Researchers at the University of Calgary say a new treatment plan for an aggressive brain cancer called glioblastoma is showing promise.

A combination of two drugs increased the lifespan of animals in test trials by 30 per cent, according to researchers at the Hotchkiss Brain Institute.

“It seems when the tumour is growing in the brain there’s multiple processes going on. So just shutting off this specific one doesn’t seem to have as much of an effect as hitting the cancer from different sides,” said Artee Luchman, one of the researchers.

“We’re just very encouraged by this study, which started as a lab inquiry research question, being moved into a human study.”

One drug is Temozolomide — already taken by most glioblastoma patients — while the other is AZD8055. Together they inhibit a pathway in the cancer cells known as mTOR signaling, causing more cancer cells to die when combined with current standard therapy.

Results of the study was recently published in the scientific journal Clinical Cancer Research.

Researchers hope to start a clinical trial next spring on people with glioblastoma, an aggressive form of brain cancer and the most common and deadly form among adults.

Daily aspirin use is associated with a modest decrease in mortality from cancer, particularly for malignancies of the gastrointestinal tract, a large retrospective study confirmed.

Individuals who were current daily users for 5 years or more at baseline had an 8% decrease in cancer mortality compared with non-users (RR 0.92, 95% CI 0.83 to 1.02), according to Eric J. Jacobs, PhD, and colleagues from the American Cancer Society in Atlanta.

The association was stronger, with a 16% decrease for those with daily use for 5 years or more, when the analysis included data collected periodically during 2 decades of follow-up (RR 0.84, 95% CI 0.75 to 0.95), the researchers reported in the Journal of the National Cancer Institute.

A recent pooled analysis of more than 50 trials involving aspirin use for cardioprotection found a 37% reduction in deaths from cancer among users, which was considerably greater than in observational studies and trials of alternate-day aspirin.

To clarify the magnitude of the association between aspirin use and overall cancer mortality, Jacobs and colleagues analyzed data from the Cancer Prevention Study II, which began in 1992 and included 100,139 participants who completed questionnaires with information on demographics, medical history, and behavioral influences.

Beginning in 1997, participants also provided information about aspirin use, and continued to provide updates every 2 years.

The 1997 questionnaire was considered the baseline for the analysis, at which time 23.8% of participants were using either low-dose or adult-strength aspirin.

More than half of participants were older than 60 and female, and almost all were white.

During the 20 years of follow-up, there were 5,138 deaths from cancer.

Among those who reported aspirin use in 1997, three-quarters said they were still taking it in 2003, while among those who were non-users at baseline, 25% had begun doing so.

Baseline aspirin users tended to be more educated, former smokers, and obese, as well as to have a history of cardiovascular disease and diabetes.

Male users also were more likely to have a history of prostate specific antigen (PSA) testing, and women users were more likely to have a history of mammography.

Overall mortality was slightly lower even for individuals who had been users for less than 5 years (RR 0.84, 95% CI 0.76 to 0.94).

Relative risks were similar for users of low-dose and full-strength aspirin, and for those with and without a history of cardiovascular disease, ranging from 0.82 (95% CI 0.72 to 0.91) to 0.95 (95% CI 0.86 to 1.04).

Current users who had never smoked had considerably lower mortality (RR 0.68, 95% CI 0.57 to 0.81), a reduction that was not seen for former smokers (RR 0.92, 95% CI 0.82 to 1.04) or those currently smoking (RR 0.91, 95% CI 0.70 to 1.19).

Even after discounting lung cancer deaths, the only lower mortality among aspirin users was for never-smokers (RR 0.67, 95% CI 0.56 to 0.81).

A possible explanation for the lack of effect on cancers other than those in the lung among ever-smokers is that smoking may attenuate the antiplatelet activity of aspirin, and activated platelets are thought to promote tumor metastases, the researchers explained.

Aspirin use at the 1997 baseline was not significantly associated with mortality from specific cancers, but differences were seen when data through 2008 were included in the analysis:

• Cancers within the gastrointestinal tract, RR 0.61 (95% CI 0.44 to 0.84)
• Cancers outside the gastrointestinal tract, RR 0.88 (95% CI 0.78 to 1)
• Colorectal cancer, OR 0.64 (95% CI 0.42 to 0.98)
• Esophageal and stomach cancer, RR 0.56 (95% CI 0.37 to 0.86)

“The reduction in overall cancer mortality was driven by both a substantial reduction in mortality from gastrointestinal tract cancers and a small, but statistically significant, reduction in mortality from cancers outside the gastrointestinal tract,” they stated.

They noted that their study was observational, which was an important limitation, in that confounding factors could have resulted in either an underestimate or an overestimate of the effects of aspirin on mortality.

Also, the absolute risk for cancer mortality between non-users and daily long-term aspirin users — approximately 100 per 100,000 person-years for men and about 40 per 100,000 person-years for women — would represent an important benefit of aspirin use if it were causal, the authors stated.

“However, even if causal, differences in absolute rates are likely to differ between our predominantly elderly population and younger populations at much lower risk of cancer mortality,” they warned.

They concluded that the “relatively modest benefit” seen in their analysis could “meaningfully influence the balances of risks and benefits of prophylactic aspirin use.”

In an accompanying editorial, John Baron, MD, of the University of North Carolina in Chapel Hill, offered a word of caution. Baron was the lead author of the meta-analysis on aspirin use and cancer risk.

“Just because aspirin is effective does not mean it necessarily should be used,” he argued.

“Aspirin is a real drug, with definite toxicity. As for any preventative intervention, the benefits must be balanced against the risks, particularly when the benefits are delayed whereas the risks are not,” Baron stated.

In patients identified with the IDH1-mutation and who had less than 2 cc of residual tumor, survival was greater than 95% over nearly 17 years, compared with a survival of 20% among patients with a larger residual tumor (P=0.01), said Daniel Cahill, MD, PhD, assistant professor of neurosurgery at Harvard.

“This is personalized surgery for these patients,” Cahill told MedPage Today at the annual meeting of the American Society of Clinical Oncology.

He said that the test to determine if the astrocytoma is wild type or is the mutant form requires no special testing. “It takes about a week to determine if the tumor is mutant or wild type. It is just an immunohistochemistry test. It is part of a routine, final pathology report.”

Cahill and colleagues reviewed data collected prospectively on 407 patients diagnosed with malignant astrocytomas from the University of Texas MD Anderson Cancer Center dataset. Researchers identified 121 patients for whom mutant status was determined. They had longer survival than patents with wild-type status.

When stratified by extent of residual tumor, the survival advantage was dramatic, Cahill demonstrated.

He said the study indicates that “with the finding of IDH1 status, you might do a second stage resection if necessary, because if we can get the residual tumor level to less than 2 cc we have patients out more than 20 years. You are basically cured,” he said.

The average survival for patients with the IDH1 mutation was 163.4 months, while the average survival for patients diagnosed with wild-type disease was 14.7 months. The patients with mutant disease were generally younger – 36.9 years of age compared with 55.9 years of age for those with wild-type disease.

Most of the patients with IDH1 mutant status were diagnosed with astrocytomas (87 of 121 patients), while the others were diagnosed with glioblastoma multiforme. He reported that 212 patients with wild-type status were diagnosed with glioblastoma and 43 were diagnosed with astrocytoma.

Overall, astrocytoma is a more favorable diagnosis, said Jennifer Clarke, MD, assistant professor of neurology and neurological surgery at the University of California San Francisco. “The IDH1 mutation tends to show up in patients whose tumors start as less aggressive and transform over time into more aggressive,” Clarke said.

“We are finding that IDH1-positive tumors and glioblastomas that are IDH1-negative are two different animals, and the question is whether we can translate that finding into differential treatment,” she told MedPage Today.

Clarke indicated that there may be subgroups of patients who respond differently to extent of surgery and to different medical regimens.

She said the mutation is much more common in low-grade tumors than in tumors first diagnosed as glioblastoma. “Glioblastoma is a grade 4 astrocytoma.”