Targeted cancer therapy kills prostate tumor cells, study finds

ScienceDaily (June 6, 2011) — A new targeted therapy for prostate cancer halts tumor growth in animals with advanced prostate cancer that is resistant to hormone therapy, a new study finds.

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The results are being presented at The Endocrine Society's 93rd Annual Meeting in Boston.

"This targeted therapy may provide a treatment breakthrough that will extend the lives of men with advanced, hormone-refractory prostate cancer," said lead investigator Shuk-mei Ho, PhD, chairwoman of the Department of Environmental Health at the University of Cincinnati.

Men with prostate cancer that has recurred or has spread outside the prostate routinely receive androgen deprivation therapy, which blocks the action of the male hormones. This castration occurs through surgical removal of both testes or more often with medications. Although effective, this hormone-blocking treatment eventually stops working in some patients, Ho said.

"These patients are left with very few treatment options and usually succumb quickly to the disease," she said.

Ho's team previously found they can inhibit the growth of prostate cancer cell lines in culture by targeting and activating a protein called G protein-coupled receptor 30 (GPR30) using the experimental drug G-1, a GPR30 agonist, or stimulator.

In their new study, funded by the Veterans Affairs and the National Institutes of Health, Ho and her co-workers tested G-1 in an animal model of castration-resistant prostate cancer. They implanted human prostate cancer cells beneath the skin of male mice. The established tumor regressed upon castration and after the cancer relapsed, they injected the mice with a low dose of G-1. They also gave G-1 to noncastrated, or "intact," male mice that had prostate tumors. In these intact mice that still had male hormones, G-1 did not stop growth of the prostate tumors or cause substantial death of tumor cells (necrosis), they found.

"Surprisingly, G-1 was highly effective in halting the growth of the tumors that re-emerged after castration," Ho said.

The castration-resistant tumors showed a 65 percent necrosis. These mice had increased expression of GPR30 after castration, which Ho believes sensitized prostate tumors to the cell growth-inhibiting effects of G-1.

"These results mean G-1 won't work without androgen deprivation therapy," she said.

Therefore, Ho reported, the window of time when this targeted therapy might be effective for treating hormone-resistant prostate cancer is after androgen deprivation therapy. She said she believes G-1 can make androgen blockade more effective. G-1 caused no harm to the prostate or other vital organs in mice, she added.

Although GPR30 may have a role in cell growth in female tissues, Ho said it appears to have the opposite effect in men with hormone-resistant prostate cancer. "The beauty of this GPR30 is that it does not have any estrogen, and so it will not cause any side effects of estrogen," she said.

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Early transplants are no better than chemotherapy followed by transplant for non-Hodgkin lymphoma patients, study finds

ScienceDaily (June 3, 2011) — Patients with a very aggressive form of non-Hodgkin lymphoma who receive a stem cell transplant after standard chemotherapy during their first remission have comparable survival rates to those who receive the same standard therapy alone and, if needed, a transplant when they relapse.

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These findings from a U.S. and Canadian clinical trial of 370 patients conducted at 40 clinical institutions were presented by Patrick Stiff, MD, lead investigator and director, Loyola Cardinal Bernardin Cancer Center, at the annual meeting for the American Society of Clinical Oncology (ASCO).

"The trial was based on several preliminary studies that indicated a survival benefit to early stem cell transplants," Dr. Stiff said. "These findings may save some patients from undergoing a stem cell transplant unnecessarily."

However, a subset with all of the possible poor risk factors with this form of non-Hodgkin lymphoma did seem to have a higher chance of survival in a sub- analysis.

"Additional research is necessary to determine the best plan of care for the highest-risk patients," Dr. Stiff said. "In the meantime, these patients will have to consult with their physician to carefully determine their treatment plan."

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Novel experimental agent is highly active in CLL patients, interim study shows

ScienceDaily (June 3, 2011) — An interim analysis of a phase II clinical trial indicates that a novel experimental agent for chronic lymphocytic leukemia (CLL) is highly active and well tolerated both in patients who are undergoing treatment for the first time and those who have relapsed and are resistant to other therapy.

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The agent, called PCI-32765, is the first drug designed to target Bruton's tyrosine kinase, whose function is essential for CLL-cell survival and proliferation.

Study leader Dr. John C. Byrd, director of the division of hematology at Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James) presented the findings June 5 at the 2011 American Society of Clinical Oncology annual meeting in Chicago.

The analysis involved the first 21 cases in the untreated-patient group and the first 27 individuals in the relapsed/refractory-patient group. One patient in each group had a complete remission, and 13 patients (62 percent) in the previously untreated group and 12 patients (44 percent) in the relapsed group had partial remissions.

"We are excited about these early findings because they suggest that PCI-32765 is a highly active oral therapeutic that produces a high rate of durable remissions -- the remissions last months on end -- with acceptable toxicity in relapsed and refractory CLL," Byrd says.

Complete remission means there is no detectable CLL in anywhere in the body; partial remission means that the individual's disease volume has decreased 50 percent or more in a sustained manner.

"It is exciting to see a drug that was shown to be active in the laboratory translate to clinical benefit for CLL patients," says researcher Dr. Amy Johnson, assistant professor of medicine at the OSUCCC -- James. Johnson co-led the pre-clinical CLL work at Ohio State with Byrd and now coordinates several correlative studies for this clinical trial.

Byrd stresses that the patients show several benefits of the treatment, such as higher platelet counts and hemoglobin levels, and that many report that they feel dramatically better overall with less fatigue, factors that are difficult to measure and report as a number.

"These responses last for many months in part because patients are willing to remain on the drug since the side effects are very tolerable," he notes.

The ongoing phase II clinical trial involves 78 patients with previously untreated or relapsed and refractory CLL or small lymphocytic leukemia. The previously untreated patients were all age 65 or older; individuals in the relapsed group all had two or more earlier treatments followed by recurrent disease.

"These are early findings, so patients with partial remissions could improve to complete remissions with further observation," Byrd says. "Usually patients with highly resistant and refractory CLL would have progressed and possibly died by this time, but 85 percent remain on PCI-32765 and continue to improve."

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Irregular breathing can affect accuracy of 4-D PET/CT, study finds

ScienceDaily (June 6, 2011) — A study presented at SNM's 58th Annual Meeting focuses on the effect that breathing irregularities have on the accuracy of 4D positron emission tomography (PET) scans and outlines a PET imaging method that reduces "motion artifacts" or image blurring arising from respiratory motion. Non-gated PET imaging with 4D computed tomography may be useful for imaging patients who do not benefit from the use of respiratory gating, most notably patients with erratic breathing.

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"Breathing irregularities can lead to significantly underestimated lesion activity in respiratory-gated PET imaging," says Boon-Keng Teo, PhD, assistant professor of radiation oncology at the University of Pennsylvania in Philadelphia, Pa. "Non-gated PET imaging corrected with 4D computed tomography (CT) may be more effective for imaging patients with irregular breathing. This could potentially lead to a more robust and quantitatively accurate reading of active tumors."

Respiratory gating technologies have dramatically improved the diagnostic quality of PET imaging, which provides functional images of physiological processes occurring in the body. Sensors in respiratory gating systems placed on or around the patient monitor the phase of the breathing cycle. They then transmit information about the patient's breathing to the scanning technology for image processing. Instead of creating one fluid image that shows so-called motion artifacts, respiratory-gated PET imaging is much like a series of photos taken during different phases of the respiratory cycle that are grouped together to create a series of images corresponding to each phase. The problem is that patients with respiratory disease, heart conditions or other serious disease are likely to be breathing unevenly. Respiratory gating systems are designed to work with normal breathing patterns, but not with irregular respiratory cycles.

Researchers conducted phantom studies to compare respiratory-gated PET imaging with non-gated PET imaging corrected with 4D computed tomography. CT uses X-ray technology and complex data processing to produce very high-resolution images of structural anatomy. Phantom studies were performed with inanimate objects and specialized motion devices that move in a controlled manner in order to simulate tumors in respiratory motion. The 4D PET and CT studies were conducted in succession with a hybrid PET/CT system. Various degrees of motion irregularities were simulated to study their impact on the accuracy of 4D PET for suppressing motion artifacts.

Results of the study show that non-gated PET with 4D CT imaging can be an alternative to respiratory-gated PET imaging for determining tumor activity in patients with highly irregular breathing. These findings could change imaging protocols for patients with uneven breathing and potentially improve overall accuracy of tumor detection, thereby informing clinicians about appropriate treatments and perhaps even surgical planning for better cancer management.

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U.S. Veterans Health Administration similar or better than private sector for cancer patients ages 65 plus, study finds

ScienceDaily (June 6, 2011) — A new study finds that the cancer care provided by the Veterans Health Administration (VHA) for men 65 years and older is at least as good as, and by some measures better than, Medicare-funded fee-for-service care obtained through the private sector. The study, reported in the June 7 issue of Annals of Internal Medicine, was led by Nancy Keating, an associate professor of health care policy at Harvard Medical School.

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Several factors could account for the high quality of VHA care. "Care in the VHA is much better coordinated than most other settings," said Keating, who is also an associate physician at Brigham and Women's Hospital. "The VHA has a good, integrated medical record. Their doctors all work together and communicate more effectively. There are no incentives for the overuse of cancer treatments because VHA physicians are not rewarded financially for prescribing more drugs or procedures. The VHA also measures quality across a wide range of conditions, so there is a culture of quality improvement."

The VHA is the largest integrated healthcare system in the United States, and veterans who are part of the VHA get almost all of their care from this system. In contrast to the fee-for-service model of care common in the private health sector, the VHA operates on a set budget to provide coordinated and comprehensive healthcare services, and its doctors are salaried. Congress has mandated periodic assessments of the VHA's performance in various domains of health care. In contracting out the VHA's cancer care evaluation, the Office of Policy and Planning of the U.S. Department of Veteran Affairs turned to Keating and her colleagues.

Keating's team pooled registry and administrative data from 2001-2004 for men 65 years and older diagnosed with the three most common cancers in men -- colorectal, lung and prostate cancers -- or hematologic cancers, such as lymphoma and multiple myeloma. The researchers used sophisticated analyses to ensure unbiased comparisons between the VHA and fee-for-service Medicare patients, and compared how well various guideline-recommended criteria for care were met in these two settings.

When compared with fee-for-service Medicare patients, Keating and colleagues found that veterans in the VHA were diagnosed with colorectal cancers at earlier-stages and had higher adjusted rates of certain recommended treatments, including surgery for colon cancer, chemotherapy for lymphoma, and bisphosphonates for myeloma. With regard to other treatments studied, care was fairly equal in quality between the VHA and fee-for-service Medicare.

Keating conducted additional analyses to further account for differences that may exist between veterans and the Medicare population that they could not measure. For example, veterans are often in worse health than the general population. When they updated their results to account for these likely differences in health status, care in the VHA was better than that in fee-for-service Medicare for most indicators. One exception was a likely delay in the adoption of certain new and expensive radiation therapy technologies for prostate cancer.

Overall, rates of recommended care were relatively low in both settings for some of the treatments studied. This may result from lack of data on the benefits versus risks of these drugs in older patients. Keating recommended that cancer clinical trials include older individuals as well as those with comorbid illnesses.

"While the ongoing national health care debate centers on expanding insurance coverage, ensuring a coordinated health care delivery system that provides high-quality care at good value is equally important to improve outcomes and keep rising health care costs in check," said Keating.

This research was funded by the Department of Veterans Affairs Office of Policy and Planning.

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Bankruptcy rates among cancer patients increase along with survival time, study finds

ScienceDaily (June 6, 2011) — An analysis linking federal bankruptcy court records to cancer registry data from nearly 232,000 adult cancer cases in western Washington during a 14-year period has found a hidden cost to survival: Insolvency rates increase along with the length of survival.

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"Patients diagnosed with cancer may face significant financial stress due to income loss and out-of-pocket costs associated with their treatment," said Scott Ramsey, M.D., Ph.D., a health care economist and internist at Fred Hutchinson Cancer Research Center who led the study. "On average, bankruptcy rates increased fourfold within five years of diagnosis." Ramsey presented the findings June 6 at the 2011 annual meeting of the American Society of Clinical Oncology in Chicago.

The study found that compared to the general population, bankruptcy rates were nearly twice as high among cancer patients one year after diagnosis, and that the median time to bankruptcy was two and a half years after diagnosis.

"The risk of bankruptcy for cancer patients is not well known, and previous studies have relied on individual self-reports about medically related reasons for bankruptcy filing," said Ramsey, a member of the Hutchinson Center's Public Health Sciences Division. "By linking two irrefutable government records of cancer and bankruptcy, we are able to determine how financial insolvency risk varies by cancer type, treatment and other factors," he said.

For the study, Ramsey and colleagues linked Washington state cancer registry data with federal bankruptcy court records in 13 western Washington counties. They measured the rate of bankruptcy after a first cancer diagnosis and identified factors that increased bankruptcy risk among people with common cancers.

They found that bankruptcy risk varies widely across cancer types. The risk is highest for lung, thyroid and leukemia/lymphoma cancer patients. In contrast, patients over 65, who are typically on Medicare, have a much lower risk of bankruptcy than younger patients. The researchers also found that bankruptcy rates among cancer patients have increased significantly since the U.S. financial crisis.

Ramsey and colleagues in the Hutchinson Center's Public Health Sciences Division, along with researchers at the University of Washington, conducted the study in collaboration with the U.S. Bankruptcy Court, Western District of Washington, Seattle.

The National Cancer Institute funded the research.

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Coffee drinking improves hepatitis C treatment response, study suggests

ScienceDaily (June 8, 2011) — Advanced hepatitis C patients with chronic liver disease may benefit from drinking coffee during treatment, according to a new study in Gastroenterology, the official journal of the American Gastroenterological Association (AGA) Institute. Patients who received peginterferon plus ribavirin treatment and who drank three or more cups of coffee per day were two times more likely to respond to treatment than non-drinkers.

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"Coffee intake has been associated with a lower level of liver enzymes, reduced progression of chronic liver disease and reduced incidence of liver cancer," said Neal Freedman, PhD, MPH, of the National Cancer Institute and lead author of this study. "Although we observed an independent association between coffee intake and virologic response to treatment, this association needs replication in other studies."

Among non-drinkers, 46 percent had an early virologic response; 26 percent had no detectable serum hepatitis C virus (HCV) ribonucleic acid at week 20; 22 percent had no detectable serum at week 48; and 11 percent had a sustained virologic response. In contrast, the corresponding proportions for those who drank three or more cups of coffee per day were 73 percent, 52 percent, 49 percent and 26 percent, respectively.

Approximately 70 to 80 percent of individuals exposed to HCV become chronically infected. Worldwide, these individuals are estimated to number between 130 and 170 million. Higher coffee consumption has been associated with slower progression of pre-existing liver disease and lower risk of liver cancer. However, the relationship with response to anti-HCV treatment had not been previously evaluated. Treatment with peginterferon and ribavirin resolves chronic hepatitis C in about half of patients. It is unknown whether coffee will improve response with the addition of new drugs that were recently approved for use in the U.S.

Because patients in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial also had previously failed interferon therapy, it is not clear whether the results can be generalized to other patient populations. Future studies among patients with less advanced disease, those who are treatment-naïve to prior therapy, or who are being treated with newer antiviral agents are needed.

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Study confirms safety, cancer-targeting ability of nutrient in broccoli, other vegetables, researchers say

ScienceDaily (June 9, 2011) — Sulforaphane, one of the primary phytochemicals in broccoli and other cruciferous vegetables that helps them prevent cancer, has been shown for the first time to selectively target and kill cancer cells while leaving normal prostate cells healthy and unaffected.

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The findings, made by scientists in the Linus Pauling Institute at Oregon State University, are another important step forward for the potential use of sulforaphone in cancer prevention and treatment. Clinical prevention trials are already under way for its use in these areas, particularly prostate and breast cancer.

It appears that sulforaphane, which is found at fairly high levels in broccoli, cauliflower and other cruciferous vegetables, is an inhibitor of histone deacetylase, or HDAC enzymes. HDAC inhibition is one of the more promising fields of cancer treatment and is being targeted from both a pharmaceutical and dietary approach, scientists say.

"It's important to demonstrate that sulforaphane is safe if we propose to use it in cancer prevention or therapies," said Emily Ho, a principal investigator in the Linus Pauling Institute, lead author on the study and associate professor in the OSU Department of Nutrition and Exercise Sciences.

"Just because a phytochemical or nutrient is found in food doesn't always mean its safe, and a lot can also depend on the form or levels consumed," Ho said. "But this does appear to be a phytochemical that can selectively kill cancer cells, and that's always what you look for in cancer therapies."

The findings were published in Molecular Nutrition and Food Research, a professional journal. Research was supported by the National Cancer Institute, National Institute of Environmental Health Sciences and the OSU Agricultural Experiment Station.

The Linus Pauling Institute has conducted some of the leading studies on sulforaphane's role as an HDAC inhibitor -- one, but not all, of the mechanisms by which it may help prevent cancer. HDACs are a family of enzymes that, among other things, affect access to DNA and play a role in whether certain genes are expressed or not, such as tumor suppressor genes.

Some of the mechanisms that help prevent inappropriate cell growth -- the hallmark of cancer -- are circumvented in cancer cells. HDAC inhibitors can help "turn on" these silenced genes and restore normal cellular function.

Previous OSU studies done with mouse models showed that prostate tumor growth was slowed by a diet containing sulforaphane.

"It is well documented that sulforaphane can target cancer cells through multiple chemopreventive mechanisms," the researchers wrote in their study. "Here we show for the first time that sulforaphane selectively targets benign hyperplasia cells and cancerous prostate cells while leaving the normal prostate cells unaffected."

"These findings regarding the relative safety of sulforaphane to normal tissues have significant clinical relevance as the use of sulforaphane moves towards use in human clinical trials," they said.

The results also suggest that consumption of sulforaphane-rich foods should be non-toxic, safe, simple and affordable.

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Less toxic combination of erlotinib and bevacizumab is effective non-small cell lung cancer patients, study suggests

ScienceDaily (June 1, 2011) — The standard treatment for patients with advanced non-small cell lung cancer (NSCLC) is a combination of two old-fashioned cytotoxic chemotherapy drugs. The combination, however, comes with substantial toxicity. Now, Fox Chase Cancer Center researchers report that a combination of two molecularly-targeted agents may provide similar therapeutic benefit with less toxicity.

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"These results seem to be better than standard of care," says Hossein Borghaei, DO, medical oncologist at Fox Chase, who will present the results at the 2011 Annual Meeting of the American Society of Clinical Oncology on June 4. "Of course, the problem with a phase II trial always is that the patients tend to be a select patient population. But when you look at the numbers, the patients appear to be benefiting from the treatment. They stay on treatment longer and the time to progression on average was a little bit better. And we don't have a lot of toxicities, like major hair loss or nausea, and we don't have a lot of neutropenia or anemia."

"So overall it looks like a well tolerated regimen and it appears to be an effective front-line therapy in this patient population," he says.

Until recently, clinicians assumed that older patients were more likely to suffer from serious toxicities associated with standard chemotherapy. Therefore, Borghaei's team focused their current study on patients 65 years and older, enrolling 33 patients with a median age of 74 years. All patients had previously untreated, advanced NSCLC. Patients received standard dose erlotinib (a small molecule inhibitor of the epidermal growth factor receptor) and bevacizumab (an antibody that blocks the vascular endothelial growth factor pathway) every 21 days until patients either progressed or stopped treatment due to adverse events.

Six patients remain on therapy and have received 4 to 40 cycles of treatment. Of the 24 patients off therapy, the median number of cycles received was 4, with a range of one to 40. The estimated progression-free survival for all patients is 6.6 months. The estimated one-year survival is 56.6%, with 12 patients remaining alive, and the estimated median overall survival is 14.1 months.

"With standard chemotherapy we can only give four to six cycles," Borghaei says. "But with this biologic regimen we can continue therapy because there is less toxicity. They are on continuous drugs, which might be one reason that they appear to have longer progression free survival. We have to wait for the final data and analyze it before we know -- and the big test would be a head-to-head phase III trial with chemotherapy."

The most common serious adverse events in the trial were grade 3 hypertension, which occurred in five patients, and grade 3 rash, which occurred in three patients. Additionally, the following grade 3 toxicities affected one patient each, fatigue, anorexia, neutropenia with infection, bowel perforation, and abnormal blood tests. Two patients had grade 3 diarrhea and one patient had grade 4 diarrhea.

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Two-thirds of newly diagnosed U.S. cancer patients unable to obtain oncology appointments, study suggests

ScienceDaily (June 1, 2011) — Newly diagnosed cancer patients frequently face hurdles in obtaining an appointment for care with an oncologist, according to new research from the Perelman School of Medicine at the University of Pennnsylvania that will be presented on June 4 at the 2011 annual meeting of American Society of Clinical Oncology. Even callers with private health insurance had difficulty scheduling an appointment, with just 22 percent of them obtaining a slot, compared to 29 percent of uninsured patients and 17 percent of patients on Medicaid, according to results of a study in which research assistants posed as patients seeking an initial evaluation.

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"Although healthcare reform is likely to expand health insurance coverage to more Americans, our research shows that even with insurance, patients face barriers when they try to access cancer care," says lead author Keerthi Gogineni, MD, an instructor in the division of Hematology-Oncology at Penn's Abramson Cancer Center. "Given the typical pre-appointment expectations for new patients -- which typically involve referral requirements, paperwork and routing of medical records and test results -- both insured and uninsured patients must contend with many challenges that delay care with a specialty cancer provider."

In the study, research assistants attempted to call 160 U.S. hospitals under three different circumstances each, varying only their insurance status as they explained their scripted patient situation, which involved a new diagnosis of an inoperable liver cancer. Callers reached a scheduler 79 percent of the time, but only 29 percent of those callers received appointments. Of the appointments ultimately scheduled, 35 percent required multiple calls to complete the process. In nearly a quarter of cases, callers failed to reach staff even after three attempts. Among reasons for denial of appointments or inability to schedule: Demand for medical records (39 percent), not being able to reach appropriate schedulers (24 percent), and referral requirements (18 percent).

The authors note that the access problems revealed in the study may become more urgent in the coming years, given Institute of Medicine and ASCO projections showing a widening gap between the number of people living with cancer and the number of practicing oncologists available to care for them.

Gogineni and her co-author, Katrina Armstrong, MD, MSCE, chief of the division of General Internal Medicine and associate director of Outcomes and Delivery in the Abramson Cancer Center, suggest that more patient navigator programs could play a critical role at coaching patients through this initial phase of their care. Since literacy issues or lack of guidance from a referring physician may impede patients' ability to locate the proper number to call for help at some hospitals, they also urge centers to train staff at locations other than appointment hotlines or intake centers to point new patients to the proper location.

"Patients who are newly diagnosed with cancer may be confused or frightened," Armstrong says. "Asking them to find their way through the complex process of obtaining imaging studies and other tests or collecting records from another doctor prior to scheduling an appointment may pose an undue burden, and cancer centers should be prepared to provide help with those preliminary steps."

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Intensity modulated radiation therapy cuts GI side effects from prostate cancer in half vs. 3D-CRT, study shows

ScienceDaily (June 1, 2011) — Intensity modulated radiation therapy, a newer, more precise form of radiation therapy, causes fewer gastrointestinal side effects when combined with hormone therapy than using three-dimensional radiation therapy, according to a study published in the June issue of the International Journal of Radiation Oncology•Biology•Physics, the official scientific journal of the American Society for Radiation Oncology (ASTRO).

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Three-dimensional radiation therapy (3D-CRT) combined with hormone therapy has been proven very effective at treating men with intermediate to high-risk prostate cancer. However, these treatments can cause very uncomfortable gastrointestinal side effects due to exposure of the rectum to radiation during treatment.

Researchers at Fox Chase Cancer Center in Philadelphia conducted a study to see if IMRT, which allows doctors to better concentrate radiation in the prostate and limit rectal exposure, reduces the side effects while continuing to deliver the necessary radiation to successfully treat the cancer.

Two hundred ninety-three men were studied -- 170 received 3D-CRT and 123 received IMRT. With a mean follow-up of 86 months, a multivariate analysis shows that patients treated with 3D-CRT were more than twice as likely to develop gastrointestinal toxicity compared to patients treated with IMRT.

"The use of IMRT significantly reduces the risk of late GI toxicity in men undergoing concurrent radiation therapy and hormone therapy for prostate cancer," Mark Buyyounounski, MD, MS, a radiation oncologist at Fox Chase Cancer Center, said. "I encourage men with prostate cancer receiving hormone therapy and radiation therapy to talk their doctors about whether IMRT has advantages over other types of radiation therapy."

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Surgery deaths drop nationwide in U.S. for high-risk surgeries, according to study

ScienceDaily (June 2, 2011) — Surgery death rates have dropped nationwide over the past decade, according to a University of Michigan Health System study that reveals cancer surgeries have seen the most dramatic improvement in safety.

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The U-M study in this week's New England Journal of Medicine shows surgery mortality dropped substantially for eight different high-risk surgeries performed on 3.2 million Medicare patients from 1999 to 2008.

More patients are surviving open heart surgery and replacement of diseased aortic valves, but research shows high volume hospitals and their expertise drove a 67 percent decline in deaths for pancreatectomy, a 37 percent decline in deaths from cystectomy, surgery to remove the bladder, and a 32 percent drop in esophagectomy mortality.

"Patients should take solace in knowing that all high-risk surgeries have become safer in the last decade," says lead author Jonathan F. Finks, M.D., clinical assistant professor of surgery at the U-M Health System. "In cancer surgery, in particular, mortality has dropped in large part because more patients are having their surgery in safer, higher volume hospitals."

One of the more interesting findings by the U-M's Center for Healthcare Outcomes and Policy is that hundreds of low-volume U.S. hospitals stopped doing high-risk cancer surgery.

For example, the number of Medicare patients needing surgery to treat pancreatic cancer increased by 50 percent, but the number of hospitals performing the surgeries decreased by 25 percent, from 1,308 hospitals to 978.

As a result, the volume of surgeries a hospital may do in a year rose from five cases of pancreatectomies a year to 16.

There have been numerous efforts in the United States to concentrate selected operations at high volume hospitals.

The Leapfrog group, a consortium of large corporations and public agendas that purchase health care largely for their employees, has been among the most prominent advocates of volume-based referrals. In 2000, it placed a minimum volume standard on hospitals for several surgical procedures to guide where employees get medical care.

The U-M analysis shows volume-based referrals have been successful for certain surgeries, but the effort to make surgery safer takes more than one fix, authors say.

"For some procedures, however, strategies such as operating room checklists, outcomes measurement programs, and quality improvement collaboratives are likely to be more effective than volume-based referral," says John Birkmeyer, M.D., professor of surgery and director of the U-M Center for Healthcare Outcomes and Policy.

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Drug combination extends survival in refractory lung cancer patients, study finds

ScienceDaily (June 2, 2011) — Scientists have identified a drug combination, when used in advanced lung cancer patients, shows a survival advantage in patients who no longer respond to existing therapies. They found that bexarotene and erlotinib can each repress the critical cell cycle regulator: cyclin D1. The drug combination also broadened the reach to include a specific subset of patients, such as those resistant due to the presence of a ras mutation in their cancer.

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The study was published in the June issue of Cancer Prevention Research.

"Erlotinib has been found to be most effective in women of Asian descent who are never smokers with bronchioalveolar carcinoma, and who tend to have activating mutations of the epidermal growth factor receptor," said Ethan Dmitrovsky, M.D., an Associate Scientific Director of the Samuel Waxman Cancer Research Foundation and a senior author on the study. "None of the patients in our study fit that demographic profile."

In fact, the patients in the cohort who exhibited the greatest response included non-Asian men who were smokers. Advanced lung cancer patients with refractory disease have a survival of four months or less with traditional chemotherapy. The results of the study showed a median survival of five and a half months and longer. Three patients from the trial are now living two to four years beyond the expected average.

The study's results were recently duplicated by a group of MD Anderson scientists, noted Konstantin Dragnev, M.D., who led this trial and is an associate professor at Dartmouth Medical School, in Hanover, N.H.

The most exciting part of the research, which was funded in part by the Samuel Waxman Cancer Research Foundation, "is that scientists were able to make a dent in the ras mutation subset of patients," said Dmitrovsky, who is a professor at Dartmouth Medical School. "This area is an unmet medical need. These are often times the most difficult lung cancers to treat."

"This study gives hope to a large group of lung cancer patients who currently have very few options," said Linda Wenger, the Executive Director of Uniting Against Lung Cancer. "It's critical for nonprofit foundations to continue supporting research in underserved areas to bring new ideas to the clinic."

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Higher doses of radiation in fewer treatments proved safe, effective for low-risk prostate cancer, study finds

ScienceDaily (June 2, 2011) — In a multicenter clinical trial, UT Southwestern Medical Center researchers have found that higher doses of stereotactic radiation therapy requiring fewer treatments are safe and effective for patients with low-to-intermediate-risk prostate cancer.

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Results of the trial, available in the Journal of Clinical Oncology, showed that stereotactic body radiation therapy (SBRT), which delivers ultra-precise radiation, was effective in treating patients with localized prostate cancer in five 30-minute sessions every other day over two weeks. That compares to the typical radiation protocol for prostate cancer of 42 to 45 daily treatments administered over eight to nine weeks.

"We were trying to develop a fast, convenient, outpatient, non-invasive treatment," said Dr. Robert Timmerman, vice chairman of radiation oncology and professor of neurological surgery and senior author of the study. "In the low-risk population, there are a lot of good options, but none of them are altogether convenient. The most convenient treatment would finish quickly without the need for a prolonged recovery."

SBRT has been used in the last decade to treat patients with lung, liver and brain cancers. The current study tested whether high-potency treatments would work in a moving target like the prostate, which moves considerably due to normal bladder and bowel filling.

"We're trying to kill the prostate cancer, but without injuring the urethra, the bladder or the rectum," Dr. Timmerman said. "Each treatment had to be very potent in order to get the full radiation effect in only five treatments."

To avoid injury to healthy tissue, researchers used beams of radiation that were just millimeters larger than the target itself. That narrow scope helped avoid consequences such as rectal injury, impotence and difficulty urinating.

Prostate cancer is the most common cancer in men, with some 200,000 diagnosed each year in the U.S. About half of those who are treated undergo radiation therapy, typically for eight weeks. Not everyone is cured, however, because some tumors are resistant to radiation.

In the current clinical trial, researchers tested escalating doses for safety levels in 45 patients enrolled from November 2006 to May 2009. In a 90-day follow-up procedure, they looked at how much injury occurred in adjacent areas, including the rectum or urethra, and any changes to the patients' quality of life.

"There were a few more complications associated with higher doses, but they were fairly predictable and rarely severe," said Dr. Yair Lotan, associate professor of urology and a co-author of the study. "By giving these higher doses, we might be able to kill more resistant tumors with shorter treatments."

In the next stage of the clinical trial, a larger group of patients will be treated at one dosage level, and follow-up will be 18 months.

Other UT Southwestern researchers involved in this study were Dr. Paul DeRose, radiation oncology resident; Dr. Xian-Jin Xie, associate professor in the Harold C. Simmons Comprehensive Cancer Center; Jingsheng Yan, statistician; Dr. Ryan Foster, assistant professor of radiation oncology; Dr. David Pistenmaa, professor of radiation oncology; and Susan Cooley, senior research nurse in radiation oncology.

The study was supported by the Department of Defense.

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Therapeutic melanoma vaccine improves response rate, progression-free survival, study finds

ScienceDaily (June 2, 2011) — A vaccine for one of the most lethal cancers, advanced melanoma, has improved response rate and progression-free survival for patients when combined with the immunotherapy drug Interleukin-2, according to research led by scientists from The University of Texas MD Anderson Cancer Center and Indiana University Health Goshen Center for Cancer Care.

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The findings, published in the June 2 New England Journal of Medicine, mark the first vaccine study in the disease -- and one of the first in cancer overall -- to show clinical benefit in a randomized Phase III clinical trial. It's also the first cancer vaccine to show an improved response rate in patients.

The research was first presented on the plenary session of 2009 American Society of Clinical Oncology.

According to the American Cancer Society, melanoma has one of the fastest growing incidence rates of all cancers. In 2010, more than 68,130 people in the U.S. were diagnosed with melanoma and 8,700 died from the disease. The five-year survival rates for those with regional and metastatic disease are 65 percent and 16 percent, respectively.

"Obviously, this is a disease, in its advanced setting, in need of better therapies for patients," said Patrick Hwu, M.D., professor and Chair of the Department of Melanoma Medical Oncology and the study's senior author. "This study serves as a proof-of-principle for the role of vaccines in melanoma and in cancer therapy overall. If we can use the body's own defense system to attack tumor cells, we provide a mechanism for ridding the body of cancer without destroying healthy tissue."

During their tenure at the National Cancer Institute NCI), Hwu and Douglas Schwartzentruber, M.D., the medical director of the Goshen Center for Cancer Care, were involved in the vaccine's development and early basic and clinical studies. The peptide vaccine, known as gp100:209-217 (200M), works by stimulating patients' T cells, known for controlling immune responses.

"This vaccine activates the body's cytotoxic T cells to recognize antigens on the surface of the tumor. The T cells then secrete enzymes that poke holes in the tumor cell's membrane, causing it to disintegrate," explained Schwartzentruber, the study's principal investigator and corresponding author.

After an NCI-led Phase II study combining the vaccine with Interleukin-2 (IL-2) showed response rates of 42 percent in metastatic melanoma patients, a Phase III randomized trial with the two agents opened more than a decade ago.

Conducting a large, multi-institutional trial with IL-2, however, had its own set of unique challenges, explained Hwu, as not all cancer centers and community hospitals are capable of administering the immunotherapy. A highly specialized therapy associated with such significant side effects as low blood pressure and capillary leak syndrome, which poses risks to the heart and lung, IL-2 is often delivered in intensive care units. MD Anderson is one of the few centers with a dedicated in-patient unit exclusively designed for the drug's delivery; before, the institution was offering the therapy in its ICU.

In the Phase III trial, 185 patients at 21 centers across the country were enrolled in the study. All had advanced metastatic melanoma and were stratified for cutaneous metastasis, a known indicator of response to IL-2. Patients were randomized to receive either high dose IL-2, or IL-2 and vaccine. In the IL-2 arm, 94 patients were enrolled and 93 were treated and evaluated for response; 91 were enrolled and 86 treated and 85 were evaluated for response in the IL-2 and vaccine arm. The primary endpoint of the study was clinical response; the secondary endpoints were toxic effects and progression-free survival.

The study found that those who received the vaccine had a response rate of 16 percent, and progression-free survival of 2.2 months, compared to 6 percent and 1.6 months respectively in those that did not. The study was not powered to look at overall survival, but for those receiving the vaccine, it trended positive, 17.8 months vs. 11.1 months.

"This is one of the first positive randomized vaccine trials in cancer and the findings represent a significant step forward for treatment of advanced melanoma," said Schwartzentruber. "However, the vaccine only can be given to half of those with melanoma because it has to match a patient's tissue type, or HLA. A major priority for us is to figure out ways to broaden our approach and use mixtures of peptides, for example, so that more patients are eligible."

The researchers would like to improve upon it by including other immune-stimulatory agents, such as newer vaccine adjuvants, other cytokines and antibodies that further activate immune cells.

"This is a very exciting time for the field of melanoma. During the last few years, the entire landscape has changed -- with the addition of targeted therapies such as those that target BRAF as well as those that stimulate the immune system. Still, these drugs work in a small number of patients, and/or resistance often develops," said Hwu. "Now, our focus will need to turn toward studying these novel therapies in combination and continue our quest for better vaccines, as well as researching ways to make the study inclusive of more metastatic melanoma patients."

The study was funded, in part, by the National Cancer Institute.

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Antifungal drug delays need for chemo in advanced prostate cancer, study suggests

ScienceDaily (June 2, 2011) — The oral antifungal drug itraconazole, most commonly used to treat nail fungus, may keep prostate cancer from worsening and delay the need for chemotherapy in men with advanced disease. Details of the finding, from a clinical trial led by Johns Hopkins experts, are scheduled for presentation on June 4 at the 2011 American Society of Clinical Oncology (ASCO) annual meeting.

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Currently, the drug is approved to treat fungal infections in nails and other organs. Serious side effects can include heart failure, and Johns Hopkins experts caution that itraconazole needs further study before it can be considered for prostate cancer treatment.

Identified as a potential anticancer drug after Hopkins scientists scoured a database of more than 3,000 FDA-approved drugs, itraconazole appears to block tumor blood vessel growth -- the only drug in its class to do so -- much like the anticancer drug bevacizumab (Avastin). The antifungal also disrupts a key cancer-initiating biological pathway called Hedgehog. Laboratory testing by Johns Hopkins scientist Jun Liu, Ph.D., has shown that human prostate tumors implanted in mice shrink when treated with itraconazole.

"The most effective therapy we have right now for metastatic prostate cancer is hormone therapy, and when it doesn't work, the next step is usually chemotherapy," says Emmanuel Antonarakis, M.D., assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center. In a search for compounds that could put off chemotherapy, the Johns Hopkins team turned to itraconazole.

For the study, patients with prostate cancer that had spread to other organs and did not respond to hormone therapy were randomly assigned to receive low or high doses of itraconazole.

Over 24 weeks of daily treatment with oral itraconazole, the investigators tracked the length of time for each patient's prostate cancer to worsen (called progression-free survival). Evidence of worsening disease was measured by a 25 percent increase in their blood level of prostate specific antigen (PSA), a marker for prostate cancer.

Early in the trial, preliminary analysis of 17 men receiving low doses of itraconazole showed that only two of them (11.8 percent) had stable or declining PSA. Because of the limited response, no further men were given low doses of the drug.

However, 11 of 24 (48.4 percent) men taking high doses of itraconazole had stable or declining PSA levels lasting at least 24 weeks. In addition, nearly a third of men taking the high dose had PSA reductions of 30 percent or more. Metastatic prostate cancer patients receiving no treatment typically would worsen in eight to 12 weeks, according to Antonarakis.

The investigators also found that 12 of 14 men taking high doses of itraconazole had lower levels of circulating tumor cells present in their blood after therapy, compared with their baseline levels.

Seven patients experienced side effects, including low potassium, hypertension and fluid retention, but the problems were resolved with potassium replacement pills, anti-hypertension drugs, and diuretics.

"We also tested whether itraconazole acted as hormone therapy by tracking levels of testosterone and DHEA (a testosterone derivative) in the blood, and we found no reductions of either testosterone or DHEA," says Antonarakis. "This finding shows that itraconazole is not just another hormone therapy, and has a unique mechanism of action."

Antonarakis and colleagues next plan to examine blood and skin samples taken from study participants specifically to look for levels of proteins linked to tumor blood vessel formation and the Hedgehog pathway.

"With these results, we believe that high-dose itraconazole is worth studying in a larger group of men with advanced prostate cancer," adds Antonarakis.

The clinical trial was funded by the Department of Defense (DoD) Prostate Cancer Research Program, the Commonwealth Foundation for Cancer Research, the David H. Koch Charitable Foundation, a 2009 American Society of Clinical Oncology (ASCO) Young Investigator Award granted to Antonarakis, and the National Institutes of Health/National Cancer Institute.

In addition to Antonarakis, other investigators participating in the research on behalf of the Prostate Cancer Clinical Trials Consortium included Amanda Blackford, Serina King, Anja Frost, Seun Ajiboye, Sushant Kachhap, Michelle Rudek, and Michael Carducci from Johns Hopkins; Elisabeth Heath from the Karmanos Cancer Institute; David Smith from University of Michigan, Ann Arbor; and Dana Rathkopf and Daniel Danila from Memorial Sloan Kettering Cancer Center.

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C-reactive protein levels predict breast cancer survival rates, study finds

ScienceDaily (June 1, 2011) — Levels of C-reactive protein (CRP) are increased in response to acute inflammation, infection and tissue damage. There are also reports that CRP levels are elevated because of cancer. New research published in BioMed Central's open access journal Breast Cancer Research shows that elevated CRP levels are predictive of a poor prognosis for breast cancer sufferers.

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C-reactive protein is produced by the liver, in response to infection or injury, when stimulated by the cytokine IL-6. Tumor sites are often associated with inflammation and this inflammation contributes to tumor growth, invasion and metastasis. While elevated CRP has been found associated with a poor outcome for many solid tumors, including endometrial, cervical, prostate and colorectal cancer, there has been some discussion about whether this is true for breast cancer.

Researchers from Denmark looked at data from over 2000 breast cancer patients and followed their progress for up to seven years from diagnosis (average follow up was three years). The researchers found that regardless of lifestyle, menopause status and presence of cardiovascular disease, increasing levels of CRP resulted in increasingly poor prognosis. The five-year survival decreased from 90% for low CRP to 74% for high levels of CRP, disease-free survival reduced from 87% to 74%, and deaths from breast cancer increased from 11% to 20%.

Dr Kristine Allin, from Herlev Hospital, said, "Elevated CRP at time of diagnosis remained predictive of overall survival rates regardless of patient's age, tumor size, lymph node status, or presence of metastasis, and whether or not the patient was estrogen receptor positive. It was still true even when we excluded patients which we believed to have bacterial infections because of their very high CRP levels."

Dr Allin continued, "While measuring CRP levels gives a general indication of health and longevity, measuring CRP levels for breast cancer patients seems to be an easy way to predict the severity of the patient's disease. This may allow clinicians to alter their treatment tactics and improve cancer survival rates."

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Vaccine extends recurrent glioblastoma survival rates by 2 to 3 times, study finds

ScienceDaily (June 3, 2011) — In data presented at The American Society of Clinical Oncology (ASCO) Annual Meeting, cancer researchers found that the brain tumor vaccine HSPPC-96 for treating recurrent glioblastoma (GBM) has a favorable safety profile and extends survival by two to three times more than the current median survival rate.

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Patients in the study, conducted at University Hospitals Case Medical Center, University of California, San Francisco and Columbia University, were found to have a median survival of 11 months compared to current three to five month survival.

"The findings are very favorable for patients with this deadly form of brain cancer," said Andrew Sloan, MD, one of the authors of the study presented at ASCO and Director of the Brain Tumor and Neuro-Oncology Center at University Hospitals Case Medical Center. "The vaccine is one of the few immune therapies designed specifically for patients who are not newly diagnosed, and these encouraging results make this a promising therapy for a more extensive Phase 3 trial."

HSPPC-96 isolates the heat shock protein, which is part of the immune system. The protein from the patient's tumor is then reinjected into the skin with an adjuvant, or an agent added to a drug to increase its effect.

The vaccine was developed by Andrew Parsa, MD, PhD, principal investigator of the Brain Tumor Research Center at the University of California, San Francisco. He is collaborating with the Lexington, Massachusetts biotech company called Agenus. Columbia University also is part of the ongoing Phase 2 study designed to evaluate overall survival and immunologic response with HSPPC-96 in patients with first or subsequent recurrence of GBM.

All patients underwent surgery prior to vaccine therapy. However, since the vaccine is made from the patient's own tumor, the surgery had to be performed at one of the participating sites. The vaccine therapy begins within 5 weeks after surgery and consists of four weekly injections, followed by bi-weekly injections for up to 52 weeks.

"The vaccine is made from a patient's own cells, so it takes into account what is unique about the patient's particular tumor -- it's the ultimate in 'personalized medicine'," said Dr. Sloan who also is the Peter D. Cristal Chair in Neurosurgery and an Associate Professor of Neurological Surgery at Case Western Reserve University School of Medicine.

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No tie found between PTEN and response to breast cancer drug herceptin, according to new study

ScienceDaily (June 3, 2011) — Contrary to what many oncologists had thought, a tumor suppressor protein known as PTEN does not reduce the effectiveness of the breast cancer drug herceptin, according to a study by Mayo Clinic and North Central Cancer Research Group (NCCTG) investigators.

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The study, which looked at tumors from 1,802 patients enrolled in the NCCTG N9831 clinical trial, found that patients with HER2-positive breast cancer and had either a loss of PTEN functioning or normal PTEN activity did equally well when herceptin was added to chemotherapy to prevent breast cancer recurrence.

The researchers presented their findings during the American Society of Clinical Oncology Annual Meeting in Chicago.

"This is the largest study to date evaluating PTEN's presence or loss in the context of antiHER2 therapy, and we found no connection," says the study's lead investigator, oncologist Edith Perez, M.D., director of the Breast Clinic at Mayo Clinic in Jacksonville, Fla., and the Serene M. and Frances C. Durling Professor. "Our research team is very pleased to be able to test an important question in treatment of breast cancer and arrive at a definitive answer."

The researchers stained the samples for PTEN expression and linked that data with disease-free survival. They found that PTEN status did not impact disease-free survival significantly; there was only a slightly greater benefit of adding herceptin for patients with PTEN-tumors.

Preclinical studies and some small patient studies had suggested that tumors with loss of PTEN expression would not benefit from herceptin, Dr. Perez says. As a result, investigators were considering using PTEN biomarkers in clinical studies as a test of herceptin resistance, and patients who tested positive for PTEN loss might then be offered other therapies, or invited to participate in clinical trials.

"We have all been interested in biomarkers that predict for benefit to antiHER2 therapy," Dr. Perez says, "but PTEN is not one that we should pursue further, based on our rigorous analysis."

The tumor samples examined in the study came from NCCTG N9831, a phase III randomized, multicenter clinical trial that tested adjuvant herceptin given with, or following, chemotherapy with paclitaxel, compared with chemotherapy alone.

The study was funded by the National Cancer Institute, the National Institutes of Health and Genentech. The study includes 16 co-authors; nine are from the Mayo Clinic campuses in Florida, Minnesota, and Arizona.

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Study reveals origins of a cancer affecting the blood and bone marrow

ScienceDaily (May 16, 2011) — A new study by the NYU Cancer Institute, an NCI-designated cancer center, sheds light on the origins of myeloid leukemia, a type of blood cancer that affects children and adults. The researchers discovered that novel mutations in an intracellular communication pathway called Notch led to the cancer, pointing to a potential new target for treating this disease. Notch has already been implicated in another type of blood cancer called T-cell acute lymphoblastic leukemia, but the new research found an unexpected role for it in myeloid leukemia.

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The study is published in the May 12, 2011 issue of the journal Nature.

"This study shows the power of the Notch signaling pathway in myeloid leukemias," says Iannis Aifantis, PhD, associate professor in the Department of Pathology at NYU Langone Medical Center and a member of the NYU Cancer Institute, who led the new study. "This discovery," he says, "suggests a potential for future targeted therapies." Dr. Aifantis is also a Howard Hughes Medical Institute Early Career Scientist.

Last year, acute myeloid leukemia was diagnosed in more than 12,000 adults and the disease claimed nearly 9,000 lives in the United States, according to the National Cancer Institute. The blood cancer is the most common type of acute leukemia in adults. Normally, the bone marrow makes blood stem cells (immature) that mature over time. Some of these are a form called myeloid and others are lymphoid. The lymphoid stem cell develops into a white blood cell, while the more-versatile myeloid stem cell develops into red blood cells, white blood cells, and platelets, which prevent clotting. Cancer occurs when too many immature myeloid stem cells are produced in the blood and bone marrow.

The Notch signaling pathway, the complex web of intracellular interactions that occurs after a protein called Notch is activated on the cell's surface, is a well known actor in cancer, but the new study reveals that the varied members of this pathway function in unexpected ways to produce disease. Notch is named for a particular kind of mutation, first identified almost 100 years ago, that gives fruit flies notched wings.

The study evaluated mutations in the Notch pathway in mice models of the disease, and also in blood samples from patients with chronic myeloid leukemia. Researchers identified several mutations that inactivated or silenced the pathway, leading to the accelerated accumulation of abnormal blood cells. Most importantly, the study also revealed that the reactivation of the silenced genes in the pathway blocked the disease, providing additional support for the potentially crucial role that Notch might play in the development of cancer.

In a commentary accompanying the study in Nature, Demetrios Kalaitzidis and Scott A. Armstrong of Dana Farber Cancer Institute and Children's Hospital Boston, note that the study defines a new role for Notch signaling as a suppressor of leukemia development. They note that further research is needed to understand the intricacies of Notch signaling in normal and cancerous tissue, which will help determine "the best approaches to manipulating this pathway for optimal therapauetic response."

This research study was funded by the Howard Hughes Medical Institute.

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