National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
October 18, 2011 • Volume 8 / Number 20

Cancer Research Highlights

Higher-Dose Radiation Does Not Improve Survival in Some Lung Cancer Patients

A higher dose of radiation therapy does not improve survival in patients with stage III non-small cell lung cancer (NSCLC) who are not candidates for surgery, researchers reported last week. The findings come from an interim analysis of a phase III randomized clinical trial presented at the American Society for Radiation Oncology (ASTRO) annual meeting in Miami.

“I think [this] changes practice,” said the trial’s principal investigator, Dr. Jeffrey Bradley of the Washington University School of Medicine, during a news briefing.

The trial, conducted by the NCI-sponsored Radiation Therapy Oncology Group, initially compared a radiation dose of 74 Gy to the standard 60 Gy dose in combination with standard chemotherapy with or without cetuximab (Erbitux). The investigators stopped enrollment in the high-dose radiation arms of the trial in June 2011, after the interim analysis revealed that, based on the number of deaths (90) at that point in the trial, there was no statistical chance that overall survival would be improved in patients treated with the 74 Gy radiation dose.

At the time of the interim analysis, 423 patients were enrolled in the study. There were more deaths related to treatment in the high-dose radiation therapy arms (7 versus 3), but that discrepancy did not account for the lower survival in that patient group, the analysis found.

This trial was the first in three decades to compare different radiation doses in patients with stage III NSCLC that had spread no further than to nearby lymph nodes, Dr. Bradley explained. The trial is continuing with two arms, comparing radiation therapy at 60 Gy and chemotherapy with or without cetuximab.

Although the 60 Gy dose has been considered a standard for patients with stage III lung cancer, Dr. Bradley said, several studies conducted at single institutions had suggested that survival could be improved without additional adverse side effects by using a higher radiation dose. Dr. Tim Williams, a former ASTRO president from Boca Raton Regional Hospital, said the higher dose has been the standard at his hospital for the past 5 years.

The findings, said Dr. Giuseppe Giaccone, chief of the Medical Oncology Branch in NCI's Center for Cancer Research, strongly suggest that high-dose radiation therapy should be abandoned in this patient population.

BRCA Gene Mutations May Influence Survival, Treatment Response in Ovarian Cancer

Women with ovarian cancer who have a mutated form of the BRCA2 gene may be more likely to respond to standard chemotherapy and have better overall and progression-free survival than women without the mutation, according to a new study published October 12 in JAMA. The findings also suggested that women with BRCA1 mutations had better overall and progression-free survival than women whose tumors lacked the mutations, but these latter findings were not statistically significant.

To conduct the observational study, Dr. Da Yang of the University of Texas M. D. Anderson Cancer Center and his colleagues analyzed genomic and clinical data from the tumors of 316 women with high-grade serous ovarian cancer. The data were made available in 2009 and 2010 from the NCI-supported The Cancer Genome Atlas (TCGA) program. Most of the women in the study (219) had nonmutated forms of the BRCA1 and BRCA2 genes. Only 27 women had BRCA2 mutations, and 35 had BRCA1 mutations.

Overall, 61 percent of women with BRCA2 mutations were alive after 5 years compared with 25 percent of women with non-mutated BRCA1 and BRCA2 genes and 44 percent of women with BRCA1 mutations. All of the women with BRCA2 mutations responded to chemotherapy, whereas 85 percent of women with wild-type BRCA genes and 80 percent of women with BRCA1-mutations responded.

“Our observations provide evidence that BRCA1 and BRCA2 mutations are differentially associated with patient survival compared with [non-mutated] BRCA and that this difference may be a result of distinct response to platinum-based treatment and different associations with genome instability,” the study authors wrote. Because of the relatively small size of the study, they acknowledged, more research is needed to validate the findings.

The study results provide “a major advance” in the understanding of how to test new treatments in women with ovarian cancer, wrote Drs. Victor Grann and Ramon Parsons of the Columbia University Medical Center in an accompanying editorial. They cited, for example, clinical trials that could test PARP inhibitors in women with ovarian cancer to test whether patients with BRCA1 or BRCA2 mutations respond differently.

A larger, NCI-led study presented earlier this year at the American Association for Cancer Research annual meeting had similar findings, including improved overall survival in women with ovarian cancer whose tumors had BRCA2 mutations.

Further reading: "Study Suggests How the BRCA1 Protein May Help Suppress Tumors"

Newer Cancer Drugs May Cause Thyroid to Function Abnormally

Over the last decade, many patients with cancer have benefited from the development of new targeted therapies and immunotherapies. But a common side effect of these agents may be unintended effects on the thyroid gland, according to a report published online today in the Journal of the National Cancer Institute.

Ole-Petter R. Hamnvik of Brigham and Women’s Hospital and his colleagues reviewed the scientific literature on thyroid dysfunction and newer anticancer therapies. They found that thyroid dysfunction occurred in an estimated 20 percent to 50 percent of patients who received the newer therapies, which include tyrosine kinase inhibitors and immunotherapies such as ipilimumab.

A common side effect of the newer cancer therapies is hypothyroidism, which causes symptoms such as fatigue and constipation. These conditions are common among cancer patients and may therefore be difficult to distinguish from symptoms caused by the underlying malignancy or by medications used for symptom control. Symptoms of thyroid dysfunction can also be confused with other treatment-related toxic effects, which may lead doctors to reduce treatment dosages or frequency.

Hamnvik and his colleagues recommended that doctors closely monitor patients receiving these treatments for signs of thyroid dysfunction. “This may allow early recognition and treatment of thyroid disease, allowing continued treatment of the underlying cancer, as well as improving the quality of life of the patient,” they wrote.

The report’s authors also recommended that doctors monitor thyroid function in all clinical trials involving new anticancer agents.

More research is needed to understand the mechanisms of the thyroid abnormalities associated with these treatments and to explore the many unanswered questions in the field, the authors added, noting that most of the published data are from small or preliminary studies.

“Treatment for thyroid diseases is safe and likely to enhance patient quality of life, as well as potentially allow effective treatments for the underlying cancer to continue,” the authors concluded.

Bacterium Linked to Colorectal Cancer in Two Independent Studies

Two independent research groups have identified a bacterium that is associated with colorectal cancer in the first studies to identify a potential link between this common cancer and an infectious agent. Further research is needed, however, to validate the findings and determine whether the bacterium plays a causative role in colorectal cancer, researchers from both groups stressed. The studies were published online October 18 in Genome Research.

The microbe Fusobacterium is not abundant in the human colon, which houses trillions of bacteria and thousands of microbial species. Nevertheless, Fusobacterium species have been associated with a number of conditions, including inflammatory bowel diseases, such as ulcerative colitis, an established risk factor for colorectal cancer.

The two research groups used similar approaches in their studies. A British Columbia Cancer Agency team, led by Dr. Robert Holt, initially identified an overabundance of Fusobacterium by analyzing 11 colorectal tumor samples and adjacent healthy colon tissue from the same patients using high-throughput RNA sequencing. A group from the Broad Institute at the Massachusetts Institute of Technology and Harvard University, led by Dr. Matthew Meyerson, used whole-genome sequencing to identify bacterial DNA in 9 paired cancerous and normal colon tissue samples.

Both groups used polymerase chain reaction (PCR) technology to validate the findings in a larger group of paired cancerous and normal colon tissue samples (88 and 95 samples, respectively).

Among the samples analyzed by Dr. Holt and his colleagues using PCR, “the mean overall abundance of Fusobacterium was found to be 415 times greater in the tumor samples…than in the matched normal samples,” they reported. Although Dr. Meyerson’s group had similar findings, “only a subset of the cancers showed dramatic enrichment of Fusobacterium species,” they noted.

Dr. Meyerson and his colleagues also found Fusobacterium in 2 out of 11 samples of colorectal cancer metastases.

“The presence of this bacterium may simply represent an opportunistic infection at an immunocompromised site, but the possibility of a role in tumor etiology, perhaps through pro-inflammatory mechanisms, deserves further scrutiny,” Dr. Holt and his colleagues wrote.

The bacterial composition of the tumors analyzed and their matched control tissue were more similar to each other than the bacterial composition of tumor samples from different patients, noted Phil Daschner of NCI’s Division of Cancer Biology. This suggests that “a patient’s gastrointestinal ecosystem—including the individual’s genetics, other bacteria, and cellular- and dietary-derived components and metabolites—is more important in shaping the microbial communities in the tumor than the tumor's microenvironment,” he continued.

The findings also suggest the possibility that prevention, diagnosis, and treatment strategies could be formulated based on the colon’s bacterial makeup, Daschner noted.