In the 1990s, European trials showed that adding preoperative chemoradiation to standard treatments for locally advanced rectal cancer reduced the risk of local recurrence. Those findings helped establish the current standard of care for Stage II and Stage III rectal cancers, which calls for neoadjuvant chemoradiation followed by total mesorectal excision and chemotherapy.
But David W. Larson, M.D., of Mayo Clinic in Minnesota, says reduced recurrence and improved long-term survival come at a price.
"Pelvic radiation is associated with significant morbidity," he explains. "Patients who undergo curative resection without radiation average two or three bowel movements a day with slightly more urgency than normal. Radiation doubles the number of daily bowel movements and increases urgency. For patients with low anastomoses, radiation therapy can lead to functional disability and long-term risk of a permanent stoma."
Growing concern about the acute and late toxicities of current regimens is reinforced by data indicating that preoperative radiation may not be necessary or beneficial for every patient.
"We've been able to show that this is likely the case," Dr. Larson points out. "We've looked at our own patients who refuse or are too ill to undergo radiation therapy and it appears that local recurrence in that population is exactly the same as in patients who get radiation."
For example, retrospective review of 655 rectal cancer patients treated at Mayo Clinic with surgery alone from 1990 to 2006 found a five-year local recurrence rate of 4.3 percent. Disease-free survival was 90 percent and cancer-specific survival 91.5 percent.
Dr. Larson says other respected institutions have seen similar results. "We know what we think is true and what we have shown retrospectively is true. But what we've been lacking is Level 1 evidence that it is true."
Providing that evidence is the aim of the Preoperative Radiation and Evaluation before Chemotherapy and Total Mesorectal Excision (PROSPECT) trial. The phase II/III multicenter trial will compare the current standard of preoperative 5-Fluorouracil and pelvic radiation with neoadjuvant FOLFOX and selective use of chemoradiation. PROSPECT thus has the potential to change the current paradigm of rectal cancer treatment by reducing the use of radiation in patients who may not need it.
The trial's endpoints are R0 resection rate, time to local recurrence and disease-free survival. Observation will last up to five years and event monitoring up to eight years from randomization.
Eligible patients include adults with clinical stage IIA, IIIA or IIIB rectal adenocarcinoma whose tumor is located 1.9 to 4.7 inches (5 to 12 cm) from the anal verge. Patients with lower tumors are not eligible for this trial, but will likely be candidates for future trials.
"We've already looked at people with the very lowest tumors — less than 2 inches (5 cm) — retrospectively," Dr. Larson says, "and local recurrence is exactly the same in patients who undergo radiation as in patients who don't. But that's not ready for prime time absent a randomized, controlled trial, so that would likely be next.
Mayo Clinic in Minnesota hopes to enroll around 100 patients for the current PROSPECT trial. For most of them, mesorectal excision will be performed robotically to minimize pain, disability and recovery time. "Under the current standard of care, unless a Stage II or III rectal cancer patient is enrolled in a clinical trial, it's impossible to avoid having pelvic radiation recommended," Dr. Larson notes.
When the Swedish and Dutch trials were conducted two decades ago, European surgeons were generally less experienced in rectal cancer surgery than their American counterparts.
"What was known here wasn't known there," Dr. Larson says. "We knew our surgical techniques were good, and we believed radiation would offer little benefit to many patients. But the standard as defined by the European trials led surgeons in America to recommend radiation and thus potentially overtreat patients. PROSPECT should provide the linchpin we've been missing for the last decade that will allow us to say we can treat patients very well with good surgery alone. We don't need radiation to fix bad surgery."