PITTSBURGHAttempts 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