National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
September 7, 2010 • Volume 7 / Number 17

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Cancer Research Highlights

For Women with BRCA Mutations, Prophylactic Surgery Reduces Cancer Risk

Also in the Journals: Diabetes Drug Metformin Prevents Lung Tumors in Mice

The diabetes drug metformin has helped prevent tumors in mice that were exposed to a cancer-causing agent found in tobacco, Dr. Phillip A. Dennis of NCI’s Center for Cancer Research and his colleagues reported this spring. Based on the findings, researchers are considering clinical trials of metformin in people at highest risk of developing lung cancer. Final results from the study in mice appeared September 1 in Cancer Prevention Research.

Prophylactic surgery to remove the breasts and ovaries is an effective way to reduce the risk of breast and ovarian cancer among women with inherited mutations in the BRCA1 or BRCA2 genes, according to one of the largest prospective studies on the subject to date. The findings, published September 1 in JAMA, provide estimates of the benefits of mastectomy and salpingo-oophorectomy (removal of the ovaries and fallopian tubes) in reducing the risk of cancer and death among carriers of disease-associated BRCA1 or BRCA2 gene mutations. These mutations confer a 56 to 84 percent lifetime risk of breast cancer.

The results also show that the risk reduction occurs regardless of whether the mutation is located in the BRCA1 or BRCA2 gene or whether a woman had cancer previously. Researchers at 22 medical centers in Europe and North America tracked nearly 2,500 women with a disease-associated BRCA1 or BRCA2 mutation. Almost half of the women had one of the prophylactic surgeries.

During 3 years of follow-up, none of the women who had a mastectomy developed breast cancer, while 7 percent of the women who didn’t have the surgery were diagnosed with breast cancer. And only 1 percent of the women who underwent risk-reducing salpingo-oophorectomy developed ovarian cancer during 6 years of follow-up, compared with 6 percent of women who did not have the surgery.

“This study reinforces the message that genetic testing has value,” said Dr. Timothy Rebbeck of the University of Pennsylvania, the study’s senior author. Women who know that they have inherited a high-risk mutation can, with the appropriate genetic counseling, take steps to reduce their risk of cancer through prophylactic surgery, he continued.

Although many women choose prophylactic surgery, many do not, the study authors noted. Just 10 percent of the women in the study chose prophylactic mastectomy and 38 percent chose salpingo-oophorectomy. “For women who have these genetic mutations, we think we can save lives,” Dr. Rebbeck stressed. “And that’s an important message.”

The authors of an accompanying editorial in JAMA echoed this message and noted that options for prophylactic surgeries have changed and improved. For example, laparoscopic salpingo-oophorectomy is a relatively low-risk procedure that can be done in an outpatient setting, while new techniques for mastectomy produce a more natural appearance, wrote Drs. Laura Esserman of the University of California, San Francisco, and Virginia Kaklamani of Northwestern University.

Less-intensive Treatment Regimen Effective against Multiple Myeloma

Treating patients who have multiple myeloma with less-intensive dosing of bortezomib (Velcade) reduced toxic side effects without making the treatment less effective, Spanish researchers found. Their study, reported online in The Lancet Oncology on August 23, concluded that less-intensive induction therapy with a bortezomib-based regimen, followed by maintenance treatments, was “a safe and effective treatment for elderly patients newly diagnosed with multiple myeloma.”

While bortezomib benefits many patients with multiple myeloma, some who take the drug have experienced severe nerve pain, known as peripheral neuropathy. To test less-intensive dosing, the researchers randomly assigned 260 patients to induction therapy of lower-intensity bortezomib plus melphalan and prednisone (VMP) or lower-intensity bortezomib plus thalidomide and prednisone (VTP), followed by one of two types of maintenance therapy for up to 3 years. With both induction regimens, bortezomib was given once a week after the first cycle rather than in the typical twice-weekly schedule.  

Both of the less-intensive regimens led to response rates of more than 80 percent. In addition, 36 patients in the VTP group (28 percent) and 26 in the VMP group (20 percent) had complete remission. The regimens were associated with fewer cases of severe (grade 3 or higher) peripheral neuropathy and gastrointestinal symptoms than had been seen in a similar study known as the VISTA trial, in which more intensive-dosing of bortezomib was used.

“This is an important study that immediately affects clinical practice and provides important answers about how new agents such as bortezomib can be incorporated effectively in the overall treatment strategy,” wrote Dr. Vincent Rajkumar of the Mayo Clinic in an accompanying editorial. “Although the trial was undertaken in newly diagnosed patients, the findings might also be of value in relapsed and refractory disease,” he added.

The regimen “could be a platform for further refinement of an optimized treatment for elderly patients with multiple myeloma through use of lenalidomide instead of thalidomide and by reducing adverse effects through early intervention and prophylactic measures,” Dr. Maria-Victoria Mateos of the University Hospital of Salamanca and her colleagues concluded.

Lower-dose Treatments for Early-stage Hodgkin Lymphoma Do Not Compromise Results

In a phase III trial, patients with early-stage, low-risk Hodgkin lymphoma who received lower doses of chemotherapy and/or radiotherapy had clinical outcomes that were no worse than those of patients who received higher doses. The results of the study, which tested strategies to reduce the toxic effects of treatment while maintaining efficacy, appeared August 12 in the New England Journal of Medicine.

Dr. Andreas Engert of the University Hospital of Köln, Germany, and his colleagues from the German Hodgkin Study Group studied 1,190 patients newly diagnosed with stage I or II Hodgkin lymphoma and no clinical risk factors (including advanced age, previous treatment for Hodgkin lymphoma, or concurrent disease) who had been assigned to one of four groups. Two groups received four cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) and either 30 Gy or 20 Gy of involved-field radiotherapy (IFRT). The other two groups received only two cycles of ABVD chemotherapy, with one getting the higher and the other the lower amount of IFRT.

After 7.5 years, 96.6 percent of all patients had a complete remission and 8-year survival was 94.5 percent. Patients who received two rounds of chemotherapy did not fare worse than those who received four rounds; similarly, those who received 20 Gy of IFRT did not fare worse than those who received 30 Gy.

However, half of all patients getting the higher dose of chemotherapy reported serious adverse events—including infections, hair loss, anemia, and other blood disorders­­—compared with one-third of patients who received the lower dose. Six of the seven treatment-related deaths were in patients who received the higher dose of chemotherapy. Serious toxic effects from radiation were about three times more likely with the higher than the lower dose of radiation.

Although this trial did not include a no-radiotherapy comparison group, some experts believe that, given the long life expectancy of Hodgkin lymphoma patients with early-stage favorable disease, radiation therapy should be avoided when possible to minimize the risk of second cancers. “I would recommend that physicians evaluate patients after two cycles of ABVD chemotherapy with PET imaging and possibly avoid radiotherapy altogether, unless there is a compelling reason to use radiotherapy,” said Dr. Richard Little, senior investigator in the Clinical Investigation Branch in NCI’s Division of Cancer Treatment and Diagnosis.

Chemotherapy Affects Brain Structure of Breast Cancer Patients

A new study has provided some of the strongest direct evidence to date that chemotherapy has physical effects on areas of the brain that, when altered, could result in the array of cognitive symptoms that is often called “chemobrain.” The study was published online August 6 in Breast Cancer Research and Treatment.

In a small study of women with breast cancer, researchers from the Indiana University School of Medicine used MRI scans to show that chemotherapy was associated with a decrease in the density of brain gray matter. The affected areas include those involved in memory and in the ability to process information. Although several other studies have shown similar changes in these areas of the brain, this was the first study to follow women prospectively and to compare scans before and after chemotherapy.
“The alterations in gray matter density observed in the [chemotherapy] group are… consistent with the pattern of cognitive complaints and impairment found in neurocognitive studies,” wrote Dr. Andrew J. Saykin and colleagues.

The study included 17 women with breast cancer who underwent chemotherapy after surgery, 12 women with breast cancer who did not receive chemotherapy after surgery, and a control group of 18 healthy women. The initial MRI scans, performed shortly after surgery in the participants with cancer, showed no notable differences in gray matter density among the three groups. One month after completion of chemotherapy, however, MRI scans revealed notable decreases in gray matter density in women with breast cancer, as well as changes in gray matter density in women who received surgery only, although the changes for these women were not as great. No changes were seen in women in the control group. After 1 year, women treated with chemotherapy had recovered gray matter losses in some regions, but other deficits persisted.

Exactly how chemotherapy may be causing these changes is unclear, said study co-author Dr. Brenna McDonald. “However, the finding that the changes appear to resolve naturally to some degree in the first year after chemotherapy is completed is a very positive one,” she wrote in an e-mail message. Because of the limited follow-up in the study, she continued, it’s unclear how much further recovery may occur naturally. A number of studies have shown that such cognitive effects can persist for many years, she added. Additional studies are investigating whether other therapies, such as tamoxifen, may have similar effects on brain structure.

For more information on this topic, see: “Delving Into Possible Mechanisms for Chemobrain.”

Consuming High Levels of Red Meat and Fat May Increase Liver Cancer Risk

A recent prospective study found that higher consumption of red meat or saturated fat was associated with increased risks of both death from chronic liver disease (CLD) and incidence of liver cancer, while eating white meat was associated with decreased risks for both outcomes. The results were published online August 20 in the Journal of the National Cancer Institute.

Researchers analyzed data from nearly 500,000 men and women participating in the NIH-AARP Diet and Health Study. Participants whose self-reported levels of red meat intake were in the highest 20 percent were 2.6 times more likely to die from CLD and 74 percent more likely to develop hepatocellular carcinoma (HCC), the most common type of liver cancer, than participants in the lowest 20 percent of red meat intake.

In contrast, participants in the top 20 percent of self-reported white meat intake were half as likely to die from CLD or develop HCC as those in the lowest 20 percent of white meat intake. And whereas high fat consumption was associated with increased risks for both CLD and HCC, eating saturated fat was associated with the highest risk: those in the top 20 percent of saturated fat intake had 3.5 times the risk for CLD and nearly twice the risk for HCC as those in the lowest 20 percent.

The researchers adjusted for alcohol use, diabetes, obesity, and other dietary and lifestyle factors in their analyses to avoid confounding by these risk factors. Although they noted that residual confounding could still exist, it is unlikely because risk estimates for participants who reported abstaining from alcohol, whose BMI was in the healthy range, and who did not report a diagnosis of diabetes were similar to those in the total population.

A number of plausible mechanisms could underlie a causal association between red meat, CLD death, and HCC risk, the research team noted, including exposure to saturated fat, iron, and carcinogens formed from high-temperature cooking, such as heterocyclic amines and polycyclic aromatic hydrocarbons. However, in this study, although saturated fat was associated with both endpoints and heme iron was associated with CLD death, neither specific heterocyclic amines nor high-temperature cooking methods (other than pan-frying) was associated with CLD death or HCC risk. The mechanism by which white meat might reduce cancer risk is not clear.

“While these results are provocative, few studies have investigated these associations,” said study author Dr. Neal Freedman of NCI’s Division of Cancer Epidemiology and Genetics. “Though red meat and saturated fat have been associated with cancer at other sites, additional studies of HCC and CLD are needed. If we see similar results in other populations, dietary change may be an effective strategy to reduce the incidence of HCC and CLD.”

The researchers did not know participants’ history of hepatitis B and C infections, which is the main cause of HCC in most populations. The association between these viruses and meat and fat in the diet should be examined for HCC and CLD, Dr. Freeman noted.

Cancer Patients Leaving Hospice Early Boost Medicare Expenditures

An analysis of hospice patients with terminal cancer indicates that those who disenrolled from hospice care had higher rates of hospitalization, were more likely to die in a hospital, and incurred higher Medicare expenditures between hospice enrollment and death than patients who continued hospice care until death. The researchers adjusted for a number of factors, including the number of days from hospice enrollment until death, and found that total Medicare expenditures were $2,475 higher, on average, among the patients who disenrolled from hospice. The analysis was published online in the Journal of Clinical Oncology August 30.

Dr. Melissa Carlson of Mount Sinai School of Medicine and her colleagues analyzed the linked SEER-Medicare database for 90,826 hospice patients age 66 or older who died with a primary diagnosis of cancer between 1998 and 2002. The average patient age at death was 78.5 years, and 86 percent were non-Hispanic whites.

Of the 10.9 percent of patients (9,936) who disenrolled from a hospice program, 25 percent were hospitalized within 48 hours and 57 percent died within 30 days. Nearly 40 percent of patients who disenrolled from hospice subsequently re-enrolled. The researchers could not evaluate the causes or consequences of this pattern, nor did they have data on the reasons for disenrollment. The extra Medicare expenditures came primarily from hospitalizations and physician visits.

“Forty percent of Medicare’s total expenditures for hospice users with cancer were accounted for by only 5 percent of hospice users with cancer,” wrote the authors, “and a primary correlate of higher Medicare expenditures was whether a patient disenrolled from hospice.” 

More than a million Medicare beneficiaries are currently receiving hospice care, and about one third of them have a cancer diagnosis. With annual Medicare hospice payments of over $11 billion, policymakers are considering tightening the criteria for eligibility for the Medicare hospice benefit, the authors noted. They suggested that examining why patients disenroll from hospice—including the rates of disenrollment from specific hospice programs—may lead to effective ways to reduce Medicare expenditures without restricting access to the hospice benefit.

The authors also proposed that the use of outpatient palliative care teams that can provide symptom control and end-of-life planning may be an effective way to help patients who disenroll from hospice avoid hospitalization while maintaining contact with an oncology clinic. 

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