Association of Delayed Surgery With Oncologic Long-term Outcomes in Patients With Locally Advanced Rectal Cancer Not Responding to Preoperative Chemoradiation

Abstract

IMPORTANCEExtending the interval between the end of neoadjuvant chemoradiotherapy (CRT) and surgery may enhance tumor response in patients with locally advanced rectal cancer. However, data on the association of delaying surgery with long-term outcome in patients who had a minor or poor response are lacking.OBJECTIVE To assess a large series of patients who had minor or no tumor response to CRT and the association of shorter or longer waiting times between CRT and surgery with shortand long-term outcomes.DESIGN, SETTING, AND PARTICIPANTS This is a multicenter retrospective cohort study. Data from 1701 consecutive patients with rectal cancer treated in 12 Italian referral centers were analyzed for colorectal surgery between January 2000 and December 2014. Patients with a minor or null tumor response (ypT stage of 2 to 3 or ypN positive) stage greater than 0 to neoadjuvant CRT were selected for the study. The data were analyzed between March and July 2020.EXPOSURES Patients who had a minor or null tumor response were divided into 2 groups according to the wait time between neoadjuvant therapy end and surgery. Differences in surgical and oncological outcomes between these 2 groups were explored. MAIN OUTCOMES AND MEASURESThe primary outcomes were overall and disease-free survival between the 2 groups.RESULTS Of a total of 1064 patients, 654 (61.5%) were male, and the median (IQR) age was 64 (55-71) years. A total of 579 patients (54.4%) had a shorter wait time (8 weeks or less) 485 patients (45.6%) had a longer wait time (greater than 8 weeks). A longer waiting time before surgery was associated with worse 5-and 10-year overall survival rates (67.6% [95% CI, 63.1%-71.7%] vs 80.3% [95% CI, 76.5%-83.6%] at 5 years; 40.1% [95% CI, 33.5%-46.5%] vs 57.8% [95% CI, 52.1%-63.0%] at 10 years; P < .001). Also, delayed surgery was associated with worse 5-and 10-year disease-free survival (59.6% [95% CI, 54.9%-63.9%] vs 72.0% [95% CI, 67.9%-75.7%] at 5 years; 36.2% [95% CI, 29.9%-42.4%] vs 53.9% [95% CI, 48.5%-59.1%] at 10 years; P < .001). At multivariate analysis, a longer waiting time was associated with an augmented risk of death (hazard ratio, 1.84; 95% CI, 1.50-2.26; P < .001) and death/recurrence (hazard ratio, 1.69; 95% CI, 1.39-2.04; P < .001). CONCLUSIONS AND RELEVANCEIn this cohort study, a longer interval before surgery after completing neoadjuvant CRT was associated with worse overall and disease-free survival in tumors with a poor pathological response to preoperative CRT. Based on these findings, patients who do not respond well to CRT should be identified early after the end of CRT and undergo surgery without delay.

TNT: Raising more questions than answers?

“…[5][6][7] And could the 25%-40% of patients who have a good response to CRT alone avoid the additional toxicity of TNT? 5,6,16,17 Similarly, in OPRA, did all patients need neoadjuvant chemotherapy, when a substantial minority remain TME-free after CRT alone? 3 And are there options to improve outcomes for poor responders to TNT?…”

“…A retrospective Italian study of 1064 poor responders to CRT reported worse outcomes (including OS) if surgery was delayed >8 weeks. 16 While GRECCAR-6 (n = 265) showed no difference in oncological outcomes by treatment response when surgery was performed 7 or 11 weeks after CRT, 22 an ongoing RCT (n = 340) comparing surgery 8 or 12 weeks after CRT may help to clarify this question. 23 The role of adjuvant chemotherapy in poor responders has not been resolved either, with its administration in poor responders in the Italian study showing improved OS compared to those not treated with it, an observation supported by pooled and meta-analysis of other trials.…”

“…23 The role of adjuvant chemotherapy in poor responders has not been resolved either, with its administration in poor responders in the Italian study showing improved OS compared to those not treated with it, an observation supported by pooled and meta-analysis of other trials. 16,[24][25][26] Prospective (or retrospective) determination of the neoadjuvant rectal score in randomized trials might help to determine whether poor responders to CRT benefit from adjuvant chemotherapy. 26,27 Tailoring treatment according to response requires sensitive and specific methods to assess this, and appropriate endpoints for such studies.…”

“…But there are other questions arising from these trials. While the RAPIDO and PRODIGE 23 strategies increased the proportion of good responders, and oncological outcomes for the whole cohort, what impact could their strategies have on organ preservation, especially given the advantage of consolidation over induction chemotherapy in OPRA? 5–7 And could the 25%–40% of patients who have a good response to CRT alone avoid the additional toxicity of TNT? 5,6,16,17 Similarly, in OPRA, did all patients need neoadjuvant chemotherapy, when a substantial minority remain TME‐free after CRT alone? 3 And are there options to improve outcomes for poor responders to TNT? These and other questions are being investigated in trials aiming to individualize treatment for patients to maximize oncological outcomes while minimizing treatment modalities, and their adverse consequences on quality of life 4 …”

A prognostic nomogram for stage II/III rectal cancer patients treated with neoadjuvant chemoradiotherapy followed by surgical resection

“…For patients with locally advanced rectal cancer (LARC), neoadjuvant chemoradiotherapy (NCRT) followed by surgical resection has become the standard therapy [ 1 ]. NCRT can help to downstage tumors, increase the rate of curative resection, and decrease the rate of local recurrence [ 2 ]. According to data from the Surveillance, Epidemiology, and End Results (SEER) database, about 35.7% of patients with rectal cancer in stage II/III received NCRT [ 3 ].…”