Clinical trial NCT01814969: Preoperative Hyperfractionated Radiotherapy or Radiochemotherapy in Locally Advanced Rectal Cancer.
Official title: Preoperative Hyperfractionated Radiotherapy Versus Combined Radiochemotherapy for Patients With Locally Advanced Rectal Cancer: a Phase III Randomized Trial.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Rectal Cancer
Keywords: Rectal neoplasm
Preoperative hyperfractionated radiotherapy
Preoperative hyperfractionated radiochemotherapy
Lead sponsor: Maria Sklodowska-Curie National Research Institute of Oncology
Sponsor class: OTHER
First posted: 2013-03-20
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Clinical objective of the study is to compare the rates of pathologic response, acute toxicity and sphincter preservation with two schedules of preoperative regiment in patients with locally advanced rectal cancer.

Detailed description: Overview of randomized trials conducted in patients with advanced colorectal cancer with the use of preoperative radiotherapy or radiochemotherapy clearly shows the superiority of combined therapy over surgery alone. In these studies documented a significant reduction in tumor mass as a result of preoperative radiotherapy or radiochemotherapy theoretically increases the chance of performing operations with sphincters preservation, even in cases originally eligible for abdomino - perineal resection. There is the question whether the combination of preoperative hyperfractionated radiotherapy and concurrent chemotherapy may cause the further improvement of treatment outcome in patients with locally advanced rectal cancer. Published in 2012 by Gerard et al. meta-analysis of randomized trials dedicated to the treatment of patients with advanced colorectal cancer, confirms a higher percentage of sphincters preservation in patients operated after more than 5-week interval between neoadjuvant therapy and surgery.

Analysis of these issues will be taken in the current study. Comparison of the two treatment regimens as preoperative phase III study with stratification for time interval between the end of radiotherapy or radiochemotherapy and surgery may show differences that have not been seen in previously published data.

Eligibility criteria: Inclusion Criteria:

1. Karnofsky Index 80% or better (Zubrod 0-1)
2. Histological proved diagnosis of rectal cancer (adeno- or mucinous carcinoma)
3. Primary rectal cancer:

   3.1. Maximum 12 cm above dentate line (upper limit) 3.2. Staged T2N+ or T3N0 or T3N+ (by endorectal ultrasound or Computed Tomography \[CT\]/Magnetic Resonance Imaging \[MRI\] scan)
4. No evidence of metastatic disease as determined by chest X-ray and abdominal ultrasound (or CT-scan of chest and abdomen or other investigations such as Positron Emission Tomography \[PET\] scan or biopsy if required)
5. Adequate bone marrow function with platelets more than 100 × 10\^9/l and neutrophils more than 2.0 × 10\^9/l
6. Creatinine clearance more than 50 ml/min
7. Serum bilirubin less than 2.0 × Upper Limit of institutional Normal range (ULN)
8. Written informed consent is obtained prior to commencement of trial treatment (confirmed the signature on the consent form for the proposed project and the standard medical consent form for radiotherapy within the abdominal cavity).

Exclusion Criteria:

1. Rectal cancer other than adeno- or mucinous carcinoma
2. Previous or concurrent malignancies, with the exception of adequately treated basal cell carcinoma of the skin
3. Patients with locally advanced inoperable disease, such as T4-tumour
4. Presence of metastatic disease or recurrent rectal tumour
5. Any previous chemotherapy or radiotherapy, and any investigational treatment for rectal cancer
6. Concurrent uncontrolled medical conditions
7. Pregnancy or breast feeding
8. Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease) or myocardial infarction within the last six months
9. Evidence of hereditary colorectal cancer (Hereditary Non-Polyposis Colorectal Cancer \[HNPCC\] and Familial Adenomatous Polyposis \[FAP\])
10. Medical or psychiatric conditions that compromise the patient's ability to give informed consent
11. No agreement for randomisation

Primary outcomes:
measure: • The rate of patients with downstaging after radiotherapy or radiochemotherapy to pathological response or disease with negative margins
timeFrame: Surrogate endpoint available immediatly after surgery
Secondary outcomes:
measure: The rate of local failures
timeFrame: 3 years
measure: Progression-free long-term survival
timeFrame: 3 years
measure: The rate of distant metastases
timeFrame: 3 years
measure: Overall long-term survival
timeFrame: 3 years
measure: The rate of late toxicity according to the RTOG/EORTC scale
timeFrame: 3 years
measure: The rate of postoperative complications
timeFrame: 3 months
measure: The rate of early toxicity of neoadjuvant treatment according to the NCI CTCAE (version 4.0)
timeFrame: 3 months
Other outcomes:
Locations:
city: Gliwice
country: Poland
facility: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch
state: Wybrzeze AK 15
Study officials:
affiliation: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
name: Rafal Suwinski, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Suwinski R, Wzietek I, Tarnawski R, Namysl-Kaletka A, Kryj M, Chmielarz A, Wydmanski J. Moderately low alpha/beta ratio for rectal cancer may best explain the outcome of three fractionation schedules of preoperative radiotherapy. Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):793-9. doi: 10.1016/j.ijrobp.2007.03.046. Epub 2007 May 17.
citation: Suwinski R, Wydmanski J, Pawelczyk I, Starzewski J. A pilot study of accelerated preoperative hyperfractionated pelvic irradiation with or without low-dose preoperative prophylactic liver irradiation in patients with locally advanced rectal cancer. Radiother Oncol. 2006 Jul;80(1):27-32. doi: 10.1016/j.radonc.2006.05.001. Epub 2006 May 26.
citation: Gerard JP, Rostom Y, Gal J, Benchimol D, Ortholan C, Aschele C, Levi JM. Can we increase the chance of sphincter saving surgery in rectal cancer with neoadjuvant treatments: lessons from a systematic review of recent randomized trials. Crit Rev Oncol Hematol. 2012 Jan;81(1):21-8. doi: 10.1016/j.critrevonc.2011.02.001. Epub 2011 Mar 5.
citation: Idasiak A, Galwas-Kliber K, Rajczykowski M, Debosz-Suwinska I, Zeman M, Stobiecka E, Mrochem-Kwarciak J, Suwinski R. Tumor regression grading after preoperative hyperfractionated radiotherapy/chemoradiotherapy for locally advanced rectal cancers: interim analysis of phase III clinical study. Neoplasma. 2021 May;68(3):631-637. doi: 10.4149/neo_2021_201217N1366. Epub 2021 Feb 24.
citation: Idasiak A, Galwas-Kliber K, Behrendt K, Wzietek I, Kryj M, Stobiecka E, Chmielik E, Suwinski R. Pre-operative hyperfractionated concurrent radiochemotherapy for locally advanced rectal cancers: a phase II clinical study. Br J Radiol. 2017 Jun;90(1074):20160731. doi: 10.1259/bjr.20160731. Epub 2017 May 23.