Deborah Schrag, a gastrointestinal medical oncologist and health services researcher from Memorial Sloan Kettering Cancer Center presented the results of the NCI sponsored Alliance “PROSPECT trial” at the plenary session of the 2023 ASCO annual meeting. The paper detailing the work was simultaneously published in the New England Journal of Medicine. Dr. Schrag and her colleagues asked and answered the question “Can some patients with localized rectal cancer avoid pelvic radiation without compromising their chances for cure?”. Her patients, particularly her patients with early onset disease who wanted both to be cured and to have children raised the issue. She knew at the time of the trial’s design that this would be a controversial trial. She solicited input from medical, surgical, and radiation oncologists and the patient/patient advocacy community in constructing the study. They felt that this was not an approach that should be attempted in all patients with nonmetastatic rectal cancer. PROSPECT focused on the subset of patients presenting with localized, intermediate risk, mid-rectal cancers that were classified based on preoperative staging as T2N1, T3N0, or T3N1. The trial opened to accrual in 2012, and despite the skepticism expressed by many, Dr. Schrag’s painstaking attention to its design and intense advocacy for its accrual, led to its successful completion and to the practice changing results presented at the meeting.
At the time the study was designed we knew from decades during we universally recommended it for patients with Stages II and III rectal cancer that is reduced the risk of local recurrence. We also knew that it had both short- and long-term toxicities. Commonly observed long-term issues included sterility and early ovarian failure in women, sexual dysfunction, augmented risk of pelvic fracture, and bowel dysfunction characterized by urgency and soiling. At the time of the study design, we had recently learned that pelvic MRI added precision to preoperative staging. Because pelvic MRI was not yet universally available at the time the study was being developed, CT scanning with endorectal ultrasound was permitted as an alternative staging option.
The improvement in adjuvant chemotherapy with the addition of oxaliplatin to 5-FU, the acceptance of neoadjuvant chemotherapy as a strategy for downstaging disease prior to surgery, and the refinement of rectal surgery to include total mesorectal excision had all been shown to reduce the risk of local recurrence. Dr. Schrag was an early adopter of the notion that as we developed better tools, perhaps we could deescalate care without compromising cure rates. By eliminating radiation in the treatment plan, some of the compromises that our patients endured once they completed therapy some of which persisted for life, in order to maximize their odds of cure could potentially be reduced or averted. So, the PROSPECT study was designed as a noninferiority study with a novel endpoint, informed by patient and clinician input, to determine if the omission of radiation would lead to a less than 5% decrease in overall survival. Selecting who among the patients presenting with rectal cancer to include demanded careful consideration. The surgeons were required to certify that an individual was a candidate for sphincter sparing surgery that did not require a permanent colostomy. Patients with distal tumors within 5 cm of the anal verge were not permitted to enroll. Patients with T4 and N2 tumors are known to have higher local recurrence rates and they were also excluded. These consensus-based selection criteria were developed to optimize the chances of the trial’s success.
The study randomized nearly 1200 patients to FOLFOX before and after surgery or to 5-FU + radiation before and FOLFOX after surgery. Careful restaging was done and patients who had been assigned to receive preoperative FOLFOX were treated with 5-FU + RT if they had a poor response to neoadjuvant chemotherapy. That group comprised 9% of the individuals assigned to the neoadjuvant FOLFOX arm. Patients with a good response to neoadjuvant FOLFOX went directly to surgery without getting radiation and received postoperative adjuvant therapy.
Noninferiority trials are large and this one required nearly 1200 patients to meet its statistical goals. This effort also required long follow up to reach its overall 5-year survival endpoint. Careful assessment of surgical endpoints such as pathologic complete remission rates which were 22% without and 24% with radiation were built into the study. The short term toxicity profiles of the two regimens as assessed by the treatment team and the patients (using the validated CTCAE-PRO questionnaire) were as predicted from prior experience. Tissue and blood samples were collected and will be the subject of future analyses.
The primary goal of the study was met as the overall 5-year survival for the patients randomized to the non-radiation arm was 89.5% and that for the radiation arm was 90.2%. The difference did not reach statistical significance, was less than the predetermined 5% difference, and the strategy met its primary endpoint. We now know that we can advise selected patients with localized rectal cancer that omitting radiation will not compromise the success of their treatment and can spare them from potential long-term toxicity.
While the trial was accruing and maturing, other trials were conceived and executed. The field evolved further to embrace the notion of total neoadjuvant therapy and to identify patients with mismatch repair deficient tumors for early therapy with checkpoint inhibitors. The notion of managing rectal cancer with nonsurgical approaches in selected patients has become a reality. Together, these endeavors are both enhancing cure rates and reducing treatment related morbidity. Practitioners and patients have clearly benefited from these incremental results.
Dr. Goldberg Associate Group Chair of the Alliance, who sponsored this trial.
Illustration by Diana Connolly
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