Use of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer

Abstract

IMPORTANCETotal neoadjuvant therapy (TNT) is often used to downstage locally advanced rectal cancer (LARC) and decrease locoregional relapse; however, more than one-third of patients develop recurrent metastatic disease. As such, novel combinations are needed.OBJECTIVE To assess whether the addition of pembrolizumab during and after neoadjuvant chemoradiotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score compared with treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and chemoradiotherapy alone. DESIGN, SETTING, AND PARTICIPANTSIn this open-label, phase 2, randomized clinical trial (NRG-GI002), patients in academic and private practice settings were enrolled. Patients with stage II/III LARC with distal location (cT3-4 Յ 5 cm from anal verge, any N), with bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), at high risk for metastatic disease (cN2), and/or who were not candidates for sphincter-sparing surgery (SSS) were stratified based on clinical tumor and nodal stages. Trial accrual opened on August 1, 2018, and ended on May 31, 2019. This intent-to-treat analysis is based on data as of August 2020.INTERVENTIONS Patients were randomized (1:1) to neoadjuvant FOLFOX for 4 months and then underwent chemoradiotherapy (capecitabine with 50.4 Gy) with or without intravenous pembrolizumab administered at a dosage of 200 mg every 3 weeks for up to 6 doses before surgery. MAIN OUTCOMES AND MEASURESThe primary end point was the NAR score. Secondary end points included pathologic complete response (pCR) rate, SSS, disease-free survival, and overall survival. This report focuses on end points available after definitive surgery (NAR score, pCR, SSS, clinical complete response rate, margin involvement, and safety).RESULTS A total of 185 patients (126 [68.1%] male; mean [SD] age, 55.7 [11.1] years) were randomized to the control arm (CA) (n = 95) or the pembrolizumab arm (PA) (n = 90). Of these patients, 137 were evaluable for NAR score (68 CA patients and 69 PA patients). The mean (SD) NAR score was 11.53 (12.43) for the PA patients (95% CI, 8.54-14.51) vs 14.08 (13.82) for the CA patients (95% CI, 10.74-17.43) (P = .26). The pCR rate was 31.9% in the PA vs 29.4% in the CA (P = .75). The clinical complete response rate was 13.9% in the PA vs 13.6% in the CA (P = .95). The percentage of patients who underwent SSS was 59.4% in the PA vs 71.0% in the CA (P = .15). Grade 3 to 4 adverse events were slightly increased in the PA (48.2%) vs the CA (37.3%) during chemoradiotherapy. Two deaths occurred during FOLFOX: sepsis (CA) and pneumonia (PA). No differences in radiotherapy fractions, FOLFOX, or capecitabine doses were found.CONCLUSIONS AND RELEVANCE Pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was suggested to be safe; however, the NAR score difference does not support further study.

MRI‐detected extramural vascular invasion (mrEMVI) as the best predictive factor to identify candidates to total neoadjuvant therapy in locally advanced rectal cancer

“…These schemes are now being considered as a valid alternative to the classic neoadjuvant chemoradiation strategy in the most recently published guidelines and will progressively enter into routine clinical practice. Promising preliminary data of other ongoing TNT studies are indicative of a paradigm change, that may move the systemic therapy in the preoperative phase in future years 9,10 …”

“…11,12 The recently published long-term results of the 33 and the PRODIGE 23 34 in the preoperative phase in future years. 9,10 Thus, reliable predictors of systemic progression other than and before knowing the final pathologic report are strongly needed.…”

“…These could represent an undue delay in the control of the systemic disease. To overcome these therapeutic drawbacks, the anticipation of chemotherapy in a preoperative setting (total neoadjuvant therapy [TNT]) is currently being investigated in several trials 9–13 …”

“…To overcome these therapeutic drawbacks, the anticipation of chemotherapy in a preoperative setting (total neoadjuvant therapy [TNT]) is currently being investigated in several trials. [9][10][11][12][13] The transition of chemotherapy into the preoperative phase requires robust predictive factors to guide patient selection. Among the predictors of distant recurrence, extramural vascular invasion (EMVI) detected by preoperative MRI is emerging as one of the most accurate.…”

Efficacy and safety of different radiotherapy doses in neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: A retrospective study

“…Notably, outcomes of nCRT vary widely among LARC patients, with more than one-third of patients experiencing recurrent or metastatic diseases ( 12 ). Moreover, some patients can achieve pathological complete remission (pCR) while others barely respond to nCRT.…”