Total Neoadjuvant Therapy Research Articles

Total neoadjuvant therapy for locally advanced rectal cancer: a narrative review.

Locally advanced rectal cancer has traditionally been treated with chemoradiotherapy (CRT) followed by surgery and adjuvant chemotherapy. However, a new strategy, total neoadjuvant therapy, involves the administration of CRT and neoadjuvant chemotherapy with the aim of eradicating micrometastases earlier and achieving greater control of the disease. The use of total neoadjuvant therapy has shown higher rates of pathological complete response and resectability compared with CRT, including improved survival. Nevertheless, distant relapse is the main cause of morbidity and mortality in locally advanced rectal cancer. To address this, new biomarkers are being developed to predict disease response.

Total Neoadjuvant Therapy (TNT) with Full Dose Concurrent Chemotherapy in Locally Advanced Rectal Adenocarcinoma Including Signet Ring and Mucinous Cancers.

Total neoadjuvant therapy (TNT) with pre-operative chemotherapy and chemoradiotherapy results in improved survival and is becoming the new standard of care in locally advanced rectal cancer (LARC). We describe our experience with TNT consisting of induction chemotherapy followed by chemoradiotherapy using full dose 5FU without oxaliplatin. Adults with biopsy-proven, newly diagnosed LARC with high-risk characteristics on pelvic MRI (T4a or T4b, extramural vascular invasion, N2, mesorectal fascia involvement, enlargement/tumor deposits on lateral lymph nodes) were included. The TNT protocol comprised of six biweekly courses of modified FOLFOX6 followed by pelvic RT with four concurrent cycles of biweekly 5-FU 2600mg/m2 + LV 200mg/m2 without oxaliplatin to complete 20 uninterrupted weeks of full dose 5FU. Surgery was planned 11-13weeks after completing chemoradiotherapy. Eighty-four LARC patients, including 26% with signet-ring cell carcinoma, with high-risk MRI characteristics were treated with the TNT protocol with a 96% completion rate. Significant (> grade 3) toxicities included neutropenia (23.8%), diarrhea (14.2%) anemia (10.7%), and two deaths. The median DFS at 2years was 22.5months with better survival noted for those who underwent surgery or had cCR (with NOM) compared to those who did not undergo surgery (due to progression, inadequate regression, or patient preference despite residual disease) -mDFS 27.7months versus 11.4months, p = < 0.0001 and mOS 29.2months versus 15months p = < 0.0001. The hybrid TNT regimen was administered without significant dose delays or interruptions. Toxicity was manageable but with two treatment-related deaths. Ability to undergo surgery after TNT predicted for improved DFS and OS.

The feasibility of sequential short-course radiation therapy and chemotherapy in the neoadjuvant treatment of rectal adenocarcinoma: Cases series treated in a Brazilian public health service

Introduction: Total Neoadjuvant Therapy (TNT) is now recognized as the preferred standard for the treatment of locally advanced rectal cancer. With recent progress in surgery, radiotherapy and chemotherapy, management strategies have become more complex but also more refined, in order to adapt to each situation

Short-term outcomes of a prospective multicenter phase II trial of total neoadjuvant therapy for locally advanced rectal cancer in Japan (ENSEMBLE-1).

To evaluate the feasibility and safety of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC) in Japan. This prospective, multicenter, open-label, single-arm phase II trial was conducted at five institutions. The key eligibility criteria were age ≥ 20 years, LARC within 12 cm from the anal verge, and cT3-4N0M0 or TanyN+M0 at the time of diagnosis that enabled curative resection. Preoperative short-course radiation therapy (SCRT) 5 Gy × 5 days (total 25 Gy) + CAPOX (six courses) followed by total mesorectum excision (TME) was the treatment protocol. Non-operative management (NOM) was allowed if clinical complete response (cCR) was obtained in the preoperative evaluation. The primary endpoint was the pathological complete response (pCR) rate. Thirty patients (male, n = 26; female, n = 4; median age, 62.5 [44-74] years; cT [T2, n = 1; T3, n = 25; T4, n = 4]; cN [N0, n = 13; N1, n = 13; N2, n = 4]) were enrolled. The final analysis included 30 patients in total. The completion rates were 100% for SCRT and 83% for CAPOX. TME and NOM were performed in 20 and seven patients, respectively. pCR was observed in six patients (30% [95% CI 14.0%-50.8%]). The primary endpoint was met. pCR+cCR was observed in 13 (43.3%) patients. There were no treatment-related deaths. Grade ≥3 (CTCAE ver. 5.0) adverse events (≥20%), including diarrhea (23.3%) and neutropenia (23.3%). The median follow-up period was 15.6 (10.5-22.8) months, with no recurrence or regrowth in NOM. ENSEMBLE-1 demonstrated satisfactory pCR and cCR, and well-tolerated safety of TNT for patients with LARC in Japan.

Management of rectal cancer in the era of total neoadjuvant therapy and watch and wait: A multidisciplinary team discussion at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting 2022.

Rectal cancer is a common malignancy. The management of rectal cancer has recently evolved and has undergone a paradigm shift with the advent of treatment approaches such as total neoadjuvant therapy and the watch-and-wait approach. However, despite the recently available evidence, there is no consensus on the optimal management approach in the setting of locally advanced rectal cancer. To address some of the controversies, a joint multidisciplinary panel discussion was conducted at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting in November 2022. Members from different subspecialties formed two panels and discussed three clinical cases in a debate format. Each case represented some of the complex issues faced by clinicians in this setting. The discussion is now presented in this manuscript, which depicts the different available management approaches and reiterates the importance of a multidisciplinary approach.

ShorTrip Trial: A Prospective, Multicentric Phase II Single-Arm Trial of Short-Course Radiotherapy Followed by Intensified Consolidation Chemotherapy With the Triplet FOLFOXIRI as Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer

BackgroundIn patients with locally advanced rectal cancer (LARC) treated with preoperative (chemo) radiotherapy and surgery, adjuvant chemotherapy is poorly feasible and its benefit is questionable. In the last years, several total neoadjuvant treatment (TNT) strategies, moving the adjuvant chemotherapy to the neoadjuvant setting, have been investigated with the aim of improving compliance to systemic chemotherapy, treating micrometastases earlier and then reducing distant recurrence. Patients and MethodsShorTrip (NTC05253846) is a prospective, multicentre, single-arm phase II trial where 63 patients with LARC will be treated with short-course radiotherapy followed by intensified consolidation chemotherapy with FOLFOXIRI regimen and surgery. Primary endpoint is pCR. Among the first 11 patients who started consolidation chemotherapy, a preliminary safety analysis showed a high rate of grade 3 to 4 neutropenia (N = 7, 64%) during the first cycle of FOLFOXIRI. Therefore, the protocol has been emended with the recommendation to omit irinotecan during the first cycle of consolidation chemotherapy. After amendment, in a subsequent safety analysis focused on the first 9 patients treated with FOLFOX as first cycle and then with FOLFOXIRI, grade 3 to 4 neutropenia was reported in only one case during the second cycle. Aim of the studyThe aim of this study is to assess the safety and activity of a TNT strategy including SCRT, intensified consolidation treatment with FOLFOXIRI and delayed surgery. After protocol amendment, the treatment seems feasible without safety concern. Results are expected at the end of 2024.

Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: 7-year results of PRODIGE 23 phase III trial, a UNICANCER GI trial.

LBA3504 Background: We have reported that neoadjuvant chemotherapy (NACT) with FOLFIRINOX followed by chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ACT) significantly improved outcomes in patients (pts) with locally advanced rectal cancer (LARC) compared with pts who received standard CRT, surgery, and ACT. We now report the primary and secondary endpoints with mature follow-up (F/U). Methods: PRODIGE 23 is a phase III randomized clinical trial. Eligible pts had cT3 or cT4, M0 rectal adenocarcinomas &lt;15 cm from the anal verge, age 18-75 years, and WHO PS ≤1. Randomization was stratified by center, T stage, N status, T location, and T extramural spread. Arm A pts received preoperative CRT (50 Gy, 2 Gy/fr; 25 fr + capecitabine), surgery, then ACT for 6 months (mos). Arm B pts received 6 cycles of mFOLFIRINOX, then the same preoperative CRT, surgery and 3 mos of ACT, mFOLFOX6 or capecitabine. From 6/2012 to 6/2017, pts were randomly assigned in Arm A (n=230) and B (n=231) by 35 participating centers. Analysis was performed on intent-to-treat population. For survival outcomes, HR and 95% CI were estimated by a stratified Cox proportional hazard (PH) model. However, we observed non-PH. So we used the restricted mean survival time (RMST) to evaluate the treatment effect (Liang F &amp; al Ann Oncol 2018, Pak K &amp; al JAMA Oncol 2017). Results: With a median F/U of 82.2 mos, death was reported for 55 pts in arm A and 42 in Arm B. All survival endpoints were better for Arm B vs Arm A. The absolute increase in 5-year survival were 7.6% for Disease-Free Survival (DFS), 6.9% for Overall Survival (OS), 9.9% for Metastasis-Free Survival (MFS), and 5.7% for Cancer Specific Survival (CSS) in Arm B compared to Arm A. Survival results at 7 years are presented in the Table. 7-year cumulative incidence of locoregional relapses are 5.3% in arm B vs 8.1% in arm A (p= 0.38). Conclusions: NACT with mFOLFIRINOX followed by CRT, surgery, and ACT significantly improved all outcomes, including OS in pts with LARC vs those who received standard CRT, surgery, and ACT. Clinical trial information: NCT01804790 . [Table: see text]

Total neoadjuvant therapy for locally advanced rectal cancer: A western Australian experience.

e15582 Background: Despite the widespread application of standard chemoradiotherapy (CRT) followed by total mesorectal excision with adjuvant chemotherapy, the mortality reduction for locally advanced rectal cancer (LARC) has slowed in recent years. Total neoadjuvant therapy (TNT) is a novel therapeutic strategy in LARC which incorporates both systemic chemotherapy and neoadjuvant CRT prior to surgery. Recent studies have associated TNT with better treatment adherence, decreased toxicity, improved complete clinical response and anal sphincter preservation rates. However, real-world experience with TNT in the management of LARC remains limited. Methods: Records from patents with LARC who underwent TNT at two oncology centres in Western Australia since 2018 were screened. Patient demographics, diagnostic workup, treatment regimens, surgical, pathological reports, post-operative surveillance scans and adverse effects’ documentation were reviewed. TNT regimens included neoadjuvant chemotherapy (NAC) with oxaliplatin in combination with either 5-FU (FOLFOX) or capecitabine (CAPOX) with chemoradiation given prior or after NAC, which is then followed by surgery. Patients who had radiological complete response (rCR) were given the option of “watch and wait (W&amp;W)” instead of proceeding to surgery. Outcomes assessed included radiological complete response (rCR), pathological complete response (pCR) rate, proportion of patients with progressive disease, type of surgery, rate of R0 resection, proportion of patients who completed planned cycles of chemotherapy and radiotherapy and treatment-related adverse effects. Results: 29 patients with LARC have thus far have completed TNT followed by surgery. The mean age was 59 years (range 34-84), 58% and 42% of patients were male and female respectively. 11 (38%), 16 (55%) and 2 (7%) patients were ECOG 0, 1 and 2 respectively. The majority of patients were stage 3 (90%), with the remaining 3 patients at stage 1, 2 and 4 at time of presentation. 3 (10%) and 7 (24%) patients had pCR and rCR respectively, of which 4 opted for W&amp;W approach. Treatment was well-tolerated with 86% and 96% of patients completing the planned total course of chemotherapy and radiotherapy respectively although dose reductions and/or delay were required for many. Common adverse effects included neuropathy, neutropenia, anaemia and fatigue, most of which were grade 1. Of the 22 patients who underwent surgery, 19 (82%) and 4 (18%) patients had R0 resection and R1 resection respectively. Majority of the patients who underwent surgery had an anterior resection with temporary loop ileostomy (64%) while the remaining had an abdominoperineal resection (36%). After a median follow up time of 27 months, 10 (34%) patients had progressive disease. Conclusions: TNT is a well-tolerated, effective and promising strategy for the management of LARC. Further data is needed to determine the standard TNT protocol.

Perioperative versus total neoadjuvant chemotherapy in gastric cancer.

Perioperative chemotherapy is standard of care management for locally advanced gastric cancer (GC), but a substantial proportion of patients do not complete adjuvant therapy due to postoperative complications and prolonged recovery. Administration of all chemotherapy prior to surgery in the form of total neoadjuvant therapy (TNT) may optimize complete delivery of systemic therapy. We performed a retrospective review of GC patients who had surgery at Memorial Sloan Kettering Cancer Center (MSKCC) from May 2014 to June 2020. One hundred and forty-nine patients were identified; 121 patients received perioperative chemotherapy and 28 patients received TNT. TNT was chosen if patients had interim radiographic and/or clinical response to treatment. Baseline characteristics were well-balanced between the two group except for chemotherapy regimen; more TNT patients received FLOT compared to the perioperative group (79% vs. 31%). There was no difference in the proportion of patients who completed all planned cycles, but TNT patients received a higher proportion of cycles containing all chemotherapy drugs (93% vs. 74%, P<0.001). Twenty-nine patients (24%) in the perioperative group did not receive intended adjuvant therapy. There was no significant difference in hospital length of stay or surgical morbidity. The overall distribution of pathologic stage was similar between the two groups. Fourteen percent of TNT patients and 5.8% of perioperative patients achieved a pathologic complete response (P=0.6). There was no significant difference in recurrence free survival (RFS) or overall survival (OS) between the TNT and perioperative groups [24-month OS rate 77% vs. 85%, HR 1.69 (95% CI: 0.80-3.56)]. Our study was limited by a small TNT sample size and biases inherent to a retrospective analysis. TNT appears to be feasible in a select population, without any increase in surgical morbidity.

Clinical outcomes of patients who underwent total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC): A single center experience.

e15630 Background: Total neoadjuvant therapy (TNT) has been mainstay of treatment for locally advanced rectal cancer (LARC), with a primary purpose of eradicating minimal residual disease, preserving the rectum, and achieving pathological complete response (pCR). Currently, there lacks consensus on chemotherapy regimen, sequencing, and modality of radiation therapy. The objective of this real-world retrospective analysis is to describe various TNT strategies employed and report patient centered outcomes. Developing a standard protocol based on available evidence and institutional retrospective data is crucial to reduce care variations. Methods: From January 2019 to January 2023, 61 patients with locally advanced rectal cancer were initiated on TNT. Patients were included regardless of whether they received treatment at our academic center or private practice. Retrospective chart review was performed to collect demographic data, chemotherapy regimens, toxicities, dose interruption, dose reduction, timeline of treatment, response rate as well as surgical intervention. Data cutoff was set to 3 years after TNT completion. Combined MRI and flexible sigmoidoscopy were used to evaluate final response. Results: Average age at diagnosis was 59 years old. Majority of patients were stage IIIB (52%), had low rectal disease (51%), received chemotherapy followed by long-course concurrent chemoradiation (80%) and had chemotherapy in an academic center (65%). Complete clinical response (cCR) rate was 36% in the overall cohort. Four out of 22 patients with cCR underwent surgery and the rest were initiated on watch and wait strategy, among these, only one patient had local recurrence requiring surgery. Among all the patients who had surgery, pCR rate was 15.6%. No difference existed in cCR between CAPOX and FOLFOX groups (34.5% vs 33%), however, grade 3/4 toxicities (27% vs 14%), dose reduction (17% vs 7%), dose interruption (11% vs 6%) and hospitalization (6% vs 0%) rates were higher in patients who received CAPOX. Of note, 7 patients received FOLFIRINOX. In this group, disease stage ranged from 2A to oligometastatic stage IV; however, over 50% obtained a cCR with comparable or better toxicity profile. Conclusions: Despite wide range of variations observed in treatment approaches to TNT across the organization and local institutions, organ preservation and complete clinical response rates were observed at the same rate of 1 out of 3 patients. In those patients who pursued surgical intervention, the pCR was lower than expected from trials. Patients who received FOLFOX tolerated treatment better with the same clinical response rate as CAPOX. Greater numbers will be required to determine response rate and superiority of FOLFIRINOX compared to doublet therapy. Further process standardization would likely improve patient outcomes with LARC receiving TNT.

Total neoadjuvant treatment without surgery for locally advanced rectal cancer: Prospective study to assess tumor response, circulating genetic, and epigenetic biomarkers, and stromal transcriptome to interpret clinical outcome (NO-CUT trial).

TPS3633 Background: Total neoadjuvant therapy (TNT) has recently become a standard therapy for locally advanced rectal cancer (LARC). All nonsurgical interventions, including chemotherapy and concurrent chemoradiotherapy (CRT), are administered before either surgical resection of the rectum or non-operative management (NOM), depending on response to TNT. In the case of NOM, the impact of distant relapse on survival remains to be elucidated and circulating tumor DNA (ctDNA) monitoring has been proposed as a tool for early detection of relapse. Furthermore, predictive biomarkers of response to TNT are warranted for the early identification of patient candidates for NOM. In this regard, stromal contribution to sensitivity to pre-operative CRT is investigated by a transcriptomic signature on baseline tumor samples, as previously proposed by Isella C et al., Nature Genet, 2015. Methods: NO-CUT is a multicenter one-stage phase II trial aimed at assessing if a TNT approach with CAPOX followed by CRT can safely spare demolitive surgery in patients with LARC achieving a clinical complete response without increasing the risk of distant metastatic relapse. A Brookmeyer and Crowley approach was chosen to test the null hypothesis that the true distant relapse-free survival at 2.5 years rate is ≤75% against a one-sided alternative. The NOM cohort of the trial needs to accrue 44 evaluable patients and to be followed for at least 2.5 years. Such design yields a type I error rate of 10% and power of 80% when the true 2.5 years distant RFS proportion is 87%. Since it is assumed that the proportion of patients entering in the NOM cohort of the trial is at least 25%, a total of 180 patients are to be enrolled in NO-CUT study. Patients with medium-low LARC undergo TNT (4 cycles of CAPOX: capecitabine 1000 mg/m2 bid days 1-14 q 3 weeks; oxaliplatin 130 mg/m2 day 1 q 3 weeks) and 5 weeks of standard pelvic CT-RT, then restaging with imaging (MRI, CT-scan, and ultrasound endoscopy), and tumor biopsy. According to an algorithm defined for assessing tumor response, patients enter either NOM or surgery cohorts. During the follow-up phase of the trial, the NOM cohort is followed with intensive pelvic imaging and periodic blood samplings for 5 years. Tumor samples and ctDNA are studied at baseline, after TNT, and during follow-up. As of January 2023, 161 of planned 180 patients in 4 centers have been enrolled. Supported by grants from Associazione Italiana Ricerca Cancro (AIRC IG 2017-20685) and Fondazione Oncologia Niguarda. Clinical trial information: EudraCT 2017-003671-60 .

Sustained organ preservation in patients with rectal cancer treated with total neoadjuvant therapy: Long-term results of the OPRA trial.

3520 Background: The preliminary results of the OPRA trial demonstrated that a substantial number of patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT) could achieve organ preservation. Although most tumor regrowths seem to occur within the first 3 years, longer follow-up is needed to assess the ongoing risk of regrowth. Here, we report the long-term organ preservation rate and oncologic outcomes of the OPRA trial. Methods: A prospective, multi-institutional phase II trial, in which patients with stage II or III rectal cancer were randomized to receive either induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients underwent reassessment for treatment response 8-12 weeks after TNT. Patients who achieved a complete or near-complete response after finishing TNT were offered a watch and wait approach (WW). Those with incomplete response were recommended total mesorectal excision (TME). We report 5-year disease-free survival (DFS), organ preservation (defined as TME-free survival), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS) for each treatment group. We also compared DFS between patients who underwent upfront TME after restaging and patients who underwent TME after tumor regrowth. All analyses followed the intention-to-treat principle and groups were compared using the log-rank test. Results: Of the 324 patients randomized, 158 were assigned to the INCT-CRT group and 166 to the CRT-CNCT group. Median follow-up was 56 months; 85 DFS events were observed. The rates of 3- and 5-year DFS, TME-free survival, LRFS, DMFS and OS are listed in the Table. In total, 80 of the 225 (36%) patients who started WW developed a regrowth; 94% occurred within 2 years and 99% occurred within 3 years. The rate of TME-free survival at 5 years was significantly higher for CRT-CNCT (54%) than in INCT-CRT (39%). 5-year DFS was similar for patients who underwent TME after restaging (61%) compared to patients who underwent TME after regrowth (62%, p = 0.86). Conclusions: In patients with rectal cancer treated with TNT and WW, the majority of tumor regrowths occur in the first 2 years, and regrowth after 3 years is vanishingly rare. Salvage TME for tumor regrowth during WW appears to offer similar outcome to immediate TME after incomplete response to TNT. Distant metastases remain the most frequent cause of treatment failure, with similar rates in the two treatment groups. Clinical trial information: NCT02008656 . [Table: see text]

Organ preservation and total neoadjuvant therapy for rectal cancer: Investigating long course chemoradiation versus short course radiation therapy.

3617 Background: The efficacy of long course chemoradiation (LCRT) vs. short course radiation therapy (SCRT) relative to organ preservation (OP) in rectal cancer (RC) is unknown. We compared OP rates between SCRT and LCRT total neoadjuvant therapy (TNT) strategies. Methods: During the COVID-19 pandemic we established an institutional SCRT mandate with no exceptions. For comparison, we identified RC patients treated with LCRT immediately before and after the mandate period. After completion of TNT, patients were restaged by clinical exam, endoscopy, and MRI. A watch and wait (WW) approach was recommended for patients with a clinical complete response (cCR), defined by the MSK regression schema. Total mesorectal excision (TME) was recommended for non-cCR patients. OP was defined as remaining TME-free with no evidence of disease in the pelvis. We performed survival analysis for: local regrowth rate, OP, disease-free survival (DFS), and overall survival (OS). The validated low anterior resection syndrome (LARS) questionnaire (LARS-Q) was used to determine percentage of patients with major LARS. Results: We identified 332 consecutive patients with non-metastatic rectal adenocarcinoma treated with TNT (Jan. 2018-Jan. 2021). Patient and tumor characteristics were similar in the LCRT (n = 256) and SCRT (n = 76) cohorts. No significant differences in high-risk features were noted. Most patients had clinical stage III disease (82% in LCRT vs. 83% in SCRT). Induction chemotherapy followed by consolidative radiation was the most common treatment order (78% (LCRT) vs. 70% (SCRT)). The median interval from end of TNT to clinical restaging was 8 weeks (LCRT) and 9 weeks (SCRT). The cCR rate was 46% in both cohorts. Among patients with a cCR, the likelihood of WW management was similar (98% (LCRT) vs. 94% (SCRT)). From start of TNT, the median follow-up was 32 and 28 months respectively for LCRT and SCRT. The 2-year OS (95% vs. 92%), DFS (78% vs 70%), and distant recurrence (20% vs. 21%) rates were similar. Among all patients, the 2-year OP rate was 40% (95% CI 35-47%) for LCRT and 29% (95% CI 20-42%) with SCRT. In those patients managed by WW, the 2-year local regrowth rate was 20% (95% CI 12-27%) with LCRT vs. 36% (95% CI 16-52%) with SCRT. Percentage of patients reporting major LARS symptoms were similar among WW patients post TNT: baseline (23% (LCRT) vs. 18% (SCRT)), 6-months (41% (LCRT) vs. 42% (SCRT)), and 12-months (25% (LCRT) vs. 15% (SCRT)). Conclusions: In this nonrandomized comparison, while cCR rates were similar, we observed a numerically higher local regrowth rate with SCRT-TNT than with LCRT-TNT. Rate of major-LARS symptoms were similar with LCRT-TNT than with SCRT-TNT. The ongoing ACO/ARO/AIO-18.1 trial, hypothesizing that LCRT-TNT will increase OP rates relative to SCRT-TNT, will definitively address this question.

Neoadjuvant chemotherapy (NAC) followed by total mesorectal excision (TME) and adjuvant chemotherapy versus TME followed by adjuvant chemotherapy in very low-lying clinical (c) T3 rectal cancer (NAIR): A multicenter, randomized, open-label, phase 2/3 trial.

3519 Background: Chemoradiotherapy and total neoadjuvant therapy are the standard treatments for locally advanced rectal cancer (LARC). Although radiotherapy (RT) is an integral part of treatment, it negatively impacts anal function after TME for cases of very low-lying LARCs. This trial examined the efficacy, safety, and influence on postoperative anal function of NAC without RT in patients (pts) with very low-lying cT3 LARCs. Methods: Pts with cT3N0-2M0 adenocarcinomas located within 5 cm from the anal verge, whose anuses were expected to be preserved, were randomly assigned (1:1) to either the NAC group (preoperative chemotherapy with six cycles of mFOLFOX6 or four cycles of CAPOX followed by TME; then, postoperative identical regimen) or the TME group (upfront TME followed by postoperative chemotherapy with 12 cycles of mFOLFOX6 or 8 cycles of CAPOX), stratified by cN stage, center, and sex. The primary endpoint was the 3-year recurrence-free survival (RFS), which was compared between groups using a stratified log-rank test at a one-sided alpha level of 20%. Results: Between February 2013 and March 2019, 130 pts were enrolled and randomly assigned to a treatment group. A total of 127 pts were evaluable (65 in the NAC group and 62 in the TME group). All but one patient with early progression completed preoperative chemotherapy in the NAC group, and all pts in both groups underwent TME. After a median follow-up of 37.4 months (IQR 36.5-40.5), the 3-year RFS was 75.5% (95% CI 62.5-84.5) in the NAC group vs. 70.9% (95%CI 57.2-80.9) in the TME group (hazard ratio 0.67, 95% CI 0.34-1.32; P = 0.098), and the primary endpoint was met. There were no differences in the occurrence of grade 3 or higher postoperative complications (20% in the NAC group vs. 21% in the TME group [P = 1.000]), chemo-associated grade 3 or higher adverse events (28% in the NAC group vs. 23% in the TME group [P = 0.551]), or any grade of peripheral sensory neuropathy lasting for 3 years (22.7% in the NAC group vs. 38.5% in the TME group in pts treated with mFOLFOX6 [P = 0.3163], 7.1% in the NAC group vs. 33.3% in the TME group in pts treated with CAPOX [P = 0.1038]), between the groups. No treatment-related deaths occurred in either of the groups. At 3 years after randomization, 61 pts in the NAC group (93.8%) and 52 pts in the TME group (83.9%) could defecate via their anuses (P = 0.092). The median Wexner incontinence score was 11.0 in the NAC group and 10.0 in the TME group (P = 0.3405). Conclusions: For pts with very low-lying cT3 LARC, NAC followed by TME and adjuvant chemotherapy achieved significantly better RFS and anus-preserving rates compared to upfront TME followed by adjuvant chemotherapy, without deteriorating postoperative complications or postoperative anal function. Clinical trial information: UMIN000009510 .

New Opportunities for Minimizing Toxicity in Rectal Cancer Management.

Advances in multimodal management of locally advanced rectal cancer (LARC), consisting of preoperative chemotherapy and/or radiotherapy followed by surgery with or without adjuvant chemotherapy, have improved local disease control and patient survival but are associated with significant risk for acute and long-term morbidity. Recently published trials, evaluating treatment dose intensification via the addition of preoperative induction or consolidation chemotherapy (total neoadjuvant therapy [TNT]), have demonstrated improved tumor response rates while maintaining acceptable toxicity. In addition, TNT has led to an increased number of patients achieving a clinical complete response and thus eligible to pursue a nonoperative, organ-preserving, watch and wait approach, thereby avoiding toxicities associated with surgery, such as bowel dysfunction and stoma-related complications. Ongoing trials using immune checkpoint inhibitors in patients with mismatch repair-deficient tumors suggest that this subgroup of patients with LARC could potentially be treated with immunotherapy alone, sparing them the toxicity associated with preoperative treatment and surgery. However, the majority of rectal cancers are mismatch repair-proficient and less responsive to immune checkpoint inhibitors and require multimodal management. The synergy noted in preclinical studies between immunotherapy and radiotherapy on immunogenic tumor cell death has led to the design of ongoing clinical trials that explore the benefit of combining radiotherapy, chemotherapy, and immunotherapy (mainly of immune checkpoint inhibitors) and aim to increase the number of patients eligible for organ preservation.

Alliance A022104/NRG-GI010: A randomized phase II trial testing the efficacy of triplet versus doublet chemotherapy to achieve clinical complete response in patients with locally advanced rectal cancer—The Janus Rectal Cancer trial.

TPS3640 Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients (pts) with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated it as a primary endpoint. Collaborating with a multidisciplinary oncology team and pt groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation and improve quality of life for pts. Methods: In this Alliance for Clinical Trials in Oncology randomized phase II trial (1:1), up to 312 pts with microsatellite stable LARC, clinical stage T4N0, any T, N+ or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Pts will be randomized to receive neoadjuvant long course CRT (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks (w) + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Pts will undergo assessment 8-12 w post-TNT completion for the primary endpoint of cCR per previously validated criteria and recommended WW and surveillance if cCR is achieved or TME if an incomplete response is noted. Secondary objectives include time-to event outcomes (disease-free and overall survival, organ preservation time and time to distant metastasis) and adverse effects. Statistical power, based on cCR, incorporates a one-sided alpha = 0.048 and power = 90% yielding 312 patients (156 per arm). Biospecimens including archival tumor tissue, matched / normal blood samples and serial rectal MRI will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and is actively recruiting. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . U10CA180868 (NRG); U10CA180888 (SWOG); Clinicaltrials.gov ID: NCT05610163 Clinical trial information: NCT05610163 .

P-65 The role of total neoadjuvant therapy (TNT) in elderly patients with locally advanced rectal cancer: A mono-institutional retrospective study

P-65 The role of total neoadjuvant therapy (TNT) in elderly patients with locally advanced rectal cancer: A mono-institutional retrospective study

P-139 Total neoadjuvant therapy for locally advanced rectal cancer: A UK cohort

P-139 Total neoadjuvant therapy for locally advanced rectal cancer: A UK cohort

P-66 Retrospective analysis of the use of total neoadjuvant therapy in high-risk locally advanced rectal cancer in a single institution

P-66 Retrospective analysis of the use of total neoadjuvant therapy in high-risk locally advanced rectal cancer in a single institution

Is there an increase in elective utilization of non-operative management for rectal cancer?

e15533 Background: There is growing evidence for the efficacy of a watch-and-wait or nonoperative management (NOM) strategy following chemoradiation with or without total neoadjuvant therapy for rectal cancer as an approach to organ preservation. Consequently, there has been growing interest and acceptance of this approach among both patients and providers. This study aims to analyze the use of the NOM strategy for patients with non-metastatic rectal cancer over the past decade and the patient and facility-level factors associated with its utilization. Methods: We performed an observational cohort study identifying patients from the National Cancer Database diagnosed between 2010-2020 with invasive, non-metastatic rectal adenocarcinoma. Patients who received chemotherapy and radiation without surgery were categorized as having received NOM. All other patients who received curative-intent surgery with or without chemotherapy and radiation were classified as the standard of care (SOC) cohort. Utilization of NOM was analyzed over time. Logistic regression analysis was utilized to identify patient and facility-level factors associated with NOM. Results: In total, 107,786 patients were included for analysis, of which 14,870 (13.8%) received NOM over the study period and 92,916 (86.2%) received SOC. The use of NOM steadily increased over the study period, from 10.3% in 2010 to 20.7% in 2020. Compared to SOC, NOM was associated with patients who were Black (16.9% vs 13.6% White, p &lt; 0.001), had Medicaid or no insurance (15.3% vs 13.4% Private/Medicare insurance, p &lt; 0.001), were older than 75 years (18.9% vs 12.8% younger than 75, p &lt; 0.001), and had high Charlson-Deyo comorbidity score (16.2% vs 14.0% no comorbidities, p &lt; 0.001). Facility factors associated with greater use of NOM included treatment at community cancer programs (OR 1.44, 95% CI 1.35-1.54, p &lt; 0.001) compared to treatment at comprehensive cancer centers. Facilities stratified by incident rectal cancer patient volume demonstrated an inverse relationship with NOM management, with low volume institutions having the highest NOM rate (p &lt; 0.001). Subgroup analysis of patients &lt; 75 years old, with private insurance, and without co-morbidities treated at institutions in the top quartile of volume showed NOM rates to similarly increase over the study period, from 6.4% to 13.7% (p &lt; 0.001). Conclusions: The use of the NOM strategy for patients with non-metastatic rectal cancer has increased over the past decade. While traditionally an approach for patients who were poor surgical candidates, the increasing trend for NOM among younger patients with fewer comorbidities and private insurance suggests that there is growing interest in elective NOM over the past decade. Ongoing prospective studies of NOM will shed light regarding the long-term efficacy of this approach compared to traditional surgical SOC.