NEWS

Chemoradiation Protocols Offer Only Incremental Gains for Pancreatic Cancer Patients

Charles Bankhead

Despite the apparent success of several chemoradiation regimens in converting patients with inoperable pancreatic cancer to resectable status, investigators at a recent meeting of the American Society for Therapeutic Radiation and Oncology (ASTRO) lamented the lack of progress against a cancer that continues to have an almost universally poor prognosis and called for new therapeutic strategies to improve outcomes.

"The trials in pancreatic cancer all have a little bit of the feel of rearranging the deck chairs on the Titanic," said Harvey Mamon, M.D., Ph.D., a radiation oncologist at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston.

Nevertheless, some trials presented at the ASTRO meeting suggest that chemoradiation protocols may offer at least some benefit. A trial of alternating cycles of full-dose, split-course radiation and gemcitabine led to resection in four of 27 patients initially classified as unresectable. Among patients who remained unresectable after treatment, the regimen appeared to provide good palliation and might have prolonged survival, said Robert Myerson, M.D., a radiation oncologist at Washington University in St. Louis, Mo.

In another study, concurrent hyperfractionated radiation therapy and weekly paclitaxel led to complete responses in two patients and partial responses in five patients with locally advanced, unresectable pancreatic cancer. An additional 10 patients had stable disease, and two others had disease progression, reported Hani Ashamalla, M.D., an associate attending radiation oncologist at New York Methodist Hospital in Brooklyn, N.Y.

"Hyperfractionation allowed us to give a 15% higher radiation dose than what is recommended in most trials, which is about 50 Gy. We reached 64 Gy without significant morbidity," said Ashamalla. "Theoretically, we should be able to achieve about 15% better local control. We plan to take this regimen forward to a phase II clinical trial."

The two complete responses achieved with this regimen are a rarity in pancreatic cancer, Ashamalla noted. Moreover, the treatment improved pain scores and reduced the dose of pain medications in 15 of 17 patients. The treatment also reduced or stablized levels of the CA 19-9 tumor marker.

A retrospective analysis of three clinical trials of radiation therapy and concurrent gemcitabine showed that nine of 67 initially borderline or unresectable patients subsequently underwent successful surgeries for their pancreatic cancer.

"There was no apparent increase in morbidity or mortality following resection in pancreatic cancer patients who have previously received gemcitabine and radiation therapy," said John Ammori, M.D., a general surgery resident at the University of Michigan in Ann Arbor. "A prolonged interval between completion of radiation therapy and surgical exploration does not preclude resection."

Two other studies reported at ASTRO demonstrated feasibility and tolerability for chemoradiation regimens, but efficacy has yet to be determined. In one trial, twice-weekly gemcitabine and concurrent abdominal radiation was associated with a median survival of 14.5 months in a multicenter trial of 37 patients with negative-margin resected pancreatic cancer. To date, 22 patients are still alive, including 18 with no evidence of disease progression, reported John Palermo, M.D., a radiation oncologist at Wake Forest University in Winston-Salem, N.C.

Investigators in Boston reported concurrent cisplatin, gemcitabine, and radiation to be feasible and well tolerated in 20 patients with resected or unresected pancreatic cancer. Grade 3 to 4 toxicity consisted of three cases of thrombocytopenia and seven cases of neutropenia, reported Candice Aitken, M.D., a radiation oncology resident at Beth Israel Deaconess Medical Center and Harvard Medical School.

Some investigators at the ASTRO meeting expressed reservations about the current therapeutic approaches.

"When it comes to gemcitabine and other conventional drugs, we have marginal improvement," said Abram Recht, M.D., a radiation oncologist Beth Israel Deaconess and Harvard. "I could be surprised by the results of the [ongoing] intergroup adjuvant trial, but I suspect we’re not going to see gemcitabine make a huge difference in the risk of distant failure."

The trial, called RTOG 97-04, is comparing 5-fluorouracil and gemcitabine administered before and after chemoradiation in resected patients. Patient accrual for the trial ended last summer. Recht expressed hope that cooperative group evaluations of biologic agents or other strategies has produced some potential "magic bullets" for pancreatic cancer.

However, Dana-Farber’s Mamon, who is a member of the gastrointestinal committee of the Cancer and Leukemia Group B (CALGB), said that nothing under evaluation has given reason for much optimism at this point.

"We need something revolutionary," said Mamon. "We need a bigger change than tweaking the current therapies, as we are currently doing. The CALGB is looking at this, as everyone is, and knows where the field needs to go, but I don’t know that CALGB or any of the other [cooperative groups] have the answer yet. The answer clearly is going to come from better cancer biology. It is not going to come from adjusting our [radiation] fields or treating lymph nodes or giving gemcitabine once versus twice a week."



             
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