Organ Preservation in Rectal AdenoCa Using Hypofractionated Pelvic RT(Hypo-OPRA)

Official title

Organ Preservation in Rectal Adenocarcinoma Using Hypofractionated Pelvic Radiotherapy (Hypo-OPRA): A Phase II Clinical Trial

Overview

The combination of preoperative pelvic RT - either long-course chemoradiotherapy (LCCRT) or short-course radiotherapy (SCRT)- followed by surgery has been the standard of care in the curative treatment of locally advanced adenocarcinoma of the rectum for decades. Some patients however achieve a complete clinical response (cCR) to their preoperative treatment which opens the possibility of avoiding surgery and consequently preserving the rectum. There now exists a growing body of data from centres around the world validating the safety of a surveillance approach in clinical complete responders treated with LCCRT.

Detailed description

At McGill, SCRT is used routinely as a pre-operative radiotherapy schedule for locally advanced adenocarcinomas of the rectum. Likewise SCRT followed by chemotherapy is already used routinely at McGill as a pre-operative regimen for locally advanced rectal cancer with high risk features. Compelling registry data from Scandinavia shows that enduring clinical complete responses can be achieved after SCRT. To date, however, nearly all of the published data supporting a surveillance strategy in complete clinical responders is based on LCCRT. The present study proposes to explore further the organ preservation potential of SCRT.

Adopting a non-operative strategy in rectal cancer patients who achieve complete tumour regression avoids the risks of surgical morbidity and mortality, notably a sparing of the rectal sphincter muscles in the case of low-lying tumours and consequently avoidance of a permanent stoma.

Although multiple phase III trials support the routine use of SCRT in the pre-operative setting for locally advanced rectal adenocarcinoma, to date nearly all of the published data supporting a surveillance strategy in complete clinical responders is based on LCCRT. Compelling registry data from Scandinavia does show that enduring clinical complete responses can be achieved after short-course pelvic radiotherapy. Furthermore, the Rectal Cancer and Pre-operative Induction Therapy Followed by Dedicated Operation (RAPIDO) study demonstrated that, compared with LCCRT, SCRT followed by chemotherapy (SCRT-CH) has a higher pathologic complete response rate (29% versus 14%), less disease-related treatment failure, and superior distant metastasis-free survival.

Short-course pelvic radiotherapy with or without sequential chemotherapy can induce enduring clinical complete responders and the use of SCRT as part of a non-operative organ preservation strategy merits further prospective exploration. At McGill, SCRT is already used routinely as a pre-operative dose schedule for clinically node negative/N1 locally advanced adenocarcinomas of the rectum where downsizing is not required to achieve a sphincter sparing R0 resection. Likewise, since the publication of the RAPIDO trial, SCRT followed by FOLFOX/CAPOX chemotherapy has emerged as the preferred regimen at McGill for patients with high risk features (cT4 disease, cN2 and/or extramesorectal nodes, EMVI+, threatened or involved mesorectal fascia and/or sphincter muscles). The present phase II prospective study proposes to explore further the organ preservation potential of SCRT combined with a simultaneous integrated boost on sites of gross disease..

Interventions

• Radiation Radiation Therapy
  High Dose Hypofractionated Radiotherapy 35 Gy over 5 fractions.
• Drug FOLFOX regimen
  Radiosensitizing chemotherapy
• Drug Capecitabine
  Radiosensitizing chemotherapy

Primary outcome measures

• Feasibility of Hypo-fractionated Approach in 5 fractions for a dose of 35Gy [Time frame: One year]

Eligibility criteria

Inclusion criteria

• Histologically confirmed invasive adenocarcinoma of the rectum
• Pelvic MRI defined disease (at least one of the following):

mesorectum involved or breached - includes involvement of adjacent organ(s) (T3-T4)

• Patients are considered medically fit for oncologic resection
• ECOG performance status 0 or 1
• No evidence of established metastatic disease (CT chest and abdomen)
• Absolute neutrophil count >1.5x109/L; platelets >100x109/L,
• Serum transaminase <3 x ULN;
• Adequate renal function (Cockroft Gault estimation >50 mL/min)
• Bilirubin <1.5 x ULN
• Ability to comply with oral medication
• Willingness and ability to give informed consent and comply with treatment and follow up schedule
• Age 18 or over

Exclusion criteria

• Previous chemotherapy
• Previous radiotherapy to the pelvis (including brachytherapy)
• Uncontrolled cardiorespiratory comorbidity (includes patients with inadequately controlled angina or myocardial infarction within 6 months of randomisation)
• T1 or T2 N0 disease without extra-mural venous invasion
• Unequivocal evidence of metastatic disease (includes resectable metastases)
• Major impairment of bowel function without defunctioning stoma/ileostomy (baseline grade 3 diarrhoea or clinically significant faecal incontinence
• Known dihydropyrimidine dehydrogenase deficiency
• History of another malignancy within the last 5 years except successfully treated basal cell cancer of skin or carcinoma in situ of uterine cervix.
• Known Gilberts disease (hyperbilirubinaemia)
• Taking warfarin or phenytoin or sorivudine
• Gastrointestinal disorder which would interfere with oral therapy and its bioavailability
• Pregnant, lactating, or pre-menopausal women not using adequate contraception
• Unfit to receive any study treatment or subsequent surgical resection

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 1 center

• McGill University Health Centre — Montreal

Publications

• Kim H, Pedersen K, Olsen JR, Mutch MG, Chin RI, Glasgow SC, Wise PE, Silviera ML, Tan BR, Wang-Gillam A, Lim KH, Suresh R, Amin M, Huang Y, Henke LE, Park H, Ciorba MA, Badiyan S, Parikh PJ, Roach MC, Hunt SR. Nonoperative Rectal Cancer Management With Short-Course Radiation Followed by Chemotherapy: A Nonrandomized Control Trial. Clin Colorectal Cancer. 2021 Sep;20(3):e185-e193. doi: 10.1016/j.cl PMID 34001462
• Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID, Beets-Tan RGH, Blomqvist LK, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes A, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versu PMID 33301740
• Nilsson PJ, Ahlberg M, Kordnejad S, Holm T, Martling A. Organ preservation following short-course radiotherapy for rectal cancer. BJS Open. 2021 Sep 6;5(5):zrab093. doi: 10.1093/bjsopen/zrab093. PMID 34686879
• Temple LK, Bacik J, Savatta SG, Gottesman L, Paty PB, Weiser MR, Guillem JG, Minsky BD, Kalman M, Thaler HT, Schrag D, Wong WD. The development of a validated instrument to evaluate bowel function after sphincter-preserving surgery for rectal cancer. Dis Colon Rectum. 2005 Jul;48(7):1353-65. doi: 10.1007/s10350-004-0942-z. PMID 15868235
• Jorge JM, Wexner SD. Etiology and management of fecal incontinence. Dis Colon Rectum. 1993 Jan;36(1):77-97. doi: 10.1007/BF02050307. PMID 8416784
• Appelt AL, Ploen J, Harling H, Jensen FS, Jensen LH, Jorgensen JC, Lindebjerg J, Rafaelsen SR, Jakobsen A. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol. 2015 Aug;16(8):919-27. doi: 10.1016/S1470-2045(15)00120-5. Epub 2015 Jul 5. PMID 26156652
• Glynne-Jones R, Hughes R. Critical appraisal of the 'wait and see' approach in rectal cancer for clinical complete responders after chemoradiation. Br J Surg. 2012 Jul;99(7):897-909. doi: 10.1002/bjs.8732. Epub 2012 Apr 27. PMID 22539154
• Maas M, Beets-Tan RG, Lambregts DM, Lammering G, Nelemans PJ, Engelen SM, van Dam RM, Jansen RL, Sosef M, Leijtens JW, Hulsewe KW, Buijsen J, Beets GL. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011 Dec 10;29(35):4633-40. doi: 10.1200/JCO.2011.37.7176. Epub 2011 Nov 7. PMID 22067400

Identifiers

NCT: NCT06991465 · 2023-9472

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗