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The Academy: July/August 2007

OBTN, July/August 2007, Volume 1, Issue 6

The Academy delivers the latest news on biotech and oncology research, providing a link between the clinical world of cancer care and the university researchers who are pushing farther in pursuit of knowledge and new discoveries. In this issue we highlight presentations from the 43rd annual ASCO meeting as well as research being done at Massachusetts General Hospital and Dana-Farber Cancer Institute in Boston and the University of Texas Southwestern Medical Center in Dallas.

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â–º ASCO SPOTLIGHT Mayo Clinic, Jacksonville, FL MRI Detects What Mammograms Missed

Based on MRI and mammography use at the Mayo Clinic in Jacksonville, FL, oncologists at the clinic have found that MRI can find additional tumors in a breast in which cancer has already been diagnosed using mammography. They have also found that MRI is better than mammography in detecting new tumors in a patient’s healthy breast. The researchers, led by Laura Vallow, MD, a radiation oncologist at the Multidisciplinary Breast Clinic in Jacksonville presented their results at the ASCO annual meeting.

Oncology & Biotech News

Dr. Vallow and her colleagues compared results from both mammograms and MRI scans of hundreds of women screened at the clinic. In a study comparing the two screening methods for ipsilateral tumors, they found that MRI detected tumors missed by mammograms, ultrasound and physical examinations in 16% of 390 women. Women with MRI-detected ipsilateral tumors tended to be younger, the researchers found, or they had a primary breast tumor that was at least 1 centimeter in size. In addition, the newly diagnosed tumors were different from the primary tumors in 29% of women. “Patients who may benefit from preoperative bilateral breast MRI are younger women with newly diagnosed breast cancer who are considering breast conservation,” Dr. Vallow told .

In a second study, comparing screening for contralateral breast cancer, the oncologists found that MRI detected tumors missed by mammograms in 3.2% of 401 women. Patients whose contralateral tumors were detected by MRI were typically postmenopausal and had an ER-positive tumor. Detecting contralateral tumors before a newly diagnosed patient is treated is important because the patient could then undergo treatment for both tumors simultaneously rather than going through the trauma of another tumor detection after several years, according to the researchers.

According to Dr. Vallow, many doctors feel that there is a learning curve to breast MRI interpretation and that it is not a standardized evaluation at this time. “We feel our data support our continued routine use of MRI in women with newly diagnosed breast cancer,” she said. “As breast MRI becomes more standardized and more centers obtain the ability of MRI-guided biopsy the use of breast MRI will increase.” She does caution, however, that these results are based entirely on the experience at the Mayo Clinic in Jacksonville. “Other centers will evaluate for themselves whether this data is enough to support the use of MRI in their patient population.”

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ASCO SPOTLIGHT Fox Chase Cancer Center, Philadelphia, PA Counting Circulating Tumor Cells Could Tell Doctors When or If to Change Colorectal Cancer Treatment

Results of an international study presented at ASCO on June 3 have shown that counting circulating tumor cells before and after the start of metastatic colorectal cancer treatment could help doctors in deciding when or if a patient’s treatment should be changed.

Researchers led by Neal Meropol, MD, director of the gastrointestinal cancer program at Fox Chase Cancer Center in Philadelphia, PA, studied the association between the number of circulating tumor cells (CTC) and progression-free and overall survival in 430 metastatic colorectal cancer patients. They measured CTC count at baseline, one month and at other points after the patients had started treatment. From an initial analysis, the researchers defined 3 or more CTCs per 7.5 milliliters (mL) of blood as unfavorable, and less than 3 CTCs per 7.5 mL as favorable.

At baseline, the researchers found that 53% of patients had no detectable CTC numbers. These patients had much better median survival times compared with those patients who had detectable CTCs.

Further, patients with a favorable CTC count had better progression-free survival and overall survival than those with an unfavorable count. Those with a favorable CTC number had a median overall survival almost double that of those with an unfavorable number. The median progression- free survival was 7.9 months for patients with a favorable CTC number compared to 4.5 months for those who had an unfavorable number.

The predictive value of CTC numbers could become a valuable tool in the clinic, Dr. Meropol said. “If we had a way to know early on that a tumor isn’t responding to a particular drug, we could switch to a different treatment before growth of the cancer if seen on a CAT scan,” he said. “If we could determine that the tumor was destined to grow after a few weeks of treatment, we’d be able to alter course even before the first scan.”

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ASCO SPOTLIGHT Barbara Ann Karmanos Cancer Institute, Detroit, MI Combining Capecitabine and Docetaxel Improves Prostate Cancer Remission and Survival

An oral dose of capecitabine (Xeloda) combined with a weekly intravenous dose of docetaxel works better than docetaxel alone in patients with metastatic prostate cancer, researchers at the Barbara Ann Karmanos Cancer Institute in Detroit, MI have found. The combination therapy improves patient remission and survival outcomes, according to Shanthi Marur, MD, a fellow at Karmanos and one of the researchers on the recently completed phase II clinical trial. Ulka Vaishampayan, MD, chair of the genitourinary multidisciplinary team at Karmanos, and principal investigator of the story presented the results at the annual ASCO meeting on June 3.

The researchers found that patients who undergo current standard of care see an average decline of 45% in their PSA levels. By contrast, of the 30 patients who received the combination chemotherapy, 73% saw at least a 50% decline in prostate- specific antigen (PSA) levels and about a third of patients had at least a 90% decrease.

Oncology & Biotech News

The patients also had other benefits. “With the decrease in PSA we also noted a dramatic improvement in bone pain and stabilization of their bone metastases,” Dr. Marur told . “This shows that there is meaningful clinical benefit in addition to increased overall survival and time to progression compared to phase II data on docetaxel therapy alone.”

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ASCO SPOTLIGHT M.D. Anderson Cancer Center, Houston, TX Black Women Have Lower Breast Cancer Survival Rates than White Women; Gap Widening

The breast cancer survival rates for black women with advanced disease have not improved as well as those for white women, and this gap in lifeexpectancy continues to widen. Researchers at the University of Texas M. D. Anderson Cancer Center in Houston presented these results on June 3 at the annual ASCO meeting in Chicago.

Sharon Giordano, MD, assistant professor in breast medical oncology at M. D. Anderson had found in an earlier study that the overall survival rate of stage IV breast cancer patients enrolled in clinical trials at M. D. Anderson had improved. But when Dr. Giordano and Shaheena Dawood, MD, a breast medical oncology fellow at M. D. Anderson looked at the patients by race, they were surprised by the results. “We thought we would find that there was improvement in women with stage IV breast cancer regardless if patients were white or black, with white women likely having better outcomes,” Dr. Dawood said. “Rather, over the decades, we found that black women’s survival did not improve at all.”

Using the National Cancer Institute’s Surveillance Epidemiology and End Results database, the researchers identified 15,438 women who were diagnosed with advanced breast cancer between 1988 and 2003. They adjusted for patient age, estrogen receptor status and tumor grade. They found that in women diagnosed between 1988 and 1993, the median survival was 20 months for white women compared with 17 months for black women. For women diagnosed between 1994 and 1998, the median survival was 22 months in white women and 16 months in black women. And in patients diagnosed between 1999 and 2003, white women’s median survival was 27 months as opposed to 17 months for black women.

Past research has suggested that breast cancer may be more deadly for black women because they have more aggressive tumors and because they more frequently have estrogen-receptor negative tumors.

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ASCO SPOTLIGHT University of Pittsburgh School of Medicine, Pittsburgh, PA Herceptin Does Not Increase Heart Risk in the Long Term

Trastuzumab (Herceptin) does not increase congestive heart failure risk over time in women receiving the drug as part of combination therapy for early-stage breast cancer, according to new research presented at ASCO in Chicago on June 3. Researchers from the University of Pittsburgh obtained these results from the National Cancer Institute’s National Surgical Adjuvant Breast and Bowel Project (NSABP) B-3 trial.

Genentech’s Herceptin is known to cause heart damage as a side effect in about 5% of patients, and this risk is addressed on the drug’s label. Women with existing heart conditions cannot take the drug, and some women stopped taking Herceptin fearing the risk of increased cardiac failure in the long term. But the new findings suggest that heart failure risk stays the same over 5 years.

The researchers, led by Priya Rastogi, MD, an assistant professor at the University of Pittsburgh School of Medicine, studied cardiac side effects in 1,850 women with HER-2 positive breast cancer over a 5-year period. The researchers randomly assigned the women to a Herceptin group or a control group. About 4.1% of the women taking Herceptin and undergoing chemotherapy had congestive heart failure at the end of 3 years, compared with 0.8% of women only on chemotherapy. At the 5-year follow-up, 3.8% of patients on the combination therapy had heart failure, indicating that the heart failure rate did not increase.

The researchers found that certain factors make women more susceptible to heart failure risk—being 50 or older, already having low heart function, and taking high blood pressure medication. They have built a prediction model that calculates and individual patient’s risk. “It is our hope that this model will help to individualize care for women in terms of choice of Herceptin containing treatment regimens based on their personal risk and benefits,” said Dr. Rastogi.

Massachusetts General Hospital and Dana-Farber Cancer Center Institute, Boston, MAIntegrated Palliative/Oncology Care for Advanced Lung Cancer Patients?

Researchers at Massachusetts General Hospital and Dana-Farber Cancer Institute in Boston, MA, have reported that integrating palliative care with standard oncology care for advanced lung cancer patients should be acceptable.

Journal of Clinical Oncology

Conventional medical therapy for patients diagnosed with terminal lung cancer has meant standard oncology care without palliative care. Patients typically get chemotherapy to prolong lifeand then the treatment transitions to hospice care when no more treatment options are available. But there is no reason not to integrate oncology and palliative care, the researchers assert in a study published in the June 10 issue of the .

Jennifer Temel, MD, an assistant professor at Massachusetts General Hospital in Boston, and her colleagues followed 50 patients who had been newly diagnosed with advanced small-cell lung cancer. These patients received both palliative and oncology care for six months, including monthly meetings with a palliative care team and monthly questionnaires on mood and quality of life.

Patient participation not only exceeded the researchers’ expectations, the researchers also found that patients who survived longer than six months continued to meet regularly with their palliative care team after the study was over.

“Physicians are sometimes afraid to mention palliative care because they are concerned that patients will think they are giving up on them, or that it may lead to discussions about prognosis and goals of care that physicians are afraid to have,” Dr. Temel told Oncology & Biotech News. But given the patients’ distress and a limited lifeexpectancy, it makes sense to integrate palliative care from the beginning of their treatment.

“The most important take-home message is that it’s OK to talk about palliative care and symptom management, even with patients who are newly diagnosed,” she said.

University of Texas Southwestern Medical Center, Dallas, TXTree Bark Substance Could be Potential New Lung Cancer Treatment

A substance derived from the bark of the South American lapacho tree kills certain kinds of cancer cells, according to researchers at the University of Texas Southwestern Medical Center in Dallas. The substance, beta-lapachone, shows potential for a new treatment for lung cancer.

In a study published online in the June 25 Proceedings of the National Academy of Science, David Boothman, PhD, professor in the Simmons Comprehensive Cancer Center at the Southwestern Medical School, and his colleagues outline how beta-lapachone causes cancer cell death. The researchers used a synthesized version of the tree-bark compound and found that a high dose given to human tumor cells for 2—4 hours killed all the cancer cells containing an enzyme called NQO1.

Oncology & Biotech News

The researchers found that the compound interacts with NQO1, which is present at significant levels in non-small cell lung cancer and other solid tumors. The enzyme metabolizes beta-lapachone and causes cell death without damaging non-cancerous cells. “This therapy would be specific for all tumors that have known elevated levels of the two-electron oxidoreductase NQO1,” Dr. Boothman told . “These tumors include pancreatic, non-small cell lung, prostate, and breast cancers.”

The researchers also found that beta-lapachone disrupts cancer cells’ ability to repair their DNA. Applying radiation therefore gives a stronger punch, because radiation causes DNA damage.

The new drug might allow more selective targeting of cancer cells compared with current treatment techniques. For example, the current standard of treatment for non-small cell lung cancer requires platinum-based drugs in combination with radiation. The new drug is more selective, and “will only kill if NQO1 is over-expressed as in specific tumors,” Dr. Boothman said. “Therefore, we can now discuss individualized therapy since only specific tumors have elevated levels of the drug.”

Boston, MA-based Arqule is currently conducting phase I and phase II trials for a patented delivery formula for beta-lapachone to evaluate its efficacy in treating pancreatic cancer in humans. Dr. Boothman and his colleagues plan to conduct phase I and phase II trials of the compound for non-small cell lung cancer.

In the long term, they plan to create nanoparticles that would carry beta-lapachone stealthily to the tumor to avoid the toxic effects of the drug on the body. “In the current clinical trials some red blood cell toxicity has been reported,” Dr. Boothman said. “In the long term, we believe that the drug formulations and specific functionalized nanoparticles that we are developing will be much better.”