BEVACIZUMAB APPROVED FOR RECURRENT GLIOBLASTOM

May 6, 2009 — The US Food and Drug Administration (FDA) has granted accelerated approval for bevacizumab (Avastin, Genentech) for use in patients with glioblastoma that has progressed despite previous therapy. This is the first drug to be approved for this indication in more than a decade.

This is an area of "unmet medical need," said Henry Friedman, MD, deputy director of the Preston Robert Tisch Brain Tumor Center at Duke University in Durham, North Carolina. There is currently no standard of care for such patients, and no option that produces a true meaningful benefit, he told Medscape Oncology.

Bevacizumab has unequivocally displayed benefit in these patients, he said. "It gives us a new weapon and gives patients a chance for longer survival and a chance of improvement in their quality of life," he said.

The approval comes just weeks after a unanimous vote by the Oncological Drugs Advisory Committee (ODAC), with all 10 members recommending accelerated approval, as reported by Medscape Oncology . This is despite the fact that the clinical data for this indication come from clinical trials with no comparator — the benefit seen was in comparison to historic controls.

One of the trials (known as AVF3708g, or BRAIN) involved 167 patients with glioblastoma who had progressed on radiation and temozolomide (Temodar, Schering) and who then received bevacizumab either alone or in combination with irinotecan. According to an FDA analysis of the study, tumor responses were observed in 22 of 85 patients (26%) treated with bevacizumab alone, and the median duration of response was 4.2 months.

In another trial (NCI 06-C-0064E), 56 patients with recurrent glioblastoma were treated with bevacizumab alone. Responses were observed in 11 patients (20%), and the median duration of response was 3.9 months.

There are no data so far from randomized trials for overall survival.

"There was some concern that the FDA was going to demand a comparator trial, but the totality of the data was so good in terms of response rate, progression-free survival, overall survival, the decrease in corticosteroid use, the maintenance of neurocognitive function, and the overall clinical improvement in the patients, plus the lack of any other options, proved to be compelling," Dr. Friedman said. He was principal investigator for this trial, and he acted as an advisor to the manufacturer for the design and analysis of the trial. Dr. Friedman was also on the ODAC committee.

"The benefit to the patient was real and unchallengeable," he said.

Bevacizumab has already been used in this indication in the United States, but because this is an off-label use, there were problems with third-party coverage in some instances. These problems should now disappear, he added.

Further trials are in progress, both single-group and randomized trials, looking at bevacizumab in combination with surgery, radiation, and temozolomide in patients with newly diagnosed glioblastoma.

Bevacizumab, a monoclonal inhibitor of vascular endothelial growth factor, is already approved in the United States for use in colorectal, lung, and breast cancer.

ANTIPLATELET THERAPY AND RISK OF INFECTION?

May 1, 2009 (Baltimore, Maryland) — Another potential problem of using dual antiplatelet therapy in patients due to have surgery has emerged in a new study showing that patients taking both aspirin plus clopidogrel preoperatively had an increased risk of infection after coronary artery bypass surgery [1].

The study, published in the April 27, 2009 issue of the Archives of Internal Medicine, was conducted by a team led by Dr Elena Blasco-Colmenares (Johns Hopkins University School of Medicine, Baltimore, MD). They conclude: "Our study suggests that there may be significant infectious risks due to uninterrupted preoperative use of dual antiplatelet therapy in coronary artery bypass surgery and potentially in other patient populations that are at high risk for infection."

Senior author Dr Nauder Faraday (Johns Hopkins) commented to heartwire : "This association has never been reported before, to my knowledge. We hypothesized that because of laboratory evidence showing that platelets play a role in immunity, it would be possible that inhibiting platelet function would increase the risk of infection in vulnerable populations. So we looked for a possible relationship between dual platelet therapy and infection in CABG patients, and we did indeed find such an association."

Not Due to Transfusions

Faraday said they did what they could to take account of confounding factors, but there is still the possibility that there could be residual confounders not measured, which is why more studies are required to confirm their finding. He noted that the most obvious confounder is bleeding and transfusion. Patients on dual antiplatelet therapy will bleed more and so will be in the OR longer and need more transfusions, which is a well-recognized risk for infection. But they still found a strong association after this was controlled for.

"This is just one study. It requires confirmation. And while other observational studies like ours would be useful, the best thing would be data from randomized trials. There have been many trials done of clopidogrel plus aspirin vs aspirin alone. It would be interesting to look at infection outcomes in the follow-up in these studies, particularly in those patients who ended up going on to CABG," Faraday noted.

Confusion Over Antiplatelet Therapy and Surgery

He pointed out that this idea of a possible increase in infection risk with dual antiplatelet therapy adds to the uncertainty about when to stop such therapy before surgery. "There is a lot of confusion about this already. Surgeons want to stop antiplatelet therapy several days before the operation to reduce bleeding risk, but if a patient has recently had a stent, cardiologists warn that prematurely stopping dual antiplatelet therapy might promote MI. So what do we do? Do we delay surgery for one year, or do we continue with the antiplatelet agents through the perioperative period? We really have no idea. Right now it is up to individual practitioners' discretion. There are no hard data, and the guidelines are confusing. We really need a randomized trial to look at this, and this trial could look at infection risk as well as bleeding risk."

If platelets do play an important role in immunity, the risk of infection would be sustained for as long as patients were on dual antiplatelet therapy, Faraday believes. "We looked for this in CABG patients because we thought we might be able to capture the risk over a short time period in this high-risk group, but it could also have a smaller immune-suppressing effect with long-term treatment in nonsurgery patients," he added.

For the current retrospective cohort study, the researchers collected data from their cardiac-surgery database on 1677 patients who had undergone CABG at Johns Hopkins Hospital, and they looked specifically for reports of infection that they say would be recorded for such patients.

They found that the cumulative incidence of infection at 30 days was 23.1% in patients receiving both aspirin plus clopidogrel preoperatively vs 16.1% in those who were receiving aspirin alone (HR 1.51; 95% CI 1.09–2.08). The risk of infection remained higher among patients who were receiving dual antiplatelet therapy after adjustment for demographic, socioeconomic, preoperative, and intraoperative risk factors and propensity score.

Transfusion rates were also higher among patients who were receiving dual antiplatelet therapy than among patients who were receiving aspirin monotherapy, but transfusion played a modest role in mediating the risk of infection. Mortality rates at 30 days were 5.2% in patients receiving both aspirin and clopidogrel vs 3.1% in patients on aspirin alone, but this was not significant (adjusted HR 1.44; 95% CI, 0.70–2.99).

In the paper, the researchers write: "In addition to their well-known function in primary hemostasis, platelets also participate in innate and adaptive immunity through a variety of mechanisms that depend on platelet activation." They add: "By inhibiting platelet activation, all antiplatelet agents have the theoretical potential to diminish these activation-dependent platelet immune functions. Our data are the first (to our knowledge) to suggest that pharmacologic suppression of platelet function is associated with clinical infection in a human population. Additional work is needed to confirm these observations and to determine the impact of antiplatelet therapy on host immunity in the clinical setting."

FDA should allow for greater off-label use of medications, expert argues

In an op-ed in the Wall Street Journal (5/2, A11), Richard Epstein, professor at the University of Chicago and a senior fellow at Stanford University's Hoover Institution, noted, "As President Barack Obama's new Food and Drug Administration team of Margaret Hamburg and Joshua Sharfstein take the reins, they must decide what to do with off-label uses of FDA-approved drugs." Epstein asserted that "the FDA and Congress should protect physicians' and patients' right to off-label uses -- and for the first time allow drugmakers to promote off-label uses that prove beneficial." He argued that, "once a drug passes Phase I clinical trials -- which test for high toxicity -- why not make it available for general distribution through the [National Comprehensive Cancer Network (NCCN)], which has far superior access to specialized medical expertise than the FDA?" While the idea "may sound radical...when lives are at stake, we should consider drastic measures." 

ΨΑΞΤΕ ΤΟ ΔΕΥΤΕΡΟ ΚΟΥΦΑΡΙΑ

A NEW CLASS OF ANTIDERPRESSANTS

NEW YORK (Reuters Health) Apr 21 - Vilazodone, the first of a new class of antidepressants known as indolalkylamines, has been shown in a phase III trial to be effective and well tolerated for the treatment of major depressive disorder, with a rapid onset of effect.

The researchers explain in the March issue of the Journal of Clinical Psychiatry that vilazodone "combines properties of a selective serotonin reuptake inhibitor with 5-hydroxytryptamine-1A partial agonist activity." They add that in addition to offering a rapid antidepressant effect, this agent likely has "a lower risk of sexual dysfunction" than currently available therapies.

Dr. Karl Rickels at the University of Pennsylvania in Philadelphia and colleagues report on their intention-to-treat analysis of a randomized trial in which 410 adults with major depressive disorder received either vilazodone or placebo for 8 weeks. Vilazodone was titrated from 10 mg to 40 mg once a day over the course of two weeks.

Compared to the placebo group, after 8 weeks the vilazodone group had greater mean improvements from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS; p = 0.001) and the 17-item Hamilton Rating Scale for Depression (HAM-D-17; p = 0.022).

In fact, the researchers note, the treatment group was already demonstrating significant improvements on both scales after just one week.

The vilazodone-treated subjects also had significantly higher response rates on the MADRS (p = 0.007), the HAM-D-17 (p = 0.011), and the Clinical Global Impressions-Improvement scale (p = 0.001).

Most treatment-related side effects were mild or moderate, according to the article. Five patients in each group experienced a major adverse event.

"Vilazodone is effective for the treatment of major depressive disorder in adults, with symptom relief starting at 1 week, and is well tolerated at a dose of 40 mg/day," the investigator conclude.

ADDITION OF DIURETIC EASES NOCTURIA?

NEW YORK (Reuters Health) Apr 21 - Hydrochlorothiazide combined with the alpha-blocker terazosin is effective in some men with nocturia who have failed to respond to terazosin monotherapy, according to Korean researchers.

"Hydrochlorothiazide may be an appropriate strategy in hypertensive patients with concomitant nocturia," senior investigator Dr. Jae-Seung Paick told Reuters Health, "since hydrochlorothiazide has efficacy for nocturia as well as few absolute contraindications and low cost."

In the March issue of Urology, Dr. Paick and colleagues at Seoul National University College of Medicine report on their study of 72 men who showed a <>

They went on to a further 4 weeks of daily treatment with 4 mg of terazosin and 25 mg of hydrochlorothiazide. "The patients were instructed to take the hydrochlorothiazide 8 hours before bedtime and the terazosin at bedtime," the team notes.

In all, only 53 of the men completed the study. There were no serious side effects and no dose reductions were required in any of the patients, the investigators report.

Fourteen patients had a reduction in nocturia score of 25% or more, 31 achieved a reduction of up to 24% and the remaining patients had an increased score.

Using a frequency-volume chart, 22 patients reported a reduction of 25% or more, and 31 reported no improvement or an increase in nocturia.

Polyuria resolved in 6 of the 51 patients who had such symptoms at baseline.

The researchers concede that the study had limitations including no tracking of blood pressure, something they suggest may be particularly important to do in elderly patients. These and other parameters should be monitored when combination therapy is employed.

Nevertheless, they conclude that the "findings suggest that the use of a diuretic agent, such as hydrochlorothiazide, might be a reasonable second-line treatment option for these patients, especially for those with nocturnal polyuria."

ITRACONAZOLE CONTRAINDICATED IN CHF PATIENTS

Itraconazole (Sporanox) Contraindicated in CHF Patients

On March 3, the FDA approved safety labeling revisions for itraconazole (Sporanox injection and oral solution; Johnson & Johnson Pharmaceutical Research and Development) to warn against its use in patients with congestive heart failure (CHF) and advise caution with concomitant use of certain drugs that rely on the hepatic cytochrome P 450 isoenzyme 3A4 (CYP 3A4) for metabolism.

Itraconazole should not be used in patients with evidence of left ventricular dysfunction unless life-threatening or other serious infection is suspected and the potential benefit outweighs the risk of therapy, the FDA emphasized.

Risk factors to be considered include cardiac disease such as ischemic and valvular disease, significant pulmonary disease such as chronic obstructive pulmonary disease, and renal failure and other edematous disorders. If signs or symptoms of CHF occur during treatment, alternative therapies and discontinuation of itraconazole may be required.

Itraconazole has been shown to have a dose-related negative inotropic effect; in healthy volunteers, symptoms resolved before the next intravenous dose 12 hours later. CHF has been reported during clinical studies of the drug, particularly in patients receiving a total daily dose of 400 mg.

The FDA notes that coadministration of calcium channel blockers yields additive inotropic effects, particularly because itraconazole also inhibits the metabolism of calcium channel blockers. Dose reductions may be required for dihydropyridines such as nifedipine and felodipine. Because the significant increases in nisoldipine plasma levels cannot be managed by dose reduction, use of this drug combination is contraindicated.

The agency also advised of other drug interactions with itraconazole.

Itraconazole and its metabolite, hydroxyitraconazole, are inhibitors of the hepatic metabolic CYP 3A4 enzyme. Use of the antifungal can decrease the elimination of drugs metabolized by this enzyme, leading to elevated plasma concentrations that can increase or prolong both therapeutic and adverse events.

Cilostazol and eletriptan are CYP 3A4–metabolized drugs that should be used with caution when coadministered with itraconazole. Itraconazole also enhances the anticoagulant effect of coumarin-like drugs (eg, warfarin) and can increase or prolong fentanyl plasma concentrations, leading to potentially fatal respiratory depression.

Caution is advised with concomitant use of halofantrine because high plasma concentrations of the drug have the potential to prolong the QT interval.

Concurrent administration of itraconazole decreases glucosteroid metabolism, thereby potentially increasing serum levels of budesonide, dexamethasone, fluticasone, and methylprednisolone.

Itraconazole is indicated as empiric therapy for suspected fungal infections in patients with febrile neutropenia. The oral formulation may also be used for the treatment of oropharyngeal and esophageal candidiasis; additional indications for intravenous itraconazole include blastomyocosis, histoplasmosis, and aspertillosis.

DIAMANTOPOULOS SPEAKING-ESAs INCREASE MORTALITY

April 30, 2009 — The huge meta-analysis of individual patient data that confirmed an increased mortality in cancer patients treated with erythropoiesis-stimulating agents (ESAs) has been published in the May 2 issue of the Lancet.

The researchers analyzed individual data for 13,933 cancer patients participating in 53 trials, and found that ESAs increased the relative risk for mortality by 17%. When they considered only cancer patients who were undergoing chemotherapy (10,441 patients in 38 trials), they found that ESAs increased the relative risk by 10%.

These results were first presented at the 2008 annual meeting of the American Society of Hematology (ASCO), and were reported by Medscape Oncology at the time.

"The increase in mortality is very worrisome," J. Evan Sadler, MD, PhD, from Washington University in St. Louis, Missouri, commented at the time, noting that these products should be used with "appropriate caution."

These new data will reignite concerns over the use of ESAs in cancer patients, Dr. Sadler said. But another expert, Samuel Silver, MD, PhD, FACP, from the University of Michigan in Ann Arbor, suggested that there was "no new cause for concern."

The safety of these drugs in cancer patients has already been extensively discussed by regulatory authorities in both the United States and Europe, and both have restricted their use in this patient population. In the United States, these products also carry a black-box warning stating that they can increase the risk for death in cancer patients. The restrictions are already in line with these new data, Dr. Silver said, adding that he does not anticipate any further regulatory moves in the near future.

New Data Back Regulatory Moves

Lead author of the meta-analysis, Julia Bohlius, MD, from the Institute of Social and Preventive Medicine at the University of Bern in Switzerland, said that the US Food and Drug Administration was right in restricting the use of these products in cancer patients, and that her team's results — which were not available at the time the regulatory moves were made — "back this decision." The individual patient data meta-analysis provides a clearer picture of the risk for mortality with these agents, showing a larger treatment effect and greater statistical significance than had been reported previously in literature-based meta-analyses, she said. In addition, the team was able, for the first time, to separate on-study mortality from overall survival. "I am more convinced now that the adverse effect is real," she said.

"The increased risk of death associated with treatment with these drugs should be balanced against their benefits," Dr. Bohlius and colleagues conclude in their paper.

On the benefits of ESAs, which are used to treat anemia in cancer patients, Dr. Bohlius told Medscape Oncology that she is convinced by the evidence from the literature that these products reduce the need for blood transfusions. However, she is less convinced by the evidence that they improve quality of life and reduce fatigue, because some studies are positive and others are less so, and there might be a publication bias here.

"In clinical practice, the increased risk of death and thromboembolic events should be balanced against the benefits of treatment with ESAs, taking into account each patient's clinical circumstances and preferences," the researchers write.

No Way of Identifying Patients

From a physician's point of view, one of the most perplexing issues with the use of these agents is that there is no way of identifying which cancer patients are most likely to benefit — only about 50% to 60% respond to treatment with ESAs with an increase in red blood cell count, Dr. Bohlius noted.

There is also no way to identify those in whom the risk for death is increased with the use of ESAs, she added. None of the factors that the team analyzed were predictive — not hemoglobin levels at baseline, target hemoglobin levels, or the planned doses of ESA. "But there may be something else, something that wasn't measured, or something that we don't know about yet," she added.

"The patients who respond to ESA treatment are the ones who show better survival," she said, but this might not be related to the treatment. It might be that these are the "healthier" cancer patients; the ones with the most severe anemia are likely the ones who have the most aggressive cancers and are the ones who are the most likely to die.

When asked about the mechanism by which ESAs raise the risk for mortality, senior author Andreas Engert, MD, from the Cochrane Haematological Malignancies Group at the University of Cologne in Germany, said he felt the most likely explanation was an increase in thromboembolic events.

"Increasing evidence suggests that ESAs might cause thromboembolic and cardiovascular events, independent of hemoglobin concentrations," the researchers write in the paper. In their analysis, patients with previous thromboembolic events seemed to be protected, and they speculate that this might be because they had received prophylactic anticoagulation treatment.

There are several other hypotheses explaining how ESAs increase the risk for mortality in cancer patients. One focuses on erythropoietin receptors on tumors, hypothesizing that ESAs act on these receptors and stimulate tumor growth, as previously reported by Medscape Oncology. Some studies have shown such receptors, whereas others haven't, Dr. Bohlius said.

Further study is needed to elucidate how ESAs exert this adverse effect, and to find some clinical or molecular factor that identifies patients who are most likely to be harmed and those who are most likely to benefit from these agents, she said.

CETUXIMAB IN ADVANCED NSCLC NOT COST EFFECTIVE WITHOUT SELECTION

April 30, 2009 — In patients with advanced non-small-cell lung cancer (NSCLC), the addition of the targeted agent cetuximab (Erbitux) to platinum-based chemotherapy offers a small survival advantage. Patients given chemotherapy plus cetuximab had a median overall survival of 11.3 months, compared with 10.1 months for control subjects.

However, adding cetuximab to the regimen had no effect on progression-free survival, which was the same for patients receiving cetuximab and those receiving standard treatment (median, 4.8 months).

These results from the FLEX (First-Line Erbitux in Lung Cancer) trial have been published in the May 2 issue of the Lancet. They were first presented at the 2008 annual meeting of the American Society of Clinical Oncology (ASCO), as reported by Medscape Oncology at that time.

At the ASCO presentation, Thomas J. Lynch, MD, professor of medicine at Harvard University in Boston, Massachusetts, pointed out that although the response rate was significantly improved, progression-free survival was unchanged and overall survival was only marginally improved.

Dr. Lynch, who was not involved in the FLEX trial, also said that cost has to be considered. At Harvard University, it would cost $62,000 to prolong survival by adding cetuximab to the regimen. He questioned whether a "median of 1.4 months is worth it, especially if we don't know if the quality of life has been improved."

"If we can bring survival up to 2.5 months, then it would be in line with other therapies," he said.

Cetuximab Added to Chemotherapy

Cetuximab, a monoclonal antibody directed against epidermal growth factor receptor (EGFR), is currently approved for use in metastatic colorectal cancer and head and neck cancer. It is not approved for use in lung cancer; FLEX was a phase 3 study designed to explore its use in this potential indication.

Led by Robert Pirker, MD, professor of internal medicine at the Medical University of Vienna in Austria, the FLEX trial involved 1125 chemotherapy-naive adult patients with advanced EGFR-expressing stage wet IIIB or stage IV NSCLC. The cohort was randomly assigned to chemotherapy plus cetuximab (n = 557) or chemotherapy alone (n = 568).

The chemotherapy regimen consisted of an intravenous infusion of cisplatin 80 mg/m² on day 1 and intravenous infusions of vinorelbine 25 mg/m² on days 1 and 8 of every 3-week cycle, for up to 6 cycles. An intravenous infusion of cetuximab was given over 2 hours at a starting dose of 400 mg/m² on day 1, and from day 8 onward was given over 1 hour at 250 mg/m² per week. It was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred.

The median follow-up for both groups was 23.8 months, and the addition of cetuximab was associated with a survival benefit for most patient subgroups and all histologic subgroups of NSCLC. In addition to an improvement in overall survival, response rates were better for the combination of chemotherapy plus cetuximab than for chemotherapy alone (36% vs 29%).

Potentially Fills an Unmet Medical Need

In an accompanying editorial, Roy S. Herbst, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, and Fred R. Hirsch, MD, PhD, from the University of Colorado in Denver, point out that cetuximab potentially fills an unmet medical need for patients with advanced NSCLC, especially since the FLEX trial enrolled patients with all NSCLC subtypes. This included patients with squamous cell carcinoma, who have been excluded from treatment with bevacizumab (Avastin), which acts on a different target, because of concerns about toxicity.

The editorialists say that the survival results in FLEX are noteworthy because they contrast with negative studies that used oral tyrosine kinase inhibitors of EGFR, such as erlotinib (Tarceva) and gefitinib (Iressa).

In agreement with Dr. Lynch, they note that the survival benefit is small and did not affect progression-free survival. They also question whether a more rigorous selection of patients for the molecular target might have altered the outcome in FLEX. As an example, KRAS status has become important in selecting colorectal cancer patients who are most likely to benefit from cetuximab.

Another issue that needs to be addressed is the EGFR mutation status and gene-copy number because EGFR mutations are important for response to small-molecule tyrosine kinase inhibitors of this receptor, they write.

There appears to be a role for cetuximab in the treatment of NSCLC, but it is not yet well defined, the editorialists comment. However, "a positive survival trial in lung cancer is a major advance and the treatment is worthy of consideration," they write. "Additionally, these regimens have the potential to be moved up into the earlier, more curative NSCLC setting with radiation or surgical therapy."

They also emphasize the need for new biomarkers to predict sensitivity to cetuximab, because these will be important in understanding exactly which patients will benefit most from any given therapy.

PROSTATE CANCER METASTASES ARE MONOCLONAL

NEW YORK (Reuters Health) Apr 23 - Most prostate cancer metastases, if not all, originate in a single primary cancer cell, according to a study by U.S. and Finnish researchers that was reported online on April 12 by Nature Medicine.

The study, which took more than 14 years to complete, centered on a genome-wide survey of both single nucleotide polymorphisms and copy number variations, which are deletions and duplications of large DNA segments. Both types of alterations of a cell's DNA are among the ways that cancer can begin.

The study was reportedly the first such high-resolution genomic overview of copy number changes in multiple metastatic cancers in individuals. These data enabled the researchers to conclude that "at least the vast majority of individuals with metastatic prostate cancer have cancers that originated in a single aberrant cell."

The report added that this finding is "likely to extend to other cancers."

Dr. G. Steven Bova of Johns Hopkins University School of Medicine told Reuters Health that a major challenge of this work was the "noise" created by separate subclonal changes in the cancer cells' copy number patterns. This was overcome in part, he explained, by the large number of cancer cell samples taken at autopsy from 30 men who had died of metastatic prostate cancer between 1995 and 2004. Bova estimated that he and his colleagues examined 30,000 blocks of tissue.

This study and others like it, Bova said, will bring "major clinical benefits." The idea that some day a patient who is diagnosed with cancer could receive a therapy tailored to the specific intricacies of his or her cancer is not a new one, he explained. What is new is that this study presents a model that could help that scenario become a reality.

Bova added that a very recent study came to a similar conclusion in lung cancer.

It has been established since at least the mid-1990s that primary prostate cancers are composed of multiple genetically distinct cancer cell clones. However, it has been controversial whether these primary prostate cancers typically produce metastases that are multiclonal or monoclonal.

EGFR PLUS RADIATION RAISES DERMATITIS AND MUCOSITIS RISK

NEW YORK (Reuters Health) Apr 23 - Pooled data from studies involving numerous patients show that while addition of epidermal growth factor receptor (EGFR) inhibitors to radiotherapy has improved action against solid tumors, it has also increased radiation dermatitis.

"Whereas the pivotal study of cetuximab combined with radiotherapy against head and neck cancer did not show any greater skin toxicity," senior investigator Dr. Mario E. Lacouture told Reuters Health, "our meta-analysis of large patient groups suggests that there is a greater risk of severe skin and mucosal side effects when an EGFR inhibitor is administered concurrently with radiation."

"These findings," he added, "underscore the need for better prophylactic and management strategies for patients receiving these combined regimens."

Dr. Lacouture of Northwestern University, Chicago, and colleagues analyzed reports of radiation dermatitis, rash, and mucositis from 24 phase 1, 2, and 3 trials involving 933 patients. Randomized trials of radiotherapy and chemoradiation were used as controls.

According to their article in the March 15th issue of Cancer, the EGFR inhibitor combination regimen gave a risk ratio for radiation dermatitis of 2.38 compared with radiotherapy alone. The risk ratio for rash was 3.01, and for mucositis it was 1.76, suggesting an enhanced risk of dermatologic toxicities.

"With increasing use of EGFR inhibitors plus radiation," concluded Dr. Lacouture, "greater skin side effects are important not only because they affect quality of life, but they may also impact consistent administration of therapy, affecting cancer control and patient survival."

WOMEN IN THEIR 50s STILL AT RISK FOR CERVICAL CANCER

NEW YORK (Reuters Health) Apr 23 - The risk for invasive cervical cancer is as high after age 50 as it is younger women, even when the older women have had several negative Pap smears, according to a prospective study conducted in the Netherlands. Therefore, routine screening should be continued among those in their 50s, the research team advices in the April 24 issue of BMJ Online First.

The incidence of preinvasive cervical lesions appears to be lower in older women with negative screening histories, Dr. Matejka Rebolj, at Erasmus Medical Center in Rotterdam, and her associates note. For the current study, however, rather than looking for cervical intraepithelial neoplasia, the researchers analyzed the incidence of invasive cancer, which "enables a more conclusive evaluation of whether there is more reason to relax screening" in older women than in younger women with similar histories of negative screening exams.

Their analysis involved data from the Dutch registry of histopathology and cytopathology (PALGA) from roughly 218,000 women aged 45-54 and 445,000 women aged 30-44 who had three consecutive negative smear tests.

During 10 years of follow-up, the difference in the cumulative incidence rate between age groups never reached significance, the report indicates. Overall, 42 older women and 105 younger women developed cervical cancer. Cumulative incidences at 10 years were 36/100,000 in the older group and 41/100,000 in the younger women (p = 0.46).

"The continued risk for cervical cancer is consistent with the considerable rate of (apparently) incident human papillomavirus infections throughout the age span we focused on," the authors point out.

They caution, however, that their data "do not permit a simple extension of our study to older ages."

In a linked commentary, Dr. Bjorn Strander, from Sahlgren's University Hospital in Goteborg, Sweden, advises researchers to "pay close attention to developments in invasive cancer in age groups above the cut-off point for screening and be prepared to adjust the screening ages as we learn more."

MRI PREDICTS RESPONSE AFTER ONLY ONE CYCLE OF BEVACIZUMAB

April 30, 2009 (Denver, Colorado) — A new technique that measures vascular normalization on magnetic resonance imaging (MRI) scans can predict whether or not a patient with recurrent glioblastoma will respond to treatment with a vascular endothelial growth factor (VEGF) inhibitor after only 1 dose of the drug.

The finding comes from a phase 2 study of the investigational drug cediranib (under development by AstraZeneca); it needs to be confirmed in large phase 3 trials, say the researchers. They presented the results at a plenary session here during the American Association for Cancer Research 100th Annual Meeting.

Anti-VEGF therapy is becoming a standard in the care of glioblastoma, and some dramatic responses have been seen, Dan Duda, PhD, DMD, from Massachusetts General Hospital in Boston, told the meeting. "The problem is that only some patients respond," he said.

The dramatic responses have been seen with cediranib and with bevacizumab (Avastin, Genentech/Roche), both of which target vascular endothelial growth factor (VEGF), although cediranib is an oral drug and bevacizumab is injectable.

"These drugs show efficacy but their mechanism of action remains unclear," Dr. Duda said. "They prune and normalize tumor vasculature, but it remains unclear if this benefits patients."

Tumor blood vessels are highly abnormal, they are very dilated and leaky, he explained, and this frequently results in edema within the brain, which is controlled by steroids, and which affects morbidity and mortality, he explained.

The researchers developed a vascular normalization index (VNI), which measures on an MRI scan the extent to which the drug reduces tumor vascular permeability, dilation, and the vascular basement membrane thickness.

They used this index, together with blood biomarkers, in 33 patients with recurrent glioblastoma who took part in a phase 2 trial of cediranib, and found that patients with the highest VNI values had the longest survival. "Some lived for 2 years, whereas the average survival for these patients is about 1 year," noted lead author Rakesh Jain, PhD, also from Massachusetts General Hospital.

The index was predictive of response and survival after 1 dose of cediranib, Dr. Jain noted during a press conference.

To show this after just 1 dose "is remarkable," said the discussant of this paper, Alfred Young, MD, from the department of neuro-oncology at the University of Texas MD Anderson Cancer Center in Houston. "Even if the mechanism of action of these drugs is to reduce cerebral edema, patients who respond show an increase in survival."

Dr. Young said that further work is warranted to establish what VNI actually means, and to understand how 1 dose could have such a predictive effect.

More work is underway, Dr. Duda said. The team is now using VNI in patients taking various anti-VEGF drugs in 5 phase 3 clinical trials currently in progress at Massachusetts General Hospital.

"If this approach is validated in larger studies, we could use these tools to keep patients on therapies that their tumors respond to, and shift nonresponders to other therapies," Dr. Jain explained.

Tumors that do not respond to VEGF inhibitors could have a preponderance of other growth factors, Dr. Jain noted, such as basic fibroblast growth factor (BFGF) and stromal derived factor 1 (SDF1). He told Medscape Oncology that this has been shown in other tumor types; colorectal cancer patients not responding to bevacizumab and hepatocellular cancer patients not responding to sunitinib (Sutent, Pfizer) have shown high levels of SDF1. Drugs targeting SDF1 were originally developed for use against human immunodeficiency virus, but were unsuccessful in that case; there are now efforts to "resurrect" these products. Drugs against BFGF are in early development (phase 1 clinical trials).

UPDATE FOR SWINE FLU

1 May 2009 -- The situation continues to evolve rapidly. As of 06:00 GMT, 1 May 2009, 11 countries have officially reported 331 cases of influenza A(H1N1) infection.

The United States Government has reported 109 laboratory confirmed human cases, including one death. Mexico has reported 156 confirmed human cases of infection, including nine deaths.

The following countries have reported laboratory confirmed cases with no deaths - Austria (1), Canada (34), Germany (3), Israel (2), Netherlands (1), New Zealand (3), Spain (13), Switzerland (1) and the United Kingdom (8).

Further information on the situation will be available on the WHO website on a regular basis. WHO advises no restriction of regular travel or closure of borders. It is considered prudent for people who are ill to delay international travel and for people developing symptoms following international travel to seek medical attention, in line with guidance from national authorities.

There is also no risk of infection from this virus from consumption of well-cooked pork and pork products. Individuals are advised to wash hands thoroughly with soap and water on a regular basis and should seek medical attention if they develop any symptoms of influenza-like illness.

UPDATE FOR SWINE FLU

April 30, 2009 — Editor's note: The outbreak of swine influenza A (H1N1) viral disease is continuing to grow in the United States and globally, with 91 laboratory-confirmed US cases and 1 death, according to US Centers for Disease Control (CDC) information updated April 29 at 11 am EST. The World Health Organization (WHO) has issued a phase 5 pandemic alert, and the CDC has implemented its emergency response and warned that the more recent illnesses suggest a pattern of more severe disease associated with this virus in the United States. Because most people are not immune to this new viral strain, the CDC expects more confirmed cases, more hospitalizations, and more deaths in the near future.

To learn more about the potential impact of H1N1 viral disease on public health, as well as treatment and prevention strategies, Medscape Infectious Diseases interviewed Neal A. Halsey, MD, professor in the Department of International Health, Bloomberg School of Public Health, Johns Hopkins University in Baltimore, Maryland. Dr. Halsey's primary research and teaching effort is directed toward the prevention of infectious diseases with the safest vaccines possible. He has conducted or participated in epidemiologic studies of vaccine-preventable diseases and phase 1, 2, and 3 vaccine trials for influenza, hepatitis B, hepatitis A, inactivated polio virus, pertussis, Haemophilus influenzae type B, tetanus, Lyme disease, rotavirus, and Argentina hemorrhagic fever viruses

Medscape: How serious is the swine flu situation?

Dr. Halsey: The swine flu changes things and will change priorities for many people. The evidence that we have so far is that this does represent a potential threat to global public health, and a lot of resources are going to have to go into trying to prepare as best we can to minimize the impact.

That will include development, as rapidly as possible, of vaccines against this new strain and making those vaccines rapidly available. If we see more widespread transmission, especially this year, then drug therapy will be an important part, especially here in the developed world.

We need low-cost drugs against influenza in the developing countries as well, because we won't have enough vaccines to protect the population against this new virus. We don't have sufficient vaccine production capacity in the world to make enough vaccine for everybody.

The biggest concern I have is that this will distract us from use of other vaccines that also can protect against disease, like the new pneumococcal vaccine, and even the push to continue to introduce the Hib vaccine. But this new influenza is a serious threat.

Medscape: Are existing influenza vaccines effective against the new strain?

Dr. Halsey: No.

Medscape: How long would it take for a new vaccine to be developed and produced against this virus?

Dr. Halsey: That's what the manufacturers are going to be asked this week, and the answer, with the traditional method, is that we usually give manufacturers 4 to 6 months. They find out about the virus that's going to go in at the end of January, beginning of February, each year, and they make the vaccine, and make it available beginning as early as the end of September, beginning of October.

They've already been making the vaccine they thought was going to be in widespread use, and the key question is whether they should stop what they're doing and put the effort into producing vaccine against this new strain, and that will have to be answered.

There are some new technologies that are being used that may be more rapid in terms of making new vaccine, but they have not yet been widely used. All vaccines currently approved for use require eggs for production, and the supply of eggs is likely to be limited and the manufacturers do not have the capacity to produce enough vaccine for everyone, so there will be shortages.

A number of the manufacturers are experimenting with making cell-based vaccines that don't require eggs; that also could speed up the process, but so far, none of those vaccines that I know of has been approved for use. If we had the production capacity using these cell-based vaccines, it could be more rapid.

I'm sure that both the CDC and WHO are meeting with manufacturers of flu vaccines, and they're all looking at this, trying to determine what their capability will be, but we don't have any answers yet.

Medscape: Are antiviral drugs such as Tamiflu effective against this strain?

Dr. Halsey: Oseltamivir, or Tamiflu, and zanamivir (Relenza) are effective against this strain, but amantadine and the older drugs are not. They've tested the virus and it is susceptible to oseltamivir and zanamivir, which is the only good news out of what we've heard so far.

Medscape: Are there any concerns, with this new strain being a mixture of swine and avian and human strains, that this was in any way genetically engineered or terrorist-related?

Dr. Halsey: No, it doesn't look that way to me. We have been anticipating a potential pandemic from a virus that would come through that same kind of mixing. We know that especially pigs, or swine, are a great mixing bowl, because they are susceptible not only to the swine flu, but also influenza from birds and influenza from humans. So the same pig can have in its body simultaneously several different infections with several different viruses and allow for that mixing. This happens naturally, and that's part of why, especially in Asia, we've been seeing some problems with transmission. You don't need to invoke any concern about bioterrorism to explain how this may have happened.

Medscape: What do you see as the overall potential impact of this swine flu?

Dr. Halsey: The swine flu epidemic, or if it turns out to be a pandemic, which is what we're all concerned about, may turn out not only to have a significant effect on public health and potential mortality, but it could also potentially impair everything else we're trying to do with regard to immunization, in terms of using everybody available to deal with this problem.

It also could have a significant exacerbating effect on the global economy. They've already shut the schools in Mexico; they didn't have audiences for the soccer matches. You can imagine the impact it will have with regard to travel. Some individual countries in the European Union have issued some statements, or cautionary advisories, with regard to travel.

Imagine what the economic impact of loss of tourism in Mexico is going to be, and potentially the United States. So I see this as rapidly having an exacerbating effect on the current recession. This is not a small issue.

ADT INCREASES FRACTURES AND CARDIOVASCULAR MORTALITY

April 30, 2009 — Androgen-deprivation therapy (ADT) is a common treatment for men with prostate cancer, but patients who do undergo this therapy are at an increased risk for skeletal fracture, incident diabetes, and cardiovascular-related mortality.

According to an analysis of 14 studies published online April 27 in Cancer, patients who received ADT had a 23% increase in the risk for overall fracture and a 17% increase in cardiovascular-related mortality, compared with men who did not undergo treatment with ADT. Data from 2 large studies also indicated significant elevations in the risk for diabetes.

But lead author Lockwood G. Taylor, MPH, cautioned that although they did observe significant relative risks for skeletal fracture and cardiovascular-related death, the absolute risks for these adverse events are still very low.

"However, our findings do suggest physicians may want to closely monitor their patient's bone mineral density, lipoprofile, and body mass index during and following treatment, especially if the patient is already at risk for skeletal fracture or cardiovascular disease prior to undergoing ADT," said Mr. Taylor, a doctoral candidate in the Division of Epidemiology, University of Texas School of Public Health in Houston.

"While the physician may wish to communicate these risks to the patient, it is imperative to convey that these risks are small in terms of minimal increase in absolute risk," he told Medscape Oncology. "The benefits of ADT likely outweigh the risks we observed for most patients undergoing ADT."

ADT is currently the most common form of treatment for advanced prostate cancer, and is being increasingly used as adjuvant therapy with radiotherapy for localized disease and as salvage therapy for increasing prostate-specific antigen levels after localized treatment. The authors note that although ADT has been successful in improving overall quality of life in patients with advanced prostate cancer, it can cause potential adverse events.

To gain a better understanding of the magnitude of skeletal and cardiovascular adverse effects associated with ADT, Mr. Taylor and colleagues conducted a review that included summary risk estimates for specific outcomes. Their analysis examined 14 studies published from 1966 to 2008 that met their inclusion criteria.

Fracture Risk

There were 5 studies that investigated risk for fracture as a major adverse effect from ADT, 4 of which were retrospective cohort studies. The pooled results yielded a summary random-effects estimate of 1.23 (95% confidence interval [CI], 1.10 - 1.38) and a fixed-effects estimate of 1.17 (95% CI, 1.12 - 1.23).

In addition, 3 studies reported an increased risk for osteoporosis or lower bone mineral density in patients treated with ADT, compared with those who were not. In 2 studies that specifically evaluated osteoporosis as an outcome, there was an elevated association between ADT and osteoporosis. However, the authors note that only 1 of the studies found the association to be statistically significant. The data also indicated that the duration of ADT is associated with osteoporosis and fracture risk; longer duration of ADT is associated with a higher risk.

Diabetes and Cardiovascular Morbidity

Of the 3 studies that investigated incident diabetes and other cardiovascular morbidity secondary to ADT treatment, all reported a significantly increased risk for diabetes or cardiovascular morbidity. The 3 studies were all retrospective cohort studies.

Two of the studies reported significantly increased risk for incident diabetes (between 36% and 49%), but the researchers caution that "further research beyond those 2 studies is needed to confirm the consistency and magnitude of the association."

ADT also increased the risk for cardiovascular morbidity, according to 1 paper in this subgroup. Patients who underwent treatment with ADT had a 20% increased risk for cardiovascular morbidity, compared with men who did not, and the duration of treatment was significantly associated with this risk.

Cardiovascular-Related Mortality

The authors also found that the results of studies investigating cardiovascular-related mortality secondary to ADT were relatively consistent. Of the 4 papers included in this analysis, 2 were retrospective cohort studies and 2 were randomized clinical trials.

The retrospective cohort studies both found significantly increased risks for cardiovascular-related mortality among patients who received ADT treatment, whereas the randomized trials reported slightly elevated but nonsignificant increases in cardiovascular-related mortality secondary to ADT.

The researchers point out that the absolute risk for cardiovascular-related mortality is low. Based on the assumption that the risk for cardiovascular-related mortality among men with prostate cancer who did not receive ADT is 9 or 10 deaths per 1000 person-years, they write, the observed 17% increase in relative risk would result in the increase of the absolute risk to 10.5 or 11.7 deaths per 1000 person-years, respectively, for men who underwent ADT.

Preventive Steps Might Reduce Risk

Even though the absolute risks for fracture and cardiovascular mortality are low, preventive treatments could further reduce the risk for these potentially serious adverse events. "Preventive therapies to reduce these risks, such as lifestyle modifications or drug therapy, may be helpful, especially if the physician recognizes potential precursors to these adverse events, such as decreases in bone mineral density, an abnormal lipid profile, or a marked increase in body mass index," said Mr. Taylor.

The researchers also note that because some patients experience more benefit from ADT than others, physicians should consider each patient's overall health and prostate cancer status when weighing treatment options, and a benefit–risk analysis must be considered.

ANOTHER ADVANTAGE OF OXALIPLATIN FOR GASTRIC CANCER

J Clin Oncol. 2009 Apr 27. [Epub ahead of print]

Related Articles, LinkOut

Thromboembolism in Patients With Advanced Gastroesophageal Cancer Treated With Anthracycline, Platinum, and Fluoropyrimidine Combination Chemotherapy: A Report From the National Cancer Research Institute Upper Gastrointestinal Clinical Studies Group.

Starling N, Rao S, Cunningham D, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR.

Royal Marsden Hospital National Health Service Foundation Trust, Surrey and London; Southampton University Hospital National Health Service Trust, Southampton; Salisbury Hospital National Health Service Foundation Trust, Salisbury; Oncology-Anchor Unit, Aberdeen Royal Infirmary, Aberdeen; Northern Centre for Cancer Treatment, Newcastle-Upon-Tyne; St Luke's Cancer Centre, Guildford; and Plymouth Oncology Centre, Plymouth, United Kingdom.

PURPOSE: Data concerning the prevalence of and outcomes related to thromboembolic events (TEs) in patients with advanced gastroesophageal cancer who are undergoing chemotherapy are limited. PATIENTS AND METHODS: This was a prospective, exploratory analysis of TEs in a randomized, controlled trial of 964 patients recruited between 2000 and 2005 and treated with epirubicin/platinum/fluoropyrimidine combination chemotherapy for advanced/locally advanced gastroesophageal cancer. Regimens were epirubicin (E), cisplatin (C), fluorouracil (F; ECF); E, C, capecitabine (X; ECX); E, F, oxaliplatin (O; EOF); and EOX. Continuously infused F was administered via a central venous access device (CVAD) with 1 mg of warfarin for thromboprophylaxis. The principal outcome was the incidence of TEs (venous and arterial) in the whole treated patient cohort, according to chemotherapy, associated with CVADs and TE-related prognoses. RESULTS: The incidences of any, of venous, and of arterial TEs among 964 treated patients were 12.1% (95% CI, 10.7 to 14.3), 10.1% (95% CI, 8.3 to 12.3), and 2.2% (95% CI, 1.4 to 3.4) respectively. There were fewer TEs in the O compared with the cisplatin groups (EOF/EOX v ECF/ECX: 7.6% v 15.1%; P = .0003). C was identified as a risk factor for TE in multivariate analysis (hazard ratio [HR], 0.51; 95% CI, 0.34 to 0.76; P = .001). There was no difference in the incidence of TEs for the F group compared with the capecitabine groups. The incidence of CVAD-related thrombosis was 7.0% (ECF/EOF arms). Overall survival was worse for patients who experienced TEs versus no TEs (median survival, 7.4 v 10.5 months; HR, 0.8; 95% CI, 0.64 to 0.99; P = .043). CONCLUSION: This analysis has prospectively quantified the incidence/pattern of TEs among patients with advanced gastroesophageal cancer who were treated with four triplet regimens, has demonstrated a differential thrombogenic effect according to platinum use, and has noted a poorer outcome associated with TE during treatment. Chemotherapy-related TE should contribute to the risk/benefit assessment of treatment.

Researchers forecast 45 percent surge in cancer cases by 2030.

Bloomberg News (4/30, Chase) reports, "Cancer cases may surge 45 percent by 2030, amid an aging and racially diverse population that will require better access to healthcare," according to a study published in the Journal of Clinical Oncology. The study shows that the increase will be "due mostly to the aging of the population, because cancer occurs more commonly in older people." But, "the expected increase in cancer may be particularly hard for uninsured people, who have lower survival rates from malignancies, compared with the insured," the researchers noted. Commenting on the findings, Richard Schilsky, president of the American Society of Clinical Oncology (ASCO), stated that "these are eye-popping statistics." 
  HealthDay (4/29, Gardner) reported that Schilsky noted the "profound divide between those with access to" improved treatment and screening methods, and "those without access," stating that "people lacking health insurance are less likely to survive cancer." For the study, "announced Wednesday at a news conference sponsored by" ASCO, researchers analyzed "data from a national health database to project rates of future cancer diagnoses." They found that "between 2010 and 2030, total incidence of all cancers will increase...from 1.6 million to 2.3 million, though the total population will increase by only 19 percent." Among older Americans, "cancer incidence is expected to increase 67 percent...vs. 11 percent in the younger age group and to double among minorities, compared with a 31 percent increase among whites." ASCO also released a policy statement vowing "to work towards eliminating cancer disparties through increased awareness [and] better access to care," among other efforts. Reuters (4/30, Steenhuysen) also covers the story. 

Researchers say physicians should contribute to Wikipedia pages on medical topics.

The AP (4/30, Metz) reports, "Researchers are suggesting that doctors could be spending more time writing and editing Wikipedia pages on medical topics, despite questions that have been raised about the collaborative online encyclopedia's credibility." According to a paper in the Journal of the American Medical Informatics Association, "medical professionals should recognize that Wikipedia has become a major online source of health information for consumers." For the study, researchers "measured how often Wikipedia entries showed up among the top results from main web search engines" when they "entered health-related terms." They found that "in 71 percent to 85 percent of search words tested at various search engines, Wikipedia came up within the first 10 results." And, because "Wikipedia's editing policy" allows "anyone to submit or make changes to articles," the researchers said that physicians, "along with patient groups and associations, can help improve quality at Wikipedia by participating." 

PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab

J Clin Oncol. 2009 Apr 27. [Epub ahead of print]

PTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the
Prediction of Benefit From Cetuximab Plus Irinotecan for Patients With Metastatic
Colorectal Cancer.

Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi G, Graziano
F, Cremolini C, Rulli E, Canestrari E, Funel N, Schiavon G, Petrini I, Magnani M,
Tonini G, Campani D, Floriani I, Cascinu S, Falcone A.

Department of Oncology, Azienda Unità Sanitaria Locale 6, Istituto Toscano
Tumori, Livorno; Division of Pathology; and Medical Oncology Unit, Azienda
Ospedaliero-Universitaria and University of Pisa; and Department of Oncology,
Transplants and New Technologies in Medicine, University of Pisa, Pisa;
Department of Biomolecular Sciences, University of Urbino, Urbino; Clinica di
Oncologia Medica, Azienda Ospedaliera Ospedali Riuniti, Università Politecnica
delle Marche, Ancona; Medical Oncology Unit, University Campus Biomedico, Rome;
Medical Oncology Unit, San Salvatore Hospital, Pesaro; and Istituto di Ricerche
Farmacologiche Mario Negri, Milan.

PURPOSE: PTEN, AKT, and KRAS are epidermal growth factor receptor (EGFR)
downstream regulators. KRAS mutations confer resistance to cetuximab. This
retrospective study investigated the role of PTEN loss, AKT phosphorylation, and 
KRAS mutations on the activity of cetuximab plus irinotecan in patients with
metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: A cohort of patients
with irinotecan-refractory mCRC who were treated with cetuximab plus irinotecan
was tested for PTEN immunoreactivity (ie, immunohistochemistry; IHC), pAKT IHC,
and KRAS mutations. Analyses were performed both on primary tumors and on related
metastases, and the association among IHC, mutational results, and treatment
outcomes was investigated. RESULTS: One-hundred two patients were eligible.
Ninety-six primary tumors, 59 metastases, and 53 paired samples were available.
Forty-nine primary tumors (58% of assessable samples) had a preserved PTEN
expression (PTEN-positive), whereas 35 (40% of assessable samples) were
pAKT-positive. Levels of concordance between primary tumors and metastases were
60%, 68%, and 95% for PTEN, pAKT, and KRAS, respectively. PTEN status on primary 
tumors and pAKT status both on primary tumors and on metastases did not predict
response or progression-free survival (PFS). On metastases, 12 (36%) of 33
patients with PTEN-positive tumors were responders compared with one (5%) of 22
who had PTEN-negative tumors (P = .007). The median PFS of patients with
PTEN-positive metastases was 4.7 months compared with 3.3 months for those with
PTEN-negative metastases (hazard ratio [HR], 0.49; P = .005). Patients with
PTEN-positive metastases and KRAS wild type had longer PFS compared with other
patients (5.5 months v 3.8 months; HR, 0.42; P = .001). CONCLUSION: PTEN loss in 
metastases may be predictive of resistance to cetuximab plus irinotecan. The
combination of PTEN IHC and KRAS mutational analyses could help to identify a
subgroup of patients with mCRC who have higher chances of benefiting from EGFR
inhibition.

PMID: 19398573 [PubMed - as supplied by publisher]