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Patients with cT3a-bN0-1aM0 mid rectal cancer who undergo the treatment modality of 'radical surgery + adjuvant chemotherapy (ACT)'

Patients with cT3a-bN0-1aM0 mid rectal cancer who undergo the treatment modality of 'NCRT + radical surgery + ACT'

Patients with cT4NanyM0 or cTanyN2M0 mid/low rectal cancer who undergo the treatment modality of 'NCRT with combined chemotherapy (Capox regimen) + radical surgery + ACT'

Patients with cT4NanyM0 or cTanyN2M0 mid/low rectal cancer who undergo the treatment modality of 'NCRT with single-agent chemotherapy (Capecitabine) + radical surgery + ACT'

Patients with locally advanced rectal cancer, being clinically staged cCR after NCRT, who undergo the transanal endoscopic microsurgery (TEM) excision of the lesion.

Patients with locally advanced rectal cancer, being clinically staged cCR after NCRT, who undergo the radical resection of the lesion.

without the preoperative concurrent chemoradiothearpy (no neoadjuvant chemoradiation)

non-NCRT

the preoperative concurrent chemoradiothearpy (neoadjuvant chemoradiation)

NCRT

combined chemotherapy with capecitabine with oxaliplatin

capecitabine with oxaliplatin

single-agent chemotherapy with capecitabine

capecitabine

transanal endoscopic microsurgery (TEM) excision of the lesion

radical resection

Jiaolin Zhou, MD.

Guole Lin, MD.

At present, the combined modality treatment of preoperative neoadjuvant chemoradiotherapy (NCRT) followed by radical surgery has become the standard of care for the locally advanced mid/low rectal cancer, having been proved to substantially improve the local control of the disease, whereas not being able to improve the long-term survival. According to present clinical practice guidelines, all patients with cT3-4N0M0 or cTanyN1-2M0 mid/low rectal cancer are recommended to undergo the preoperative long-term radiotherapy with concurrent 5FU based chemotherapy, followed by the radical resection of the tumor. After surgery, adjuvant chemotherapy (ACT) is recommended for all these patients without considering the postoperative pathological results. Recently, however, some authors proposed that different strategy of combined modality therapy should be applied in different patients according to their risk of relapse, instead of using the uniform NCRT strategy. In this research, on the basis of investigator's previous clinical practice and researches, investigators plan to stratify the patients with cT3-4N0M0 or cTanyN1-2M0 mid/low rectal cancer into several subgroups according to tumor stages and the risk of relapse. Different therapeutic strategy will be applied in different groups, at the aim of improving the overall therapeutic effects, as well as reducing the treatment adverse effects.

This research consists of four trials.

Trial A: A multicenter, prospective, randomized trial to compare neoadjuvant chemoradiotherapy (NCRT) followed by radical surgery with surgery alone for cT3a-bN0-1aM0 mid rectal cancer.

Research objects: Patients with locally advanced rectal cancer, being clinically staged T3a-bN0-1aM0 by rectal MRI and/or endorectal ultrasonography (ERUS), the tumor being located 6-12 cm above the anal verge.

After giving fully informed consent, the prospective participants will be randomly divided into two groups, receiving the following two treatment modalities.

Group A1: radical surgery + adjuvant chemotherapy (ACT) Group A2: NCRT + radical surgery + ACT

Trial B: A multicenter, prospective, randomized trial to compare combined versus single-agent chemotherapy with concurrent radiotherapy for cT4NanyM0 or cTanyN2M0 rectal cancer.

Research objects: Patients with locally advanced rectal cancer, being clinically staged cT4NanyM0 or cTanyN2M0 by rectal MRI and/or ERUS, or patients with any other risk factors for tumor relapse.

After giving fully informed consent, the prospective participants will be randomly divided into two groups, receiving the following two treatment modalities.

Group A1: NCRT with combined chemotherapy (Capox regimen) + radical surgery + ACT Group A2: NCRT with single-agent chemotherapy (Capecitabine) + radical surgery + ACT

Trial C: A multicenter, prospective, randomized trial to compare transanal ndoscopic microsurgery (TEM) excision versus radical resection of rectal cancer being staged clinical complete response (cCR) after NCRT.

Research objects: Patients with locally advanced rectal cancer, being clinically staged cCR after NCRT.

After giving fully informed consent, the prospective participants will be randomly divided into two groups, receiving the following two treatment modalities.

Group A1: TEM excision + ACT Group A2: radical surgery + ACT

Trial D: A prospective, observational study to determine the value of circulating tumor DNA (ctDNA) for predicting the therapeutic effects of NCRT for locally advanced rectal cancer and the patients' long-term prognosis.

Research objects: Patients with locally advanced mid/low rectal cancer (cT3-4N0M0 or cTanyN+M0) who undergo NCRT.

After giving fully informed consent, the prospective participants will undergo the classical 'NCRT + radical surgery + ACT' comprehensive treatment. Serial analysis of ctDNA will be performed at specific time points including pre-NCRT, post-NCRT, postoperative week 1, post-ACT, postoperative year 1, 2, and 3. The next-generation sequencing of surgical specimens will be performed as well. Participants will be observed and examined during the entire course of treatment and the follow-up period. The pathological results of the surgical specimen and the 3 year disease free survival (3y-DFS) will be the main end-points.

Multicenter, Prospective, RCT：Investigation of Combined Modality Therapy for Locally Advanced Mid/Low Rectal Cancer.

A Multicenter, Prospective, Randomized Clinical Trial to Investigate the Combined Modality Therapy for Locally Advanced Mid/Low Rectal Cancer.

pathological complete tumor response rate

Beijing Hospital

Beijing Chao Yang Hospital

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Peking University People's Hospital

Peking University Cancer Hospital & Institute

Beijing Friendship Hospital

Geneplus-Beijing Co. Ltd.

Peking Union Medical College Hospital

Professor

Antipyretics

Anti-Inflammatory Agents

Antirheumatic Agents

Fibrinolytic Agents

Analgesics

Platelet Aggregation Inhibitors

Aspirin

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase Inhibitors

Enzyme Inhibitors

Induction chemotherapy followed by chemoradiotherapy with aspirin Aspirin 100mg daily during the chemoradiotherapy

Induction chemotherapy followed by chemoradiotherapy without aspirin Placebo daily during the chemoradiotherapy

chemoradiotherapy with capecitabine and aspirin Aspirin daily during chemoradiotherapy

chemoradiotherapy with capecitabine and placebo Placebo daily during chemoradiotherapy

Placebo Oral Tablet

Luiz Henrique Araujo, MD, PHD

The benefit of aspirin in cancer of the colon and rectum is already known. Recently, it was described its potential activity during chemoradiotherapy, with higher rate of tumor downstaging. Furthermore, induction chemotherapy followed by chemoradiation represents an attractive approach, with more favorable compliance and toxicity profiles. The aim of this study was to evaluate the efficacy of total neoadjuvant treatment and assess the efficacy and feasibility of aspirin use during chemoradiotherapy for high-risk rectal cancer.

Methods: This is a randomized trial to evaluate induction treatment with XELOX and Capecitabine-based chemoradiotherapy with or without aspirin in a high-risk population selected by MRI. High-risk will be defined by presence of at least one of the following criteria on high-resolution thin-slice MRI (3 mm): tumors extending to within 1 mm of, or beyond the mesorectal fascia; tumor extending 5 mm or more into perirectal fat; resectable cT4 tumors; lower third; nodal involvement; extramural vascular invasion. Random assignment of treatment will be stratified by MRI tumour regression grade. All the patients enrolled in the study will receive XELOX every 21 days for four cycles, unless unacceptable toxicity or progression is detected. After this treatment, patients will be randomized to receive Capecitabine-based chemoradiotherapy with aspirin or placebo (Capecitabine 850 mg/m² 5 days per week combined with radiotherapy with total dose of 50.4 Gy in 28 days). After 8-10 weeks, they will be evaluate by MRI. Patients with incomplete clinical response will be referred to immediate surgery and patients with complete clinical response will be managed with "watch and wait" approach. Patients with progression disease during the treatment phase will be withdrawn from the study and will receive their treatment according to the investigator's judgment.

The sample size was calculated according to Simon's optimal two-stage design. Accordingly, 11 patients must be included in each group during the first stage and 20 during the second stage. A treatment regimen will be considered effective if more than 18 patients of the total 31 show downstaging (final analysis), reaching 80% power with an alpha of 0.05 level of significance.

preoperative induction chemotherapy followed by combined radiochemotherapy with capecitabine and aspirin

Induction Chemotherapy Plus Chemoradiotherapy With or Without Aspirin in High Risk Rectal Cancer

Phase II Randomized Study of Induction Chemotherapy Followed by Chemoradiotherapy With or Without Aspirin in High Risk Locally Advanced Rectal Cancer

This will be assessed by MR imaging 8-10 weeks after chemoradiotherapy and it will be considered tumor downstaging if mrTRG 1 to 3

This will be assessed by MR imaging after induction chemotherapy

Amount of tumor regression after surgery according to the guideline including Mandard

it will be defined as the absence of residual invasive cancer on pathological evaluation of the complete resected rectal specimen

defined as the time from surgery to relapse or death, whichever occurred first

defined as the time from surgery to death, whichever occurred first

Instituto Nacional de Cancer, Brazil

PREHABILITATION DURING NEOADJUVANCY AND BEFORE SURGERY

Control of the physical, nutritional and psychological preparation of the patient who will undergo rectal cancer surgery

prehabilitation

Laura Mora

Laura Mora, Dr

Laura Mora, Dr.

Control of the effect of prehabilitation on postoperative morbidity, assessed by the Comprehensive Complication Index (CCI), in patients diagnosed with rectal cancer that will receive neoadjuvant Quimiorradiotherapy (NCRT) and subsequent surgery, performed at the beginning of NCRT or before surgery.

According to the annual report of the Spanish Medical Oncology Association (SEOM), in Spain and without differentiating by sex, colorectal cancer will be the cancer with the highest incidence by 2021; with 43.581 new cases estimated for such year, 14.209 of these will be of rectal cancer. In rectal cancer, surgery remains the cornerstone; however, it is already known that local recurrences are frequent. That is why one of the main milestones rectal cancer treatment, is the multimodal therapy approach. It consists of implementing a neoadjuvant chemoradiotherapy treatment (NCRT) prior to surgical intervention. With this, local control of the disease is achieved, metastases are reduced have resulted in a five-year survival. Subsequently, depending on the definitive pathological results, patients should also complete treatment with postoperative chemotherapy. It is known that patients undergoing neoadjuvant treatment experience a wide variety of side effects, which can cause loss of muscle and cardiovascular function, loss of their functional capacity and increased fatigue. This worsens the quality of life of the patient and can sometimes cause the interruption of neoadjuvant treatment and have repercussions on the prognosis. Not only do these side effects affect the course of neoadjuvant treatment, but also declines the physiological reserve, making the patient arrive in sub-optimal conditions for surgery. This has an impact on postoperative morbidity and mortality, and secondarily, in the increase of hospital stay.

The concept of functional capacity appears ¨as the nutritional, physical and emotional state that a person has to face a stressful situation, such as surgical treatment. It is believed that if functional capacity is enhanced, postoperative morbidity can be reduced and the patient's recovery can also be improved. That is why trimodal programs are created, specifically selected for their potential cumulative or synergistic effects on health outcomes to prepare patients to face surgery at all three levels. These programs are known as prehabilitation.

Currently there are studies that show that prehabilitation improves the results of patients who must undergo different major surgical procedures, among them in colorectal surgery. Our group has recently presented a study that shows that trimodal prehabilitation contributes to reducing postoperative morbidity and overall hospital stay in patients operated on for colorectal neoplasia. There are also systematic reviews that conclude that prehabilitated patients who must undergo major surgery (speaking of 435 patients and 9 studies) present a decrease in the incidence of major postoperative complications. On the other hand, there are studies that show that prehabilitation in patients who must receive neoadjuvant therapy reduces the decrease of functional capacity that treatment produces on patients. As also shown by the Rex Trial, a randomized study on 48 patients. In an attempt to unite the two lines start the study, it will be a novel one , with only two previously published studies in this area. The intention is demonstrate that when prehabilitation is started before commencing neoadjuvant therapy in patients who are diagnosed with rectal cancer and who are subject to neoadjuvant therapy, will reduce the effect on functional capacity, and that patients will present less postoperative morbidity and better postoperative recovery.

due to the characteristics of the study, it is not possible to perform masking

Prehabilitation in Rectal Cancer: During Neoadjuvant Therapy vs Preoperative

Randomized Controlled Trial Comparing the Effect of a Multimodal Prehabilitation Program During Neoadjuvant Treatment Versus a Multimodal Prehabilitation After Neoadjuvant Treatment for Patients Undergoing Resection of Rectal Cancer.

Morbidity after surgery of rectal cancer: CCI - value 0-100

Walking test that helps calculation of the number of daily steps to be carried out (5.000 to 10.000) daily steps

Calculation of level of anxiety or depression in mild, moderate or severe. Allows referral of the patient to the psychology service

Corporacion Parc Tauli

PhD, MD, Colorrectal Surgeon, Associate Professor

Central Nervous System Depressants

Anesthetics

Arm 1 will receive tailored surgery. If there are no cancer cells or the margin is negative in the local excision/biopsy during surgery, the operation will be terminated. And if the final pathology result is T2-4, or cancer cells and margin are positive in the frozen section during surgery, or the result of digital rectal examination and visual examination using anoretractor under general anesthesia is not suitable for local excision (visible and palpable tumor nodules), a total mesorectal excision will be performed.

Arm 2 will receive TME. Surgery including high ligation of the inferior mesenteric artery and total mesorectal excision will be performed under the lithotomy position. After pelvic dissection, double-stapled anastomosis or transanal anastomosis will be performed, followed by diverting stoma. Abdominoperineal resection with permanent stoma is included.

Procedure: Tailored surgery based on intraoperative local excision/biopsy

Tailored surgery

Procedure: Total mesorectal excision for all allocated patients

Total mesorectal excision (TME)

Sung-Bum Kang

Sung-Bum Kang, M.D., Ph.D

Duck-Woo Kim, M.D., Ph.D.

Heung-Kwon Oh, M.D., Ph.D.

The purpose of this study is to show that tailored treatment based on local excision can expand the target of non-radical treatment in ycT2-3N0M0 patients after neoadjuvant chemoradiotherapy for low rectal cancer and that the oncologic safety is not inferior to that of total mesorectal excision.

Target number of subjects and calculation basis This study aims to show that the tailored treatment based on intraoperative local excision/biopsy is not oncologically inferior to total mesorectal excision. The 5-year overall survival rate expected from the existing standard treatment was 85% (van der Valk. 2018, Rullier. 2020). The non-inferior margin of the customized treatment was 10%, type 1 error 0.10, power 80%, 1:1 ratio. When calculated with a 10% dropout rate, a total of 346 people, 173 in each group, needs to be recruited.

Study Subject Recruitment Plan

1. Selection and enrollment of subjects: Subjects in clinical trials must be enrolled by the investigator before starting surgical treatment.
2. Document consent: To the patient who is considered to be able to participate in the clinical trial as a subject, an oral explanation of this clinical trial will be presented to the participants, and the written consent to participate in the clinical trial shall be obtained.
3. Preoperative evaluation A pre-treatment examination to determine the selection of subjects and their underlying condition will be conducted. Pre-treatment examination will be performed to review whether the subject meets the selection and exclusion criteria, and subjects with significant abnormalities will be excluded.

Control group setting and randomization method Tailored treatment based on local excision and total mesorectal excision are randomly assigned 1:1 by web-based random number table (REDCap).

Statistical Analysis The statistical analyses will be conducted using intention-to-treat, and per-protocol approaches. Multiple imputation for missing covariates will be performed to determine whether there are systematic differences in terms of missing data. Analyses of the primary and secondary outcomes will be adjusted for potential co-variates.

Results of the quality of life and sexual/urinary function questionnaires will be compared using linear generalized estimating equations (GEE), adjusted for baseline values, the time effect, and the interaction effect between time and treatment.

Clinical and pathological variables will be compared using χ2 tests or Fisher's exact test for categorical variables, or with Student's t-test for continuous variables. Disease-free survival, relapse-free survival, and overall survival curves will be plotted using the Kaplan-Meier method, and differences in survival curves will be compared using the log-rank test. Multivariable analyses using the Cox regression hazard model will be conducted to identify the factors that are independently associated with disease-free survival, relapse-free survival, and overall survival. All statistical tests will be two-sided and values of p\<0·05 will be considered statistically significant.

Comparison Between Tailored Surgery Versus Total Mesorectal Excision in ycT2-3N0M0

Comparison of Oncologic Outcomes Between Tailored Surgery According to Intraoperative Local Excision Biopsy Versus Total Mesorectal Excision in ycT2-3N0M0 on Magnetic Resonance Imaging After Neoadjuvant Chemoradiotherapy for Low Rectal Cancer

The percentage of people in a study or treatment group who are alive five years after their diagnosis or the date of randomization

Postoperative recovery index, surgery-related complications, and mortality comparison (Clavien-Dindo classification III-V), histopathologic examination of the proximal/distal/peripheral margins

Rate of Disease-free Survival/Relapse-free Survival/Stoma-free Survival/Regrowth-free Survival through physical examination including digital rectal examination, carcinoembryonic antigen test (CEA), liver function test (AST/ALT), chest and abdominal CT and colonoscopy

The Korean version of EORTC QLQ 30 which is an evaluation instrument for the quality of life of cancer patients, and the Korean version of EORTC QLQ-CR29 which is an evaluation instrument for the quality of life of colon cancer patients.

IPSS (International Prostate Symptom Score) for urinary function test, IIEF-5 (5-item Version of the International Index of Erectile Function) for male sexual function test, FSFI (Female Sexual Function Index) for female sexual function test.

MSKCC questionnaire, fecal incontinence severity index (FISI), low anterior resection syndrome (LARS) score questionnaire and fecal incontinence quality of life index (FIQL), manometry

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Multicenter, Prospective, RCT：Investigation of Combined Modality Therapy for Locally Advanced Mid/Low Rectal Cancer.	NCT03042000	Rectal Cancer, ... Neoadjuvant Che...	non-NCRT NCRT capecitabine wi... capecitabine TEM radical resecti...	18 Years - 75 Years	Peking Union Medical College Hospital
Induction Chemotherapy Plus Chemoradiotherapy With or Without Aspirin in High Risk Rectal Cancer	NCT03170115	Rectal Cancer, ... Locally Advance... Chemoradiation	Aspirin Placebo Oral Ta...	18 Years - 75 Years	Instituto Nacional de Cancer, Brazil
Prehabilitation in Rectal Cancer: During Neoadjuvant Therapy vs Preoperative	NCT05286086	Rectal Cancer, ... Chemoradiothera...	prehabilitation	18 Years -	Corporacion Parc Tauli
Comparison Between Tailored Surgery Versus Total Mesorectal Excision in ycT2-3N0M0	NCT05164315	Rectal Cancer, ...	Tailored surger... Total mesorecta...	18 Years - 80 Years	Seoul National University Hospital
Comparison Between Tailored Surgery Versus Total Mesorectal Excision in ycT2-3N0M0	NCT05164315	Rectal Cancer, ...	Tailored surger... Total mesorecta...	18 Years - 80 Years	Seoul National University Hospital
Prehabilitation in Rectal Cancer: During Neoadjuvant Therapy vs Preoperative	NCT05286086	Rectal Cancer, ... Chemoradiothera...	prehabilitation	18 Years -	Corporacion Parc Tauli

Spots Global Cancer Trial Database for rectal cancer, adenocarcinoma