A paradigm shift in rectal cancer treatment: The PROSPECT trial

The “Miles” procedure, or abdominal-perineal resection (APR), recently celebrated a 100-year anniversary, which should remind us that while some things change, others remain the same. Whereas the APR is still practiced, numerous additional options have evolved, including sphincter-preserving procedures to improve quality of life, and neoadjuvant and adjuvant radiation and chemotherapy to reduce rates of local, regional, and systemic relapse. Indeed, our current paradigm calls for neoadjuvant radiation and sensitizing chemotherapy followed by surgery and postoperative chemotherapy as the standard of care for Stage II and Stage III rectal cancer. This standard is now challenged by rising concerns about the long-term toxicities of current regimens and new standards are encouraged by improvements in surgery and radiographic imaging and chemotherapy options.

To safely challenge the existing paradigm, the Alliance for Clinical Trials in Oncology Cooperative Group is launching a new trial titled the “PROSPECT” trial. PROSPECT is the acronym for Preoperative Radiation Or Selective Preoperative Radiation and Evaluation before Chemotherapy and Total Mesorectal Excision (TME).

Schema of N1048

The PROSPECT trial, by offering preoperative radiation or selective preoperative radiation and evaluation before chemotherapy and TME, provides the opportunity of reducing the use of pelvic radiation in patients who might not benefit from this treatment. In this phase II/III multicenter trial, neoadjuvant FOLFOX (Oxaliplatin, Leucovorin, and 5-Fluorouracil) with selective use of chemoradiation (5-Flouroracil and pelvic radiation), is being tested against the current standard of preoperative chemoradiation (5-Flouroracil and pelvic radiation) for rectal cancer patients undergoing low anterior resection with TME (NCCTG-N1048; N1048; NCT01515787; see figure).

The rationales for conducting the trial are as follows: (1) pelvic radiation is associated with significant morbidities; (2) neoadjuvant chemoradiation may over-treat some patients whose risk of local failure is low after TME alone; and (3) moving systemic chemotherapy more proximately in the treatment regimen may benefit some patients. The trial’s primary endpoints are R0 resection rate, time to local recurrence, and disease-free survival.

Adult patients (ages >18 years) with biopsy-proven rectal adenocarcinoma of the following characteristics are eligible:

  • Clinical stage T2N1, T3N0, or T3N1 (stage IIA, IIIA, or IIIB) as determined by operative surgeons’ exam, computed tomography scan, pelvic magnetic resonance imaging (MRI), or endorectal ultrasound
  • Tumor located at 5 to 12 cm (inclusive) of the anal verge on endoscopy
  • Candidate for sphincter preservation TME before any neoadjuvant therapy

Additional criteria include: Adequate performance status; satisfactory laboratory studies; at least 3 mm of circumferential tumor clearance to mesorectal fascia; no obstructive symptoms; no prior pelvic radiation, chemotherapy, or malignancy.

Surgeons and the American College of Surgeons (ACS) Clinical Research Program of the Alliance group are integral to the success of this clinical trial for several reasons:

  • Surgeons represent a port of entry for enrolling patients. Surgeons are often the first referral physicians for patients with newly diagnosed rectal cancer, and are responsible for coordinating subsequent multidisciplinary oncologic care. Surgeons are thus well-positioned to introduce this trial to potentially eligible patients, and to shepherd enrolled patients through the trial.
  • Surgeons play a key role in the evaluation and identification of potential patients. Operative surgeons’ assessment of clinical tumor stage, circumferential resection margin, endoscopic tumor location, and most importantly, candidacy for sphincter preservation, form the very basis for determining eligibility for this trial.
  • Surgeons must maintain high-quality tumor resection by TME technique for trial results to be interpretable. The common backbone of this trial is high-quality TME. Because TME and pelvic radiation are the key local treatment modalities for rectal cancer, and because the feasibility of omitting radiation is being tested by the trial, the quality of TME must be carefully and uniformly maintained. Participating surgeons must be credentialed in TME surgery through a process described in the sidebar on this page.

In summary, the Alliance and its American College of Surgeons (ACS) Clinical Research Program are poised to conduct this new clinical trial, which has the potential to dramatically change the current paradigm of rectal cancer treatment. Surgeon participation is pivotally important to this trial, and you are invited to participate. The study co-chairs include Alessandro Fichera, MD, FACS, a colorectal surgeon from the University of Chicago (IL); Debra Schrag, MD, a medical oncologist from Dana-Farber Cancer Institute, Boston, MA; and Robert McWilliams, MD, a medical oncologist from Mayo Clinic, Rochester, MN. The National Cancer Institute Adult Central Institutional Review Board has fully approved the trial.

For additional information regarding the credentialing process, contact Dr. Fichera at afichera@surgery.bsd.uchicago.edu. Any additional information about this trial may be obtained by contacting Dr. Schrag at deb_schrag@dfci.harvard.edu.

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