N Engl J Med 2023 Jun 04
Preoperative Treatment of Locally Advanced Rectal Cancer.
Abstract
Background
Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain.
Methods
We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects.
Results
From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy.
Conclusions
In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).
Related Questions
What treatment sequence do you follow for patients with rectal cancer who are candidates for both PROSPECT and TNT/Watch and wait?
Thanks for this question. I am not sure whether this is up to us. This is up to our patients to choose which modality they would like to omit (radiation vs surgery). I would point out that a good quality MRI rectum should be performed to r/o any T4/N2 disease or potential requirement for APR. Otherw...
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In an N+ rectal adenocarcinoma treated via PROSPECT with neoadjuvant FOLFOX with omission of CRT and no treatment response in the primary on pathology (ypN+), would you offer adjuvant chemotherapy or chemo-radiation?
Adjuvant FOLFOX was allowed in PROSPECT, and most patients received it. Presumably, patients with ypN+ disease were most likely to receive adjuvant FOLFOX. We do not (yet) have recurrence data broken down by ypN stage, but as the overall LR rate was less than 2%, I would not consider the lack of his...
Which patients, if any, treated according to PROSPECT for an early stage rectal cancer, would you offer surveillance if they achieved cCR after neoadjuvant chemotherapy?
Thanks for the important question. This is a nice but also challenging situation given, at this time, we do not have evidence for organ preservation with chemotherapy alone. Nonetheless, the PROSPECT trial did show approximately 20% of patients indeed achieved pathological compete response (was quit...
What systemic therapy would you use in T3N1M1 MMR proficient rectal cancer with solitary liver lesion when going for curative intent (chemo>short course RT> resection of primary and liver met)?
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How was treatment response assessed on the PROSPECT trial?
Dr. Harvey reached out to his colleague, Dr. Marc Gollub, director of radiology at Memorial Sloan Kettering with expertise in gastrointestinal imaging (and who was the radiologist who collaborated on PROSPECT), for his thoughts on this question. Here is his answer: I had to “create” a non-volum...
In which patients with early stage rectal cancer treated according to the PROSPECT paradigm do you recommend adjuvant chemotherapy?
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Would you recommend additional post-operative chemoradiation for a T2N1 proximal rectal cancer having received adjuvant capecitabine/oxaliplatin?
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Would you offer treatment according to the PROSPECT trial for rectal cancer in which an involved lymph node approaches the circumferential resection margin (CRM)?
Yes, if the goal is fertility preservation. One can start with Folfox chemotherapy and restage afterwards. If good response and the CRM is clear then proceed with surgery and if not, you can discuss doing chemoRT at that time.
For what patients are you adopting the PROSPECT approach into your rectal cancer practice?
Yes, the results of the trial are certainly factored into a multidisciplinary discussion. It is important to have a multidisciplinary discussion and to have shared decision-making with the patients. We often incorporate response to FOLFOX in this setting to decide. Although it is very subjective, we...
Should we be shrinking rectal cancer fields?
I think this is a good point. However, I think we need to consider the nuances of the question. First PROSPECT included: patients that "had cT2N+, cT3N-, cT3N+ rectal cancers deemed appropriate for neoadjuvant therapy prior to low anterior resection with TME. Patients with distal, T4 tumors, threate...
Would you alter radiation recommendations for a patient with locally advanced rectal cancer and a history of abdominopelvic lymphoma radiation 40 years ago?
In the case of more recent RT, I would get the records in order to inform treatment recommendations. However, records are typically impossible to get in this situation. We have several options here. The first is the avoidance of radiation, as was recently reported in the PROSPECT study. (Schrag et a...
What are your top takeaways in GI Cancers from ASCO 2023?
It was a big year for rectal cancer treatment! PROSPECT (Deb Schrag et al.,) - for selected “high” rectal cancers we can likely omit radiation if they have a good response to FOLFOX. Notable exceptions: tumors that require an APR, are stage T4 or N2. About 10% of patients will not have at least a 20...
How will the PROSPECT trial presented at ASCO 2023 change your current management of early rectal cancer?
I can’t overstate how much credit the Principal Investigator, Dr. @Dr. First Last, deserves for successfully completing the PROSPECT trial. The oncology community, particularly the radiation oncology community, was concerned that omitting radiation would put patients at risk. It was difficult and ch...