News Reports: May 2007

Preventive Health Exams May Lead to Cancer Screenings

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new report by researchers at the University of California, Davis (UCD), shows that health plan members who receive regular preventive exams are more likely to undergo screening for colorectal, breast, and prostate cancers. The UCD researchers, led by Joshua Fenton, presented their findings in the March 26 issue of Archives of Internal Medicine.

The researchers evaluated 64,288 people age 52 to 78 who were enrolled in a Washington State health plan from 2002 to 2003. This population included 39,475 enrollees eligible for colorectal cancer screening, 31,379 women eligible for breast cancer screening, and 28,483 men eligible for prostate cancer screening. The researchers divided the patients into two groups—those who had a preventive health exam or general physical during the two-year period and those who did not. About half of the patients had a preventive health exam from 2002 to 2003.

After controlling for factors that influence cancer screening rates, such as patient demographics and historical use of medical care, the researchers found that patients who received general health exams were significantly more likely to undergo cancer screening. Men and women who had a general checkup were more than three times as likely as the others to receive colorectal cancer screening, and men were three times as likely to be tested for prostate cancer.

The corresponding difference was smaller in women eligible for breast cancer screening—about 74% of women who had general health exams got screened as compared to about 56% of women who did not have general checkups. This is because the Washington State health plan “has a longstanding, innovative breast cancer screening program that operates independently of primary care,” Fenton told Oncology & Biotechnology News. Women receive mailed reminders about mammography and can schedule mammograms without a physician’s referral. “This may diminish the impact of a physical on mammography in this population,” he said.

In addition to reinforcing the value of health plan coverage for regular wellness visits, these results should provide a significant lesson to doctors and patients. Some doctors have questioned the value of regular check-ups, Fenton said, but check-ups may give them time to think about prevention and recommend screening tests. In comparison, the study suggests that visiting the doctor only when ill does not have the same effect. “Doctors may simply be too busy to be effective advocates of prevention when they’re taking care of acute or chronic illness,” Fenton said.

— Prachi Patel-Predd

Canine Cancer Vaccine Being Investigated for Use in Humans

First therapeutic vaccine approved by FDA in either animals or humans

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joint research effort between one of the nation’s leading cancer centers and a major veterinary hospital has yielded a DNA-based therapeutic vaccine to treat melanoma in dogs. Researchers hope the breakthrough will open the door for treatment in humans as well.

The vaccine recently received conditional approval from the United States Department of Agriculture (USDA), making it the first therapeutic cancer vaccine approved in the United States to treat cancer in either animals or humans.

“Both humans and dogs develop this cancer in exactly the same way,” said Dr. Jedd D. Wolchok, an oncologist at New York’s Memorial Sloan-Kettering Cancer Center, who handled the human arm of the laboratory research. “By conducting trials in humans and in animals that live in the same surroundings as humans, there can be a synergy that we hope will result in improved cancer treatment for all.”

With the USDA’s conditional approval, the vaccine will be marketed for veterinary use while additional safety and efficacy tests are conducted.

Dr. Philip Bergman of New York’s Animal Medical Center—just blocks away from Memorial Sloan-Kettering—conducted the vaccine trial in dogs. Dogs in the clinical trial had longer lifespans, even those with advanced-stage melanoma. In dogs, melanoma often starts in the mouth or paws and spreads rapidly, with death often occurring within one to five months once it has spread beyond the primary site. In contrast, the median survival time for dogs in the vaccine therapy group was more than one year.

“Historically speaking, treatment of oral melanoma with surgery, radiation, or chemotherapy has not been very effective,” Dr. Berman said.

The novel vaccine will also be delivered in a new way. It will be administered to dogs via Canine Transdermal Device through the skin instead of a traditional needle. The delivery mechanism was developed by Vical Incorporated and Bioject.

From a business standpoint, the USDA’s conditional approval of the vaccine also represents a breakthrough for veterinary pharmaceutical maker Merial, a joint venture of Merck & Co., Inc. and sanofi-aventis. Both Merck and sanofi-aventis have been aggressively seeking ways to increase their investment in biotech in recent years, with mixed results.

Melanoma, the most serious type of skin cancer, is primarily caused by overexposure to UV light and can be deadly if not diagnosed and treated early.

— Diane West

Antirejection Drug Shows Promise In Preventing Lung Cancer in Smokers

Drug already approved for organ, bone marrow and cardiac stent recipients slows the development of cellular changes associated with smoking-related lung cancer

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drug normally used as an antirejection agent in organ and bone-marrow recipients is showing early clinical promise in the prevention of lung cancer in smokers.

The drug, rapamycin, was shown to block the activity of Akt and mTOR, proteins found in lung cells which, when activated, are associated with precancerous changes. Nicotine and its carcinogenic byproduct, NNK, kick these two proteins into gear, making smokers susceptible to lung cancer. Rapamycin targets mTOR and blocks it from activating, potentially preventing the cells lining the walls of the lungs from becoming precancerous and developing into malignant tumors.

“By exploring methods of chemoprevention via agents such as rapamycin, we may be able to further reduce lung cancer risk,” NCI director John E. Niederhuber, MD, said.

In the study, conducted by the National Cancer Institute and published in the April issue of Clincial Cancer Research, one group of mice injected with NNK received rapamycin one week after exposure to the tobacco-specific carcinogen, while another group was given rapamycin six months after exposure. Mice given rapamycin after one week showed a 90 percent decrease in the number of tumors they developed compared to the other group. Early rapamycin recipients also demonstrated a 74 percent decrease in the size of tumors they did develop and their cancer cells showed fewer abnormalities. Lung tumors which developed in mice, which were given their first dose of rapamycin six months after exposure to NNK shrank, but the rate of tumor cell growth remained unchanged.

Whether rapamycin can prevent lung cancer in cigarette smokers remains to be seen. “The critical question is whether this approach would be safeand effective in smokers at high risk of developing lung cancer,” NCI’s Dr. Phillip Dennis said. “Given that rapamycin is relatively inexpensive and FDA-approved for other indications, we are designing clinical trails in humans to address these questions and hope to have these answers in the near future.”

— Diane West

Colon Cancer Survival Linked to Number of Lymph Nodes Examined

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n analysis of 17 studies found that the more lymph nodes that are removed and examined during surgical treatment of colon cancer, the better the outcome. The study results suggest that removal of the nodes takes away a reservoir for potentially lethal cancer and that knowing how far a cancer has spread leads to better treatment, according to researchers at The University of Texas M.D. Anderson Cancer Center.

“The importance of adequate lymph node evaluation is not a new concept, but the data have never been evaluated in a systematic fashion such as this before,” noted lead author, George Chang, MD, assistant professor in the department of surgical oncology at M.D. Anderson. “The important message is that surgeons need to adhere to the principles of cancer surgery that are already in place. But, the surgeons are not the only ones responsible for adequate lymph node evaluation; the pathologist must find the

lymph nodes within the resected specimen.

“There are many factors that are at play, but the surgeon and pathologist both appear to be important variables in lymph node recovery rates. This is an important issue that potentially impacts not only prognosis but treatment decisions.”

The results of this study should help efforts to consider a minimum number of lymph nodes that are extracted and examined during the surgery, continued Dr. Chang. “Surgeons do not decide how many lymph nodes to remove. Surgeons perform a cancer-directed operation with en bloc resection of the associated colonic mesentery. Within the mesentery are the lymph nodes. Depending on how adequately the mesentery is resected, there will be more or fewer lymph nodes.

“In a recent evaluation of the SEER registry by Baxter et al, JNCI 97(3):219-25, only 37% of patients had 12 or more lymph nodes evaluated,” Dr. Chang added. Surgeons sometimes leave nodes because less mesentery is removed than should be. Another reason is that some surgeons believe that the identification of lymph node metastasis was only prognostic, therefore there is no need to remove all of the lymph nodes once metastatic lymph nodes are identified, according to Dr. Chang.

One of the 17 studies examined, a national clinical trial that enrolled more than 3,200 patients to look at the effects of chemotherapy on colon cancer recurrence after surgical resection, demonstrated a 14% increase in five-year survival if more than 20 lymph nodes were examined, compared with less than 11 nodes in patients with Stage II cancer. The survival advantage was even greater—23%—in patients with Stage IIIA and IIIB cancer if more than 40 nodes were evaluated, compared with less than 11 nodes.

All but one study of Stage II cancer showed the same association between the number of nodes evaluated and improved outcome. Also, four of six studies of more advanced cancer showed similar associations, Chang said.

“This tells us,” Dr. Chang pointed out, “that surgeons and pathologists involved in the care of colon cancer patients should make every effort to improve their collection and evaluation of lymph nodes.”

Because all of the studies examined were observational, the researchers asserted that they cannot definitively say increasing the number of lymph nodes examined leads to improved survival. Only a randomized, controlled clinical trial, ethically impossible to do, would be able to make such a definitive statement, the researchers explained.

— Querida Anderson

Combined Therapies Improve Breast Cancer Survival

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omen with early-stage breast cancer who are given a combination treatment of chemotherapy and tamoxifen have a higher survival rate compared to women who receive only tamoxifen, according to two new studies published in the April 4 Journal of the National Cancer Institute (JNCI). The studies also showed that there were no additional benefits from a combination of ovarian suppression and tamoxifen.

“These results are important for oncologists and health professionals, because they support current research initiatives to evaluate anti-estrogen strategies in addition to tamoxifen in premenopausal women who avoid chemotherapy or [women] with preserved ovarian function after chemotherapy,” the study’s chief investigator, John Yarnold, who is professor of clinical oncology at the Institute of Cancer Research in Sutton, England, told Oncology & Biotechnology News.

Treatment with tamoxifen, chemotherapy or ovarian suppression individually is known to increase the survival rate in early-stage breast cancer patients. In 1992, the Adjuvant Breast Cancer Trials were initiated to assess the additional benefits of combined therapies. The studies published in JNCI are the results of two international randomized clinical trials, the ABC Chemotherapy (CT) trial and the ABC Ovarian Ablation or Suppression (OAS) trial, that were undertaken by Yarnold, professor of clinical trials Judith Bliss, and their colleagues at the Institute of Cancer Research.

The two randomized, controlled phase III trials included a total of 3,854 women with early-stage breast cancer. All of these patients were treated with tamoxifen for five years.

In the ABC (CT) trial, about half of 1,991 women between the ages of 26 and 81 were randomly assigned to receive chemotherapy while the rest did not. Of the 619 premenopausal women in this group, 244 received ovarian suppression. Bliss and her colleagues found that chemotherapy in combination with tamoxifen led to modest improvements in relapse-free and overall survival. They also found that patients younger than 40 years benefited less from chemotherapy than those who were between 40 and 49 years old. Moreover, the benefit was higher for premenopausal women who did not receive ovarian suppression.

For the ABC (OAS) trial, nearly half of the 2,144 premenopausal women were randomly assigned to receive ovarian suppression while the others did not. Some of the patients also received chemotherapy. The research team found that neither relapse-free nor overall survival was affected by adding ovarian suppression to the tamoxifen treatment of early-stage breast cancer. However, the results pointed to a possible benefit of adding ovarian suppression for a small group of women less than 40 years of age who have ER-positive tumors. This was especially true when the patients were not receiving chemotherapy.

— Prachi Patel-Predd

Mapping the Cancer Genome

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he Cancer Genome Atlas (TCGA) (cancergenome.nih.gov) is a comprehensive and coordinated effort to understand the molecular basis of cancer through the application of genome analysis technologies that was launched in December 2005. It will begin with a pilot project to determine the feasibility of a full-scale effort to systematically explore the universe of genomic changes involved in all types of human cancer. The National Cancer Institute (NCI) and National Human Genome Research Institute have each committed $50 million over three years to the TCGA Pilot Project.

“TCGA will analyze genomic changes in lung, brain, and ovarian cancers with a goal of identifying all alterations in genes for these three tumors. The Cancer Genome Characterization Centers (CGCC) will identify genomic aberrations, such as copy number changes and/or chromosomal translocations, that will enable the development of targeted diagnostics and therapies for cancer patients and provide a path to more personalized cancer medicine,” reports NCI deputy director for advanced technologies and strategic partnerships, Anna D. Barker, PhD. The CGCC will use high-throughput methods similar to those employed in the Human Genome

Project. In addition, the CGCC will also work to identify other types of larger-scale genomic changes that contribute to cancer

development and/or progression.

So far, awards have been made to seven institutions to establish CGCC: Broad Institute of MIT and Harvard, Harvard Medical School and Brigham and Women’s Hospital, Lawrence Berkeley National Laboratory, Memorial Sloan-Kettering Cancer Center, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University and the University of Southern California/Norris Comprehensive Cancer Center, Stanford University School of Medicine, and The University of North Carolina Lineberger Comprehensive Cancer Center.

Additionally, SRA International has been selected to develop the Data Coordinating Center (DCC) for the TCGA Pilot Project. The DCC will track data produced by components of TCGA, ensuring that this data meets quality standards set for the project, and make TCGA data publicly accessible through databases supported by NCI’s Cancer Biomedical Informatics Grid and the National Library of Medicine’s National Center for Biotechnology Information.

Recently, the project has come under attack by other cancer researchers as a waste of government resources. The opponents of this project believe that mapping all of the genetic variations of a tumor, which is incredibly heterogeneous, would take a long time and produce vast amounts of data on insignificant genetic variations. With research increasingly implicating cancer stem cells as the culprit of tumor growth and metastasis, the projects opponents suggest that the money would be better spent on identifying and understanding these cancer cells as well as determining the mechanism for metastasis. In an interview with Newsweek, George Gabor Miklos, who works on the Human Genome Project, was quoted as saying, “What matters for survival is not the primary tumor but the rare cells—1 in 50,000—in it that give rise to metastases. From a clinical and drug perspective, the cancer-genome project is so shallow it’s worthless.”

— Nick Rose

Gleevec May Decrease Risk of Recurrence in Patients with Primary Gastrointestinal Stromal Tumor

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reliminary results from a large, randomized, placebo-controlled clinical trial performed in patients with primary gastrointestinal stromal tumor (GIST), showed that patients who were treated with Gleevec (imatinib mesylate) after complete resection of tumor were significantly less likely to have a recurrence compared to those who did not receive imatinib. The trial was sponsored by the National Cancer Institute (NCI) of the National Institutes of Health (NIH), and conducted by a consortium of investigators led by the American College of Surgeons Oncology Group (ACOSOG).

Approximately 5,000 to 6,000 new patients are diagnosed with GIST each year in the United States.

Gleevec inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF), stem-cell factor (SCF), and c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-kit mutation.

The study investigators enrolled patients with primary tumors greater than or equal to 3 cm that had been completely resected. Patients were randomized to receive either imatinib 400 mg/day or placebo for one year. Patients who developed a recurrence while receiving the study drug were unblinded to their treatment assignment. Those who had been on placebo subsequently received imatinib and those who had been on imatinib continued their imatinib therapy, but at a higher dose. There was no difference in overall survival for patients in the two treatment arms.

According to Elias A. Zerhouni, MD, director of the NIH, “The standard treatment for primary GIST is complete surgical removal of the tumor without additional therapy. It is excellent news that the addition of this well-tolerated cancer pill to the treatment regimen can have such a positive impact on decreasing the risk of recurrence.”

Study investigators reported that approximately 97% of patients who received one year of treatment with Gleevec after surgery did not have a recurrence, compared with 83% of those who received placebo for one year. Imatinib therapy was well tolerated by most patients enrolled in the study. The types of side effects observed in this trial were similar to those observed in other clinical trials with imatiniband included nausea, diarrhea, and swelling.

“These results have major implications for patients with primary GIST,” stated Ronald DeMatteo, MD, Memorial Sloan-Kettering Cancer Center, New York, and the principal investigator of the study. “Conventional chemotherapy agents have been notoriously ineffective in GIST. This study, for the first time, demonstrated that targeted molecular therapy reduces the rate of recurrence after complete removal of a primary GIST.”

— John D. Zoidis, MD

PROSTATE CANCER SPOTLIGHT

Dendreon Closes in on Offering First Prostate Cancer Vaccine

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endreon reported that the FDA Office of Cellular, Tissue, and Gene Therapies Advisory Committee recommended to the FDA that there is substantial evidence of efficacy and safety of Provenge (sipuleucel-T) for the treatment of patients with asymptomatic, metastatic, androgen-independent (also known as hormone refractory) prostate cancer. If approved for marketing by the FDA, Provenge would become the first active cellular immunotherapy and the first biologic approved to treat prostate cancer.

The Advisory Committee was asked if the submitted data established that Provenge is reasonably safeand whether there is substantial evidence that the product is efficacious. The Advisory Committee voted 17 to 0 in favor of the safety of Provenge in response to the question and 13 to 4 in favor of the efficacy question.

Previously, Dendreon had filed their Biologics License Application (BLA) on January 15 of this year, and the BLA was assigned Priority Review status. Priority Review is granted to products that, if approved, would provide a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious or life-threatening disease. Dendreon expect the FDA to complete its review by May 15.

The BLA submission is based primarily on an improvement in overall survival observed in Study D9901, a phase III study, the results of which were published in the July 2006 issue of the Journal of Clinical Oncology.

“This trial is an important milestone in the development of new treatments for prostate cancer patients,” reported Eric J. Small, MD, when the results were first published, according to Dendreon’s press release. “The survival benefit that was observed has the potential to offer important benefits to patients and represents the first time an immunotherapy has provided a survival advantage in prostate cancer. In addition to the observed survival benefit, Provenge has a favorable toxicity and safety profile, with the most common side effects being low grade fevers and chills. A favorable benefit-to-risk profile will be appealing to patients with advanced stage prostate cancer who currently have few appealing treatment options available to them,” concludes Dr. Small who is professor of medicine and urology at the University of California, San Francisco and lead author of the publication.

The phase III study showed that the group of men with prostate cancer who received Provenge had a median survival time of 4.5 months longer than the median survival seen in the group that had been assigned to receive a placebo. For the men who received Provenge, there was a 41% overall reduction in the risk of death. In addition, 34% of patients receiving Provenge were still alive 36 months after treatment compared to 11% of patients randomized to receive a placebo.

Analysts speculate that the FDA will either grant a full approval or it will issue an approvable letter, which would require further clinical data before approval.

— Nick Rose

PSA Kinetics is a Poor Predictor of Lethal Prostate Cancer

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SA levels at the time of prostate cancer diagnosis and PSA kinetics thereafter do not adequately predict lethal prostate cancer, according to a study in the April 4 issue of Journal of the National Cancer Institute.

Prostate cancer takes longer than other cancers to develop into a lethal form. Hence, to avoid unnecessary treatment, researchers are trying to develop tests to more accurately identify which patients are most at risk of dying from the disease.

Typically, rate of increase of PSA has been associated with the patient’s prognosis, which suggests that early measurements of PSA may predict the behavior of the tumor. While PSA levels is a good prognostic marker for prostate cancer development, Katja Fall, MD, PhD, of the Karolinska Institute in Stockholm, Sweden found that it is not sufficient to predict lethality of the disease.

Dr. Fall and colleagues analyzed the rate of change of PSA levels in 267 men from Sweden, Finland, and Iceland who were diagnosed with early localized prostate cancer between 1989 and 1999. The researchers recorded the PSA levels for the first two years after diagnosis to capture the patients’ early PSA patterns. While the men received therapy to keep the cancer at bay, they did not get any curative treatments for the first two years.

At the end of the follow-up in December 2003, 34 patients had died from prostate cancer and 18 had developed metastatic prostate cancer but were still alive. Although initial PSA values and the rate of change were associated with later development of lethal prostate cancer, they were not accurate enough to use as a prediction tool.

“We conclude that PSA measurement is associated with prostate cancer prognosis and continues to be an important monitoring tool,” the authors wrote. “However, early PSA characteristics perform poorly in distinguishing those who develop a lethal prostate cancer from those at low or no risk of disease progression.

“Therefore, better decision tools are needed for active monitoring of patients with early disease,” Dr. Fall concluded.

Dipen Parekh, MD, assistant professor at the University of Texas Health Science Center at San Antonio, concurred with Dr. Fall’s findings and conclusions. He noted that such a prospective study in prostate cancer patients is tough to do but important as it is better than a retrospective survey. He also felt that data collected over several years was robust and analysis was accurate.

Dr. Parekh reiterated the need for a better prediction method for lethality of prostate cancer. “We need to look beyond PSA and PSA kinetics and find other markers for prostate cancer.” He believes that there can be no single biomarker but instead several biomarkers will need to be assessed. He also pointed to factors such as age, ethnicity and history of the disease as important to consider.

— Querida Anderson