Neoadjuvant PD-1 Blockade Combined With Chemotherapy Followed by Concurrent Immunoradiotherapy in Locally Advanced Anal Canal Squamous Cell Carcinoma Patients: Antitumor Efficacy, Safety and Biomarker Analysis

BackgroundAnal canal squamous cell carcinoma (ACSCC) is an exceedingly rare malignant neoplasm with challenges in sphincter preservation, treatment toxicities and long-term survival. Little is known concerning the activity of PD-1 antibodies in locally advanced ACSCC. This study reports on the efficacy and toxicities of a neoadjuvant PD-1 blockade combined with chemotherapy followed by concurrent immunoradiotherapy in ACSCC patients, and describes biomarkers expression and mutation signatures.MethodsIn this cohort study, patients were treated as planned, including four cycles of neoadjuvant PD-1 antibody toripalimab combined with docetaxol and cisplatin, followed by radiotherapy and two cycles of concurrent toripalimab. Multiplex immunofluorescence staining (mIHC) with PD-L1, CD8, CD163, Pan-Keratin and DAPI was performed with the pretreatment tumor tissue. Whole exome sequencing was performed for the primary tumor and peripheral blood mononuclear cells. The primary endpoint was the complete clinical response (cCR) rate at 3 months after overall treatment. Acute and late toxicities graded were assessed prospectively.ResultsFive female patients with a median age of 50 years old (range, 43-65 years old), finished treatment as planned. One patient had grade 3 immune related dermatitis. Two patients had grade 3 myelosuppression during neoadjuvant treatment. No severe radiation-related toxicities were noted. Four patients with PD-L1 expression >1% achieved a cCR after neoadjuvant treatment. and the other patient with negative PD-L1 expression also achieved a cCR at 3 months after radiotherapy. All the patients were alive and free from disease and had a normal quality of life, with 19.6-24 months follow up. Inconsistent expression of PD-L1 and CD163 was detected in 3 and 5 patients, respectively. TTN, POLE, MGAM2 were the top mutation frequencies, and 80 significant driver genes were identified. Pathway analysis showed enrichment of apoptosis, Rap1, Ras, and pathways in cancer signaling pathways. Eight significantly deleted regions were identified.ConclusionsThis small cohort of locally advanced ACSCC patients had quite satisfactory cCR and sphincter preservation rate, after neoadjuvant PD-1 antibody toripalimab combined with chemotherapy followed by concurrent immunoradiotherapy, with mild acute and long-term toxicities.

Evaluation of the Learning Curve for Conformal Sphincter Preservation Operation in The Treatment of Ultra-Low Rectal Cancer

Background: To investigate the learning curve of conformal sphincter preservation operation (CSPO) in the treatment of ultra-low rectal cancer and to further expore the influencing factors of operation time.Methods: From August 2011 to April 2020, 108 consecutive patients with ultra-low rectal cancer underwent CSPO by the same surgeon in the department of colorectal surgery of Changhai Hospital. The moving average and cumulative sum control chart (CUSUM) curve were used to analyze the learning curve. The preoperative clinical baseline data, postoperative pathological data, postoperative complications and survival data were compared before and after the completion of learning curve. The influencing factors of CSPO operation time were analyzed by univariate and multivariate analysis.Results: According to the results of moving average and CUSUM method, CSPO learning curve was divided into learning period (1-45 cases) and learning completion period (46-108 cases). There was no significant difference in preoperative clinical baseline data, postoperative pathological data, postoperative complications and survival data between the two stages. Compared with the learning period, the operation time (P < 0.05), blood loss (P < 0.05), postoperative flatus and defecation time (P < 0.05), liquid diet time (P < 0.05) and postoperative hospital stay (P < 0.05) in the learning completion period were significantly reduced, and the difference was statistically significant. Univariate and multivariate analysis showed that distance of tumor from anal verge (≥ 4cm vs. <4cm, P=0.039) and T stage (T3 vs. T1-2, P=0.022) were independent risk factors for prolonging the operation time of CSPO.Conclusions: For surgeons with laparoscopic surgery experience, about 45 cases of CSPO are needed to cross the learning curve. At the initial stage of CSPO, beginners are recommended to select patients with ultra-low rectal cancer whose distance of tumor from anal verge is less than 4cm and tumor stage is less than T3 for practice, which can enable beginners to reduce the operation time, accumulate experience, build self-confidence and shorten the learning curve on the premise of safety.

Retrospective study of total neoadjuvant therapy for locally advanced rectal cancer

Aim: To compare treatment outcomes of total neoadjuvant therapy (TNT) and the standard treatment for locally advanced rectal cancer (LARC). Materials & methods: Patients with LARC (cT2-4 and/or cN1-2) who were treated with preoperative chemoradiotherapy plus induction and consolidation chemotherapy followed by surgery or the standard treatment were recruited. Pathologic complete response (pCR) rate, overall survival, disease-free survival and the sphincter preservation rate as well as safety were evaluated. Results: 49 cases were treated with TNT and 71 cases received the standard treatment. Multivariate analysis demonstrated that TNT and tumor size were independent risk factors for pCR. Grade 3 chemoradiotherapy toxicity and postoperative complications were similar between the two groups. Conclusion: TNT improved the pCR rate for patients with LARC, with tolerable toxicities.

Quality of Life in a Randomized Trial Comparing Two Neoadjuvant Regimens for Locally Advanced Rectal Cancer – INCAGI004.

Background: Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the standard of care for locally advanced rectal cancer (LARC), but the emergence of different drug regimens may result in different response rates. Good clinical response translates into greater sphincter preservation, but quality of life (QOL) may be impaired after treatment due to chemoradiotherapy and surgical side effects. Objective: To prospectively evaluate the QOL in a randomized trial comparing two neoadjuvant regimens for locally advanced rectal cancer.Methods: Stage II and III rectal cancer patients were randomized to receive neoCRT with either capecitabine (Group 1) or 5-Fu and leucovorin (Group 2) concomitant to long course radiotherapy. Clinical downstaging was accessed using MRI 6-8 weeks after treatment. EORTCs QLQ C30 and CR38 were applied before treatment (T0), after neoCRT (T1), after rectal resection (T2), early after adjuvant chemotherapy (T3), and one year after end of treatment or stoma closure (T4). Wexner scale was used for continence evaluation at T4. A C30SummaryScore (Geisinger et cols) was calculated to compare QOL results. Results: 32 patients were assigned to Group 1 and 31 to Group 2. Clinical downstaging occurred in 70.0% of Group 1 and 53.3% of Group 2 (p=0.288). pCR was 23.3% in group 1 and 10.0% in Group 2(p=0.165). Sphincter preservation was 83.3% in Group 1 and 80.0% in Group 2(p=0.111). No difference in QOL was detected comparing the two treatment groups before and after neoCRT. C30SummaryScore detected improvement comparing T0 to T1 and deterioration comparing T1 to T2 (p=0.025), and global health status improved at T1 and T4 compared to T0(p=0.004). Mean Wexner scale score was 9.2, and a high score correlated with symptoms of diarrhea and defecation problems at T4.Conclusions: Clinical and pathological response rates were equivalent in both treatment groups. QOL was improved after neoCRT corresponding to clinical response but decreased following rectal resection. Wexner score was high after sphincter preservation. C30SummaryScore was a useful tool to detect differences in overall QOL in EORTCs multiple item questionnaire.Trial registration: NCT03428529. Registered 02/09/2018 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03428529.

1441 Real-World Comparison of Curative Open, Laparoscopic and Robotic Resections for Sigmoid and Rectal Cancer - Single Center Experience

Aim There is an increase in the utilization of robotic surgery in addition to traditional open or laparoscopic approaches. The aim of this study is to compare the short-term outcomes for open, laparoscopic, and robotic surgery for rectal and sigmoid cancer. Method One hundred and forty-seven patients (open n = 48, laparoscopic n = 49, robotic n = 50) undergoing curative resections by two surgeons, using a standardized technique, between 2013 and 2020 were included. Data analyzed included patient demographics, tumor characteristics, length of stay, post-operative outcomes, and pathologic surrogates of oncologic results, including total mesorectal excision (TME) quality, circumferential resection margin (CRM) involvement and lymph node (LN) yield. Results Median age of population was 68 years (IQR 59-73), majority (68%) were males. Median distance from anal verge in robotic surgery group was 8 cm, compared to 15 and 14.5 cm in the open and laparoscopic groups respectively, p = 0.029, (laparoscopic vs robotic, p = 0.005 and open vs robotic, p = 0.027). Proportion of patients who received neoadjuvant radiotherapy in robotic surgery group was higher, p = 0.04. In sub-group of tumors between 3 and 7 cm from anal verge more patients in the robotic surgery group had sphincter preservation, p = 0.006. Length of stay, maximum C-reactive protein, and white blood cell rise favored minimally invasive approaches compared to open surgery. There were no differences in post-operative complications, lymph node yield or CRM positivity rate between the three groups. Conclusions Robotic surgery approach is safe and allows sphincter preservation without compromising TME quality in rectal cancer surgery.

Can Pre-Treatment Inflammatory Parameters Predict the Probability of Sphincter-Preserving Surgery in Patients with Locally Advanced Low-Lying Rectal Cancer?

There is evidence suggesting that pre-treatment clinical parameters can predict the probability of sphincter-preserving surgery in rectal cancer; however, to date, data on the predictive role of inflammatory parameters on the sphincter-preservation rate are not available. The aim of the present cohort study was to investigate the association between inflammation-based parameters and the sphincter-preserving surgery rate in patients with low-lying locally advanced rectal cancer (LARC). A total of 848 patients with LARC undergoing radiotherapy from 2004 to 2019 were retrospectively reviewed in order to identify patients with rectal cancer localized ≤ 6 cm from the anal verge, treated with neo-adjuvant radiochemotherapy (nRCT) and subsequent surgery. Univariable and multivariable analyses were used to investigate the role of pre-treatment inflammatory parameters, including the C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) for the prediction of sphincter preservation. A total of 363 patients met the inclusion criteria; among them, 210 patients (57.9%) underwent sphincter-preserving surgery, and in 153 patients (42.1%), an abdominoperineal rectum resection was performed. Univariable analysis showed a significant association of the pre-treatment CRP value (OR = 2.548, 95% CI: 1.584–4.097, p < 0.001) with sphincter preservation, whereas the pre-treatment NLR (OR = 1.098, 95% CI: 0.976–1.235, p = 0.120) and PLR (OR = 1.002, 95% CI: 1.000–1.005, p = 0.062) were not significantly associated with the type of surgery. In multivariable analysis, the pre-treatment CRP value (OR = 2.544; 95% CI: 1.314–4.926; p = 0.006) was identified as an independent predictive factor for sphincter-preserving surgery. The findings of the present study suggest that the pre-treatment CRP value represents an independent parameter predicting the probability of sphincter-preserving surgery in patients with low-lying LARC.

Phase II trial of neoadjuvant mFOLFOX 6 with panitumumab (P) in T3 rectal cancer with clear mesorectal fascia (MRF) and KRAS, NRAS, BRAF, PI3KCA wild type (4WT). GEMCAD 1601 PIER trial.

3512 Background: Patients with advanced colorectal cancer with 4WT tumors achieve increased response rates with chemotherapy and anti-EGFR therapy as compared with chemotherapy alone. In clinically staged (c) T3 rectal cancer neoadjuvant oxaliplatin/fluoropyrimidine combination has shown to induce encouraging pathological complete response (pCR). We hypothesize that combining FOLFOX and P could improve outcomes in 4WT tumors. Methods: PIER was an investigator-initiated phase II, single-arm, multicentre clinical trial to evaluate the safety and efficacy of neoadjuvant mFOLFOX6 with P in pts < 75-y, with 4WT rectal cancer of the middle third staged as T3 by centrally-reviewed magnetic resonance imaging (MRI) and clear MRF, who were candidate for a R0 resection with sphincter preservation surgery. Pts received 6 cycles and underwent re-staging with MRI and sigmoidoscopy. Pts without progression underwent total mesorectal excision 4 weeks after the last cycle. Patients with progression were treated with pre-op chemoradiotherapy. The primary endpoint was pCR. The study followed a 2-Stage Simon’s MiniMax design (P0 of 16%, P1 of 35%, alpha and beta of 0.1). The target sample size was 35 patients and if 9 or more achieved a pCR, the results would be compatible with efficacy. We present primary and early secondary endpoints. Results: Between 9/2017 and 6/2020, 90 patients were screened (56 excluded; 42 were excluded due to mutations, 12 were excluded due to discrepancies with central review of radiology) of whom 34 were enrolled. In the ITT population a pCR was observed in 11 pts (32.3%; [95% CI 17.39-50.53]) and a near-complete pathological response (Mandard 1+2) was observed 17 pts (52.9%). Clinical complete or near complete response was achieved in 50% and there were no progressions. R0 resection rate and pathological circumferential resection margin neg- were 100%. Full compliance with induction was 88%. Neoadjuvant G3/4 toxicity occurred in 54% and was consistent with FOLFOX/P safety profile. G3/4 postoperative related toxicity was 19% with one reoperation. Conclusions: The study met the threshold for efficacy. mFOLFOX6 with P as neoadjuvant therapy can be effective and safe without unexpected toxicities in mrT3, clear MRF and 4WT rectal cancer and resulted in a higher rate of pCR compared with our previous series (GEMCAD 0801; The Oncologist 2014) in a similar molecular-unselected population. This study was funded by Amgen S.A. Clinical trial information: NCT03000374.

Phase II study of preoperative (PREOP) chemoradiotherapy (CTRT) plus avelumab (AVE) in patients (PTS) with locally advanced rectal cancer (LARC): The AVANA study.

3511 Background: Preop CTRT is considered the standard of care in the management of LARC. RT can induce antigen release from a low neoantigen-burden tumor (such as a mismatch repair proficient colorectal cancer) and activate dendritic cells leading to a CD8+ T lymphocyte-mediated anticancer immune response. In LARC patients, neoadjuvant CTRT increases PD-L1 expression in tumor cells, strongly suggesting a neoadjuvant combinatory strategy with RT and PD-1/PD-L1 pathway blockade. Based on such considerations, we have designed the AVANA study to investigate the role of Ave in combination with preop CTRT in LARC. Methods: This is an Italian multi-center, phase II study. Pts with resectable LARC, defined by the presence of at least one of the following features: cN+, cT4, high risk cT3, received standard preop CTRT (capecitabine 825 mg/sqm/bid 5 days/week+ 50.4 Gy in 28 fractions over 5.5 weeks) plus 6 cycles of Ave 10 mg/Kg every 2 weeks. Surgery with total mesorectal excision was performed at 8-10 weeks after the end of CTRT. The primary end-point was the pCR rate, defined as complete histological regression with no available tumor cells ypT0N0. Secondary end-points were R0 resection rate, tumor downstaging, local recurrence, sphincter preservation rate, progression-free survival, overall survival, safety profile, and the evaluation of exploratory predictive and/or prognostic biomarkers. Assuming as null hypothesis p0 a pCR rate of 15%, a significance level of 5% (one-side), and a power of 80%, a sample size of 101 pts was needed to detect an absolute increment of 10% in pCR rate (from 15% to 25%). The experimental regimen is considered for further studies if, in at least 22 pts, we observe a pCR. Results: From April 2019 to November 2020, a total of 101 resectable LARC pts were enrolled in 10 Italian Centers. The median age was 63 years (23-82), 62 (61.4%) pts were male, 93 (92%) had ECOG PS 0. At baseline, 94 (93%) and 16 (16%) pts had cN+ and cT4 LARC, respectively. All pts completed the induction phase. Out of 96 pts evaluable for pathological response, 22 (23%) pts achieved a pCR and 59 (61.5%) pts a major pathological response (a central review is ongoing). At this time, microsatellite status is available only in 39 pts, of which only one was instable. The rate of grade 3-4 non-immune and immune-related adverse events was 8% and 4%, respectively. Avelumab was early interrupted in 9 pts out 101, mainly due to toxicity. Conclusions: The combination of preop CTRT plus Ave showed a promising activity and a feasible safety profile. According to our statistical considerations, the experimental regimen will be considered for further studies. Updated results will be presented during the Congress. Sponsored by GONO and partially supported by Merck. EUDRACT 2017-003582-10. Clinical trial information: NCT03854799.

Total neoadjuvant treatment versus standard chemoradiation to increase the sphincter preservation rate for distal locally advanced rectal cancer (TESS).

TPS3615 Background: Standard treatment of rectal cancer is neoadjuvant capecitabine chemotherapy with radiotherapy, followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, suggests organ preservation as an alternative to rectal excision in good responders after neoadjuvant chemoradiotherapy to decrease surgical morbidity and increase quality of life. RAPIDO and PRODIGE-23 trials showed that TNT strategy could improve the pathological complete response (pCR) rateand reduce the risk of distant metastasis. The objective of this trial is to increase the proportion of sphincter preservation rate for distal rectal cancer patients by optimizing tumor response, by using TNT regimen as compared to conventional chemoradiotherapy. TESS (clinicalTrials.gov, NCT03840239), a prospective, open label, multicenter, randomized phase 2 study, is underway. Methods: Main inclusion criteria include: cT3-4aNany or cTanyN+ rectal adenocarcinoma aged 18-70y; ECOG performance 0-1; distance≤5cm from anal verge. 168 patients will be randomized 1:1. Patients in the TNT group will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplation) before, during and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as watch and wait) and adjuvant chemotherapy capecitabine 2 cycles. Patients in the standard treatment group will receive neoadjuvant radiotherapy 50Gy/25 fractions combined with capecitabine 5 weeks before TME (or other treatment decisions, such as watch and wait), and adjuvant chemotherapy Capeox 6 cycles. Primary endpoint is the rate of sphincter preservation rate (absence of stoma). Secondary endpoints include: Ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; acute toxicity; surgical complications; long-term anal function; late toxicity; ECOG standard score; disease-free survival; overall survival. First site opened in January 24, 2019. Clinical trial information: NCT03840239.