Preoperative Chemoradiotherapy In Patients Research Articles

Artemis as Predictive Biomarker of Responsiveness to Preoperative Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer.

The aim of this study was to identify Artemis as a predictive biomarker for guiding preoperative chemoradiotherapy in locally advanced rectal cancer. The resection specimens were collected from 50 patients with rectal cancer who underwent preoperative chemoradiotherapy. Artemis expression in biopsy tissues was evaluated using immunohistochemical staining according to the percentage of positively stained cells combined with staining intensity. Among the 50 patients, 36 (72%) had a weakly positive Artemis protein expression, 10 (20%) had a moderately positive expression, and 4 (8%) showed a strongly positive expression. The criteria of magnetic resonance imaging tumor regression grade (mrTRG) and pathological rectal cancer regression grade (RCRG) were used to assess the tumor response to chemoradiotherapy. Correlation analysis shows that there is a significant negative correlation between high Artemis immunoscore and treatment response (r = -0.532, p < 0.001). The results imply that high Artemis expression was associated with poor treatment response. Our study suggested a potential role of Artemis as a predictive biomarker of the tumor response to preoperative chemoradiotherapy in patients with locally advanced rectal cancer.

The efficacy of neoadjuvant chemoradiotherapy in signet ring cell carcinoma of the rectum: a retrospective propensity-score matched study

INTRODUCTION: there is a lack of information chemoradiotherapy (CRT) efficacy in signet ring cell carcinoma of the rectum (SRCCR). The aim of our research was to investigate the efficacy of preoperative CRT in patients with SRCCR.PATIENTS AND METHODS: we conducted a retrospective analysis of medical records from the archive of Research Institute FSBI “N.N. Blokhin Cancer Research Center” of the Ministry of Health of Russia and multicenter registry of the Russian Society of Specialists in Colorectal Cancer (RSSCC) from 2000 to 2020 and included in the study group patients with histologically confirmed primary SRCCR who received preoperative CRT. A control group with rectal adenocarcinoma was created using propensity-score matching from the institutional database 1:1 taking into account sex, age, tumor size, the cT and cN clinical stage. We estimated the rate of Dworak tumor regression grade 3-4, RECIST, 5-year overall survival (OS) and disease-free survival (DFS) rates.RESULTS: the study and control group included 22 patients each. The study group included 11 patients (50%) with cT3 and cT4 clinical stage. 10 (45,5%) patients had cT3 clinical stage and 12 (54,5%) patients had cT4 clinical stage in the control group (p = 0,763). The number of patients with cN1-2 clinical stage was 17 (77,3%) and 16 (72,7%) in the study and control group, respectively (p = 0,728). The rate of Dworak tumor regression grade 3–4 was 40,9% in the group of patients with SRCCR and 45,5% in the group of patients with rectal adenocarcinoma (p = 0,761).When assessed by RECIST scale, 9 (40,9%), 12 (54,5%) and 1 (4,5%) patients with SRCCR had partial tumor response, stabilization and progression, respectively. Partial response was observed in 18 (81,8%) patients and stabilization — in 4 (18,2%) patients with rectal adenocarcinoma (p = 0,018). Median followup was 58,8 months. The 5-year OS was 34% in the SRCCR group and 71,3% in the group with rectal adenocarcinoma (p = 0,024), and the 5-year PFS was 30,2% with SRCCR and 52,2% with adenocarcinoma (p = 0,115).CONCLUSIONS: CRT leads to comparable grade 3–4 tumor regression in SRCCR and rectal adenocarcinoma, but the objective response rate is lower. This histological subtype has significantly lower OS values.

Total neoadjuvant therapy with short-course radiotherapy Versus long-course neoadjuvant chemoradiotherapy in Locally Advanced Rectal cancer, Korean trial (TV-LARK trial): study protocol of a multicentre randomized controlled trial

BackgroundFor locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) may enhance tumour response, reduce recurrence, and improve patient compliance compared to upfront surgery. Recent studies have shown that chemoradiotherapy (CRT) followed by consolidation chemotherapy leads to higher rate of pathologic complete response (pCR) than induction chemotherapy followed by CRT. However, an optimal TNT regimen that maximise the pCR rate and minimise toxicity has not been established. Therefore, the aim of this trial was to investigate whether preoperative short-course radiotherapy followed by chemotherapy with four cycles of CAPOX can double the pCR rate compared to a standard schedule of long-course preoperative CRT in patients with LARC.MethodsThis is a multi-centre, prospective, open label, randomised controlled trial. Patients with clinical primary tumour stage 3 and higher or regional node-involved rectal cancer located within 10 cm from the anal verge were randomly assigned equally to short-course radiotherapy (25 Gy in 5 fractions over 1 week) followed by four cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) (TNT) or CRT (50.4 Gy in 28 fractions over 5 weeks, concurrently with concomitant oral capecitabine 825 mg/m2 twice a day). After preoperative treatment, total mesorectal excision was performed 2–4 weeks in the TNT group and 6–10 weeks in the CRT group, followed by optional additional adjuvant chemotherapy. The primary endpoint is the pCR rate, and secondary endpoints include disease-related treatment failure, quality of life, and cost-effectiveness. Assuming a pCR rate of 28% and 15% in the TNT and CRT groups, respectively, and one-side alpha error rate of 0.025 and power of 80%, 348 patients will be enrolled considering 10% dropout rate.DiscussionThe TV-LARK trial will evaluate the superiority of employed TNT regimen against the standard CRT regimen for patients with LARC. We aimed to identify a TNT regimen that will improve the pCR rate and decrease systemic recurrence in these patients.Trial registrationCris.nih.go.kr ID: KCT0007169 (April 08, 2022). The posted information will be updated as needed to reflect the protocol amendments and study progress.

Is RAPIDO too rapid for rectal cancer?

Is RAPIDO too rapid for rectal cancer?

Toxicity, Disease Control, and Survival Outcomes of Intensified Preoperative Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer: A Single-Institution Study.

The standard treatment regimen of preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) is still controversial. The purpose of this study was to analyze the efficacy and safety of preoperative intensive CRT in our institution. A retrospective data collection and analysis of 181 LARC patients receiving oxaliplatin (85%) of standard doses in capecitabine-based preoperative CRT and two additional cycle of neoadjuvant chemotherapy between the end of concurrent CRT and surgery. The compliance of the preoperative CRT was satisfactory with 99.4%patients completed radiotherapy and 97.19%patients completed all 2 cycles of concurrent chemotherapy. Except for 20 patients diagnosed clinical complete remission (cCR) managed according to watch and wait strategy, 160 patients received R0 radical surgery. The pathological complete response (pCR) rate was 23.75% (38/160) and tumor regression grade (TRG) 0/1 was 40% (72/180). In terms of tumor downstaging, 89 (55.63%) had T downstaging while 115 (71.88%) had N downstaging. The 1-overall survival (OS),2-OS,3-OS and 5-OS were 98.7%, 96.5%, 91.4% and 81.5%, respectively. The total rate of sphincter preservation was 86.25% (138/160) and the rate of patients with low rectal cancer was 73.0% (54/74) without affecting local control rates and survival rates. Both acute adverse reactions to preoperative CRT and postoperative complications were tolerable and controllable. In this retrospective study, preoperative intensive CRT of patients with LARC achieved satisfied disease control and survival outcomes and well acquired the sphincter retention rate in recent years in our institution. On the basis of these findings, a Phase III study to definitively test the intensified preoperative CRT strategy is warranted.

Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER PRODIGE 23): Health-related quality of life longitudinal analysis

BackgroundResults from the phase 3 PRODIGE 23 study showed that neoadjuvant chemotherapy (NAC) with mFOLFIRINOX and preoperative chemoradiotherapy improved disease-free survival compared with preoperative chemoradiotherapy in patients with locally advanced rectal cancer. We aimed to assess the health-related quality of life (HRQOL) outcomes from this study. Patients and methodsA total of 461 patients (231 versus 230 patients) from 35 French hospitals were randomly assigned to either NAC with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, fluorouracil 2400 mg/m2 over 46 h intravenously every 2 weeks for 6 cycles) followed by preoperative chemoradiotherapy or chemoradiotherapy only. HRQOL was assessed at baseline, during treatments and at 2-year follow-up using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR29 questionnaires. ResultsCompared to baseline, HRQOL scores during NAC were better for tumour symptoms but worse for global health status, functional domains, fatigue, nausea/vomiting and appetite loss. During follow-up, improved emotional functioning was observed, but deterioration of body image, increased urinary incontinence, and lower male sexual function were observed. Linear mixed model exhibited a treatment-by-time interaction effect for nausea/vomiting and insomnia symptoms showing a greater deterioration in the standard-of-care group. Only treatment arm and baseline physical functioning were independent significant favourable prognostic factors. ConclusionNAC improved tumour-related symptoms and transitorily reduced most functional scores. Adding NAC before chemoradiotherapy and increased physical functioning at baseline were independent significant prognostic factors for longer disease-free survival.

The value of post-operative chemotherapy after chemoradiotherapy in patients with high-risk locally advanced rectal cancer—results from the RAPIDO trial

Pre-operative chemoradiotherapy (CRT) rather than radiotherapy (RT) has resulted in fewer locoregional recurrences (LRRs), but no decrease in distant metastasis (DM) rate for patients with locally advanced rectal cancer (LARC). In many countries, patients receive post-operative chemotherapy (pCT) to improve oncological outcomes. We investigated the value of pCT after pre-operative CRT in the RAPIDO trial. Patients were randomised between experimental (short-course RT, chemotherapy and surgery) and standard-of-care treatment (CRT, surgery and pCT depending on hospital policy). In this substudy, we compared curatively resected patients from the standard-of-care group who received pCT (pCT+ group) with those who did not (pCT- group). Subsequently, patients from the pCT+ group who received at least 75% of the prescribed chemotherapy cycles (pCT ≥75% group) were compared with patients who did not receive pCT (pCT-/- group). By propensity score stratification (PSS), we adjusted for the following unbalanced confounders: age, clinical extramural vascular invasion, distance to the anal verge, ypT stage, ypN stage, residual tumour, serious adverse event (SAE) and/or readmission within 6 weeks after surgery and SAE related to pre-operative CRT. Cumulative probability of disease-free survival (DFS), DM, LRR and overall survival (OS) was analysed by Cox regression. In total, 396/452 patients had a curative resection. The number of patients in the pCT+, pCT >75%, pCT- and pCT-/- groups was 184, 112, 154 and 149, respectively. The PSS-adjusted analyses for all endpoints demonstrated hazard ratios between approximately 0.7 and 0.8 (pCT+ versus pCT-), and 0.5 and 0.8 (pCT ≥75% versus pCT-/-). However, all 95% confidence intervals included1. These data suggest a benefit of pCT after pre-operative CRT for patients with high-risk LARC, with approximately 20%-25% improvement in DFS and OS and 20%-25% risk reductions in DM and LRR. Compliance with pCT additionally reduces or improves all endpoints by 10%-20%. However, differences are not statistically significant.

Surgical outcomes of robotic, laparoscopic, and open low anterior resection after preoperative chemoradiotherapy for patients with advanced lower rectal cancer.

We investigated the surgical outcomes of robotic low anterior resection (LAR) for lower rectal cancer after preoperative chemoradiotherapy (pCRT). A total of 175 patients with lower rectal cancer who underwent LAR after pCRT between 2005 and 2020 were stratified into open (OS, n = 65), laparoscopic (LS, n = 64), and robotic surgery (RS, n = 46) groups. We compared the clinical, surgical, and pathological results among the three groups. The RS and LS groups had less blood loss than the OS group (p < 0.0001). The operating time in the RS group was longer than in the LS and OS groups (p < 0.0001). The RS group had a significantly longer mean distal margin than the LS and OS groups (25.4mm vs. 20.7mm and 20.3mm, respectively; p = 0.026). There was no significant difference in the postoperative complication rate among the groups. The local recurrence rate in the RS group was comparable to those in the LS and OS groups. Robotic LAR after pCRT was performed safely for patients with advanced lower rectal cancer. It provided a longer distal margin and equivalent local control rates.

Efficacy of preoperative chemoradiotherapy in patients with cT2N0 distal rectal cancer.

This study was designed to determine the feasibility of preoperative chemoradiotherapy (PCRT) in patients with clinical T2N0 distal rectal cancer. Patients who underwent surgery for clinical T2N0 distal rectal cancer between January 2008 and December 2016 were included. Patients were divided into PCRT and non-PCRT groups. Non-PCRT patients underwent radical resection or local excision (LE) according to the surgeon's decision, and PCRT patients underwent surgery according to the response to PCRT. Patients received 50.0 to 50.4 gray of preoperative radiotherapy with concurrent chemotherapy. Of 127 patients enrolled, 46 underwent PCRT and 81 did not. The mean distance of lesions from the anal verge was lower in the PCRT group (P=0.004). The most frequent operation was transanal excision and ultralow anterior resection in the PCRT and non-PCRT groups, respectively. Of the 46 patients who underwent PCRT, 21 (45.7%) achieved pathologic complete response, including 15 of the 24 (62.5%) who underwent LE. Rectal sparing rate was significantly higher in the PCRT group (11.1% vs. 52.2%, P<0.001). There were no significant differences in 3- and 5-year overall survival and recurrence-free survival regardless of PCRT or surgical procedures. PCRT in clinical T2N0 distal rectal cancer patients increased the rectal sparing rate via LE and showed acceptable oncologic outcomes. PCRT may be a feasible therapeutic option to avoid abdominoperineal resection in clinical T2N0 distal rectal cancer.

Circulating miRNA Signature Predicts Response to Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer.

We analyzed two genome-wide microRNA (miRNA) expression profiling data sets from tumor tissue samples for in silico discovery (GSE68204) and validation (GSE29298). We prioritized biomarkers in pretreatment plasma specimens from clinical training (n = 41; 15 responders and 26 nonresponders) and validation (n = 65; 29 responders and 36 nonresponders) cohorts of patients with LARC. We developed an integrated miRNA panel and established a risk assessment model, which was combined with the miRNA panel and carcinoembryonic antigen levels. Our comprehensive discovery effort identified an 8-miRNA panel that robustly predicted response to PCRT, with an excellent accuracy in the discovery (area under the curve [AUC] = 0.95) and validation (AUC = 0.92) cohorts. We successfully established a circulating miRNA panel with remarkable diagnostic accuracy in the clinical training (AUC = 0.82) and validation (AUC = 0.81) cohorts. Moreover, the predictive accuracy of the panel was significantly superior to conventional clinical factors in both cohorts (P < .01) and the risk assessment model was superior (AUC = 0.83). Finally, we applied our model to detect patients with pathologic complete response and showed that it was dramatically superior to currently used pathologic features (AUC = 0.92). Our novel risk assessment signature for predicting response to PCRT has a potential for clinical translation as a liquid biopsy assay in patients with LARC.

Clinical significance and predictors of complete or near-complete histological response to preoperative chemoradiotherapy in patients with localized pancreatic ductal adenocarcinoma

BackgroundThe clinical value and predictors of a favorable histological response to preoperative chemoradiotherapy (CRT) in pancreatic ductal adenocarcinoma (PDAC) remains undefined. ObjectiveTo assess the significance and predictors of a favorable histological response to preoperative CRT in patients with localized PDAC. MethodsThe study included 203 patients with localized PDAC undergoing curative-intent resection after CRT. The rate of R0 resection and overall survival (OS) and recurrence-free survival (RFS) were correlated with the grading of histological response to determine optimal stratification. Clinical factors associated with a significant histological response were evaluated using multivariate regression analysis. ResultsAmong all patients, eight patients (3.9%) had a grade 4 (pCR); 40 (19.4%) had a grade 3 estimated rate of residual neoplastic cells <10% (near-pCR); and 155 (76.7%) had a grade 1/2 limited response. The 48 patients with pCR/near-pCR achieved significantly higher R0 resection rate (100%) than those with grade 1/2 (80.0%). The 5-year OS and RFS rates were significantly higher in the patients with pCR/near-pCR (45.3% and 36.5%) than in those with grade 1/2 (27.1% and 18.5%). Gemcitabine plus S-1 based CRT, serum CA19-9 level after CRT <83 U/mL, and interval from initial treatment to surgery ≥4.4 months were independent predictive factors for pCR/near-pCR. ConclusionspCR or near-pCR to preoperative CRT contributed to achieving a high rate of R0 resection and improving survival for localized PDAC. The use of gemcitabine plus S-1 as a radiosensitizer, lower serum CA19-9 level after CRT, and longer preoperative treatment duration were significantly associated with pCR or near-pCR.

Genetic prognostic factors for neoadjuvant chemoradiotherapy for colorectal cancer

Introduction. There has been a recent trend toward a gradual increase in the incidence of rectal cancer and a decrease in the average age of patients. These changes interpret the need to personalize treatment in each case.Objective – to evaluate the association of polymorphic variants of some genes with the results of neoadjuvant chemoradiotherapy of rectal cancer.Materials and methods. We analyzed polymorphic variants of MTHFR, XPD, XRCC1, XRCC1, P53, VEGF, EGFR, TNF, CHEK2 and MMP1 genes in 76 patients with rectal cancer who underwent preoperative chemoradiation therapy followed by surgical treatment. Genotyping was performed by DNA isolation from venous blood leukocytes of the subjects followed by polymerase chain reaction with electrophoretic detection of the result.Results. Statistical analysis of the association of polymorphic variants of the studied genes with the treatment pathomorphosis revealed significance in relation to the MMP1-1607 gene (1G &gt;2G) (p = 0.033). There was also an association of co-carrying polymorphic variants of TNF (G / A) + MMP1 (2G / 2G) genes with grade III–IV therapeutic pathomorphosis (p = 0.007).Conclusion. Carriage of recessive allele of MMP1 gene can be a predictor of favorable prognosis of preoperative chemoradiotherapy in patients with rectal cancer.

A multicenter phase II trial of preoperative chemoradiotherapy with S-1 plus oxaliplatin and bevacizumab for locally advanced rectal cancer.

We clarified the safety and efficacy of preoperative chemoradiotherapy for locally advanced rectal cancer using a multidrug regimen (S-1 + oxaliplatin + bevacizumab). This multicenter phase II trial involved 47 patients with locally advanced rectal cancer. All patients received S-1 orally (80mg/m2/day on days 1-5, 8-12, 15-19, and 22-26) and infusions of oxaliplatin (50mg/m2 on days 1, 8, 15, and 22) and bevacizumab (5mg/kg on days 1 and 15). The total radiation dose was 40Gy delivered in daily fractions of 2Gy via the four-field technique. The primary endpoint was the pathological complete response rate. The secondary endpoints were safety (incidence of adverse events) and clinical response, relapse-free survival, overall survival, local recurrence, R0 resection, downstaging, and treatment completion rates. All 47 patients received chemoradiotherapy, and 44 patients underwent curative resection. Two patients refused surgery and selected a watch-and-wait strategy. The pathological complete response rate was 18.2% in patients who underwent curative resection. The clinical response rate was 91.3% in 46 patients. Concerning hematotoxicity, there was one grade 4 adverse event (2.1%) and seven grade 3 events (14.9%). Diarrhea was the most frequent non-hematotoxic event, and the grade 3 event rate was 25.5%. Although preoperative chemoradiotherapy for patients with locally advanced rectal cancer using the S-1 + oxaliplatin + bevacizumab regimen did not achieve the expected pathological complete response rate, this regimen led to an improved clinical response rate.

Surgical Complications after Preoperative Chemoradiotherapy in Patients with Resectable and Borderline Resectable Pancreatic Cancer in a Multicentre, Randomised Controlled Clinical Trial (PREOPANC-1)

Surgical Complications after Preoperative Chemoradiotherapy in Patients with Resectable and Borderline Resectable Pancreatic Cancer in a Multicentre, Randomised Controlled Clinical Trial (PREOPANC-1)

Impact of Total Neoadjuvant Therapy vs. Standard Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Randomized Trials.

Simple SummaryMultimodality therapy is the standard of care for patients with locally advanced rectal cancer (LARC). The optimal treatment sequence is, however, a matter of debate. Neoadjuvant radiotherapy with concurrent fluoropyrimidines followed by surgery and adjuvant chemotherapy has been the standard treatment for the past years. Alternative therapeutic strategies such as total neoadjuvant treatment (TNT) are gaining momentum, although results from individual clinical trials are not conclusive regarding its impact on survival. In this context, we aimed to systematically review available evidence from randomized trials comparing different sequencing strategies. The results from our meta-analysis show that TNT not only provides increased complete pathological response rates, but also improves disease-free and overall survival at 3 years compared to standard neoadjuvant chemoradiotherapy, with no substantial increase in severe adverse events. These results support the use of induction or consolidation chemotherapy before surgery in LARC and TNT as a valuable treatment strategy in these patients.Multimodality treatment is a standard of care for LARC, but the optimal sequencing of the treatment modalities remains unclear. Several randomized clinical trials (RCTs) compared total neoadjuvant treatment (TNT) vs. standard neoadjuvant chemoradiotherapy (CRT) with inconsistent results. A systematic review and meta-analysis was performed to evaluate the efficacy of TNT in terms of complete pathological response (pCR) rate, disease-free and overall survival vs. standard CRT in LARC. A systematic search was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and meeting abstracts up to May 2020. RCTs comparing CRT vs. TNT followed by surgery in LARC were eligible for the study. Study selection and data extraction were done following PRISMA guidelines by two independent reviewers. The Mantel–Haenzel method was used to obtain a fixed-effects model of pooled odds or hazard ratios for the main outcomes. Eight RCTs, including 2301 patients, met the eligibility criteria. TNT significantly improved pCR rate (OR = 1.99, 95% confidence interval (CI) 1.59–2.49; p < 0.001), 3-year disease-free-survival (DFS) (HR = 0.82, 95%CI 0.71–0.95; p = 0.01) and 3-year overall survival (OS) (hazard ratio (HR) = 0.81, p = 0.04). Grade 3–4 adverse events were not significantly different in both strategies (OR = 1.58; p = 0.14). An improved pCR rate was documented regardless of the type of radiotherapy administered (long vs. short fractionation schedules). No significant heterogeneity was found. The results of this meta-analysis show that TNT improves pCR and survival rates vs. standard preoperative CRT in patients with LARC. TNT may become a new standard of care in LARC, although longer follow-up is needed to properly assess its long-term impact on survival.

SO-37 Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stability and microsatellite instability-high, locally advanced rectal cancer (EPOC 1504)

Chemoradiotherapy (CRT) followed by radical surgery is the standard therapy for patients with locally advanced rectal cancer (LARC). Sequential use of an anti-PD-1 antibody after radiation demonstrates synergistic effects in in vivo models, and an anti-PD-1 antibody is effective in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer. We studied nivolumab and radical surgery following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. phase I investigated the feasibility of 240 mg q2 weeks x 5 cycles of nivolumab and radical surgery after the quality-assured CRT. In phase II, the efficacies and safeties for both patients with microsatellite stable (MSS) (cohort A1) and MSI-H (cohort A2) LARC were evaluated. In cohort A-1, the primary endpoint was a centrally confirmed pathological complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR=10% and 30% was 37 patients, with a 1-sided alpha of 5% and power of 90%. In Cohort A-2, 5 patients were included in an exploratory manner. Sequential use of nivolumab 240 mg q2 weeks x 5 cycles and radical surgery were well tolerated. From Jan/2017 to Oct/2019, a targeted number of patients was included and assessed. In cohort A-1, 30% (11/37; 90% CI 18-44%) of pCR (AJCC grade 0) rate and 38% (14/37) of major pathological response (MPR) (AJCC grade 0+1) rate were observed. Clinical CR was observed in one additional patient (3%) refusing surgery after nivolumab. The median neoadjuvant rectal (NAR) score was 8.4 (range: 0.0-50.4). pCR rates of 60% (6/10) and 19% (5/27) were seen in patients with tumor cells with PD-L1 ≥1% and < 1% immunohistochemistry staining, respectively (p=0.038, Fisher exact test), performed on biopsy samples taken pre-CRT. pCR rates of 62% (8/13) and 10% (1/10) were seen in 23 patients with pre-CRT tumor samples analyzable by flow cytometry, according to CD8+ T cell /effector regulatory T cell (CD8/eTreg) ratios ≥2 and < 2, respectively (p=0.029, Fisher exact test). In cohort A-2, 60% (3/5) of pCR rate and 0.9 (range: 0.9-20.4) of median NAR score were observed. As of Jan/2020, only 2 patients (1 local and 1 metastatic) in cohort A-1 and none in cohort A-2 recurred. Immune-related severe adverse events were observed in 3 patients (grade 3 myasthenia, grade 3 interstitial nephritis, and grade 2 peripheral motor neuropathy); all fully recovered and received radical surgery. During the follow-up period, one additional patient with grade 2 colitis was observed. No treatment-related deaths were observed. Promising pCR rates of 30% and 60%, with mild toxicities, were shown in MSS and MSI-H LARC patients treated with nivolumab plus radical surgery after CRT, suggesting that it is a candidate therapy for the future non-surgical approach.

Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer.

4100 Background: Chemoradiotherapy (CRT) followed by radical surgery (S) is standard therapy for patients (pts) with locally advanced rectal cancer (LARC). Sequential use of an anti-PD-1 antibody after radiation demonstrates synergistic effects in in vivo models, and an anti-PD-1 antibody is effective in pts with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivolumab (nivo) and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: After the quality-assured CRT, 240 mg q2 weeks x 5 cycles of nivo and radical S were investigated. In cohort A-1, for pts with microsatellite stable (MSS) LARC, the primary endpoint was a centrally confirmed pathological complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR = 10% and 30% was 37 pts, with a 1-sided alpha of 5% and power of 90%. In Cohort A-2, 5 pts with MSI-H LARC were included in an exploratory manner. Results: From Jan/2017 to Oct/2019, a targeted number of pts was included and assessed. In cohort A-1, 30% (11/37; 90% CI 18-44%) of pCR (AJCC grade (gr) 0) rate and 38% (14/37) of major pathological response (MPR) (AJCC gr 0+1) rate were observed. Clinical CR was observed in one additional pt (3%) refusing S after nivo. In cohort A-2, 60% (3/5) of pCR rate and 60% (3/5) of MPR rate were observed. As of Jan/2020, only 2 pts (1 local and 1 metastatic) in cohort A-1 and none in cohort A-2 recurred. Immune-related severe adverse events were observed in 3 pts (gr 3 myasthenia, gr 3 interstitial nephritis, and gr 2 peripheral motor neuropathy); all fully recovered and received radical S. During the follow-up period, one additional pt with gr 2 colitis was observed. No treatment-related deaths were observed. Conclusions: Promising pCR rates of 30% and 60%, with mild toxicities, were shown in MSS and MSI-H LARC pts treated with nivo plus radical S after CRT, suggesting the candidate therapy for the future non-surgical approach. Clinical trial information: NCT02948348 .

Oncological Impact of Lateral Lymph Node Dissection After Preoperative Chemoradiotherapy in Patients with Rectal Cancer.

To evaluate the efficacy of selective lateral lymph node dissection (LLND) and the effect of preoperative chemoradiotherapy (PCRT) in patients with LLN ≥ 5mm. Patients who underwent PCRT for rectal cancer were classified: (A) total mesorectal excision (TME)-only with LLN < 5mm (2001-2009, n = 474), (B) TME-only with LLN < 5mm (2011-2016, n = 273), (C) TME-only with LLN ≥ 5mm (2001-2009, n = 102), and (D) TME-LLND with LLN ≥ 5mm (2011-2016, n = 69). Subgroup analysis was performed in patients with LLN ≥ 5mm based on the reduction in LLN size to < 5mm or not on restaging MRI after PCRT. Oncological outcomes did not differ between groups A and B. Group D had lower 3-year local recurrence (LR) (20.13% vs 5.39%, P = 0.0013) and higher relapse-free survival (RFS) (65.83% vs 77.11%, P = 0.0436) than group C, while the 3-year overall survival (OS) was not significantly different between the two groups (87.64% vs 93.53%, P = 0.0670). In patients with reduction of LLN size from ≥ 5mm to < 5mm, LLND significantly reduced LR than did TME alone, but there were no significant differences in survival outcomes. In patients without reduction of LLN size to < 5mm, LLND reduced LR and improved RFS compared with TME alone. Selective LLND reduced LR and improved RFS in patients with LLN ≥ 5mm. Selective LLND reduced LR in patients with reduction of LLN size from ≥ 5mm to < 5mm after PCRT, and improved both LR and RFS in patients without reduction of LLN size to < 5mm.

A Nine-Gene Signature for Predicting the Response to Preoperative Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer.

Preoperative chemoradiotherapy (PCRT) and subsequent surgery is the standard multimodal treatment for locally advanced rectal cancer (LARC), albeit PCRT response varies among the individuals. This creates a dire necessity to identify a predictive model to forecast treatment response outcomes and identify patients who would benefit from PCRT. In this study, we performed a gene expression study using formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples from 156 LARC patients (training cohort n = 60; validation cohort n = 96); we identified the nine-gene signature (FGFR3, GNA11, H3F3A, IL12A, IL1R1, IL2RB, NKD1, SGK2, and SPRY2) that distinctively differentiated responders from non-responders in the training cohort (accuracy = 86.9%, specificity = 84.8%, sensitivity = 81.5%) as well as in an independent validation cohort (accuracy = 81.0%, specificity = 79.4%, sensitivity = 82.3%). The signature was independent of all pathological and clinical features and was robust in predicting PCRT response. It is readily applicable to the clinical setting using FFPE samples and Food and Drug Administration (FDA) approved hardware and reagents. Predicting the response to PCRT may aid in tailored therapies for respective responders to PCRT and improve the oncologic outcomes for LARC patients.

Predictive immunohistochemical features for tumour response to chemoradiotherapy in rectal cancer.

BackgroundReduced expression of cluster of differentiation (CD) 133 and cyclo‐oxygenase (COX) 2, and increased density of CD8+ tumour‐infiltrating lymphocytes, are associated with a favourable tumour response to preoperative chemoradiotherapy (CRT). This study aimed to evaluate these markers in relation to tumour response after preoperative CRT in two rectal cancer cohorts.MethodsPatients with low rectal cancer who underwent radical resection and preoperative short‐term CRT in 2001–2007 (retrospective cohort) and long‐term CRT in 2011–2017 (prospective cohort) were analysed. Pretreatment biopsies were stained immunohistochemically using antibodies to determine CD133 and COX‐2 expression, and increased CD8+ density. Outcome measures were tumour regression grade (TRG), tumour downstaging and survival.ResultsFor 95 patients in the retrospective cohort, the incidence of TRG 3–4 was 67 per cent when two or three immunohistochemistry (IHC) features were present, but only 20 per cent when there were fewer features (P < 0·001). The incidence of tumour downstaging was higher in patients with at least two IHC features (43 versus 22 per cent with fewer features; P = 0·029). The 49 patients in the prospective cohort had similar rates to those in the retrospective cohort (TRG 3–4: 76 per cent for two or more IHC features versus 25 per cent with fewer features, P < 0·001; tumour downstaging: 57 versus 25 per cent respectively, P = 0·022). Local recurrence‐free survival rates in patients with more or fewer IHC features were similar in the retrospective and prospective cohort (P = 0·058 and P = 0·387 respectively).ConclusionAssessment of CD133, COX‐2 and CD8 could be useful in predicting a good response to preoperative CRT in patients with lower rectal cancer undergoing neoadjuvant therapy. Further studies are needed to validate the results in larger cohorts and investigate a survival benefit.