Randomized Multicentre Phase III study of short course radiation therapy followed by prolonged pre-operative chemotherapy and surgery in primary high risk rectal cancer compared to standard chemoradiotherapy and surgery and optional adjuvant chemotherapy (RAPIDO study)

In patients with a newly diagnosed rectal cancer at high risk of failing
locally and/or systemically standard therapy is long-course preoperative
radiotherapy with concomitant chemotherapy followed by surgery after 6-10
weeks. Despite lack of strong scientific evidence, postoperative adjuvant
chemotherapy is added in many centres.
To achieve higher compliance and better effect of chemotherapy, the aim is to
deliver the systemic treatment pre-operatively. Most standard adjuvant
chemotherapy schedules in colorectal cancer have a duration of 24 weeks.
Modifications of current standard therapy could theoretically include increase
of dose or number of chemotherapy agents for the concomitant therapy but this
would increase toxicity and possibly decrease compliance. Long-course
radiotherapy takes 5-6 weeks to deliver and to postpone all locoregional
therapy in order to start with systemic chemotherapy would not gain acceptance
because of the risk of local progression. An alternative to modifications of
the present long-course schedule is to explore the possibilities of using a
short-course radiotherapy regimen in the locoregional therapy and combine this
with pre-operative chemotherapy.
A peri-operative chemotherapy regimen was successfully explored for liver
metastases of colorectal cancer in the EORTC-EPOC trial and with a similar
schedule a trial with an experimental arm consisting of 12 weeks of
chemotherapy pre-operatively followed by short-course radiotherapy and
immediate surgery and 12 weeks of post-operative chemotherapy could be
considered. This design would, however, have some drawbacks including no
locoregional therapy initially and the risk of not being able to deliver half
of the chemotherapy to a substantial proportion of the patients. Moreover, when
surgery is performed immediately after radiotherapy, the desired down-staging
on these locally advanced tumours may not occur, leading to a potential risk of
decreased local control rates.
Yet another alternative is to explore possibilities connected with using the
short-course radiotherapy with delayed surgery as the locoregional therapy.
Again there would be potential problems connected with starting with systemic
therapy whereas putting the week of radiotherapy first is an option that offers
part of the locoregional therapy first. One of the advantages of the
short-course schedule is the low toxicity (in particular acute toxicity) which
implies that a vast majority of patients would be able to start full-dose
systemic chemotherapy a week or two after radiotherapy. Data from retrospective
trials and the *M1 trial* support the notion that systemic chemotherapy also
acts on the primary tumour, thus leading to improved locoregional therapy as
compared to short-course and a *waiting period* without chemotherapy. However,
in order to minimise interval between radiotherapy and surgery and still being
able to deliver all systemic chemotherapy prior to surgery, adjustments of
standard chemotherapy schedules for colorectal cancer may be necessary. The
schedule explored in the *M1 trial* consisting of 18 weeks with
oxaliplatin/capecitabine is 6 weeks shorter than commonly used in
post-operative adjuvant schedules and offers an attractive alternative.
Bevacizumab was included in the *M1 trial* but there is no data suggesting that
bevacizumab or cetuximab improves the antitumour effects against subclinical
disease.

Primary Objective: disease related treatment failure.
Secondary Objectives: Overall survival, CRM negative (margin > 1 mm) rate,
Pathological complete response (pCR) rate, Short and long-term toxicity,
Surgical complications, Quality of life. Pharmacogenomics.

Multicenter randomized open phase III parallel group study.
Patient will be randomly allocated to either:
• Standard treatment: week 1-6 : Chemoradiotherapy (CRT): 28 x 1.8 Gy at
working days combined with capecitabine b.i.d. 825 mg/m2 day 1-38. 6-8 weeks
after CRT: Surgery (TME). Adjuvant chemotherapy 8 cycles of CAPOX (Capecitabine
b.i.d.1000 mg/m2 day 1-14 every 3 weeks, Oxaliplatin 130 mg/m2 day 1 every 3
weeks) is allowed according to the local protocol of the particular institute,
starting preferably 6-8 and max. 12 weeks after surgery.
• Experimental treatment: Week 1: 5 x 5 Gy. Week 3-18: 6 courses of
Capecitabine b.i.d.1000 mg/m2 day 1-14 every 3 weeks, Oxaliplatin 130 mg/m2 day
1 every 3 weeks. Week 22-24: Surgery(TME).
Follow-up until 2 years after inclusion of last patient. Total study duration
estimated 6 years.
885 patients to be included.
Independent DSMB.

Standard or experimental treatment.

Risk: adverse events and less effective experimental treatment.
Burden:
Quality of Life questionnaires (3 after OK). Optional farmacogenomics substudy:
in total 120-180 ml blood.
In hospitals with standard treatment without adjuvant chemotherapy: 6 infusions
of Oxaliplatin in the experimental arm.