Abstract
Subject terms: Gastrointestinal cancer, Gastrointestinal cancer, Translational research, Outcomes research, Clinical trials
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Introduction
Rectal cancer is one of the most frequent gastrointestinal malignancies with 253,000 new cases occurred annually in China, accounting for more than 18% worldwide.1 For locally advanced rectal cancer (LARC), which is defined here as T3–4 or N positive (T3-4aN0M0 and T1-4aN1-2M0), neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) was preferred as standard treatment by National Comprehensive Cancer Network (NCCN) guidelines to reduce recurrence rate.2,3 However, only 11–15% of patients could reach pathological complete response (pCR) after neoadjuvant CRT.4,5 LARC patients might benefit from higher pCR rate with fewer complications, higher quality of life, organ preservation, and better oncological prognosis. Consequently, more effective neoadjuvant options against LARC are in the urgent need.
Immune checkpoint inhibitors (ICIs), including programmed cell death ligand 1 (PD-L1), programmed cell death 1 (PD-1), and CTL-associated protein 4 (CTLA-4) blockade, have been proven effective in various solid tumors.6,7 ICIs were proven with excellent clinical benefits in locally advanced colorectal cancers (CRCs) of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) type, which could achieve 75%-100% complete response after neoadjuvant immunotherapy.8,9 Unfortunately, MSI-H/dMMR prevalence has been reported with a gradual decrease in its distribution from the proximal colon to the rectum and even less than 5% in LARC.10,11 Unsatisfactory efficacies of ICIs were reported in the subtype of microsatellite stable (MSS) / mismatch repair-proficient (pMMR) CRCs.12,13 Thus, various improved and collaborative therapeutic trials were carried out to solve this problem of immunotherapies in recent years.14–16
Meanwhile, various clinical studies reported that combinations of ICIs with radiotherapy have superior antitumor efficacies and higher response rates.17,18 Radiotherapy could reinvigorate exhausted T cells, modulate tumor-associated macrophages (TAMs), inhibit M2 polarization, and reduce tumor burden to affect the therapeutic sensitivity of ICIs like PD-1/PD-L1 inhibitors.19–21 As for LARC, the VOLTAGE-A study from Japan reported mild toxicities and a 30% (11/37) pCR rate after treatment with preoperative CRT and the subsequent five cycles of nivolumab in LARC.22 Another single-arm trial reported 48.1% (13/27) pCR rate with 96.7% (29/30) treatment-related adverse events (TRAEs) rate using the scheme of short-course radiotherapy (25 Gy/5 f, 5 Gy/f, 5 days), followed by two subsequent 21-day cycles of CAPOX (capecitabine day 1–14 and oxaliplatin day 1) plus camrelizumab (day 1).23 The only reported randomized controlled trial in 2021 using FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) followed by CRT plus pembrolizumab yielded negative results.12 The primary endpoint of mean NAR score was 11.53 vs 14.08 (p = 0.26) in the pembrolizumab arm compared to the control arm, while pCR rate was 31.9% (22/69) vs 29.4% (20/68).
However, previous studies did not focus on ICIs plus concomitant and sequential CRT as the neoadjuvant scheme. Additionally, both subtypes of MSI-H/dMMR and MSS/pMMR LARC patients were involved. Taking the consideration above, we reported results from this NECTAR study to identify the safety and efficacy of PD-1 blockades (tislelizumab) plus CRT as neoadjuvant in patients with LARC.24
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Results
Patient characteristics
From June 2021 to November 2022, 60 patients were screened, and 50 patients were enrolled. Detailed schedules and timelines of treatments were shown in Fig. Fig.1.1. These patients were from 6 third-class hospitals in China of Beijing, Tianjin, and Xi’an. The median age was 62 (26 to 79) years, and the median distance from distal border of the tumor to anal verge was 5.4 (0.6–9.7) cm. Meanwhile, 4 (8.0%), 36 (72.0%), and 10 (20.0%) of these patients were T2, T3, T4 stage, while 18 (36.0%), 19 (38.0%), and 13 (26.0%) were N0, N1, N2 stage correspondingly. The detailed characteristics of these 46 patients are shown in Table Table11.
Fig. 1
Study design. Patients with cT3-4N0M0 and cT1-4N1-2M0 received long-course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (850–1000 mg/m2, bid, po, day1–14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by surgery 6–8 weeks after the end of radiotherapy. The primary efficacy endpoint was the pathological complete response (pCR) rate. Blood and tumor samples were collected before and after neoadjuvant for multiplex immunofluorescence and circulating tumor cells analysis
Efficacy and safety
A total of 50 patients were enrolled in this study and 47 patients completed the entire course of neoadjuvant (CRT plus 3 cycles tislelizumab). Among them, one patient achieved clinical complete response according to preoperative evaluation and refused the surgical operation. The remaining 46 patients were undergone further radical surgery to evaluate the primary endpoint, pCR (Fig. (Fig.2).2). All these 46 patients were undergone radical surgery with an R0 resection rate of 100%, sphincter-saving resection rate of 89.1% (41/46), and defunctioning ileostomy rate of 31.7% (13/46). The median time from the end of radiotherapy to surgery was 61 (43 to 84) days (Table (Table2).2). According to the swimmer plot, the pCR rate was 40.0% [20/50, 95% confidence interval (CI): 27.61–53.82%], while 15 (30.0%, 95% CI: 19.1–43.75%), 9(18.0%, 95% CI: 9.77–30.8%, and 2 (4.0%, 95% CI: 1.10–13.46%) patients reached tumor regression grade 1, 2, and 3 according to AJCC standard.25 Interestingly, 21 patients reached ypT0 and 20 of them reached pCR because 1 patient was reported as ypT0N1 through the postoperative pathological evaluation. In addition, 24 (52.2%) patients got low NAR score. In comparison, 18 (39.1%) reached intermediate and 4 (8.7%) reached high (Fig. (Fig.3a).3a). Representative response of tumors according to MRI image, endoscopic, specimen, and pathological image in patients of each TRG grade were shown (Fig. (Fig.3b3b and Supplementary Fig. S1). To ensure the accuracy of the primary endpoint, every TRG 0 patient was further evaluated through cytokeratins (CK) staining. As for clinical efficacy assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, 18 (39.1%) complete response, 18 (39.1%) partial response, and 10 (21.7%) stable disease were observed with no progressive disease (Fig. (Fig.3c).3c). However, only 11 patients reached the uniformity complete response evaluated by pathological and clinical standards (Supplementary Fig. S2). Meanwhile, 35 (76.1%) patients achieved a downstage of the clinical T category, while 28 (60.9%) of the clinical N category after the CRT plus tislelizumab (Fig. (Fig.3d).3d). Additionally, the folate receptor-positive circulating tumor cells (FR+ CTCs) levels significantly decreased after the treatment (Fig. (Fig.3e).3e). The quality of the excised specimen is next evaluated. According to the mesorectum integrity, 26 (56.5%) postoperative specimens could be evaluated as complete. Circumferential resection margins of all specimens were negative, and 95.7% (44/46) of them with vessel invasion (Supplementary Table S1). As of February 2023, no patients experienced recurrence after a median follow-up of 35.5 weeks (3.7 to 87.7).