Cancer Research Highlights
Adding Chemotherapy to Radiation Improves Survival for Some Patients with Rare Brain Cancer
Long-term follow-up results from two clinical trials confirm that certain patients with anaplastic oligodendrogliomas, which account for less than 10 percent of brain and central nervous system cancers, live substantially longer if they are treated with a combination of chemotherapy and radiation therapy rather than radiation alone.
In the trials—both of which were launched in the mid-1990s—patients whose tumor cells had missing or deleted parts of chromosomes 1 and 19 and who received the combination treatment lived substantially longer than patients whose tumors had these deletions but who received radiation therapy alone. About half of patients diagnosed with anaplastic oligodendroglioma have these chromosomal co-deletions. The combination treatment did not improve survival for patients whose tumor cells lacked the deletions.
Because of the immediate implications for patients, NCI and the Radiation Therapy Oncology Group (RTOG) announced the results of one of the trials, RTOG 9402, in January before they had been published or presented at a medical conference. Findings from both studies were presented in June at the American Society of Clinical Oncology annual meeting and published online October 15 in the Journal of Clinical Oncology.
“These studies establish a new standard of care for patients with [anaplastic oligodendroglioma] tumors that harbor the 1p19q loss. No longer is radiation considered an adequate treatment for this patient population,” wrote Dr. Mark Gilbert of the University of Texas MD Anderson Cancer Center in an accompanying editorial.
In the NCI-funded RTOG trial, participants whose tumors harbored both chromosomal deletions and who received high-dose chemotherapy with procarbazine (Matulane), lomustine (CeeNu), and vincristine (Vincasar), a regimen known as PCV, followed by radiation had a median survival of 14.7 years. Participants with the deletions who received radiation alone had a median survival of 7.3 years.
Median survival for patients whose tumors did not have the chromosomal deletions was less than 3 years, regardless of whether they received the combination therapy or radiation alone.
In the other trial, EORTC 26951, patients received radiation therapy alone or radiation followed by a standard-dose PCV regimen. The median overall survival cannot yet be calculated for patients with the chromosomal co-deletions who received the combination therapy, but there is a strong trend toward improved overall survival.
There is still some uncertainty about the preferred treatment for these patients, cautioned the RTOG trial’s principal investigator, Dr. Gregory Cairncross of the University of Calgary and his colleagues. For example, because it can improve survival in glioblastoma, has fewer side effects, and is easier to administer than the PCV regimen, many oncologists appear to prefer using temozolomide (Temodar) to treat anaplastic oligodendroglioma.
In January, enrollment was suspended for a clinical trial called CODEL that was to include only patients with 1p19q deletions and randomly assign them to radiation alone or radiation plus chemotherapy with temozolomide. Because the evidence so strongly supports the combination of chemotherapy and radiation for patients with the chromosomal deletions, a radiation-alone arm would be unethical, trial leaders explained.
According to Dr. Bhupinder Mann of NCI’s Division of Cancer Treatment and Diagnosis, the trial is being redesigned, with the hope of finalizing the changes by the end of the year.
RTOG 9402 was supported by grants from the National Institutes of Health (U10 CA21661, U10 CA32115, U10 CA25224, CA17145, CA21115, CA32102, and U10 CA37422).
HIV Linked to Rising Rates of Anal Cancer among U.S. Men
An increase in the incidence of anal cancer among men in the United States during recent decades may have been driven in part by the HIV epidemic that occurred during the same period, a new study suggests. The results, published in the Journal of the National Cancer Institute on October 4, provide a framework for understanding the rising rates of anal cancer in men and could help guide efforts to prevent the disease.
Dr. Meredith S. Shiels of NCI’s Division of Cancer Epidemiology and Genetics and her colleagues estimated that between 2001 and 2005, more than 28 percent of anal cancer cases among men were associated with HIV infection, whereas only 1.2 percent of anal cancer cases in women were associated with HIV.
Although anal cancer is rare in the United States, the incidence has been increasing since 1940. Between 1980 and 2005, the rate of anal cancer in men in the general population rose 3.4 percent per year. The authors noted that half of this increase was due to cases of anal cancer occurring in men who were infected with HIV.
Men who have sex with men are at high risk of both HIV infection and anal cancer. Human papillomavirus (HPV) infections of anal tissue and anal precancerous lesions, which increase the risk of anal cancer, are common in this group. But the extent to which the incidence of anal cancer among people infected with HIV has affected incidence rates in the general population was not clear.
To explore this question, the study authors used data from the HIV/AIDS Cancer Match Study. They looked at the number of people with anal cancer infected with HIV in 17 U.S. states and metropolitan areas.
“HIV-infected cases have had a substantial impact on trends in anal cancer rates among men in the U.S.,” said Dr. Shiels. She noted that rates among women have also increased, but the cause remains unclear. “Efforts to reduce the risk of anal cancer in HIV-infected men could have a sizeable impact on anal cancer rates at the general population level,” she concluded.
This research was supported in part by NCI's Intramural Research Program.
Further reading: "HPV Vaccine Study in Costa Rica Yields Insights on Cancer Prevention"
HIV Drug Blocks Growth of HER2-Positive Breast Cancer Cells
Nelfinavir, a drug used to treat people infected with HIV, appears to halt the growth of HER2-positive breast cancer cells. Researchers led by Dr. Joong Sup Shim of the Johns Hopkins School of Medicine showed that, in the laboratory, doses of nelfinavir used to safely treat people infected with HIV inhibited the growth of drug-resistant HER2-positive breast cancer cells. The study appeared October 5 in the Journal of the National Cancer Institute.
Although several drugs are approved to treat HER2-positive breast cancers, tumors often develop resistance to these drugs, and new treatments are needed.
The researchers exposed seven genetically characterized breast cancer cell lines to drugs cataloged in the Johns Hopkins Drug Library, including anticancer drugs and drugs used to treat other diseases. (The protein-coding genes in the cells had been sequenced to determine whether they had mutations known to drive cancer.)
After finding that nelfinavir selectively inhibited HER2-positive breast cancer cells, compared with HER2-negative cells, the researchers teased out how the drug might work in HER2-positive cells. They found that nelfinavir inhibits a protein called heat-shock protein 90 (HSP90). Heat-shock proteins act as “chaperones,” helping newly synthesized proteins to fold properly and stabilizing their structures. When the activity of HSP90 is blocked by nelfinavir, the proteins that it normally helps fold and stabilize may not work correctly.
HSP90 helps stabilize the HER2 protein and another protein in its signaling pathway called AKT. Therefore, blocking HSP90 activity may lead to the breakdown of HER2 and AKT or a decrease in their activity, explained the authors. This could slow or stop the growth of cancer cells that cannot function without abnormal HER2 signaling.
When the researchers tested nelfinavir in xenograft models of breast cancer, mice with HER2-positive tumors that were given nelfinavir had tumors less than half the size of those in mice that were not given the drug, and nelfinavir substantially reduced the levels of active HER2 (but not AKT) in the tumors. In cell-culture experiments, nelfinavir inhibited the growth of three HER2-positive cell lines that were resistant to the anti-HER2 drugs trastuzumab (Herceptin) or lapatinib (Tykerb).
The researchers hope that clinical trials will start soon. The rationale for clinical trials of nelfinavir is particularly strong for patients with resistance to the available anti-HER2 treatments, who have a poor prognosis, explained Dr. Jun O. Liu, the study’s senior author.
The advantage of using a drug already approved for another disease, he added, is that the drug can likely skip phase I trials and go straight into phase II trials if tested at a dose currently used in the clinic. Another drug the research team found using this screening process, an antifungal/antibiotic called itraconazole, which inhibits tumor blood-vessel formation, leapt directly into phase II testing in cancer patients, he noted. (See the trial details here, here, and here.)
This research was supported by grants from the National Institutes of Health (CA122814, R01AI065983, and UL1 RR 025005).
Exercise, Behavioral Therapy Reduce Menopausal Symptoms Caused by Breast Cancer Treatment
Women with breast cancer who were suffering from treatment-related menopausal symptoms experienced symptom relief with cognitive behavioral therapy, physical exercise, or both, according to a Dutch study. The findings were published October 8 in the Journal of Clinical Oncology.
Dr. Neil K. Aaronson of the Netherlands Cancer Institute and his colleagues randomly assigned 422 patients to behavioral therapy, physical activity, an intervention combining the two, or a control group that received usual care. The purpose of the study was to evaluate the effects of psychosocial interventions and exercise on menopausal symptoms, such as hot flashes and night sweats, as well as on sexual functioning, psychological well-being, and health-related quality of life. The patients reported their symptoms at the start of the study and 12 weeks and 6 months later.
Compared with the control group, women who received the interventions had statistically signiﬁcantly lower levels of endocrine and urinary symptoms, and behavioral therapy and physical activity had a positive effect on physical functioning. The researchers noted, however, that physical activity “affects primarily the frequency with which endocrine symptoms are experienced, but not the frequency of hot ﬂashes and night sweats specifically.” Cognitive behavioral therapy, in contrast, “seems to not only affect symptom frequency, but also the perceived burden of hot ﬂashes and night sweats.”
In a related editorial, Mayo Clinic researchers Drs. Debra Barton and Charles Loprinzi commented that, despite its limitations, the study demonstrated that “it is not sufficient to consider only biomedical influences [on symptoms]. …For complete symptom resolution, it may be necessary to address both the physiological expression and psychosocial context of the symptom.”