Clinical trial NCT01951521: RECTAL BOOST Study
Official title: RandomizEd Controlled Trial for Pre-operAtive Dose-escaLation BOOST in Locally Advanced Rectal Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Rectal Cancer
Keywords: Rectal cancer
Locally advanced rectal cancer
Radiotherapy
Boost
Dose-escalation
Pathological complete response
Response
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: Maastro Clinic, The Netherlands
First posted: 2013-09-26
Enrollment: 128
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: cohort multiple randomized controlled trial
Primary purpose: TREATMENT

Brief summary: Randomized controlled trial in which the effect is investigated of a radiation boost in addition to standard chemoradiation in patients with locally advanced rectal cancer on complete response rate defined as pathological complete response, in those who undergo surgery, or 2-years local recurrence-free survival (2y-LRFS), in those who opted for a wait and see approach. Secondary objectives are adverse events due to chemoradiation (acute, perioperative and late toxicity), tumor response assessed with MRI, the impact of the boost on local and distant recurrence and survival as well as patient-reported quality of life and workability. The need for this comprehensive study is emphasized by the sub-optimal (radiation-) methods, heterogeneity between and poor reporting in the few previous trials in this field.

Detailed description: Rationale: The current treatment for locally advanced rectal cancer consists of pre-operative chemoradiation treatment (CRT) (50 Gray (Gy) in 25 fractions) followed by surgical resection, according to T-/N-stage, circumferential resection margin (CRM) and tumor localization (see table 1). After this neo-adjuvant treatment approximately 15% of patients show pathological complete response (pCR), i.e.no residual tumor in the resected specimen on pathologic examination. Patients with pCR have a lower risk of local and distant recurrences and significantly longer disease-free and overall survival. Furthermore, in these patients surgery could possibly have been omitted. Selected patients with a clinical complete response (cCR), defined prior to surgery by rectoscopy, rectal examination and magnetic resonance imaging (MRI), may opt for an organ-preserving therapy, a so called wait and see approach.

Response to chemoradiation occurs in a dose dependent fashion. Therefore, recent trials aimed to improve prognosis by radiation dose-escalation that resulted in improved pCR rates. Toxicity rates associated with radiation doses above 60 Gy are manageable and differ between studies; from increased to comparable or even lower toxicity. Moreover, dose escalation may increase the proportion of patients eligible for organ-preserving therapy.

Objective: We study whether addition of a radiation boost to standard chemoradiation in patients with locally advanced rectal cancer increases the complete response rate defined as pathological complete response, in those who undergo surgery, or 2-years local recurrence-free survival (2y-LRFS), in those who opted for a wait and see approach. Secondary objectives are adverse events due to chemoradiation (acute, perioperative and late toxicity), tumor response assessed with MRI, the impact of the boost on local and distant recurrence and survival as well as patient-reported quality of life and workability. The need for this comprehensive study is emphasized by the sub-optimal (radiation-) methods, heterogeneity between and poor reporting in the few previous trials in this field.

Study design: Multicentre Randomized Controlled Trial, nested within a prospective cohort according to the 'cohort multiple randomized controlled trial' (cmRCT) design.

Study population: Rectal cancer patients participating in a prospective cohort (the PLCRC project) and diagnosed with adenocarcinoma of the rectum whom will undergo chemoradiation based on clinical criteria (see table 1 section 1.2.1).

Intervention: An irradiation boost of 15 Gy delivered to the gross tumor volume (GTV) in 5 fractions in addition to the standard chemoradiation treatment of 50 Gy. Thereby increasing the total GTV dose to 65 Gy.

Main study parameters/endpoints: The primary endpoint is complete response either defined as pathological complete response (pCR) in patients who undergo surgery, assessed by standardized pathologic examination of the surgical specimen, or 2-years local recurrence-free survival (LRFS) after chemoradiation in patients who opted for a wait and see approach. Secondary outcomes are treatment acute, perioperative and late toxicity, tumor response assessed with MRI, patient-reported quality of life and workability, local recurrence and (disease-specific) survival.

Eligibility criteria: Inclusion criteria

* Participant in the PLCRC project (ClinicalTrials.gov: NCT02070146)
* Informed consent obtained for being offered experimental interventions within the PLCRC project
* Informed consent obtained for questionnaires on patient reported outcomes within the PLCRC project
* WHO: 0-2
* Indication for chemoradiation based on primary tumor, regional nodes, metastasis (TNM) stage
* Referred for chemoradiation
* No contra-indication for MRI
* Tumor distance from ano-rectal transition ≤10 cm

Exclusion criteria

* \<18 years
* No indication for chemoradiation according to Dutch guidelines based on TNM staging.
* Inflammatory bowel disease
* Prior pelvic radiotherapy
* At least one contra-indication for Capecitabine administration (based on Dihydropyrimidine dehydrogenase (DPD)-deficiency, bloodcount, liver malfunction, renal failure (Creatinine clearance \<30 ml/min), medical history such as recent cardiac events
* Recent pregnancy ≤ 1 year ago
* Inadequate understanding of the Dutch language in speech and/or writing

Primary outcomes:
measure: Complete response rate
timeFrame: pathologic examination following surgery, at aproximately 13-15 weeks (control arm) or 14-16 weeks (boost arm) after randomization or clinical complete respons of 2 years after first response assessment.
Secondary outcomes:
measure: Acute toxicity in common toxicity criteria for adverse events (CTCAE).
timeFrame: Until surgery at 8-10 weeks post chemoradiation (which is 13-15 weeks (control) or 14-16 weeks (boost) post randomization
measure: Patient reported quality of life
timeFrame: at baseline and 3, 6, 12 and 24 months after treatment.
measure: Tumor response on Magnetic resonance imaging (MRI)
timeFrame: at week 2 during chemoradiation and week 7 post chemoradiation.
measure: Patient reported workability
timeFrame: at baseline and 3, 6, 12 and 24 months after treatment.
measure: Surgical complication
timeFrame: untill 30 days after surgery, which is 17-19 weeks (control) or 18-20 weeks (boost) post randomization
measure: (disease-free) survival
timeFrame: up to death of included patients, for a maximum of 60 years post-randomization.
Other outcomes:
Locations:
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: Imaging Division, UMC Utrecht
name: HM Verkooijen, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radiation-Oncology, MAASTRO clinic
name: M. Berbee, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Verweij ME, Hoendervangers S, Couwenberg AM, Burbach JPM, Berbee M, Buijsen J, Roodhart J, Reerink O, Pronk A, Consten ECJ, Smits AB, Heikens JT, van Grevenstein WHMU, Intven MPW, Verkooijen HLM. Impact of Dose-Escalated Chemoradiation on Quality of Life in Patients With Locally Advanced Rectal Cancer: 2-Year Follow-Up of the Randomized RECTAL-BOOST Trial. Int J Radiat Oncol Biol Phys. 2022 Mar 1;112(3):694-703. doi: 10.1016/j.ijrobp.2021.09.052. Epub 2021 Oct 8.
citation: Couwenberg AM, Burbach JPM, Berbee M, Lacle MM, Arensman R, Raicu MG, Wessels FJ, Verdult J, Roodhart J, Reerink O, Hoendervangers S, Buijsen J, Grabsch HI, Pronk A, Consten ECJ, Smits AB, Heikens JT, Appelt AL, van Grevenstein WMU, Verkooijen HM, Intven MPW. Efficacy of Dose-Escalated Chemoradiation on Complete Tumor Response in Patients with Locally Advanced Rectal Cancer (RECTAL-BOOST): A Phase 2 Randomized Controlled Trial. Int J Radiat Oncol Biol Phys. 2020 Nov 15;108(4):1008-1018. doi: 10.1016/j.ijrobp.2020.06.013. Epub 2020 Jun 19.
citation: Couwenberg AM, Burbach JPM, May AM, Berbee M, Intven MPW, Verkooijen HM. The trials within cohorts design facilitated efficient patient enrollment and generalizability in oncology setting. J Clin Epidemiol. 2020 Apr;120:33-39. doi: 10.1016/j.jclinepi.2019.12.015. Epub 2019 Dec 19.
citation: Burbach JP, Verkooijen HM, Intven M, Kleijnen JP, Bosman ME, Raaymakers BW, van Grevenstein WM, Koopman M, Seravalli E, van Asselen B, Reerink O. RandomizEd controlled trial for pre-operAtive dose-escaLation BOOST in locally advanced rectal cancer (RECTAL BOOST study): study protocol for a randomized controlled trial. Trials. 2015 Feb 22;16:58. doi: 10.1186/s13063-015-0586-4.