Comparison of Responses after two Total Neoadjuvant Treatment Protocols in Rectal Cancer: A prospective phase II Randomised Controlled Trial

Trial summary

PROTOCOL TITLE

Comparison of Responses after two Total Neoadjuvant Treatment Protocols in Rectal Cancer: A prospective phase II Randomised Controlled trial  (RETAIN)

|RATIONALE

With the emergence of data from  landmark randomized controlled trials including RAPIDO, PRODIGE-23 and OPRA, total neoadjuvant therapy (TNT) has become the standard of care for the treatment of locally advanced rectal cancer. All these trials have shown better response rates in the TNT arm as compared to standard neoadjuvant chemoradiation arms. However there is no head to head comparison between different TNT arms in terms of tumor response and the optimal sequencing of TNT is still undecided.

|AIM

The aim of this study is to compare the clinical complete response rates (cCR) rates in concurrent chemoradiation followed by chemotherapy followed by surgery(Arm A) vs short course radiotherapy followed by chemotherapy followed by surgery arm (Arm B)

|PRIMARY STUDY OBJECTIVES

The primary objective of this study is to compare the clinical complete response  rates (cCR) between concurrent chemoradiation followed by chemotherapy followed by surgery(Arm A) vs short course radiotherapy followed by chemotherapy followed by surgery arm (Arm B).

cCR is defined as flat white scar or telangiectasia on colonoscopy.There will be no ulceration or nodularity on endoscopic examination. DRE (Digital rectal examination) should be normal. MRI pelvis will show thin low signal fibrosis with no evidence of intermediate signal intensity

|STUDY DESIGN

This will be a  two-arm, parallel group, phase II open-label  randomized controlled trial. Patients will be enrolled in a phase II trial where the primary endpoint will be clinical complete response rates in two TNT arms(Arm A and Arm B).If the primary endpoint is met, a phase III trial will be initiated using the same trial design and intervention.

|TRIAL POPULATION

Inclusion Criteria:

1.Older than 18 years of age  and less than 70 years

2.Clinical stage II (T3c-T4, N0) or stage III (any T, N1-2) biopsy proven rectal adenocarcinoma staged with magnetic resonance imaging (MRI), a full colonoscopy, and computed tomography (CT) of the chest, abdomen, and pelvis.

3.Eastern Cooperative Oncology Group (ECOG) score 0-1

4.Fit for Capecitabine-Oxaliplatin(CAP-OX) or FOLFOX  based chemotherapy

5. Tumors located up to 10 cm from anal verge

6. Blood parameters: a white blood cell count of 4·0 × 10⁹ cells per L or higher, platelet count of 100 × 10⁹ per L or higher, a clinically acceptable haemoglobin level, a creatinine level indicating renal clearance of 50 mL/min or higher, and bilirubin level below 2mg/dl

Exclusion criteria:

1.Evidence of distant metastasis

2. Recurrent disease

3. Prior history of pelvic irradiation

4.Pelvic Kidney

5. Collagen vascular disease

6.ECOG performance status 2-3

7. Deranged kidney function tests

8.Not fit for Cap-OX or FOLFOX based chemotherapy

|TREATMENT REGIMEN

Arm A:

Radiotherapy will be  planned using  three dimensional conformal radiotherapy(3DCRT) or intensity modulated radiotherapy (IMRT) to deliver 4,500 cGy in 180 cGy over 25 fractions to regional pelvic nodes. A total dose of  50.4Gy  will be  delivered to the primary tumor including the mesorectum, and involved nodes with a sequential boost or simultaneous integrated boost. Patients will receive Capecitabine (825 mg/m2 twice a day orally only on the days of radiation) during radiotherapy as per our institutional protocol. After 3 weeks of concurrent chemoradiation patients will  receive 6 cycles of capecitabine and oxaliplatin (CAPEOX; oxaliplatin 130 mg/m2 on day 1 and capecitabine at 1,000 g/m2 twice a day on days 1-14, repeated on a 21-day cycle ) or  9 cycles of infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX; oxaliplatin 85 mg/m2 intravenous [IV], leucovorin 400 mg/m2 IV, FU 400 mg/m2 IV push, and FU 2,400 mg/m2 over 46-48 hours by continuous infusion, repeated on a 14-day cycle). Tumor restaging will be  performed by digital rectal examination, colonoscopic examination, MRI pelvis, and CT of the chest, abdomen, and pelvis  around 2 weeks after chemotherapy. Surgery  will be performed after 4-5 weeks of completion of the chemotherapy.

Arm B:

Radiotherapy will be  planned using  three dimensional conformal radiotherapy(3DCRT) or intensity modulated radiotherapy (IMRT) to deliver 25 Gy in 5 fractions over one week  to the primary tumor including the mesorectum, involved nodes and elective  regional pelvic nodes. After 2 weeks of  short course radiotherapy  patients will  receive 6 cycles of capecitabine and oxaliplatin (CAPEOX; oxaliplatin 130 mg/m2 on day 1 and capecitabine at 1,000 g/m2 twice a day on days 1-14, repeated on a 21-day cycle ) or  9 cycles of infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX; oxaliplatin 85 mg/m2 intravenous [IV], leucovorin 400 mg/m2 IV, FU 400 mg/m2 IV push, and FU 2,400 mg/m2 over 46-48 hours by continuous infusion, repeated on a 14-day cycle). Tumor restaging will be  performed by digital rectal examination, colonoscopic examination, MRI pelvis, and CT of the chest, abdomen, and pelvis  around 2 weeks after chemotherapy. Surgery  will be performed after 4-5 weeks of completion of the chemotherapy.

|RECRUITMENT TARGET

The study will be  designed as a phase II randomized controlled trial.Based on the observed trends in pCR rates ,we postulate that a similar pattern may be evident in the rates of achieving Complete Clinical Response (CCR) between the twoTNT and  groups(Arm A and Arm B). Therefore, it is reasonable to anticipate that the difference in CCR rates between the two treatment arms would also approximate around 10%, mirroring the discrepancy observed in pCR rates.Given that the study involves comparing means between two groups and follows a 1:1 allocation ratio, the total sample size of 212 would be evenly divided between the two groups. Therefore, approximately 106 participants would be allocated to each group. Therefore, based on this analysis, a sample size of 212 participants, with approximately 106 participants in each group, would be recommended for the study to compare means with the desired precision and coverage probability adequately.

We assume that it will take 3 years time to recruit these patients and within 6 months of recruiting the last patient we will perform primary endpoint analysis.

|PRIMARY ENDPOINT

1. Clinical Complete response rates (cCR)

|KEY SECONDARY ENDPOINTS

1. To compare the pathological complete response rates(pCR)

2. To compare the disease free survival (after 2 years  from the recruitment of the last patient)

3. To compare distant metastasis free survival between the two arms(after 2 years  from the recruitment of the last patient)

4.To compare local recurrences between the two arms(after 2 years  from the recruitment of the last patient)

5.To compare the cumulative incidence of acute and late toxicities between the two arms. Toxicity will be reported using CTCAE V.5.0.

6. To compare compliance to surgery between the two arms

|FOLLOW UP

Patients will then be reviewed 3 monthly for 2 years, and then 6 monthly till 5 years. After 5 years an annual follow up will be recommended. Each patient is planned to complete the study treatment unless disease progression occurs or toxicity (CTCAE 5.0) prohibits further therapy. At each follow-up patient will undergo a clinical evaluation to document the disease status and document late toxicities. Serum CEA levels  will be tested during each follow up. CECT Thorax and abdomen and colonoscopy exam will be done annually. The patient follow up schedule will be maintained in the REDCap database and patients will be contacted at regular intervals to ensure adherence to follow up visits. In case the patient is unable to come for a physical follow up telemedicine follow-ups are allowed