Chemoradiation and Consolidation Chemotherapy With or Without Oxaliplatin for Distal Rectal Cancer and Watch and Wait

Patients and Methods

Patients with distal rectal cancer will be eligible for the study after initial clinical, endoscopic and radiological assessment. At this point, patients will be offered to participate in the study and after informed consent, randomized to control or experimental arms as follows.

Endpoints

Primary endpoint: Decision to Watch and Wait due to clinical complete response achieved at 18 weeks from last date of radiation using clinical (DRE), endoscopic and radiological criteria (mrTRG grade) or near-complete clinical response (no progressive disease clinically, endoscopically or radiologically)

Definition of clinical complete response (cCR) available below and at the discretion of the attending surgeon.

Definition of radiological complete response as described below (centralized).

Patients will be counted as event if at 18 weeks the decision is to interrupt Watch and Wait and proceed to surgery (any kind) because of overt incomplete clinical response. In order to standardize assessment of response and reduce inter-observer variability, the decision to continue on Watch and Wait (or not) will be at the discretion of the central committee during central revision of studies.

Secondary endpoints:

* Surgery-free survival at 3 years * TME-free survival at 3 years * Distant metastases free survival at 3 years * Local regrowth-free survival at 3 years * Colostomy-free survival at 3 years

Definitions

Definition of cCR:

* Endoscopic: white scar, teleangiectasia, absence of ulceration and/or mass 6 * Clinical: no irregularity, firm area with minor induration6 * Radiological: mrTRG1: fibrosis with low signal intensity seen on T2 weighted images replacing the primary tumor; no restricted diffusion on diffusion weighted images; no nodes with border irregularity or mixed signal intensity; no extramural vascular invasion23-26

Definition of near-complete response:

* Endoscopic: residual tumor size ≤2cm (or reduction of ≥70% original tumor volume/size) 4,27,28 * Clinical: only superficial ulceration or minor (questionable) irregularities of the mucosal/rectal wall * Radiological: mrTRG2 predominant fibrosis with low signal with foci of intermediate tumor signal intensity seen on T2 weighted images with or without restricted diffusion; mrTRG1: fibrosis with low signal intensity seen on T2 weighted images replacing the primary tumor with restricted diffusion; no nodes with border irregularity or mixed signal intensity; no extramural vascular invasion 27

Central Committee

The central committee is multidisciplinary group of surgeons, medical oncologists and radiologists previously appointed at the beginning of the recruitment of patients and with previous experience with organ preservation.2, 21 This group of specialist will be responsible to assess the baseline staging and define if the patients fulfill all the inclusion/exclusion criteria prior to randomization. The committee will also be responsible to evaluate the endoscopic and radiological tumor re-assessment studies at 12 and 18 weeks from radiation completion. The definition to continue on the Watch and Wait pathway or not will be at the discretion of this committee.

Technical aspects of assessment tests:

Suggested MR protocol:

1.5T - FRFSE; TR/TE: 3300/120 (ms); slice thickness/gap: 3.0/0; Matrix: 256 x 256; NSA 8) 3.0T - FRFSE; TR/TE: 8000/150 (ms); slice thickness/gap: 3.0/0; Matrix: 288 x 288; NSA 5) DWI - inclusion of a high b-value of at least 800

Suggested Endoscopic assessment:

Endoscopic assessment using a flexible scope (gastroscope preferred for retroflexion); direct endoscopic and retroflexion view of the primary tumor/scar; endoscopic biopsies at discretion of participating center.

Radiotherapy

Preoperative radiotherapy will be delivered on a linear accelerator in prone or supine position, preferably with full bladder. The use of a belly board is allowed. Isocentric 3 or 4 fields, as well as an IMRT technique is allowed, as long as all beams are treated on a daily basis. The dose distribution and calculation should be performed on CT or MRI and specified according to the ICRU 50 guidelines.

Dose specification: All patients will receive 25 daily fractions of 1.8 Gy up to a total dose of 45 Gy to the pelvic field including the tumor bed with a margin and the regional lymph nodes. A field reduction after 45 Gy is recommended up to 54 Gy. The last 5 fractions will then be given to the tumor bed with a margin.

Target volume:

Pelvic CTV

* The primary tumor * Mesorectum: Distally, only lymph nodes or tumor deposits up to 4 cm are included. For tumors in lower rectum this means that the entire mesorectum down to the pelvic floor is included. * Presacral nodes and nodes along the rectal superior artery: Since local recurrences are very unusual above S1 - S2, lymph nodes above this level should not be included unless there are signs of radiologically positive lymph nodes presacrally. If this is the case, the cranial limit of CTV should be at least 1 cm above the most cranial radiologically positive lymph node. * Lateral lymph node stations: Until they reach the level of the obturator canal Internal iliac artery up to the bifurcation from the external iliac artery. The cranial border for the CTV is in most cases just below the bifurcation of the internal and external iliac arteries. In most patients this is at the level of S1 - S2. * Ischio-rectal fossa and the anal canal: Included in pelvic CTV only if the tumor grows into the levators or down into the anal canal. * Lymph nodes along the external iliac artery: Included if the tumor grows into anterior organs like the prostate, urinary bladder, cervix, vagina or uterus to such an extent that the external nodes are at risk for metastases.

Boost GTV:

GTV is the visible primary tumor and radiologically positive lymph nodes.

CTV boost:

GTV boost plus a margin of 2 cm within the same anatomical compartment as the tumour is in, for the dose of 45 Gy, also around radiologically engaged lymph nodes.

PTV:

The above description relates to the CTV. A PTV should normally be defined and includes CTV and internal target volume (ITV) and a margin necessary for the setup. These margins are depending upon several factors that are related to the equipment at each radiotherapy center.

Chemotherapy Protocols

Concomitant chemotherapy:

Concomitant capecitabine: 825mg/m2 bid on the radiotherapy days only

Consolidation chemotherapy:

1. Consolidation capecitabine (alone): 1000mg/m2 bid, for 14 days, in a 3 week cycle, for 4 cycles 2. Consolidation options with oxaliplatin:

2.1. mFOLFOX6: Oxaliplatin 85mg/m2 plus Leucovorin 400mg/m2 on a concomitant 2 hours infusion. 5FU 400mg/m2 on a bolus infusion, followed by 5FU 2400mg/m2 in 46 hours infusion, every 2 weeks, for 6 cycles 2.2. CAPOX: Oxaliplatin 130mg/m2 on a 2 hours infusion. Capecitabine 1000mg/m2 bid daily, for 14 days, starting on the evening of the oxaliplatin infusion. Repeat every 3 weeks, for 4 cycles

Assessment of Response

• Surgery-free survival at 3 years [Time frame: 3 years from last date of radiation]
• Total Mesorectal Excision-free survival at 3 years [Time frame: 3 years from last date of radiation]
• Distant metastases free survival at 3 years [Time frame: 3 years from last date of radiation]
• Local regrowth-free survival at 3 years [Time frame: 3 years from last date of radiation]
• Colostomy-free survival at 3 years [Time frame: 3 years from last date of radiation]