Neoadjuvant Short-course Radiotherapy Research Articles

Role of neoadjuvant rectal score in prognosis and adjuvant chemotherapy decision-making in locally advanced rectal cancer following neoadjuvant short-course radiotherapy and consolidation chemotherapy

Objectives: To assess the prognostic impact of the neoadjuvant rectal (NAR) score following neoadjuvant short-course radiotherapy and consolidation chemotherapy in locally advanced rectal cancer (LARC), as well as its value in guiding decisions for adjuvant chemotherapy. Methods: Between August 2015 and August 2018, patients were eligible from the STELLAR phase III trial (NCT02533271) who received short-course radiotherapy plus consolidation chemotherapy and for whom the NAR score could be calculated. Based on the NAR score, patients were categorized into low (＜8), intermediate (8-16), and high (＞16) groups. The Kaplan-Meier method, log rank tests, and multivariate Cox proportional hazard regression models were used to evaluate the impact of the NAR score on disease-free survival (DFS). Results: Out of the 232 patients, 24.1%, 48.7%, and 27.2% had low (56 cases), intermediate (113 cases), and high NAR scores (63 cases), respectively. The median follow-up period was 37 months, with 3-year DFS rates of 87.3%, 68.3%, and 53.4% (P＜0.001) for the low, intermediate, and high NAR score groups. Multivariate analysis demonstrated that the NAR score (intermediate NAR score: HR, 3.10, 95% CI, 1.30-7.37, P=0.011; high NAR scores: HR=5.44, 95% CI, 2.26-13.09, P＜0.001), resection status (HR, 3.00, 95% CI, 1.64-5.52, P＜0.001), and adjuvant chemotherapy (HR, 3.25, 95% CI, 2.01-5.27, P＜0.001) were independent prognostic factors for DFS. In patients with R0 resection, the 3-year DFS rates were 97.8% and 78.0% for those with low and intermediate NAR scores who received adjuvant chemotherapy, significantly higher than the 43.2% and 50.6% for those who did not (P＜0.001, P=0.002). There was no significant difference in the 3-year DFS rate (54.2% vs 53.3%, P=0.214) among high NAR score patients, regardless of adjuvant chemotherapy. Conclusions: The NAR score is a robust prognostic indicator in LARC following neoadjuvant short-course radiotherapy and consolidation chemotherapy, with potential implications for subsequent decisions regarding adjuvant chemotherapy. These findings warrant further validation in studies with larger sample sizes.

Abstract CT130: Epacadostat with preoperative chemoradiation in locally advanced rectal cancer (LARC): Results of a translational phase I clinical trial

Abstract BACKGROUND: In preclinical studies, we found that the immuno-oncology target and tryptophan metabolizing enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) promotes resistance to radiation in rectal cancer regardless of MSI status. Furthermore, IDO1 inhibition with epacadostat improved tumor radiosensitivity, abrogated immunosuppression, limited distal recurrence, and was radioprotective of the normal intestine. This trial aimed to evaluate the safety of IDO1 inhibition when combined with neoadjuvant short-course radiation (SCRT) and chemotherapy with capecitabine and oxaliplatin (CAPOX) for LARC. METHODS: The primary objective was to determine the recommended phase II dose (RP2D) of epacadostat for combination with SCRT and CAPOX. Secondary objectives included determining antitumor activity as measured by neoadjuvant rectal (NAR) score and pathological or clinical complete responses. During the dose escalation phase, 3 doses of epacadostat (300mg, 400mg, & 600mg BID) were explored. Epacadostat was combined with SCRT (5Gy x 5 fractions) followed by 6 cycles of CAPOX chemotherapy, until the day of surgery (~24 wks). Tissues and blood were collected for correlative studies. A control cohort was generated from patients receiving the same treatment without epacadostat. NCT03516708 RESULTS: Seventeen patients were enrolled from 4/2019 to 8/2023. RP2D of epacadostat in combination with SCRT and CAPOX chemotherapy was determined to be 400mg BID. Two patients experienced dose-limiting toxicities (DLT) at 600mg dose level, one with G2 elevated ALT and another with G3 maculopapular rash. No DLT was reported at other dose levels. Of six patients who underwent surgery, the mean NAR score was 7.46 (SD 7.11; range 0 - 20.4), indicating potentially better response compared to the mean NAR of 17.8 in an institutional 2:1 matched control cohort (p=0.03). Tumor tissue revealed increased IDO1 expression and kynurenine levels in all patient tumors after radiation. After epacadostat, serum levels of kynurenine were reduced while TNFα, IFNγ, and MIP1a were all increased. Global metabolomics and RNAseq revealed a distinct pattern of serum biomarkers and immunophenotype respectively in patients after treatment. Tumoroids were evaluated as ex vivo models of treatment response. CONCLUSION: Epacadostat in combination with SCRT and CAPOX was well-tolerated. An NCI supported Phase 2 trial is ongoing to further evaluate the promising disease responses reported in dose escalation phase. Citation Format: Haeseong Park, Katrina Pedersen, Katherine Huang, Matthew Mutch, Hyun Kim, Nikolaos Trikalinos, Olivia Aranha, Benjamin Tan, Rama Suresh, Lee Ratner, Moh'd Khushman, John Visconti, Kian-Huat Lim, Lauren Henke, Maddie Swiecicki, Jingxia Liu, Parag Parikh, Matthew Ciorba. Epacadostat with preoperative chemoradiation in locally advanced rectal cancer (LARC): Results of a translational phase I clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT130.

Study protocol of short-course radiotherapy combined with CAPOX and PD-1 inhibitor for locally advanced colon cancer: a randomised, prospective, multicentre, phase II trial (TORCH-C)

IntroductionThe preliminary result of the TORCH trial has shown a promising complete response (CR) for managing locally advanced rectal cancer with neoadjuvant short-course radiotherapy (SCRT) combined with chemotherapy and PD-1...

Neoadjuvant short-course radiotherapy or chemoradiation plus consolidative chemotherapy followed by radical operation for locally advanced rectal cancer.

Limited evidence compares short-course radiotherapy (SCRT) and long-course chemoradiotherapy (LCCRT), both of which are followed by consolidative chemotherapy before radical rectal surgery. We conducted a retrospective cohort study to assess treatment response, survival outcomes, and toxicity in patients with locally advanced rectal cancer. Patients (cT3-4 and/or N+) treated with SCRT or LCCRT, consolidative chemotherapy, or total mesorectal excision between 2013 and 2021 were identified. the cause-specific cumulative incidence of disease-related treatment failure, locoregional recurrence, distant metastases, and overall survival were evaluated using flexible parametric competing risk analysis and Kaplan-Meier methods, adjusted for treatment regimens and clinicopathological factors. A pathological complete response (pCR), tumor downstaging, and toxicity have been reported. Among the 144 patients, 115 (80%) underwent curative rectal surgery. The LCCRT and SCRT groups achieved pCR in 10 (18%) and seven (12%) patients, respectively (odds ratio, 1.68; 95% confidence interval [CI], 0.59-4.78). The adjusted cause-specific hazard ratio for disease-related treatment failure with LCCRT versus SCRT was 0.26 (95% CI, 0.08-0.87). Three-year cumulative probability of disease-related treatment failure was 10.0% and 25.6% for LCCRT and SCRT, respectively. No significant differences in T-downstaging, N-downstaging, significant pathologic downstaging (ypT0-2N0), locoregional failure, distant metastasis, or overall survival were found. Late rectal toxicity occurred in 10 (15%) LCCRT and two (3%) SCRT patients, respectively. LCCRT with consolidative chemotherapy demonstrated improved disease-related treatment failure compared with SCRT, despite higher late rectal toxicity. Further research is needed to assess the long-term oncologic outcomes and toxicity.

Real-world data on the pattern of recurrence of colorectal cancer at a tertiary cancer center in South India: A retrospective observational study

Background: Recurrent colorectal cancer may be amenable to curative treatment. As the debate on the ideal set of investigations and frequency of follow-up continues, it is important to review the pattern of recurrence in the real-world setting, which could help tailor future follow-up strategies. Objectives: Our primary objective was to study the varying clinical presentations and patterns of recurrence of colorectal cancer. The secondary objectives were to study the site of recurrence, method of diagnosis of recurrence, incidence of second primary colorectal cancer, and salvage rates after recurrence of colorectal cancer. Material and Methods: We reviewed the data of patients who were treated from January 2010 to December 2016 at the Malabar Cancer Center, a tertiary cancer center in Kerala, India. We recorded the clinicopathologic details of patients who were treated with curative intent and had serologic (carcinoembryonic antigen [CEA] elevation), clinical, or radiological evidence of disease recurrence. We also studied the timing and anatomical location of recurrence, symptoms, and the method by which the recurrence was diagnosed. Results: We included 675 patients in the study. There were 324 (48%) female patients; the median age was 55 years (interquartile range [IQR], 47.2-65). The primary diagnosis was colon cancer in 326 (48.3%) and rectal in 349 (51.7%) patients. Multimodality therapy was administered to 393 (58.2%) patients in the form of surgery with or adjuvant neoadjuvant chemoradiation adjuvant radiation, or neoadjuvant short-course radiation with neoadjuvant and adjuvant chemotherapy. Recurrences occurred in 109 (16.1%) patients, only 50 (45.9%) of whom were symptomatic. Recurrences were diagnosed by CEA elevation in 65 (59.6%), imaging in 12 (11%), clinical examination in 4 (3.7%), and colonoscopy in 1 (0.9%) patient. The median time to recurrence was 17 months (95% CI, 14-22). Local and distant recurrences occurred in 29 (4.2%) and 80 (11.9%) patients, respectively; 22 (27.5%) patients developed multisite distant recurrences. Recurrences occurred within the first 5 years of completion of therapy in 96 (88.1%) cases. Twelve (11%) patients received salvage therapy with curative intent. Six patients (0.9%) had a metachronous colorectal primary tumors. Conclusions: Colorectal cancer recurs most commonly in the first 5 years after therapy. Multisite distant recurrence and isolated liver metastases predominate. Recurrences are often asymptomatic and most commonly manifest as elevated CEA. Regular clinical evaluation, CEA testing, colonoscopy, and symptom-based cross-sectional imaging detect up to three-quarters of patients with recurrences, but the overall salvageability remains low.

Abandonment of Routine Radiotherapy for Nonlocally Advanced Rectal Cancer and Oncological Outcomes

Neoadjuvant short-course radiotherapy was routinely applied for nonlocally advanced rectal cancer (cT1-3N0-1M0 with >1 mm distance to the mesorectal fascia) in the Netherlands following the Dutch total mesorectal excision trial. This policy has shifted toward selective application after guideline revision in 2014. To determine the association of decreased use of neoadjuvant radiotherapy with cancer-related outcomes and overall survival at a national level. This multicenter, population-based, nationwide cross-sectional cohort study analyzed Dutch patients with rectal cancer who were treated in 2011 with a 4-year follow-up. A similar study was performed in 2021, analyzing all patients that were surgically treated in 2016. From these cohorts, all patients with cT1-3N0-1M0 rectal cancer and radiologically unthreatened mesorectal fascia were included in the current study. The data of the 2011 cohort were collected between May and October 2015, and the data of the 2016 cohort were collected between October 2020 and November 2021. The data were analyzed between May and October 2022. The main outcomes were 4-year local recurrence and overall survival rates. Among the 2011 and 2016 cohorts, 1199 (mean [SD] age, 68 [11] years; 430 women [36%]) of 2095 patients (57.2%) and 1576 (mean [SD] age, 68 [10] years; 547 women [35%]) of 3057 patients (51.6%) had cT1-3N0-1M0 rectal cancer and were included, with proportions of neoadjuvant radiotherapy of 87% (2011) and 37% (2016). Four-year local recurrence rates were 5.8% and 5.5%, respectively (P = .99). Compared with the 2011 cohort, 4-year overall survival was significantly higher in the 2016 cohort (79.6% vs 86.4%; P < .001), with lower non-cancer-related mortality (13.8% vs 6.3%; P < .001). The results of this cross-sectional study suggest that an absolute 50% reduction in radiotherapy use for nonlocally advanced rectal cancer did not compromise cancer-related outcomes at a national level. Optimizing clinical staging and surgery following the Dutch total mesorectal excision trial has potentially enabled safe deintensification of treatment.

Short-course radiation with consolidation chemotherapy does not increase operative morbidity compared to long-course chemoradiation: A retrospective study of the US rectal cancer consortium.

Neoadjuvant short-course radiation and consolidation chemotherapy (SC TNT) remains less widely used for rectal cancer in the United States than long-course chemoradiation (LCRT). SC TNT may improve compliance and downstaging; however, a longer radiation-to-surgery interval may worsen pelvic fibrosis and morbidity with total mesorectal excision (TME). A single, US-center retrospective analysis has shown comparable risk of morbidity after neoadjuvant short-course radiation with consolidation chemotherapy (SC TNT) and long-course chemoradiation (LCRT). Validation by a multi-institutional study is needed. The US Rectal Cancer Consortium database (2010-2018) was retrospectively reviewed for patients with nonmetastatic, rectal adenocarcinoma treated with neoadjuvant LCRT or SC TNT before TME. The primary endpoint was severe postoperative morbidity. Cohorts were compared by univariate analysis. Multivariable logistic regression modeled the odds of severe complication. Of 788 included patients, 151 (19%) received SC TNT and 637 (81%) LCRT. The SC TNT group had fewer distal tumors (33.8% vs. 50.2%, p < 0.0001) and more clinical node-positive disease (74.2% vs. 47.6%, p < 0.0001). The intraoperative complication rate was similar (SC TNT 5.3% vs. 4.4%, p = 0.65). There was no difference in overall postoperative morbidity (38.4% vs. 46.3%, p = 0.08). Severe morbidity was similar with low anterior resection (9.1% vs. 15.3%, p = 0.10) and abdominoperineal resection (24.4% vs. 29.7%, p = 0.49). SC TNT did not increase the odds of severe morbidity relative to LCRT on multivariable analysis (OR 0.64, 95% CI 0.37-1.10). SC TNT does not increase morbidity after TME for rectal cancer relative to LCRT. Concern for surgical complications should not discourage the use of SC TNT when aiming to increase the likelihood of complete clinical response.

LBA25 Neoadjuvant short-course radiotherapy followed by camrelizumab plus chemotherapy versus long-course chemoradiotherapy followed by chemotherapy in locally advanced rectal cancer: A randomized phase III trial (UNION)

LBA25 Neoadjuvant short-course radiotherapy followed by camrelizumab plus chemotherapy versus long-course chemoradiotherapy followed by chemotherapy in locally advanced rectal cancer: A randomized phase III trial (UNION)

Randomized Controlled Trial of Neoadjuvant Short-Course Radiotherapy Followed by Consolidation Chemotherapy Versus Long-Course Chemoradiotherapy in Locally Advanced Rectal Cancer: Comparison of Overall Response Rates.

Management of locally advanced rectal cancer (LARC) is evolving with current emphasis on the addition of chemotherapy to short course radiotherapy (SCRT). We primarily aimed to analyse the difference in overall response rates between SCRT with sequential chemotherapy and standard long-course chemoradiotherapy (LCCRT)in LARC. After randomization, patients in arm A received 45Gy in 25 fractions over 5weeks with concurrent capecitabine while patients in arm B received 25Gy in 5 fractions over 1week followed by 3 cycles of CAPOX (capecitabine and oxaliplatin) chemotherapy. Clinical and radiological response assessment was made after the completion of neoadjuvant treatment, a week prior to surgery. Adjuvant chemotherapy was added to complete 6months of peri-operative chemotherapy. Surgery was performed between 8 and 10weeks of completion of radiation treatment in both arms. Of the 33 patients recruited in this study between February 2020 to July 2021, 17 patients were randomized to arm A and 16 to arm B. The rates of complete tumour regression were 23.1% in arm A versus 35.7% in arm B (p-value = 0.683). Pathological complete response (pCR) rate was 20% arm A versus 30% in arm B (0.446). A higher number of patients in arm B experienced grade 3 diarrhoea, whereas acute skin toxicity was seen only in arm A. SCRT had fewer treatment interruptions compared to LCCRT. SCRT followed by three cycles of CAPOX chemotherapy in the neoadjuvant setting is comparable to LCCRT in terms of tumour response. This may be a better alternative regimen with fewer treatment interruptions in a resource-limited setting.

Neoadjuvant short-course radiotherapy followed by chemotherapy plus camrelizumab versus long-course chemoradiotherapy followed by chemotherapy for patients with locally advanced rectal cancer: A randomized, multicenter, open-label phase 3 trial (Union).

TPS3638 Background: Short-course preoperative radiotherapy (SCPRT) and long-course chemoradiotherapy (LCCRT) are standard neoadjuvant treatments for locally advanced rectal cancer (LARC). Further, the RAPIDO trial found that SCPRT combined with consolidation chemotherapy produced better short- and long-term outcomes than SCPRT alone for patients with high-risk LARC. A phase 2, single-arm trial of neoadjuvant SCPRT followed by camrelizumab (an anti-PD-1 antibody) plus chemotherapy demonstrated promising short-term outcomes in patients with LARC. The Union trial is evaluating the efficacy and safety of neoadjuvant SCPRT followed by camrelizumab plus chemotherapy versus LCCRT followed by chemotherapy in patients with LARC. Methods: The Union trial is enrolling patients aged 18-75 with histologically confirmed clinical stage T3-4/N+ adenocarcinoma of the rectum, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a tumor inferior margin less than 10 cm above the anal verge. Eligible patients are randomized in a 1:1 ratio to either arm A or arm B. Patients in arm A receive neoadjuvant treatment with SCPRT (a total of 25 Gy in 5 days) followed by camrelizumab (200 mg/m2 intravenous drip on day 1, every 3 weeks for 2 cycles) plus CAPOX (oxaliplatin 130 mg/m2 intravenous infusion over 2 hours on day 1, capecitabine 1000 mg/m2 oral twice daily, days 1–14, every 3 weeks for 2 cycles), surgery, and adjuvant treatment with camrelizumab plus CAPOX (6 cycles) followed by camrelizumab until the medication duration of camrelizumab reaches one year. Patients in arm B receive neoadjuvant treatment with LCCRT (capecitabine 825 mg/m2 twice daily, 5 days a week, combined with a total dose of 50.4 Gy in 28 days) followed by CAPOX (2 cycles), surgery, and adjuvant treatment with CAPOX (6 cycles). Randomization is stratified by clinical T stage (≤T3 vs T4) and clinical N stage (N0 vs N+). The primary endpoint is pathologic complete response (pCR). The secondary endpoints are 3-year event-free survival rate, overall survival, R0 resection rate, completion rate of neoadjuvant treatment, 3-year disease-free survival rate, tumor regression grading, safety, and quality of life. pCR is evaluated per the AJCC 8th Edition TRG scoring system as assessed by the blinded independent central review. Adverse events are graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Quality of life is assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. This study began enrollment in July 2021 with a planned enrollment of 230 patients. Clinical trial information: NCT04928807 .

Efficacy and safety of neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX in microsatellite stable (MSS)/mismatch repair proficient (pMMR) locally advanced rectal cancer.

134 Background: Chemoradiation is the standard neoadjuvant treatment for locally advanced rectal cancer. Microsatellite stable (MSS)/ mismatch repair proficient (pMMR) rectal cancer rarely responds to immune checkpoint inhibitor monotherapy, but combination with chemoradiation may improve sensitivity of MSS/pMMR tumors by inducing immune-stimulatory effects. Therefore, we aimed to investigate the efficacy and safety of patients treated with neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX for MSS/pMMR locally advanced rectal cancer. Methods: This is an open-label, single-center, phase ¢ò study. Patients (pts) with locally advanced rectal adenocarcinoma with MSS/pMMR were eligible. MMR protein expression was tested by immunohistochemistry (IHC) £¬and MSI status was confirmed by NGS (next generation sequencing). All pts included in this study underwent neoadjuvant short-course radiation (total dose of 5¡Á5Gy) in the first week after enrollment, then followed by 6 cycles of envafolimab (anti-PD-L1 inhibitor,150mg, d1, subcutaneous injection, QW) plus 2 cycles of CAPEOX in the next six weeks, and subsequently underwent total mesorectal excision (TME) in the ninth week. The primary endpoint is pathological complete response rate. Secondary endpoints include tumor regression grade (TRG), 3 year disease free survival, overall survival, toxicity, and quality of life (QoL). Results: This study intends to recruit 32 pts, and a total of 21 pts were enrolled from January 2022 to September 2022. Overall median age was 67 (42-79) years. 12 pts completed study designed treatment protocol (envafolimab plus CAPOX) followed with TME procedures, and 9 pts are still undergoing neoadjuvant treatment. All 12 pts achieved major partial response (MPR) evaluated by diffusion-weighted magnetic resonance imaging (DW-MRI), and 8 pts (8/12,76.6%) achieved pCR. During neoadjuvant treatment period, 20 pts (20/21, 95.2%) presented with treatment-related AEs (TRAEs) of any grade, 18 pts (18/21, 85.7%) had grade 1-2 and one each pts had grade 3 and 4 thrombocytopenia (2/21, 9.5%). The most common TRAEs were sensation of rectal tenesmus. Conclusions: Neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX in MSS/pMMR locally advanced rectal cancer achieved a promising pathologic response. Meanwhile, this combination neoadjuvant therapy is safe and worthy of application to clinical practice. (Funded by Sir Run Run Shaw Hospital Zhejiang University School of Medicine.) Clinical trial information: NCT05216653 .

Neoadjuvant Short-Course Radiotherapy Followed by Consolidation Chemotherapy before Surgery for Treating Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis.

Neoadjuvant short course radiotherapy (SCRT) followed by consolidation chemotherapy (CCT) is an alternative treatment for locally advanced rectal cancer (LARC). We performed this systematic review and meta-analysis to explore the tumor response and oncological outcomes of this new approach compared to conventional chemoradiotherapy (CRT). An online search of the PubMed, Embase, and Cochrane Library databases was performed. This review included 7507 patients from 14 different cohorts. The pCR rate was higher with SCRT + CCT than that with CRT (RR: 1.60; 95% CI: 1.35–1.91; p < 0.01). SCRT + CCT provided a higher ypN0 response (RR: 1.06; 95% CI: 1.01–1.12; p = 0.02). There were no differences in R0 resection and positive CRM rates; however, more sphincter-preservation surgeries were performed in the SCRT + CCT arm (RR: 1.06; 95% CI: 1.01–1.11; p = 0.02). There was no difference in the OS and DFS between the SCRT + CCT and the CRT arms (OS: HR: 0.85, p = 0.07; DFS: HR: 0.88, p = 0.08). The compliance and toxicity were comparable between the SCRT and CRT groups. In the subgroup analysis, patients who underwent four or more cycles of CCT had better pCR and DFS events. Therefore, SCRT followed by consolidation chemotherapy might be an effective alternative treatment for LARC.

Efficacy of Neoadjuvant Therapy in Improving Long-Term Survival of Patients with Resectable Rectal Cancer: A Meta-Analysis.

The impact of neoadjuvant therapy on long-term prognosis of patients with resectable rectal cancer is currently unknown. This study aimed to explore the long-term prognosis of patients with resectable rectal cancer following treatment with neoadjuvant therapy. Four major databases (PubMed, Web of Science, Embase, Cochrane library) were searched to identify relevant articles published between January 2000 and July 2020. The main outcome indicators were the 5-year Overall Survival (OS) and Disease-Free Survival (DFS). The meta-analysis revealed that 5-year OS (HR: 0.88, 95% Cl: 0.83-0.93) and DFS (HR: 0.95, 95% Cl: 0.91- 0.98) were higher in patients with resectable rectal cancer after receiving neoadjuvant therapy than those treated with upfront surgery. Subgroup analysis demonstrated that the long-term survival of patients in Asia and Europe could benefit from neoadjuvant therapy. The neoadjuvant short-course radiotherapy (SCRT) and neoadjuvant chemoradiotherapy (CRT) improved the 5-year OS and DFS of patients with stage II-III rectal cancer and mid/low rectal cancer. Further research found that patients with stage II only had an increase in OS, while patients with stage Ⅲ have improved 5-year OS and DFS. Neoadjuvant therapy improved the long-term survival of patients with mid/low rectal cancer in stage Ⅱ-Ⅲ (especially stage Ⅲ). Additionally, patients in Asia and Europe seemed to be more likely to benefit from neoadjuvant therapy. For the treatment, we recommend neoadjuvant SCRT and neoadjuvant CRT for resectable rectal cancer.

Efficacy and safety of sequential neoadjuvant chemotherapy and short-course radiation therapy followed by delayed surgery in locally advanced rectal cancer: a single-arm phase II clinical trial with subgroup analysis between the older and young patients.

PurposeThis study was performed to investigate the efficacy and safety of short-course radiation therapy (SCRT) and sequential chemotherapy followed by delayed surgery in locally advancer rectal cancer with subgroup analysis between the older and young patients.Materials and MethodsIn this single-arm phase II clinical trial, eligible patients with locally advanced rectal cancer (T3–4 and/or N1–2) were enrolled. All the patients received a median three sequential cycles of neoadjuvant CAPEOX (capecitabine + oxaliplatin) chemotherapy. A total dose of 25 Gy in five fractions during 1 week was prescribed to the gross tumor and regional lymph nodes. Surgery was performed about 8 weeks following radiotherapy. Pathologic complete response rate (pCR) and grade 3–4 toxicity were compared between older patients (≥65 years) and younger patients (<65 years).ResultsNinety-six patients with locally advanced rectal cancer were enrolled. There were 32 older patients and 64 younger patients. Overall pCR was 20.8% for all the patients. Older patients achieved similar pCR rate (18.7% vs. 21.8; p = 0.795) compared to younger patients. There was no statistically significance in terms of the tumor and the node downstaging or treatment-related toxicity between older patients and younger ones; however, the rate of sphincter-saving surgery was significantly more frequent in younger patients (73% vs. 53%; p=0.047) compared to older ones. All treatment-related toxicities were manageable and tolerable among older patients.ConclusionNeoadjuvant SCRT and sequential chemotherapy followed by delayed surgery was safe and effective in older patients compared to young patients with locally advanced rectal cancer.

Planning target volume margin assessment for online adaptive MR-guided dose-escalation in rectal cancer on a 1.5 T MR-Linac

PurposeThis study assessed the margins needed to cover tumor intrafraction motion during an MR-guided radiotherapy (MRgRT) dose-escalation strategy in intermediate risk rectal cancer. MethodsFifteen patients with rectal cancer were treated with neoadjuvant short-course radiotherapy, 5x5 Gy, according to an online adaptive workflow on a 1.5 T MR-linac. Per patient, 26 3D T2 weighted MRIs were made; one reference scan preceding treatment and five scans per treatment fraction. The primary tumor was delineated on each scan as gross tumor volume (GTV). Target coverage margins were assessed by isotropically expanding the reference GTV until more than 95% of the voxels of the sequential GTVs were covered. A margin with a coverage probability threshold of 90% was defined as adequate. Intra- and interfraction margins to cope with the movement of the GTV in the period between scans were calculated to indicate the target volume margins. Furthermore, the margin needed to cover GTV movement was calculated for different time intervals. ResultsThe required margins to cover inter- and intrafraction GTV motion were 17 mm and 6 mm, respectively. Analysis based on time intervals between scans showed smaller margins were needed for adequate GTV coverage as time intervals became shorter, with a 4 mm margin required for a procedure of 15 min or less. ConclusionThe shorter the treatment time, the smaller the margins needed to cover for the GTV movement during an online adaptive MRgRT dose-escalation strategy for intermediate risk rectal cancer. When time intervals between replanning and the end of dose delivery could be reduced to 15 min, a 4 mm margin would allow adequate target coverage.

SO-30 Efficacy and safety of neoadjuvant short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma: Averectal study

Total neoadjuvant therapy (TNT) for locally advanced rectal cancer is becoming an accepted approach over the last few years with increasing pathologic complete response (pCR) and compliance with chemotherapy in comparison with the current standard of care i.e., fluoropyrimidine-based chemoradiation followed by surgery and adjuvant chemotherapy. Sequential use of anti–PD-1/PD-L1 antibody after radiation therapy has demonstrated a synergistic effect in in vivo models leading to a decrease in size of irradiated and non-irradiated secondary tumors outside the radiation field (abscopal effect). Open-label, single-arm, multicenter, 2-stage phase II study. This is an investigator-initiated, open-label, single-arm, multicenter, phase II study, adopting Simon’s two-stage aiming at evaluating the pCR rate and safety of using short-course radiation therapy (25 Grays in 5 fractions), followed by 6 cycles of mFOLFOX-6 (oxaliplatin, 5-FU and leucovorin) plus avelumab, then total mesorectal excision (TME) 3-4 weeks after last dose in patients with locally-advanced, potentially resectable rectal adenocarcinoma. From July 2018 to October 2020, 44 patients were accrued and completed the 2 stages of the study. They all met the inclusion criteria and were consented. 40 patients completed at least 1 treatment cycle and TME and entered the current analysis with a median follow-up period of 13.2 (range from 3.6 to 31.9) months. 1 of the 44 patients had disease progression shortly after finishing chemotherapy, so surgery was aborted, 2 patients voluntarily withdrew from the study directly before surgery after completing all their treatment cycles and 1 patient died after the 4th cycle of chemo-immunotherapy. The study population consisted of 26 (65%) males and 14 (35%) females with median age of 58.5 (31.0, 74.0) years. The primary endpoint results revealed that 15/40 patients (37.5%) achieved pCR (tumor regression grade (TRG) =0) as compared to the historical control group with pCR of 16% (p=0.025). In addition, 12/40 (30%) had a near complete response with TRG =1 (< 10% viable cells in tumor bed). In total, 27/40 patients (67.5%) had major pathologic response rate (mpRR) (TRG 0 and 1). As for safety, 43 out of 242 (17.7%) adverse events were serious adverse events (SAEs). Of the total SAEs, 25/43 (58.1%), 5/43 (11.6%) and 1/43 (2.3%) had a toxicity grade of 3,4 and 5, respectively. In addition, none of the 31 reported grade 3-5 SAEs were related to avelumab; 11 (35%) were related to TME (including 6 anastomosis leaks), 3 (10%) to post-ileostomy closure, and 17 (55%) were miscellaneous. In terms of SAE outcomes, only 1 (3%) treatment-unrelated SAE resulted in death (cardiopulmonary arrest) while 27 (87%) resolved without sequalae and 3 (10%) are still ongoing. Based on this analysis, the primary endpoint was successfully met with significant improvement in pCR (37.5%, p=0.025) and mpRR rates in the setting of an acceptable safety profile. 3-year disease-free survival and overall survival will be reported later in the final study manuscript.

P-265 Neoadjuvant radiotherapy for locally advanced rectal cancer during the first wave of COVID19 pandemic: Guy’s cancer cohort experience

The Covid-19 pandemic is a healthcare emergency with a significant impact on cancer services provision. In March 2020, our institution adopted the ESMO expert consensus guidelines for radiotherapy management of rectal cancer during the pandemic. Here we present short-term oncological outcomes of this approach compared to the same period in 2018. Patients who underwent neoadjuvant (chemo) radiotherapy for rectal cancer between 1st March 2020 and 31 May 2020 were identified from a research ethics committee (REC)-approved research database for cancer patients (Guy’s Cancer Cohort). Patient demographics and treatment characteristics were extracted and compared with a control cohort treated in the same period in 2018. The definition of local response was based on identification of downstaging on re-staging Magnetic Resonance Imaging (MRI) post neoadjuvant treatment (mrT3c/d-4 to mrT0-2 and mrT2 to mrT0-1) and classified in a binary format (response vs no response). In addition, in patients who underwent total mesorectal excision (TME), neoadjuvant rectal (NAR) score was calculated, as described previously, and classified into low (<8), intermediate (>=8<=16) and high (>16). The frequency of MRI and pathological response was compared using non-parametric Fisher exact test. Thirty patients were treated in the three-month period in 2020 as compared with 21 in 2018 (43% increase). No statistically significant differences were observed in baseline tumour characteristics. The use of neoadjuvant short-course radiotherapy (SCRT) treatment increased significantly from 19% of cases in 2018 to 50% during the pandemic, which was reflected in reduced radiotherapy-related hospital footfall (median 15 appointments in 2020 vs 25 appointments in 2018). While the use of concomitant fluoropyrimidines was lower (47 vs 71%), the use of induction chemotherapy was higher (30 vs 19%) in 2020 compared to 2018, which may reflect more prevalent use of total neoadjuvant treatment. There was no difference in the proportion of MRI responders between cohorts (52% in 2020 vs 38% in 2018). In patients who underwent TME, there was no difference in the proportion of R1 resection (0 in 2020 vs 9% in 2018), median NAR scores (8 (1-30) in 2020 v 15 (range 4-50) in 2018) or NAR score categories (22% good responders, 64% intermediate and 14% non-responders during Covid-19 vs 9% good responders, 55% intermediate and 36% non-responders in 2018). Changes in radiotherapy treatment of rectal cancer during Covid-19 pandemic, including more frequent use of SCRT (often in combination with neoadjuvant chemotherapy), did not seem to have negatively impacted short-term oncological outcomes, as measured by MRI downstaging rates and NAR scores following TME. The effect of the pandemic on medium and long-term oncological outcomes is still awaited.

Preservation of the rectum is possible in early rectal cancer with neoadjuvant radiotherapy, delay and local excision-a 12-year single-centre experience of the evolution of early rectal cancer treatment.

Treatment of early rectal cancer (ERC) is undergoing a revolution towards rectum preservation. Adjuvant and neoadjuvant therapy alongside local excision (LE) means that organ preservation is a real possibility for most patients and a viable alternative for frailer patients. This study presents our 12-year experience as a specialist regional ERC unit, evolving towards organ preservation. Data were collected prospectively between 2006 and 2018 for all patients referred to the regional ERC multidisciplinary team with suspected or confirmed ERC. Patients considered suitable for LE, or those declining radical surgery, were offered LE or neoadjuvant short-course radiotherapy (SCRT), delay and LE with subsequent rescue surgery or contact brachytherapy for unfavourable histopathology. In all, 102 patients underwent LE. Ten patients were excluded (N=92). 45 patients underwent LE directly and 47 patients received SCRT and LE. After SCRT and LE, a pathological complete response was achieved in 44.7%. This approach also resulted in a lower rate of lymphovascular invasion (22.2% vs. 6.4%), fewer distant recurrences (4.4% vs. 0%) and a better disease-specific mortality (11.1% vs. 0%) (P<0.05). Although statistically insignificant, fewer patients required rescue surgery after SCRT (15.6% vs. 4.3%). Organ preservation with a good oncological outcome is better achieved by neoadjuvant radiotherapy, delay and LE. To achieve this, careful patient selection, thorough preoperative investigation, experienced surgical technique and a deep appreciation of tumour biology managed via a dedicated ERC network is paramount.

ASO Author Reflections: Clinical Benefit of Neoadjuvant Short-Course Radiotherapy for Upper-Third Rectal Tumors over Surgery Alone.

ASO Author Reflections: Clinical Benefit of Neoadjuvant Short-Course Radiotherapy for Upper-Third Rectal Tumors over Surgery Alone.

Neoadjuvant Short-Course Radiotherapy for Upper Third Rectal Tumors: Systematic Review and Individual Patient Data Metaanalysis of Randomized Controlled Trials.

There is no consensus on the use of neoadjuvant radiotherapy for tumors of the upper third of the rectum. Due to conflicting findings in high-quality trials and significant long-term side effects associated with neoadjuvant radiotherapy, the benefit of neoadjuvant radiotherapy for upper third rectal tumors is less certain than for lower two third rectal tumors. This metaanalysis compares oncological outcomes with neoadjuvant radiotherapy and surgery versus surgery alone for upper third rectal tumors. PubMed, Embase, and the Cochrane library databases were searched. Randomized controlled trials (RCT) comparing neoadjuvant radiotherapy and surgery versus surgery alone for resectable rectal cancer were included. Individual patient data were sought from the principal investigator of each eligible trial for comparative data on patients with upper third rectal tumors. The main outcomes measured were survival outcomes, oncological outcomes, postoperative morbidity, and late toxicity. Individual patient data from two RCTs examining outcomes in 758 patients were obtained. Published data from one further RCT containing comparable data on upper third rectal tumors were included in analysis of local recurrence. In patients with curative surgery, there was no significant reduction in local recurrence or significant improvement in overall survival or disease-free survival with neoadjuvant radiotherapy (LR RR: 0.38, 95% CI 0.14-1.04, p = 0.06) (OS RR: 1.10, 95% CI 0.98-1.24, p = 0.11) (DFS RR: 1.11, 95% CI 0.97-1.26, p = 0.13). The benefit of neoadjuvant radiotherapy for upper third rectal tumors is not certain, and surgery alone for patients with potentially curative disease at preoperative staging may be sufficient.