Chemoradiotherapy Trial With Capecitabine and Recombinant Erythropoietin to Start Soon

February 1, 2003

PITTSBURGH-Attempts to conduct randomized comparative trials of preoperative vs postoperative therapy for rectal cancer have been largely unsuccessful in the United States. Many surgeons have already decided which approach they are committed to and will not randomize patients to the alternate approach, according to Roy E. Smith, MD. As director of medical affairs and oversight for the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation in Pittsburgh, Dr. Smith has had experience in NSABP’s efforts to get comparative trials off the ground.

PITTSBURGH—Attempts to conduct randomized comparative trials of preoperative vs postoperative therapy for rectal cancer have been largely unsuccessful in the United States. Many surgeons have already decided which approach they are committed to and will not randomize patients to the alternate approach, according to Roy E. Smith, MD. As director of medical affairs and oversight for the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation in Pittsburgh, Dr. Smith has had experience in NSABP’s efforts to get comparative trials off the ground.

The current NSABP protocol, R-04 (see Figure 1), was designed to circumvent some of the problems encountered in previous trials. NSABP R-03, for example, enrolled only about 300 patients and failed to achieve its accrual target. A survey of the NSABP membership revealed that many thought the study was too complex and that there was unacceptable toxicity and a delay in surgery. In addition, because data from a Mayo Clinic study had shown improved outcomes with radiation plus continuous infusion fluorouracil (5-FU), potential participating physicians resisted using bolus 5-FU, which R-03 called for.

Experts Offer Input

"We called 55 people to Pittsburgh, including representatives from the National Cancer Institute and prominent rectal surgeons, and debated what was needed to get rectal cancer trials going," Dr. Smith explained. "The surgeons wanted a treatment that could be given orally so that we would get good patient compliance. Office-based physicians wanted a regimen that did not require a great deal of logistical support."

NSABP trial designers wanted a protocol that included both capecitabine (Xeloda) and recombinant erythropoietin. "We are quite convinced that capecitabine is not just another form of 5-FU, that there are additional advantages to it. Capecitabine has a unique interaction with radiation therapy, and we hope to take advantage of this. In addition, the NSABP’s previous rectal cancer trial indicates that about 1/3 of patient trials with preoperative therapy required blood transfusions. Tumor hypoxia is linked to malignant progression. The hypoxia-inductible factor-1 (HIF-1) pathway responds to oxygen limitation and is modulated by erythropoietin. This pathway itself may play a role in the mechanisms of malignant transformation," Dr. Smith said.

Investigators hope to enroll 1,606 patients over the next 4 years. The study will open in 2003, and planned interim analyses will occur after 44, 88, and 132 local regional relapses.

Banking Tissue Samples

R-04 investigators will also bank fresh tissue specimens for microarray analysis of tissue before and after chemoradiation. "The main goal of this is to find candidate predictive genetic patterns for response to either therapy," Dr. Smith noted.

"We hope to get as many tissue samples as possible for this task, since finding such a marker could reduce the cost of rectal cancer drug development by up to $300 million," he added. "We have a special shipping kit for fresh tissue for RNA analysis and also now have a method for assessing RNA from paraffin-embedded samples."