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Patients with low rectal cancer who have achieved a complete clinical response following chemoradiotherapy will undergo active follow-up with regular clinical visits, physical exam, endoscopy and imaging assessments at regular intervals for 2 years to assess for tumour re-growth or spread to the liver and lungs

Patients who are eligible and provide informed consent to participate in the trial will undergo non-operative management (i.e., active surveillance for 24 months) according to the schedule outlined in the study protocol.

Non-operative management

Erin Kennedy

Selina Schmocker

This is a 5 year Phase II study to evaluate the safety of non-operative management (NOM) in patients with low rectal cancer (LRC) who achieve a complete clinical response (cCR) following chemoradiotherapy (CRT). The safety of NOM will be evaluated by assessing (i) rate of local re-growth and (ii) rate of macroscopically positive resection margin (R2) when surgery is required due to local re-growth. NOM will be considered safe or as effective as surgery to achieve local control if the rate of local re-growth is equal to or less than 30% and the rate of a macroscopically positive margin is 0%.

Background: The standard treatment for low rectal cancer (LRC) involving the anal sphincter involves combined, pre-operative chemotherapy and radiotherapy (CRT) followed by surgery. Surgery involves removal of the rectum and anus and creation of a permanent colostomy and has significant long term effects on bowel and sexual function and body image. Because of the high morbidity of surgery, there has been increasing interest in non-operative management (NOM) for LRC. The NOM approach involves deferral of surgery and active surveillance of all patients with LRC who have achieved a complete clinical response (i.e., have no residual tumour) following completion CRT which occurs in approximately 30% of patients. To date, while there have been a few, prospective single institution studies that have shown favourable results with NOM, this approach has not been adopted into clinical practice due to concerns from physicians about the safety of NOM based on the limited evidence available.

Objectives: Therefore, the objective of this study is to conduct a pan-Canadian Phase II trial to assess the safety of NOM for LRC.

Methods: All patients with LRC requiring surgery and a permanent colostomy being treated at the participating centres will be assessed for complete clinical response (cCR) eight to ten weeks following the completion of CRT by the treating surgeon. For the study, a cCR will be defined as (i) no palpable tumour on digital rectal exam, (ii) no residual tumour defined as white-yellow, flat scar on endoscopy, (iii) no residual tumour on MRI, (iv) no suspicious mesorectal or extramesorectal lymph nodes on MRI and (v) normal CEA level. Patients who meet all of these criteria for cCR will be invited to participate in the study. Patients who consent to participate in the study will undergo active surveillance that will include DRE, endoscopy and pelvic MRI every 3, 6, 9, 12, 18 and 24 months; CEA levels every 3, 6, 9, 12, 15, 18, 21, 24 months and CT chest/abdomen and pelvis every 6, 12, 18 and 24 months. The primary outcome for the study will be the rate of local re-growth 2 years following the completion of CRT. Local re-growth will be defined as failure to meet the cCR criteria at any time point. NOM will be considered safe, if the rate of local re-growth is less than 30% two years after the completion of CRT. The secondary outcomes for the study will be the rate of distant recurrence, disease free and overall survival at 2 years.

Significance: The results of this study will be highly clinically relevant since it is expected that NOM for LRC will be safe and will have significant potential to change clinical practice in Canada and North America since approximately 30% of patients with LRC would be able to safely avoid surgery and a permanent colostomy and have improved bowel and sexual function and body image. Furthermore, widespread adoption of NOM has the potential to increase health care capacity and decrease treatment costs by reducing the number of surgeries, hospital admissions and costs associated with both surgery and long term surgical morbidity.

Non-operative Management for Locally Advanced Rectal Cancer

Phase II Study to Assess the Safety of Non-operative Management for Low Rectal Cancer

The safety of non-operative management will be evaluated by assessing the rate of local re-growth in the study population. This approach will be considered safe if the local re-growth rate is equal to or less than 30%.

The safety of non-operative management will be evaluated by assessing the rate of macroscopically positive resection margin following surgery in the study population. This approach will be considered safe if the rate is 0%.

Rate of overall survival in the study population assessed 2 years after completion of CRT

Rate of disease-free survival in the study population assessed 2 years after completion of CRT

Rate of colostomy-free survival in the study population assessed 2 years after completion of CRT

Quality of life will be measured using the EORTC C30 questionnaire and will be assessed at 6, 12 and 24 months.

Bowel function will be measured using the MSKCC Bowel Function Instrument and will be assessed at 6, 12 and 24 months.

Mount Sinai Hospital, Canada

Rectal resection

Observation

Ivan Cecconello, MD

Ulysses Ribeiro, MD

With the possibility of pathological complete response in surgical specimens, some authors have proposed non-operative management of the patient group, when re-staged after neoadjuvant treatment, have complete clinical response. So far, this approach remains discussed in the literature, and there are still many uncertainties that patients with clinical complete response after chemoradiotherapy in fact no detectable viable tumor and may be omitted of radical surgical treatment. It is a still investigational approach and actually gained space even for patients with very high or who refuse surgery after all clarifications surgical risk.

Hypothesis: The preservation of the rectum in patients with adenocarcinoma of the middle and distal rectum (up to 10 cm) reaching clinical complete response after neoadjuvant chemoradiotherapy have similar rate of the rectal cancer recurrence than patients who underwent surgical rectal resection.

This will be a prospective, randomized, open label phase II of surgical resection versus conservative treatment (observation) in patients with mid and distal rectal cancer who achieved complete after neoadjuvant chemoradiotherapy combined with clinical response.

The main objective of this study is to assess whether conservative approach is similar to rectosigmoidectomy with complete mesorectal excision or amputation abdminoperineal the rectum in patients with complete clinical response after neoadjuvant therapy combined chemoradiotherapy.

Patient Selection: To be eligible patients who have neoadjuvant prior histologic diagnosis of rectal adenocarcinoma, tumors located within 10 cm from the anal verge, a complete clinical response after treatment with chemoradiotherapy for rectal tumors staged clinical and radiological T3-4 N0 M0 or T (any) N + M0, absence of colorectal synchronous tumors.

Treatment: Eligible patients will be randomized 1:1 to resection of the rectum or notice. The period for randomization of patients will be 12 weeks after the last dose of radiotherapy / chemotherapy, so that we can properly assess the antitumor response as described above. After randomization, patients in the surgical group will undergo resection of the rectum with complete excision of mesorectal within 2 weeks after randomization.

Observation Versus Surgical Resection in Patients With Rectal Cancer Who Achieved Complete Clinical Response After Neoadjuvant Chemoradiotherapy

Open Randomized Study of Observation Versus Surgical Resection in Patients With Rectal Cancer Who Achieved Complete Clinical Response After Neoadjuvant Chemoradiotherapy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Non-operative Management for Locally Advanced Rectal Cancer	NCT03179540	Rectal Neoplasm...	Non-operative m...	18 Years -	Mount Sinai Hospital, Canada
Non-operative Management for Locally Advanced Rectal Cancer	NCT03179540	Rectal Neoplasm...	Non-operative m...	18 Years -	Mount Sinai Hospital, Canada
Observation Versus Surgical Resection in Patients With Rectal Cancer Who Achieved Complete Clinical Response After Neoadjuvant Chemoradiotherapy	NCT02052921	Rectal Cancer	Rectal resectio... Observation	18 Years - 75 Years	Instituto do Cancer do Estado de São Paulo

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