This year marks the 30th anniversary of the publication of the National Surgical Adjuvant Breast and Bowel Project (NSABP)-R01, a critical trial reported in the New England Journal of Medicine, which solidified the role of multimodality therapy for rectal cancer. This trial clearly showed the benefit of adding pelvic radiation to the treatment regimen for locally advanced rectal cancer, with resultant decrease in the local recurrence rate to 16 percent from 25 percent.* This changed the standard of care in the U.S., heralding modern treatment modalities for this type of cancer.
Many advances in cancer treatment have occurred over the last three decades: Optimized administration and timing of radiation, widespread adoption of total mesorectal excision (TME), and the implementation of more effective systemic chemotherapy. The current treatment standard includes neoadjuvant chemoradiation with 5-Fluorouracil as a radiosensitizer, TME, and adjuvant chemotherapy, including 5-Fluorouracil and Oxaliplatin. Reported local recurrence rates are now routinely at less than 10 percent. However, although oncologic results are impressive, trimodality therapy is arduous and sometimes is abandoned before it is completed. Consequently, there is still a need for improvement.
PROSPECT for individualized therapy
The Alliance for Clinical Trials in Oncology Cooperative Group’s Preoperative Radiation or Selective Preoperative Radiation and Evaluation before Chemotherapy and TME (PROSPECT) trial challenges the current treatment paradigm. The PROSPECT trial attempts to individualize treatment by using radiotherapy selectively rather than reflexively.
The rationale for using radiation selectively in rectal cancer patients includes:
- A better understanding of rectal cancer risk stratification—not all patients are at high risk for local recurrence
- Risk of short- and long-term toxicity
- The fact that many patients fail to complete the prescribed multi-modality regimen
- The desire to move systemic therapy proximally to potentially reduce distant recurrence, which is emerging as the major threat to longevity for locally advanced rectal cancer patients
In this phase II/III multicenter trial, neoadjuvant FOLFOX (Oxaliplatin, Leucovorin, and 5-Fluorouracil) with selective use of chemoradiation (5-Fluorouracil and pelvic radiation) is being tested against the current standard of preoperative chemoradiation (5-Fluorouracil and pelvic radiation) for rectal cancer patients undergoing low anterior resection with TME (NCCTG-N1048; N1048; NCT01515787; see figure, below).† By randomizing patients to one of these two arms, the PROSPECT trial provides an opportunity to reduce the use of pelvic radiation in patients who might not benefit from it. The primary endpoint for the phase II portion of the trial is R0 resection rate. If the trial achieves an equally high R0 resection rate in the intervention arm as in the control arm, the study will proceed to phase III. Phase III will involve evaluating time to local recurrence and disease-free survival.
Schema of N1048/PROSPECT trial
Adult patients (age ≥18 years) with biopsy-proven rectal adenocarcinoma with the following characteristics are eligible for the trial:
- Clinical stage T2N1, T3N0, or T3N1 (stage IIA, IIIA, or IIIB) as determined by examination, computed tomography scan, and either magnetic resonance imaging or ultrasound
- Candidate for sphincter preservation TME before neoadjuvant therapy
- No encroachment on the mesorectal fascia based on preoperative imaging
Additional criteria include: Adequate performance status; satisfactory laboratory studies; no obstructive symptoms; no prior pelvic radiation, chemotherapy, or malignancy.
The study is open across the U.S., and 286 patients were enrolled as of February 20. The most recent protocol amendments approved by the National Cancer Institute Adult Central Institutional Review Board were intended to facilitate participation and accrual. These revisions were as follows:
- Eliminated surgical credentialing but maintained surgical quality assurance
- Removed central radiation treatment planning but maintained radiation quality assurance
- Removed tumor height requirement, and included some administrative simplifications
The role of surgeons
Surgeons are integral to the success of this clinical trial for the following reasons:
- Surgeons represent a port of entry for accrual. Surgeons are often the first referring physicians for patients with newly diagnosed rectal cancer and are responsible for coordinating multidisciplinary care. Thus, surgeons are well-positioned to introduce this trial to eligible patients and to guide enrolled patients through the trial.
- Surgeons play a key role in evaluating and identifying potential patients. Surgical assessment of clinical tumor stage, circumferential resection margin, endoscopic tumor location, and, most importantly, candidacy for sphincter preservation form the basis for determining eligibility.
- Surgeons must maintain high-quality resection by TME for results to be interpretable. Because TME and pelvic radiation are the key local treatment modalities and this trial tests the feasibility of omitting radiation, quality of TME must be uniformly maintained.
The members of the Alliance and the American College of Surgeons Clinical Research Program find this clinical trial’s accrual rates to be encouraging and believe it has the potential to change the current paradigm of rectal cancer treatment. All U.S. cooperative groups have endorsed this trial. Surgeon participation is pivotal, and you are invited and encouraged to participate.
For additional information, contact Alessandro Fichera, MD, FACS, at email@example.com, or Martin R. Weiser, MD, FACS, at firstname.lastname@example.org.
*Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med. 1985;312(23):1465-1472.
†National Cancer Institute. Chemotherapy alone or chemotherapy plus radiation therapy in treating patients with locally advanced rectal cancer undergoing surgery. Available at: www.cancer.gov/clinicaltrials/search/view?cdrid=715321&version=HealthProfessional. Accessed February 18, 2015.