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Combining low-dose fractionated radiation therapy with gemcitabine (Gemzar) might potentiate the effect of gemcitabine, but with lower toxicity, in patients with advanced pancreatic cancer. A new study has found that this combination is not only well tolerated, but it appears to be more effective than other regimens with gemcitabine alone or combined with other systemic therapies.

Given the caveats of a small study with a heterogeneous population, study author Navesh K. Sharma, PhD, DO, noted that "we believe that low-dose fractionated radiation therapy, in conjunction with full-dose gemcitabine, may offer a novel and somewhat effective paradigm for treating advanced pancreatic cancer."

Dr. Sharma, an assistant professor of radiation oncology at the University of Maryland, Baltimore, presented the findings here at the American Society for Radiation Oncology 52nd Annual Meeting.

Treatment options for patients with unresectable disease are limited, noted Dr. Sharma. Gemcitabine has emerged as a first-line therapy for use in pancreatic cancer, but its efficacy, when used as a single agent, has been suboptimal in advanced disease.

However, it can also be used in conjunction with radiation therapy. Recent laboratory data suggest that low-dose fractionated radiation therapy can be used as a chemosensitizer in combination with gemcitabine, he explained.

On the basis of encouraging preclinical data, a phase 1 study was undertaken at the University of Kentucky, which evaluated the combination of full-dose gemcitabine and low-dose upper abdominal radiation therapy, said Dr. Sharma during his presentation. "The results demonstrated tolerability in conjunction with doses of 60 cGy with full-dose gemcitabine."

Armed with these early data, Dr. Sharma and colleagues undertook a phase 2 trial, which also assessed the effect of full-dose gemcitabine plus low-dose upper abdominal radiation therapy. "In this case, the 60 cGy had already been shown to be effective in patients with locally advanced or metastatic prostate cancer," he said.

The cohort consisted of 38 patients who were enrolled at 3 institutions. Within this group, 16 (42%) had unresectable locally advanced/recurrent disease and 22 (58%) had distant metastases, primarily to the liver (91%).

The study end points were objective response rate, toxicity profile, and overall survival.

Radiation therapy was administered at 60 cGy/fraction twice a day on days 1, 2, 8, and 9, and the upper abdominal radiation fields extended from the diaphragm to the top of the iliac crest. Gemcitabine was given at a fixed-dose rate of 1250 mg/m2 on days 1 and 8 of a 21-day cycle for 4 cycles. Follow-up imaging was performed 1 month after the completion of therapy, and response was determined by RECIST criteria.

The median follow-up was 10.7 months for the entire cohort, explained Dr. Sharma, but for living patients, it was 19.3 months. By RECIST criteria, the response rate was 8% (1 complete response and 2 partial responses).

However, Dr. Sharma pointed out that they looked at patients who did not demonstrate disease progression, "which is also an important value." Therefore, the combined response rate, including disease stabilization, was 61%. For patients who presented without metastatic disease, the response rate was 69%.

Overall survival in patients with metastatic disease was 7 months; in patients without metastases, it was 12.5 months. At 1 year, overall survival was 45% in patients with metastatic disease and 55% in those without metastases.

One patient with unresectable disease had a continuing response and was able to undergo resection 8 months after receiving therapy.

Approximately 84% of the patients completed the treatment protocol. Three patients had disease progression during the early phase of the protocol, and 3 other patients experienced gemcitabine toxicity early in the study, which required them to be taken off the protocol.

There were no reported cases of febrile neutropenia. Grade 3 hematologic toxicities were reported in 19 patients (50%) and grade 4 toxicities were reported in 17 patients (45%).

For patients who presented without metastases, there seemed to be an improvement in overall survival, explained Dr. Sharma. "The toxicities were primarily related to gemcitabine treatment."

This is an "encouraging trial," said Salma Jabbour, MD, from the Robert Wood Johnson University Hospital, New Brunswick, New Jersey.

These data add to the information we have about what our optimal combinations are, said Dr. Jabbour, who was discussant for the paper. "We need to continue a collaborative effort to enroll patients in clinical trials, to further study this disease, and to study combinations of agents with radiation."

Dr. Sharma noted that, at his institution, they are currently evaluating low-dose fractionated radiation therapy in conjunction with other systemic therapies in patients with advanced disease. "If this continues to be a low-toxicity regimen with some efficacy associated with it, we will address it in a definitive setting and it may be of use in other forms of cancer," he said.

Source: ASTRO