Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation. The RAPIDO Trial

Phase 3Active Not RecruitingNCT01558921

University Medical Center Groningen920 enrolled

Overview

Currently the 3-year disease free survival of patients with locally advanced rectal cancer is about 50%. Current standard treatment for patients at high risk of failing locally and/or systemically includes pre-operative long course radiotherapy (5 weeks) in combination with chemotherapy (so called neoadjuvant chemoradiotherapy). The neoadjuvant chemoradiotherapy has been demonstrated to improve local control, but had no effect on the overall survival. Different studies in patients with rectal cancer studying the effect of adjuvant post operative chemotherapy did not result in an improved survival. This may be due the fact that rectal cancer surgery (TME) is associated with a high complication rate so substantial proportion of patients cannot receive chemotherapy postoperatively. An alternative approach is to administer the systemic therapy preoperative. To guarantee control of the rectum tumor short-course radiotherapy (5 days) is given, as different studies showed local control of the tumor for a long time. During this waiting period the patient is in a good condition to receive an optimal dose of chemotherapy. The investigators hypothesize that with this proposed protocol both the local tumour and possible micrometastases are effectively treated and that this will result in an increased survival. The investigators will compare this with the standard treatment of neoadjuvant chemoradiation followed by TME surgery and optional adjuvant chemotherapy.

Patients will be randomized between an experimental group (arm B) in which short course 5 x 5 Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine/ 5-fluorouracil and oxaliplatin) and surgery and a control group (arm A) with long course chemoradiotherapy followed by surgery. In arm A adjuvant chemotherapy is allowed according to the local protocol of the institution. In both groups the rectal tumour will be removed by TME surgery or more extensive surgery if required because of tumour extent.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: Primary tumour characteristics: 1. Histological proof of newly diagnosed primary adenocarcinoma of the rectum 2. Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically (clinical T4a, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side wall (according to tumor node metastasis (TNM-Classification version 5)), clinical T4b, i.e. peritoneal involvement, extramural vascular invasion (EMVI+). N2, i.e. four or more lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease. Positive Mesorectal Fascia (MRF+), i.e. tumor or lymph node \< 1 mm from the mesorectal fascia. Enlarged lateral nodes (LN), \> 1 cm (lat LN+) Exclusion Criteria: 1. Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen 2. Presence of metastatic disease or recurrent rectal tumour 3. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis 4. Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years 5. Known Dihydro-Pyrimidine Dehydrogenase (DPD) deficiency 6. Any contraindications to MRI (e.g. patients with pacemakers) 7. Medical or psychiatric conditions that compromise the patient's ability to give informed consent 8. Concurrent uncontrolled medical conditions 9. Any investigational treatment for rectal cancer within the past month 10. Pregnancy or breast feeding 11. Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract 12. Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months 13. Patients with symptoms or history of peripheral neuropathy

Locations (56)

Siteman Cancer Center, Washington University Medical School

St Louis, Missouri, United States

Aalborg Universitetshospital

Aalborg, Denmark

Odense Universitetshospital

Odense, Denmark

University Medical Center Groningen

Groningen, PO BOX 30001, Netherlands

Noordwest Ziekenhuisgroep

Alkmaar, Netherlands

Outcomes

Primary Outcomes

Number of Patients With Disease Related Treatment Failure (DrTF)

DrTF = Either local or distant relapse or death caused by the rectal carcinoma whichever comes first. In case of nonrectal cancer related death patients will be censored at date of death. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour. In case of local regrowth after wait \& watch strategy, followed by no resection or R2 resection, diagnosis local regrowth is taken. Patients lost to follow-up will be censored the last date of patient visit. Survival curves for Disease related Treatment Failure after 3 years of follow-up will be constructed using the method of Kaplan and Meier.

Time frame: 3 years follow-up after surgery

Secondary Outcomes

Number of Patients Completing the Prescribe Neo-adjuvant Treatment Dose

Number of patients in the experimental arm receiving 5 fractions of x 5 Gy (5x5Gy) radiotherapy followed by at least 75% of the prescribed chemotherapy. In the standard arm receiving the prescribed chemoradiotherapy.

Time frame: 30 days after neoadjuvant treatment

Number of Patients With Negative CRM Negative

Number of patients with a Circumferential Resection Margin (CRM) \> 1 mm

Time frame: 30 days after surgery

Number of Patients With a Pathological Complete Response (pCR)

Number of patients with a Pathological Complete Response (pCR) after neo-adjuvant treatment

Time frame: 30 days after surgery

Number of Patients With Surgical Complications

Number of patients with surgical complications: wound rupture, bleeding, infection, rectal anastomotic leak

Time frame: 30 days after surgery

Quality of Life QLQ-C30 Scores

Quality of life QLQ-C30 core questionnaire EORTC quality-of-life instrument for use in international clinical trials in oncology A total Quality of Life Questionnaire (QLQ) score can range from 0 to 88, higher score means worse outcome.

Time frame: 3 year after surgery

Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (EORTC-QLQ-CIPN20)

Quality of life EORTC-QLQ-CIPN20. International EORTC questionnaire to assess Chemotherapy-Induced Peripheral Neuropathy (CIPN). A total QLQ-CIPN20 score can range from 0 to 100, higher score means worse outcome. Chemotherapy-induced peripheral neuropathy (CIPN) is a common phenomenon, often resulting in serious limitations in daily functioning and compromised quality of life.

Time frame: 3 year after surgery

Quality of Life LARS Scores

Low Anterior Resection Syndrome (LARS) scores in patients without a stoma three years after curative surgery Patient reported score (5 questions). 0-12 no LARS, 21-29 Minor LARS, 30-42 Major LARS. Higher scores mean a worse outcome.

Time frame: 3 year after surgery

Number of Patients With a Locoregional Recurrence

Number of patients with a locoregional recurrence (LRR) after an R0/R1 resection

Time frame: 5 years after surgery

Overall Survival

Overall survival will be computed as the time between randomization and colorectal cancer or treatment related death. Patients lost to follow-up will be censored the last date of patient visit. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour.

Time frame: 10 year

Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation. The RAPIDO Trial

Overview

Conditions

Interventions

Eligibility

Locations (56)

Outcomes

Primary Outcomes

Secondary Outcomes