Rectal Cancer
Conditions
Keywords
rectal cancer, radiotherapy, chemotherapy, 5x5, capecitabine, oxaliplatin, CAPOX, FOLFOX, folinic acid, fluorouracil
Brief summary
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.
Detailed description
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.
Interventions
OTHERM1 scheme
short course 5x5Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine and oxaliplatin (CAPOX)) and surgery. FOLFOX4 may be given as alternative for CAPOX
OTHERstandard long course chemoradiotherapy
long course chemoradiotherapy followed by surgery. Optional adjuvant chemotherapy (CAPOX or FOLFOX) is allowed in the control group.
Sponsors
University Medical Center Groningen
Karolinska University Hospital
Leiden University Medical Center
Uppsala University Hospital
Dutch Cancer Society
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
standard arm: 5.5 weeks chemoradiation -\> surgery -\> optional chemotherapy experimental arm: 5x5Gy -\> 12 wks chemotherapy -\> surgery
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Disease Related Treatment Failure (DrTF) | 3 years follow-up after surgery | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Completing the Prescribe Neo-adjuvant Treatment Dose | 30 days after neoadjuvant treatment | 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. |
| Number of Patients With Negative CRM Negative | 30 days after surgery | Number of patients with a Circumferential Resection Margin (CRM) \> 1 mm |
| Number of Patients With a Pathological Complete Response (pCR) | 30 days after surgery | Number of patients with a Pathological Complete Response (pCR) after neo-adjuvant treatment |
| Number of Patients With Surgical Complications | 30 days after surgery | Number of patients with surgical complications: wound rupture, bleeding, infection, rectal anastomotic leak |
| Quality of Life QLQ-C30 Scores | 3 year after surgery | 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. |
| Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (EORTC-QLQ-CIPN20) | 3 year after surgery | 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. |
| Quality of Life LARS Scores | 3 year after surgery | 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. |
| Number of Patients With a Locoregional Recurrence | 5 years after surgery | Number of patients with a locoregional recurrence (LRR) after an R0/R1 resection |
| Overall Survival | 10 year | 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. |
Countries
Denmark, Netherlands, Norway, Slovenia, Spain, Sweden, United States
Contacts
PRINCIPAL_INVESTIGATORB. van Etten, MD, PhD
University Medical Center Groningen, Department of Surgery, Groningen, The Netherlands
PRINCIPAL_INVESTIGATORB. Glimelius, MD, PhD
Akademiska Sjukhuset, Department of Oncology, Uppsala, Sweden
PRINCIPAL_INVESTIGATORG. A. Hospers, MD, PhD
University Medical Center Groningen, Department of Medical Oncology, Groningen, The Netherlands
PRINCIPAL_INVESTIGATORP. Nilsson, MD, PhD
Karolinska Universitetssjukhuset, Stockholm, Sweden
PRINCIPAL_INVESTIGATORC. J. van de Velde, MD, PhD
Leiden University Medical Center, Department of Surgery, Leiden, The Netherlands
PRINCIPAL_INVESTIGATORC.A.M. Marijnen, MD, PhD
Netherlands Cancer Institute, Amsterdam, the Netherlands
Participant flow
Recruitment details
June 2011-June 2016
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 62 years |
| Race and Ethnicity Not Collected | 0 Participants |
| Region of Enrollment Denmark | 12 participants |
| Region of Enrollment Netherlands | 180 participants |
| Region of Enrollment Norway | 12 participants |
| Region of Enrollment Slovenia | 17 participants |
| Region of Enrollment Spain | 60 participants |
| Region of Enrollment Sweden | 160 participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 162 Participants |
| Sex: Female, Male Male | 312 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 40 / 460 | 36 / 441 |
| other Total, other adverse events | 429 / 460 | 421 / 441 |
| serious Total, serious adverse events | 31 / 460 | 13 / 441 |
Outcome results
None listed