the trial because of adverse effects, whereas only 9 patients (8%) taking capecitabine alone did.

But Dr. Baselga noted that the combination "was tolerable and the side effects were mostly manageable. No new or unexpected side effects were observed."

"The results suggest that sorafenib may be a valuable addition to chemotherapy in breast cancer," Dr. Baselga said.

The study was funded by Onyx and Bayer, the manufacturers of sorafenib.

15th Congress of the European CanCer Organization (ECCO 15) and the 34th European Society for Medical Oncology (34th ESMO) Multidisciplinary Congress: Abstract 3LBA. Presented September 23, 2009.

MALARIA ALERT

HONG KONG (Reuters) Sep 23 - The World Health Organisation warned on Wednesday that the parasite that causes malaria is increasingly resistant to artemisinin, the best drug around, and failure to contain this trend would bring serious consequences.

"This (Asia Pacific) region has traditionally been the focus of resistance to antimalarial drugs and now we have artemisinin resistance primarily on the Thai-Cambodian border," said John Ehrenberg, WHO regional adviser on malaria and other vectorborne and parasitic diseases.

"If it is not contained, it can have global implications and the most serious one would be in Africa which has a high disease burden and the highest mortality rates," he told Reuters on the sidelines of a regional meeting of the WHO in Hong Kong.

Although malaria is preventable and treatable, there were still between 189 million to 327 million cases in 2006, resulting in between 610,000 to 1.2 million deaths.

Half the world's population is at risk, particularly the poor and those living in remote areas with limited healthcare access. A child dies from malaria every 30 seconds.

Artemisinin is the best drug available but misuse and over-prescription have led to the parasite becoming resistant to it.

The best way to prolong the use of the drug would be to use it in combination with other antimalarial drugs. Nearly all the Asia Pacific region countries that suffer most from the disease pledged on Wednesday to do that.

"Experts have been calling for combined therapy to make sure this problem does not arise... all endemic countries in the region, except one, have adopted (the plan) and we are hoping to get the 10th pretty soon," Ehrenberg said.

The 10 countries are Cambodia, China, Laos, Malaysia, Papua New Guinea, the Philippines, South Korea, Solomon Islands, Vanuatu and Vietnam. In 2008, these 10 states reported 248,141 confirmed cases of malaria and 1,005 deaths.

Under the agreement, the use of artemisinin alone for treating malaria must be banned by 2015.

All 10 states will also help fight counterfeit antimalarial drugs, again a major cause of deaths.

In recent years, parts of Asia have been awash with fake antimalarial drugs. They contain little or no active ingredient that would fight the disease and many people have died because of that. Some of the fakes have been traced back to illegal factories in China, according to experts.

"Low quality and counterfeit drugs is a serious concern... any inadequate way of treating malaria can lead to death. Malaria kills a lot of children especially in Africa when you don't treat it properly, it leads to death," Ehrenberg said.

"Many countries rely a lot on the private sector. Unregulated drug policy can jeopardise efforts to (drug) resistance containment. Getting the private sector onboard is critical."

PANCREATIC INCIDENTALOMA

NEW YORK (Reuters Health) Sep 18 - A substantial proportion of pancreatic "incidentalomas" - asymptomatic lesions detected incidentally -- are malignant or pre-malignant, Israeli researchers report in the September issue of the Journal of the American College of Surgeons.

Dr. Guy Lahat, at the MD Anderson Cancer Center, Houston, and his colleagues note that with improved technology, these lesions are being found more often. But, Dr. Lahat told Reuters Health, "clinicians all over the world still hesitate to refer their patients for pancreatic surgery due to its relatively high morbidity and mortality rates."

He and his team reviewed data on 475 pancreatectomies: 64 (13.5%) done for incidentalomas and 411 (86.5%) for symptomatic tumors.

Twenty-two of the subclinical lesions (34%) were malignant compared with 278 (68%) of the symptomatic tumors. However, 38 of the incidentalomas (59%) were pre-malignant, and only 4 (6%) carried little or no risk of progression.

Overall, the incidentaloma patients had a longer median disease-specific survival compared to those with symptomatic tumors (145 versus 46 months). In those with adenocarcinomas, the corresponding periods were 22 and 19 months.

Five-year disease-specific survival for patients treated for intrapapillary mucinous cystic tumor/mucinous cystadenoma was 94% with incidentalomas versus 68% with symptomatic tumors.

"The take home message," Dr. Lahat said, is that "incidental findings in the pancreas may not be innocent and therefore should be managed as potentially malignant until proven otherwise."

"Moreover," he concluded, "our data suggest that early intervention may prevent invasive cancer and improve survival."

J Am Coll Surg 2009;209:313-319.

SMOKING DOES NOT PREDICT CARDIOVASCULAR DEATH!

NEW YORK (Reuters Health) Sep 21 - Could it be good news for smokers? Current and past-smokers with coronary artery disease, cerebrovascular disease, or peripheral artery disease have less than half the cardiovascular mortality than never-smokers, the initial findings from a new study suggest.

But don't be so quick to tell your patients to light up: After accounting for potential confounders, the association was not statistically significant.

"The relationship between smoking habit and outcome in patients with established arterial disease remains controversial," Dr. M. Monreal, of Hospital Universitari Germans Trias i Pujol, Barcelona, Spain, and colleagues write in the September issue of the European Journal of Internal Medicine.

"Some studies have found that smoking may be associated with a better outcome among patients with acute coronary disease," they note. "As for patients with cerebrovascular disease or peripheral artery disease, there is little information on the influence of smoking on outcome."

The researchers used data from FRENA, an ongoing, observational registry of consecutive outpatients with symptomatic coronary artery disease, cerebrovascular disease, or peripheral artery disease, to compare the incidence of cardiovascular death during follow-up of all enrolled patients according to their smoking status.

A total of 2501 patients from 24 participating Spanish hospitals had been enrolled in FRENA as of May 2008. Of these, 439 (18%) were current smokers, 1086 (43%) were past-smokers, and 976 (39%) never smoked.

Compared to never-smokers, current and past-smokers were younger, more often male, and more likely to have chronic lung disease. Diabetes, hypertension, and heart failure were less common in current- and past-smokers.

There were a total of 250 major cardiovascular events in 239 patients (9.6% of the original 2501) over a mean follow-up of 14 months. A total of 123 (4.9%) patients died (cardiovascular death, 68) during follow-up.

Significantly lower cardiovascular mortality was observed among current smokers and past-smokers compared to non-smokers (1.1 per 100 patient-years in current smokers, 1.9 in past-smokers, and 3.5 in non-smokers). Similar results were found when patients with coronary artery disease, cerebrovascular disease, or peripheral artery disease were considered separately.

The mean age at cardiovascular death was 82 years for never-smokers, 70 years for past-smokers, and 67 years for current smokers. The mean age for non-cardiovascular death was 79, 74, and 69 years, respectively.

"On univariate analysis, age >70 years, body mass index >28, chronic lung disease, heart failure, diabetes, prior history of artery disease, non-smoking status, atrial fibrillation, renal insufficiency, and the use of some drugs were significantly associated with an increased cardiovascular mortality," Dr. Monreal and colleagues write. However, on multivariate analysis, none of the variables, including smoking status, were independent predictors of cardiovascular death.

CETUXIMAB IMPROVES SURVIVAL IN NSCLC

September 23, 2009 (Berlin, Germany) — Cetuximab (Erbitux) combined with chemotherapy improves survival in patients with nonsmall-cell lung cancer (NSCLC), according to an analysis of 4 randomized phase 3 trials.

The results of the meta-analysis, which were reported here at the 15th Congress of the European CanCer Organization and the 34th European Society for Medical Oncology Multidisciplinary Congress, demonstrated that patients who received cetuximab plus chemotherapy had a 13% lower chance of dying within 3 years of follow-up, compared with those who received chemotherapy alone. This held true regardless of the specific chemotherapy regimen.

In addition, patients who received cetuximab experienced slower disease progression and an increased likelihood of tumor shrinkage.

"The results of this study support the notion that cetuximab works," in NSCLC, said Robert Pirker, MD, professor of medicine at the Medical University of Vienna in Austria. "It strengthens the evidence thus far."

Dr. Pirker, who was approached by Medscape Oncology for independent comment, pointed out that at this time, cetuximab has not yet been approved in Europe for use in NSCLC. "Right now it is used primarily in clinical trials, although there may be some off-label use," he said.

"We are awaiting its approval, and feel it will be of benefit to these patients," he added.

As previously reported by Medscape Oncology, results of the phase 3 FLEX (First-Line Erbitux in Lung Cancer) trial showed that cetuximab added to a regimen of vinorelbine/cisplatin chemotherapy offered a small survival advantage in NSCLC patients. Three other randomized trials demonstrated similar results when cetuximab was added to different platinum doublets.

To confirm the robustness of the efficacy results of these studies, Jean-Louis Pujol, MD, chair of thoracic oncology at Montpelier Academic Hospital and professor of medicine at Montpelier University in France, and colleagues conducted a meta-analysis of these 4 studies.

There were individual data for 2018 patients who participated in the 4 studies, which Dr. Pujol and his team analyzed for overall survival, progression-free survival, and objective response rate.

"When we put all of the populations together, there was consistency, and all histologies were included in this study," said Dr. Pujol.

There were, however, some slight differences in the trials, he pointed out. For example, 2 of the 4 studies required positive immunostaining against epidermal growth-factor receptor for inclusion criteria.

Efficacy Seen at All End Points

The meta-analysis demonstrated a significant benefit across all efficacy end points for patients who received cetuximab in conjunction with their chemotherapy, compared with those who did not.

For overall survival, the hazard ratio (HR) was 0.87, which corresponded to a 13% reduction in the risk for death. This was statistically significant (P = .010).

Dr. Pujol also pointed out that patients receiving cetuximab had a longer median survival (10.3 months for chemotherapy plus cetuximab vs 9.4 months for chemotherapy alone). "The absolute benefit at 1 year was 5%," he said.

The other end points also showed a benefit for cetuximab. For progression-free survival, the HR was 0.899, corresponding to a 10% reduction in risk (P = .038). Patients who received cetuximab also had a higher chance of being responders, with an odds ratio of 1.463 (P < .001).

"This corresponds to an almost 50% greater chance of being a responder," explained Dr. Pujol. The increase rose "from 24% to 36%, and that was highly significant."

Response in Caucasians Significant

A subanalysis was conducted on the basis of ethnicity. "We know that NSCLC behaves differently according to ethnicity, so we felt it was important to look at a subgroup of Caucasians, as they are the prominent ethnic group in Europe," he said.

The researchers observed that there was a statistically significant benefit favoring cetuximab among Caucasians, and it had a more pronounced effect in this group. The HR of 0.84 corresponded to a risk for death of 16%.

Caucasian patients who received combination chemotherapy plus cetuximab proved to have a better prognosis than those who didn't, with a median survival of 9.9 months, compared with 8.8 months for those who didn't. The absolute benefit at 1 year was 6%, and the absolute benefit at 2 years was 4.5%. Both were significant (P = .012).

"This meta-analysis confirms the efficacy of cetuximab for the 3 end points, and the benefit is statistically significant and is more pronounced in the Caucasian population," Dr. Pujol concluded, "with a striking benefit at 1 and 2 years."

15th Congress of the European CanCer Organization (ECCO 15) and the 34th European Society for Medical Oncology (34th ESMO) Multidisciplinary Congress: Abstract 9005. Presented September 22, 2009.

NEW GENE VARAIANTS FOR PROSTATE CANCER RISK

September 23, 2009 — New findings of multiple gene variants associated with prostate cancer susceptibility may enable risk prediction and targeted screening of high-risk individuals, according to 4 studies published online September 20 in Nature Genetics. Notable among the risk variants is a collection of loci — some reported by each of 3 independent research groups — at 8q24 on the long arm of chromosome 8.

Two international studies were led by a group of researchers in the United Kingdom. Their first genomewide association study (GWAS) identified 7 new loci associated with prostate cancer susceptibility in a 3-stage investigation, with the final stage involving 16,229 patients with prostate cancer and 14,821 control individuals. Risk loci with genomewide significance (P = 1.6 × 10⁻⁸ to 2.7 × 10⁻³³) were found on chromosomes 2, 4, 8 (other than 8q), 11, and 22.

Several risk loci were found in or near genes such as ITGA6, which participates in cell adhesion and signaling, and NKX3.1, which codes for a protein in the HDAC1 pathway.

"This pathway is involved in chromatin modeling and is hormone driven," said lead author Rosalind A. Eeles, PhD, FRCP, FRCR, from the Institute of Cancer Research and the Royal Marsden National Health Service Foundation Trust, Sutton, Surrey, United Kingdom, in her email to Medscape Oncology. "These inhibitors reduce cell division, which is increased in prostate cancer as a result of uncontrolled chromatin remodeling," explained Dr. Eeles.

Their second study used data from stages 1 and 2 of the previous work (5504 patients with prostate cancer, 5834 control patients) to identify prostate cancer risk loci on 8q24, the region "currently considered the most important susceptibility region for [prostate cancer], or indeed for any common cancer," the authors point out. This study found 8 independent risk variants (3 previously reported) with P values from 4.2 × 10⁻⁶ to 6.8 × 10⁻²⁴.

In a genomewide association "follow-on study," scientists at deCODE genetics identified 4 additional prostate cancer risk variants, none identical to those reported above. One variant was on chromosome 3, another on chromosome 19, and 2 were in region 8q24; genomewide significance ranged from P = 6.2 × 10⁻¹⁵ to P = 4.7 × 10⁻¹⁰. This study drew on data from the Icelandic GWAS and from the replication genotyping study of the National Cancer Institute's Cancer Genetic Markers of Susceptibility project. Size of the prostate cancer and control populations differed between variants, but all exceeded 8200 and 16,900, respectively.

Region Has Important Role

"This [8q24] is a region that seems to have a very important role when it comes to controlling genetic risks for all kinds of cancers," commented senior author Kari Stefansson, MD, president and chief executive officer of deCODE genetics, Reykjavik, Iceland, in a telephone interview with Medscape Oncology. "We don't know how it does so. We don't know what fundamental biochemical perturbation is caused by variants in this region, but it is certainly one that we will be looking at." he said. "And others are working on trying to do the same."

A fourth, independent study reported the identification of a significant (P = 1.3 × 10⁻¹⁰) risk locus on 8q24, substantiating 1 of those identified in the paper by Eeles and colleagues, but in a larger population (10,286 patients with prostate cancer, 9135 control individuals). Interestingly, this report notes that region 8q24 contains no known protein-coding genes. "The 8q24 region is a 'gene desert,' " observed first author Meredith Yeager, PhD, from the Core Genotyping Facility, SAIC-Frederick, Inc, NCI-Frederick, Maryland, and Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, in an email to Medscape Oncology.

However, she added, "A very compelling proto-oncogene (MYC) is located downstream of this region. Already, some groups have published evidence of a functional relationship between one of the associated variants and this gene," said Dr. Yeager. "While the results are exciting, much more work is needed to explore the relationship among these variants, MYC, and other genes as well."

Medscape Oncology received comments from Charis Eng, MD, PhD, director and chair of the Cleveland Clinic Genomic Medicine Institute, and professor and vice chair of the Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio. " We have not utilized any of the prostate GWAS data for treatment because often the culprit genes are still uncertain," Dr. Eng explained in an email.

Risk Variants: Drug Targets or Screening Tools?

"Unlike other high-penetrance susceptibility genes...all these multiple GWAS-derived susceptibility genes have a very low one-to-one correlation.... When that is the case, one cannot (and should not) target drug treatment. Importantly, these are predisposition genes; ie, what kicks the disease off, but not what causes progression," added Dr. Eng. "Perhaps we should view them as helping in prevention and limiting initiation/progression and not cure."

Dr. Stefansson also feels that their 4 new risk genes are not potential targets: "I cannot say that these provide us with...targets. I think that would be a stretch to say that," he said.

The deCODE report went on to analyze all variants known to affect prostate cancer risk in Icelandic men and showed that men in the top 1.3% of the risk distribution have a 2.5-fold or greater risk compared with the population average. This represents a 30% lifetime risk of being diagnosed with the disease compared with the 12% risk of the general population of developing prostate cancer by age 75 years.

"These risk variants can identify approximately half a percent of the population of men who have over 3 times greater [risk] than the average risk in the population of prostate cancer," said Dr. Stefansson. He noted that the disease prevalence in Iceland and the United States is about 16%, which translates into a lifetime risk for prostate cancer of roughly 50% for the high-risk group.

"If you believe in the value of risk stratification, and can contain the damage from cancer, this absolutely would provide for a...test with risk stratification. You can find men who are at 50% risk of developing the disease. So that is what I see as the most important value of these discoveries," he emphasized. "Let's put it this way: If our society concludes that we should screen for prostate cancer, this is probably the best way to make that task manageable."

WE ARE THE CHAMPIONS

For the first time in decades, the oncology therapeutic area has overtaken cardiovascular medicine as the leading revenue contributor

16.09.09

Category: Scientific News

Sales trends by therapeutic area: 2008–2013

Michael Goodman of the AVOS Life Sciences, Morrisville, North Carolina, USA wrote in the September 2009 issue of Nature Reviews Drug Discovery that AVOS has analysed the revenue contribution of each therapeutic area to the major Rx drug portfolios (MRDP; the collection of branded drugs that are each predicted to achieve at least US$500 million in annual sales) of the 14 large-cap pharmaceutical companies. For the first time in decades, the oncology therapeutic area has overtaken cardiovascular medicine as the leading revenue contributor to the average MRDP of the group, which is mirrored in the continuing interest of companies in oncology products, despite the risks posed by issues such as uncertain trial endpoints, unprecedented biology and scarcity of trial enrollees. Average revenues from oncology products are predicted to rise from $2.9 billion in 2008 to $3.3 billion in 2013 (with a compound annual growth rate (CAGR) of 3%), accounting for 17.8% of the average MRDP in 2013, compared with 12.6% for cardiovascular medicine, which shows a 3% reduction in CAGR.

In 2008, cardiovascular medicine was the leading therapeutic area in terms of revenue for four companies (Bristol–Myers Squibb, Pfizer, Sanofi–Aventis and Schering–Plough), but is the leader for only two companies (AstraZeneca and Sanofi–Aventis) in 2013. The oncology therapeutic area is the leading revenue contributor for one company (Roche) in 2008 and for two companies (Roche and Novartis) in 2013. A major reason for the rise of oncology as a revenue contributor in the group overall is Roche's oncology franchise, sales for which are predicted to grow from $17.2 billion in 2008 to $25.9 billion in 2013 at a CAGR of 7%. This growth is driven by the success of bevacizumab, with sales of $9 billion in 2013, rituximab, and trastuzumab. Novartis's oncology MRDP has a CAGR of 4% over the forecast period, growing from $4.9 billion to $5.9 billion, driven primarily by the success of imatinib, with sales of $4.6 billion in 2013. When considering the two leading revenue contributors at each company, Merck is the only company for which both of these change from 2008 to 2013: Merck's top two therapeutic areas in 2008 (respiratory medicine and antihypertensives) switch to the metabolic therapeutic area and vaccines by 2013.

In terms of 2008–2013 growth by therapeutic area, the metabolic therapeutic area leads the peer group with 11% CAGR, followed by vaccines (9% CAGR), immunology (8% CAGR) and antifungals (4% CAGR). The therapeutic areas for which revenue most rapidly declines over the forecast period are antihypertensives (–15% CAGR), antibiotics (–14%), gastrointestinal medicine (–10%), and psychiatry (–10%). As a sign of how far revenue from the cardiovascular therapeutic area has fallen, immunology looks set to overtake it as the second highest revenue contributor just beyond the forecast horizon in 2014.

AVOS Life Sciences bases the analysis in its Large Cap Pharma Performance Outlooks (LCPPO) on sell-side investment analyst research. The source for analyst reports was Thomson One (formerly First Call). Each of the analytical perspectives offered in LCPPO was based on ~150 analyst reports from ~25 investment houses covering the 14 large-cap pharmaceutical companies. These companies are: Abbott Labs; Amgen; AstraZeneca; Bristol-Myers Squibb; Eli Lilly; GlaxoSmithKline; Johnson & Johnson; Merck; Novartis; Pfizer; Roche; Sanofi-Aventis; Schering Plough; and Wyeth. LCPPO currently tracks Pfizer, Wyeth; Merck and Schering-Plough separately and will begin to show them as merged entities when analysts begin forecasting a merged product-level model in their reports.

To allow systematic analysis, AVOS aggregated, cleaned, and aligned sell-side investment analyst forecast data to ensure that the data is rigorously consistent with respect to product names or income statement figures. The historical company-reported revenues from the previous year were used as a check to be certain that the forecasts were captured correctly. Similarly, for the income statement data, analysts often give several ‘EPS’ numbers, so AVOS relied on historical data to make sure that the correct figures are captured.

A NEW EPOTHILONE FOR FALLOPIAN AND PRIMARY PERITONEAL CANCER

EMEA approves patupilone for the treatment of primary peritoneal cancer and fallopian tube cancer

15.09.09

Category: Scientific News

Committee for Orphan Medicinal Products adopted opinions for designation of 13 medicines as orphan medicinal products

The European Medicines Agency (EMEA) Committee for Orphan Medicinal Products (COMP) held its 104th plenary meeting on 1-2 September 2009. During the meeting, members of the Committee elected the new Chairperson and the Vice-Chairperson for a term of three years. Dr Kerstin Westermark (Sweden) was elected as Chairperson, and Mrs Birthe Byskov Holm (Patient Representative nominated by the European Commission) was elected as Vice-Chairperson.

The COMP adopted 13 positive opinions recommending the following medicines for designation as orphan medicinal products to the European Commission:

• Patupilone for treatment of primary peritoneal cancer, Novartis Europharm Limited.
• Patupilone for treatment of fallopian tube cancer, Novartis Europharm Limited.

The review began on 5 June 2009 with an active review time of 90 days.

For the following anti-cancer medicines the EMEA review began on 10 July 2009 with an active review time of 55 days.

• 5'-O-(trans-9''-octadecenoyl)-1-beta-D-2'deoxy-2',2'-difluorocytidine for treatment of pancreatic cancer, Clavis Pharma ASA.
• Anti-EphA2 monoclonal antibody conjugated to maleimidocaproyl monomethylauristatin phenylalanine for treatment of ovarian cancer, MedImmune Ltd.
• Masitinib mesilate for treatment of pancreatic cancer, AB Science.
• N-[(2S)-2,3-dihydroxypropyl]-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide
• hydrochloride for treatment of pancreatic cancer, Merck KGaA.
• NGR-human tumour necrosis factor for treatment of hepatocellular carcinoma, MolMed S.p.A.

GEFITINIB FIRST LINE IN NSCLC NON SMOKERS

Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma

17.09.09

Category: Scientific News

Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia

Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non–small-cell lung cancer. In phase 3, open-label study, Dr Tony S Mok of the Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, HKSAR, China and colleagues from different East Asian sites randomly assigned previously untreated patients with advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival (PFS). The 12-month rates of PFS were 24.9% with gefitinib and 6.7% with carboplatin–paclitaxel. The study met its primary objective of showing the non-inferiority of gefitinib and also showed its superiority, as compared with carboplatin–paclitaxel, with respect to PFS in the intention-to-treat population (P <>

PERIODONTITIS AND HEAD NECK CANCER

NEW YORK (Reuters Health) Sep 11 - Chronic periodontitis may be a risk factor for head and neck squamous cell carcinoma (HNSCC) and this association is modified by smoking status, according to an article in the September issue of Cancer Epidemiology, Biomarkers, and Prevention.

At the Roswell Park Cancer Institute in Buffalo, New York, researchers found that each millimeter of alveolar bone loss increased the risk of HNSCC by 4.36-fold. This association was strongest for malignancies in the oral cavity, followed by those in the oropharynx and larynx.

Dr. Mine Tezal from the State University of New York in Buffalo and her colleagues note that 266 patients with primary HNSCC and 207 controls were involved in the study. Periodontitis, as reflected by alveolar bone loss, was diagnosed on panoramic x-rays by an examiner who was unaware of the patients' cancer status.

The link between gum disease and HNSCC was seen even in subjects who had never used tobacco or alcohol. In fact, the association between alveolar bone loss and HNSCC in never smokers (OR 5.96) was intermediate between that in current smokers (OR 2.85) and former smokers (OR 7.59).

In patients with oral cavity cancers, a higher rate of poorly differentiated disease was seen in those with periodontitis: 32.8% vs. 11.5% (p = 0.038).

"Confirmatory studies with more comprehensive assessment of smoking, such as duration, quantity and patterns of use, as well as smokeless tobacco history are needed," Dr. Tezal said in a statement.

FOUR VACCINES APPROVED FOR H1N1 INFLUENZA

September 15, 2009 —The US Food and Drug Administration (FDA) announced today that it has approved 4 vaccines against the 2009 influenza A (H1N1) virus, formerly known as "swine flu." The vaccine lots are expected to be available and distributed within the next 4 weeks.

FDA Commissioner of Food and Drugs Margaret A. Hamburg, MD, said she thought Tuesday's approval was good news for the nation's response to the H1N1 influenza virus. "This vaccine will help protect individuals from serious illness and death from influenza," she said.

The approval comes at a time when the Centers for Disease Control and Prevention (CDC) is reporting that visits to physicians around the country for influenza-like illness are increasing and are higher than expected at this time of year. The vaccines that are currently available against 3 seasonal influenza virus strains will not protect against the 2009 H1N1 virus.

The FDA said that the vaccines, based on early data, effectively elicit an immune response in most healthy adults about 8 to10 days after vaccination. Clinical studies are still underway to produce an optimal dose for children, with results expected in the near future.

Meanwhile, the CDC stresses that influenza is primarily spread through person-to-person contact, by the coughing or sneezing of infected people, and recommends that infected people stay home and limit their contact with others to keep from infecting them.

The newly approved vaccines are being made by CSL Limited, MedImmune LLC, Novartis Vaccines and Diagnostics Limited, and Sanofi Pasteur Inc. All 4 firms reportedly use the same processes to manufacture the H1N1 vaccines. As with the seasonal influenza vaccine, some lots of the H1N1 vaccine will contain the preservative thimerosal and others will not. The FDA has been continuing its efforts toward reducing thimerosal used in vaccines.

The FDA warns that persons with known allergies to chicken eggs or any other substance in the vaccine should probably not be vaccinated, although in the ongoing clinical trials, the vaccines have been well tolerated. The most common adverse effect is soreness at the injection site; other adverse effects can include a mild fever, body aches, and fatigue for a couple of days after vaccination. For the nasal spray delivery system, the most common adverse effects were runny nose, nasal congestion in all ages, sore throats in adults, and fever in children aged 2 to 6 years.

The FDA is working with different organizations regarding adverse event monitoring, information sharing, and an overall analysis during and after the 2009 H1N1 vaccination program, according to the news release. "As with any medical product, unexpected or rare serious adverse events may occur," the FDA notes.

INTEGRIN EXPRESSION AND CANCER AGGRESIVENESS

The authors believe that this finding may explain why expression of integrin-alphaVbeta3 is associated with more aggressive behavior for pancreatic cancers and a host of other tumors. Moreover, testing for this expression may help guide treatment decisions, they add.

Integrins are known to regulate adhesion-dependent growth, but the new findings suggest that integrin-alphaVbeta3 also has an adhesion-independent role, Dr. David A. Cheresh, from the University of California, San Diego, and colleagues note.

In the new study, reported in the September 6th Advance Online issue of Nature Medicine, the researchers found that alphaVbeta3 expression in carcinoma cells was associated with increased anchorage-independent tumor growth in vitro and with greater lymph node metastases in vivo.

Further analysis showed that c-Src recruitment to the beta3 integrin cytoplasmic tail was critical for the effects on tumor growth and lymph node metastases to occur.

Drug blockade of c-Src kinase activity with dasatinib or decreased expression of c-Src or alphaVbeta3 blocked anchorage-independent growth and suppressed metastasis, but had no effect on tumor cell migration or invasion.

"We discovered an unexpected pathway that accounts for increased malignancy in a population of some of the most dangerous cancers," Dr. Cheresh said in a statement. "There are features of the findings that allow us to implicate dasatinib not just for a single tumor type, but for all tumors with the malignant signature."

Nat Med 2009.

OBESITY HINDERS CHEMOTHERAPY IN PEDIATRIC LEUKEMIA

September 21, 2009 — Having previously found that obesity in children 10 years and older is associated with a 50% increased recurrence of acute lymphoblastic leukemia, researchers now have a possible explanation for these relapses.

The underlying problem might be that adipocytes, or fat cells, provide a protective niche for leukemia cells during therapy, write investigators in a paper published online September 22 in Cancer Research.

"We were surprised to find leukemia cells in the fat tissue," said the study's senior author Steven D. Mittelman, MD, PhD, in a press statement. Dr. Mittelman is an assistant professor of pediatrics, physiology, and biophysics at the Keck School of Medicine, University of Southern California in Los Angeles.

Dr. Mittelman explained that, in their new study of mice with leukemia, obese mice had higher relapse rates than lean mice after treatment with the first-line chemotherapeutic agent vincristine.

Obesity evidently impaired the effect of vincristine; progressive leukemia developed in 7 of 12 obese mice treated with vincristine but in only 3 of 12 lean control mice (P = .03).

Notably, leukemia cells were visible in "fat pads" from the mice, write Dr. Mittelman and colleagues.

The investigators cultured the cells and found that, in vitro, they were still sensitive to vincristine. "These findings support the concept that adipose tissue can be a sanctuary site for leukemia during vincristine treatment," write the study authors.

"This study provides striking experimental support for the clinical observations that obesity is associated with poor prognosis in multiple cancers," said David Hockenbery, MD, who was not involved with the study. He is a member of the Fred Hutchinson Cancer Research Center and professor of internal medicine at the University of Washington in Seattle.

Clinical Implications

In effect, adiposity may cause vincristine to be underdosed in overweight children, suggest the authors, meaning that clinical outcome can be greatly affected. And underdosing could be worsened by the fact that chemotherapies are often capped to prevent dose-dependent toxicities. Thus, if a child's body surface area, which dictates dose, indicates a higher dose, a clinician might not administer it for fear of toxicities.

If obesity does in fact cause lower vincristine exposure in children (and not just mice), then pharmacokinetic experiments in obese patients will be needed to "rigorously address this issue," write the study authors.

The current study was inspired by research led by Los Angeles–based researchers at the city's Childrens' Hospital. In a cohort of 5420 children, including 262 obese children who were 10 years or older, obesity at the time of diagnosis independently increased relapse rates by about 50% (J Clin Oncol. 2007;25:2063-2069).

Or, Did the Chemo Get Absorbed by the Fat Tissue?

The researchers considered another explanation, aside from the idea of leukemia cells finding a safe haven in fat tissue, for the different outcomes of their obese and lean mice. Namely, the possibility that the chemotherapy (vincristine) might have accumulated in the adipose tissue to such a degree that it weakened the drug's effect on the leukemia cells.

However, that did not appear to be the explanation, the authors conclude. They found that vincristine accumulates in adipocytes more than in other cells, such as fibroblasts, but they also found that this did not affect drug levels in the leukemia cells.

Whatever the exact mechanics, there is an association between adiposity and increased morbidity from leukemia and other cancers (breast, colon, and prostate), note the authors. Understanding the association is crucial in any effort to prevent patient deaths. In pediatrics, adiposity is a significant problem, with 32% of American children overweight and 16% obese, note the authors.

The new findings complement other recent cancer research, say the authors, which has found that adipocytes impair the proliferation of normal hematopoietic cells and support the growth of malignant cells, including multiple myeloma cells.

The study was supported in part by a National Institute of Child Health and Development K12 Award and by the National Cancer Institute Centers for Transdisciplinary Research on Energetics and Cancer. The researchers have disclosed no relevant financial relationships.

Cancer Res. Published online before print September 22, 2009.

REMOVAL OF PRIMARY TUMOR IN METASTATIC BREAST CANCER

September 21, 2009 (Berlin, Germany) — Surgical removal of the primary tumor in patients with metastatic breast cancer — which is not currently standard practice — could greatly improve survival. According to data from 1 study presented here at the 15th Congress of the European CanCer Organization and the 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, tumor removal was associated with a doubling of overall survival.

"Removing the tumor was associated with a 40% reduction in mortality," said study author Jetske Ruiterkamp, MD, a surgical resident at the Jeroen Bosch Hospital in Den Bosch, the Netherlands.

The median survival of patients who underwent surgery was substantially longer than those who did not (31 months vs 14 months). "The 5-year survival rates were 24.5% for patients who had their tumor removed, compared with 13.1% for those who didn't," explained Dr. Ruiterkamp during a press briefing. This 5-year survival difference was highly significant (P < .0001).

In the Netherlands, 1 of 9 women are diagnosed with breast cancer, and of this cohort, 3% to 10% have distant metastases at the time of their diagnosis. Generally, advanced-stage breast cancer is treated palliatively, and the primary tumor is removed only if it is symptomatic, Dr. Ruiterkamp said.

However, recent data suggest that removing the primary tumor could have a beneficial effect on outcome and extend survival. In a retrospective study, Dr. Ruiterkamp and colleagues analyzed the impact that surgical resection had on patient survival, after accounting for potential confounders such as age and associated comorbidities.

A total of 15,769 women were diagnosed with breast cancer in the south of the Netherlands between 1993 and 2004. Of this group, 728 patients had distant metastases at their initial diagnosis, representing 5% of all breast cancer patients in that region of the country. Approximately 40% of the patients with advanced-stage disease had undergone surgical removal of the primary tumor.

The researchers conducted stratified analyses to compare surgically and nonsurgically treated patients in subgroups that were defined by factors such as age, T-classification, comorbidity, and the number of metastatic sites. In addition, a multivariate analysis was performed to evaluate the independent contribution that surgery might have had.

The multivariate analysis showed surgery to be an independent prognostic factor for overall survival, after adjustment for age, period of diagnosis, T-classification, comorbidity, number of metastatic sites, use of locoregional radiotherapy, and use of systemic treatments.

Currently, the researchers are reviewing medical charts of selected patients and looking at factors such as the type of surgery that was performed, information about surgical margins, and whether lymph node dissection had taken place. This information will help find a biologic explanation for these results, she said.

"When we do the chart review, maybe we can also find out the reasons for having the surgery," she added.

Although these results are interesting, José Baselga, MD, president of ESMO, pointed out that surgical removal of the primary tumor is not commonly done in this patient population. "That is the bias of the study," he told Medscape Oncology when approached for independent comment.

The primary tumor is usually removed for 1 of 2 reasons, he said. "One is if the tumor is causing complications and the second is if the patient asks for it to be removed. In the latter case, the woman may be doing well and would like to remove the tumor."

It might be that the primary tumor continues to launch cells into circulation, so the surgery is a self-sealing of the primary tumor, he added. "However, these data alone are not going to lead to a change in current practice. Randomized clinical trials are needed."

Dr. Ruiterkamp agreed. Even multivariate analysis showed that surgery is an independent factor in overall survival. A randomized controlled trial should be performed to see if surgery really has any benefit, she concluded.

15th Congress of the European CanCer Organization (ECCO 15) and the 34th European Society for Medical Oncology (34th ESMO) Multidisciplinary Congress: Abstract 5005. Presented September 21, 2009.

EUROPEAN ACADEMY OF CANCER SOCIETIES

September 22, 2009 (Berlin, Germany) —The official launch of the European Academy of Cancer Sciences was announced here at the 15th Congress of the European CanCer Organization (ECCO) and the 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress. The goal of this new organization is to create a stronger, more unified approach to cancer health and research policy.

The Academy will bring together experts with outstanding scientific and academic backgrounds from all cancer disciplines and provide knowledgeable and unbiased advice on matters of policy and priorities at the national, European, and global levels. During a press briefing, Alexander Eggermont, MD, president of ECCO, said that the new initiative was designed to "help keep the interests of cancer patients at the forefront of the policy agenda and avoid policy decisions that had a negative impact on the practice of oncology medicine."

"It will provide independent, authoritative, evidence-based advice," he said, "which is very different from a lot of the consulting that goes on now in the cancer society."

Dr. Eggermont explained that by keeping a close watch on policy developments that could affect cancer care and by being able to offer expert advice and consultation, potentially detrimental decisions can be avoided. As an example, he noted that it has been generally acknowledged that the Clinical Trials Directive has had a catastrophic effect on the independent evaluation and comparison of drugs by academic clinical researchers.

The amount of academic clinical research in oncology in Europe in all therapeutic categories was greatly reduced because of that directive, he explained.

A founding group of 114 Academy members has been set up; 30 experts were selected for their expertise and reputation, and they then voted for the other members. The first group of experts includes Nobel prize winners Harald zur Hausen, DSc MD, professor emeritus and recent chair and scientific director of the German Cancer Research Centre in Heidelberg; Sir Paul Nurse, PhD, director general of the Imperial Cancer Research Fund in London, United Kingdom; Sir Richard Peto, FRS Hon FRCP, professor of medical statistics and epidemiology at the University of Oxford, United Kingdom; and Umberto Veronesi, MD, director of the European Institute of Oncology in Milan, Italy.

The founding group also includes members of the ECCO Board and Policy Committee, and Dr. Eggermont will take on the role as the first president of the Academy.

The Academy expects that questions and requests for information and advice will come from a wide number of venues, including patient organizations, healthcare professionals, policy-makers, and politicians.

Initially, the ECCO Policy Committee will flag issues in which the Academy can make use of its expertise, Dr. Eggermont explained. But as the organization evolves, it is hoped that the Academy will be able to interact directly with policymakers.

At the outset, the Academy will put its collective knowledge and experience together to prepare a strategy paper on how to boost cancer research in Europe; look at barriers to research and how these can be addressed; and propose priorities for oncopolicy, ideally by the end 2010.

It has become apparent that a European-wide structure is needed to optimize collaboration and research power and progress, according to Dr. Eggermont, and the launch at the ECCO/ESMO Congress is only the beginning of this process.

"We are optimistic that this new initiative will have a positive effect on all those associated with cancer, be they patients, doctors, scientists, or carers, and we look forward to the time when cancer takes its rightful place on the policy agenda," he said

APIRIN USE AND COLORECTAL CANCER IN LYNCH SYNDROME

September 22, 2009 (Berlin, Germany) — Using aspirin on a daily basis offers protection against colorectal cancer in individuals with Lynch syndrome, and that protection continues for years even after aspirin is discontinued, according to research presented here at the 15th Congress of the European CanCer Organization and the 34th European Society for Medical Oncology Multidisciplinary Congress.

Aspirin also reduced the risk for endometrial cancer in this population.

The results were particularly exciting, said lead author John Burn, MD, medical director and head of the Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom. "We stopped giving the aspirin after 4 years and yet the effect is continuing. It is directly correlated with the duration of aspirin use in the trial."

Results Seen Over Long Term

The chemopreventive effect of aspirin was not seen immediately. The initial results of the study were published last year (N Engl J Med. 2008;359:2567-2578), and Dr. Burn noted that they were "profoundly disappointing," because there was no difference in neoplasia at an average of 29 months after randomization. The rate of colorectal cancer was similar in those taking aspirin and those taking placebo.

However, the researchers noted that individuals who had participated in early cardiovascular trials with aspirin had fewer cases of colorectal cancer after 10 years. That was an impetus for "us to keep trying," Dr. Burn said.

About 5 years after initial trial randomization, the incidence of new malignancies in the aspirin and placebo groups began to diverge, and the number of cases of colorectal cancer in aspirin users declined. The protective effect of aspirin appeared to persist for at least 6 years after the last episode of aspirin use, and also correlated with the duration of aspirin use during the study, the researchers note.

In the original study, 1071 people with Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, were randomized to 600 mg of aspirin per day and/or 30 g of Novelose, a resistant starch that escapes digestion in the small intestine.

Dr. Burn pointed out that even though case–control and epidemiologic studies have reported that the use of nonsteroidal anti-inflammatory drugs decreases the risk for colorectal cancer, randomized controlled trials have failed to show this effect.

"We decided to take a different approach and look at Lynch syndrome," he said. "We thought it was an interesting group for a chemoprevention study, since these people are very motivated."

Adenomas Not Prevented, Bleeding Incidents Minimal

Dr. Burn emphasized that, in this study, the goal was not to prevent adenomas but to prevent cancer. About 100 study participants developed adenomas, but there was no propensity to develop cancer. "We didn't prevent the adenomas from occurring, but we prevented adenomas from becoming malignant," he said.

To date, the researchers have observed only 6 cases of colon cancer among the study participants who used aspirin, compared with 16 cases in the placebo group. Six individuals also developed multiple colorectal cancers and, of this group, only 1 was taking aspirin.

Bleeding was also not an issue, despite the high dose of aspirin. In the aspirin group, 11 participants experienced notable gastrointestinal bleeding, as did 9 in the placebo group. Individuals in the aspirin group also had a lower rate of cardiovascular events.

Extrapolating the Data

It is currently unclear how much of these data can be extrapolated to other populations. "About 1 in 6 of all colon cancers has some type of breakdown in this gene system," said Dr. Burn. "So one might say that if it prevents cancer in the inherited form of the disease, it might work well in other forms of the disease."

However, José Baselga, MD, president of ESMO, is not certain that similar results will be experienced in other patient groups. "I'm not sure that other types of colorectal cancer will respond as well," he told Medscape Oncology. "It does seem to be a very long process with a long follow-up time."

The study was funded by the Medical Research Council in the United Kingdom and by Cancer Research UK.

15th Congress of the European CanCer Organization (ECCO 15) and the 34th European Society for Medical Oncology (34th ESMO) Multidisciplinary Congress: Abstract 6000. Presented September 21, 2009

TESTOSTERONE LEVELS AND PROSTATE CANCER TREATMENT RESULTS

BJU Int. 2009 Aug 28. [Epub ahead of print]

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Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: prognostic significance?

Perachino M, Cavalli V, Bravi F.

Department of Urology, Santo Spirito Hospital, Casale Monferrato, Alessandria, and Department of Biometry, Ibis Informatica s.r.l., Milan, Italy.

OBJECTIVE To determine if the testosterone level achieved with androgen-deprivation therapy (ADT) is directly related to survival and risk of death in men with metastatic prostate cancer, as agonistic analogues of luteinizing hormone-releasing hormones (LHRH) are indicated for palliative treatment of these patients, but there is no consensus about the utility of serum testosterone measurements during the follow-up, and their possible prognostic value. PATIENTS AND METHODS We retrospectively reviewed 129 consecutive patients with a histological diagnosis of metastatic bony-only prostate cancer and previously untreated with ADT. They were treated with 3 months of goserelin. Testosterone and prostate-specific antigen (PSA) levels were measured in all patients every 3 months for the duration of the follow-up. The following variables were recorded: age, stage, Gleason score, basal PSA level, basal testosterone level, PSA nadir, time to PSA nadir, testosterone after 6 months, testosterone nadir and time to testosterone nadir. Data were analysed using Cox's proportional hazards models, with the primary endpoint being cancer-specific survival. RESULTS The mean (sd) basal PSA level was 185.8 (344.1) ng/mL, and the mean nadir PSA level 2.7 (8.6) ng/mL. The mean testosterone levels at baseline, 6 months and the nadir were 440 (200), 40 (40) and 21 (15) ng/dL. With a mean follow-up of 47.5 (29.7) months, 71 patients were dead (55%) and 78 were alive (45%) at the time of analysis. Statistical analysis using Cox's model showed that in these patients the risk of death was directly correlated not only to Gleason score (P < class="yshortcuts" id="lw_1253652648_15">hazard ratio 1.32, P < 0.05). CONCLUSION These results suggest a direct correlation between the risk of death and testosterone levels achieved during ADT. Based on the present results, lowering the testosterone level as much as possible should be the goal of ADT in patients with metastatic prostate cancer, as this might affect patient survival.

HYPOKALEMIA AND CETUXIMAB

Cancer Chemother Pharmacol. 2009 Sep 17. [Epub ahead of print]

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Meta-analysis of incidence and risk of hypokalemia with cetuximab-based therapy for advanced cancer.

Cao Y, Liu L, Liao C, Tan A, Gao F.

Department of Colorectal and Anal Surgery, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, People's Republic of China.

PURPOSE: To gain a better understanding of the incidence and risk of hypokalemia in patients who received cetuximab-based therapy. PATIENTS AND METHODS: Databases, including Pubmed, EMBASE, The Cochrane Library, annual meeting of American Society of Clinical Oncology (2000-2008), and Web of science were searched to identify relevant studies. Eligible studies were prospective phase II-III clinical trials of patients with cancer assigned cetuximab at the dose of 400 mg/m(2) IV on day 1 and 250 mg/m(2) weekly thereafter. The primary endpoint was incidence of hypokalemia. RESULTS: Eleven clinical reports were identified which included a total of 2,254 patients who were available for analysis, with 1,324 patients assigned cetuximab-based treatment. The results showed high incidence of grade 3 and 4 hypokalemia [6.2% (95% CI 4.9-7.7)] and high incidence of all-grade hypokalemia [8.0% (95% CI 4.5-13.9)] associated with cetuximab-based therapy for advanced cancer. Compared with non-cetuximab therapy, cetuximab-based therapy has higher risk of grade 3 and 4 hypokalemia [1.81 (95% CI 1.12-2.93)]. CONCLUSION: Cetuximab-based therapy is associated with a significant risk of hypokalemia. Early monitoring and effective management of hypokalemia is important for patients that received cetuximab-based therapy.

AN INTERESTING GREEK STUDY

Br J Cancer. 2009 Sep 8. [Epub ahead of print]

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Evaluation of the paclitaxel-ifosfamide-cisplatin (TIP) combination in relapsed and/or metastatic cervical cancer.

Kosmas C, Mylonakis N, Tsakonas G, Vorgias G, Karvounis N, Tsavaris N, Daladimos T, Kalinoglou N, Malamos N, Akrivos T, Karabelis A.

Second Division of Medical Oncology, Department of Medicine, 'Metaxa' Cancer Hospital, Pireaus, Greece.

Background:Recurrent or metastatic cervical cancer represents an aggressive malignancy with a high rate of locoregional and distant failure. Therefore, we evaluated the three-drug combination of paclitaxel-ifosfamide-cisplatin (TIP).Methods:Systemic chemotherapy-naive patients with advanced metastatic/relapsed cervical cancer and a World Health Organization (WHO) performance status (PS) of 0-2 were eligible. TIP chemotherapy doses were paclitaxel 175 mg m(-2) on day 1, ifosfamide 2.5 g m(-2) on days 1+2, and cisplatin 40 mg m(-2) on days 1+2, with prophylactic granulocyte-colony stimulating factor.Results:A total of 42 patients with recurrent/metastatic cervical cancer are evaluable for response and toxicity: median age: 56 (25-74) years; PS: 1 (0-2); histologies - squamous: 35, adenosquamous: 5, and adenocarcinoma: 2. Responses were overall response rate (RR): 62% (95% confidence interval (CI): 47.3-76.7%), with complete response (CR): 26% (95% CI: 12.7-39.3%), and partial response (PR): 36% (95% CI: 21.5-49.9%). Responses according to the relapse site were overall RR: 32% (95% CI: 13.7-50.3%) within previously irradiated pelvis vs 75% (95% CI: 57.7-92.3%) in extra-pelvic sites. Median time to progression (TTP) was 7 (range, 2-34+) months and median overall survival (OS) was 16.5 (range, 3-36+) months. Toxicities included grade 3-4 neutropenia: 83% (21% febrile neutropenia), grade 3-4 thrombocytopenia: 9%, no grade 3 neuropathy (35% grade 2), grade 2 asthenia/fatigue 15%, and no treatment-related deaths.Conclusion:TIP is an active regimen with acceptable toxicity in advanced/relapsed cervical cancer.British Journal of Cancer advance online publication, 8 September 2009; doi:10.1038/sj.bjc.6605305 www.bjcancer.com.

ANOTHER PREDICTIVE FACTOR OF CETUXIMAB RESPONSE IN COLORECTAL CANCER

Amphiregulin and Epiregulin mRNA Expression in Primary Tumors Predicts Outcome in Metastatic Colorectal Cancer Treated With Cetuximab.

Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J, Fieuws S, Vandesompele J, Peeters M, Van Laethem JL, Humblet Y, Pénault-Llorca F, De Hertogh G, Laurent-Puig P, Van Cutsem E, Tejpar S.

Department of Pathology, Digestive Oncology Unit, and Center for Human Genetics, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven; Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Katholieke Universtiteit Leuven, Leuven, and Universiteit Hasselt, Hasselt; Center for Medical Genetics and Digestive Oncology Unit, University Hospital Ghent, Ghent; Service de Gastro-entérologie and Centre du Cancer, Cliniques Universitaires Saint-Luc, Université catholique de Louvain; Department of Gastroenterology, Gastrointestinal Cancer Unit, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium; Department of Pathology, Centre Jean Perrin, Clermont-Ferrand; and Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, and L'Institut National de la Santé et de la Recherche Médicale, Paris, France.

PURPOSE: To study the power of the epidermal growth factor receptor (EGFR) epiregulin (EREG) and amphiregulin (AREG) ligands' expression in primary tumors to predict the outcome in patients with chemorefractory metastatic colorectal cancer (cmCRC) treated with the combination of cetuximab and irinotecan. PATIENTS AND METHODS: Gene expression measurements and KRAS mutation analysis were performed on archival formalin-fixed paraffin-embedded primary tumors of 220 cmCRC patients. Response was measured using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. The relation between ligand expression levels and outcome was evaluated using logistic regression for response and Cox regression for survival data. Receiver operating characteristics analysis was performed for response and survival data. CIs for the performance indices were obtained with a nonparametric bootstrap procedure. Findings were externally validated on a series of 67 samples treated in a similar setting. RESULTS: In KRAS wild type (WT) patients, there was a significant association between log-transformed ligand expression and response for EREG (odds ratio for objective response, 1.90; 95% CI, 1.27 to 2.83; P = .0005; concordance index [c-index], 0.681) and for AREG (odds ratio for objective response, 1.862; 95% CI, 1.22 to 2.72; P = .0017; c-index, 0.673). In a Cox regression model, dichotomized ligand expression was significantly associated with progression-free survival (PFS) and overall survival (OS). EREG PFS hazard ratio (HR) was 0.41 (95% CI, 0.274 to 0.609; P < .001; time-dependent c-index [Ctau index], 0.640), and AREG PFS HR was 0.43 (95% CI, 0.29 to 0.64; P < .001; Ctau index, 0.627). EREG OS HR was 0.42 (95% CI, 0.28 to 0.63; P < .0001; Ctau index, 0.639), and AREG OS HR was 0.40 (95% CI, 0.27 to 0.64; P < .0001; Ctau index, 0.625). There was no predictive power of ligand expression in patients with KRAS mutation. CONCLUSION: Expression of EGFR ligands in primary tumors significantly predicts outcome in KRAS WT cmCRC treated with cetuximab and irinotecan.

BEVACIZUMAB IN NSCLC PATIENTS WITH TREATED BRAIN METASTASES

J Clin Oncol. 2009 Sep 8. [Epub ahead of print]

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Safety of Bevacizumab in Patients With Non-Small-Cell Lung Cancer and Brain Metastases.

Socinski MA, Langer CJ, Huang JE, Kolb MM, Compton P, Wang L, Akerley W.

Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; University of Pennsylvania, Philadelphia, PA; Genentech, San Francisco, CA; and Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT.

PURPOSE: Patients with non-small-cell lung cancer (NSCLC) and brain metastases have previously been excluded from trials of bevacizumab because of suspected risk of CNS hemorrhage. This phase II trial, AVF3752g (PASSPORT), specifically addressed bevacizumab safety (incidence of grade >/= 2 CNS hemorrhage) in patients with NSCLC and previously treated brain metastases. PATIENTS AND METHODS: This open-label multicenter trial for first- and second-line treatment of nonsquamous NSCLC enrolled patients with treated brain metastases. First-line patients received bevacizumab (15 mg/kg) every 3 weeks with platinum-based doublet therapy or erlotinib (at physician's decision), and second-line patients received bevacizumab with single-agent chemotherapy or erlotinib, until disease progression or death. RESULTS: Of the 115 enrolled patients, 66 of 76 first-line patients received carboplatin-based chemotherapy; 22 of 39 second-line patients received pemetrexed, and nine of 39 received erlotinib. As of the June 23, 2008 data cut, among 106 safety-evaluable patients, median on-study duration was 6.3 months (range, 0 to 22 months), with a median of five bevacizumab cycles (range, one to 17), and no reported episodes of grade >/= 2 CNS hemorrhage (95% CI, 0.0% to 3.3%). Of the bevacizumab-targeted adverse events reported, two were grade 5. Both were pulmonary hemorrhages, one occurring during treatment and the other occurring 6 weeks after the data cut; there was also one grade 4, nonpulmonary/non-CNS hemorrhage. Twenty-six patients (24.5%) discontinued study treatment as a result of an adverse event, and 37 (34.9%) discontinued because of disease progression. CONCLUSION: Addition of bevacizumab to various chemotherapy agents or erlotinib in patients with NSCLC and treated brain metastases seems to be safe and is associated with a low incidence of CNS hemorrhage.