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:
Consolidation capecitabine (alone): 1000mg/m2 bid, for 14 days, in a 3 week cycle,
for 4 cycles
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
Assessment of response will be performed at 12 weeks (and 18 weeks from last date of
radiation therapy if cCR or near-complete response is detected at 12 weeks). All patients
will undergo endoscopic reassessment, DRE and high-resolution MR. Endoscopic biopsies
will be at the discretion of the attending surgeon/endoscopist.
Patients with complete or near-complete clinical response at 12 weeks will be recommended
reassessment at 18 weeks from RT. Patients with clinically overt incomplete clinical
response at 12 or 18 weeks will be referred to immediate radical surgery.
Randomization
Individuals will be randomized and allocated at a 1:1 ratio to the two groups (control
and experimental) using a permuted block design with a random block size of 4, 6, and 8.
(1-3) A randomization list will be generated electronically using appropriate software
immediately after being considered eligible.
Protocol Blinding
Patients and attending physicians will not be blinded to the treatment arm randomized for
each patient. However, as a strategy to reduce investigator's expectations and reduce
inherent bias, the central committee will be blinded to the treatment arm. It is expected
that blinding the central committee, who will be responsible for assessing the primary
endpoint, any bias related to the investigator's expectation about the treatment arm and
the chances of Watch and Wait will be nulled.
Sample size calculation
The primary endpoint (decision to WW due to cCR/near CR) was observed in 55% and 85% at
12 weeks (in contrast to the 18 weeks used in the present trial) among patients with
early cT3 and cT2 rectal cancer respectively.29 In this study, there was a distribution
of 66% of cT3 and 33% cT2. Therefore, response rates appear to be highly dependent on
exact T-stage distribution. Considering the expected inclusion of more advanced disease
(late mrT3 or even mrT4 rectal cancers) the investigators expect 40% cCR/near-CR in the
control arm. A similar difference 60% versus 40% was achieved in the preliminary report
of the outcomes of the OPRA trial. This difference in TME-free survival at 3 years was
statistically significant favoring patients undergoing nCRT with cCT in comparison to
nCRT preceded by induction chemotherapy (both regimens incorporating oxaliplatin). In
this setting, if experimental results in ≥60% cCR/near-CR, the study will be considered
POSITIVE. The incorporation of oxaliplatin to a consolidation CRT regimen that results in
≥20% increase in cCR/near-CR exceeds the potential disadvantages of treatment-related
toxicity.
The investigators will assume that the primary outcome will occur in 40% of individuals
in control group and 60% in the experimental group, which corresponds to an absolute
difference in proportions of 20%. It is estimated that a sample of 194 (97 per group)
provides 80% statistical power to detect this difference at a significance level of 5%
using the Chi-square test and assuming a two-sided significance hypothesis and
considering a 1:1 allocation. The estimated dropout rate is 10% in each group, so it is
expected to include 216 individuals (108 per group). The sample size calculation was
performed using SAS 9.4 (PROC POWER procedure).
Time-table
Patient accrual: 2 years and 6 months Patient/institution/year: 5-6 (20 institutions:
100-120/year - 2 years n=200-240)
Interim analysis:
If the arm of two drugs during consolidation shows ≥25% response rate after 72 patients,
study will be interrupted (efficacy). If the arm of two drugs shows less than 5% response
rate after 72 patients, the study will be interrupted.