Rectal Cancer
Conditions
Brief summary
The purpose of this study is to find out the effects of chemotherapy followed by less invasive surgery on patients and their early rectal cancer. The approach of this trial will be considered a success if at least 65% of participants are able to keep the rectum.
Interventions
DRUGFolfox Protocol
6 cycles of q2weekly FOLFOX, or
DRUGCapox
4 cycles of q3weekly CAPOX
Sponsors
Canadian Cancer Trials Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a two staged, single arm phase II trial of chemotherapy (FOLFOX or CAPOX) followed by tumour excision in patients with early stage rectal cancer
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed invasive well-moderately differentiated rectal adenocarcinoma diagnosed within 90 days prior to enrollment. * Tumour stage cT1-T3abN0 based on pelvic MRI * cT1N0- tumour invasion into submucosa, no radiographic evidence of mesorectal nodal metastasis, tumour deposits or vascular invasion. * cT2N0 - tumour invasion into muscularis propria, no radiographic evidence of mesorectal nodal metastasis, tumour deposits or vascular invasion. * cT3a,bN0- tumour invasion through the muscularis propria no more than 5 mm into the subserosa/perirectal tissue and clear of the circumferential radial margin (CRM). Absence of radiographic evidence of mesorectal nodal metastasis, tumour deposits or lymphovascular invasion. Note: If the tumour is not visualized in the MRI but there is histological confirmation of rectal adenocarcinoma the patient is eligible. * cN0 stage based on pelvic MRI. Any nodes ≥ 10 mm in longest dimension are considered malignant, regardless of nodal morphology. For pelvic nodes \< 10 mm in longest dimension, if nodes are seen and are deemed to be morphologically benign in the opinion of the radiologist and surgeon, the patient is eligible. Patients with visible pelvic sidewall nodes are excluded * M0 stage based on no evidence of metastatic disease by CT imaging. * Mid to low-lying tumour eligible for local tumour excision in the opinion of the treating surgeon. * Age of at least 18 years. * Medically fit to undergo radical surgery as per treating surgeon's discretion * No contraindications to protocol chemotherapy. * Adequate normal organ and marrow function as defined below (must be done within 30 days prior to enrolment): * ANC ≥ 1.5 x 109/L * platelet count ≥100 x 109/L * bilirubin \< 1.5 ULN, excluding Gilbert's syndrome * Calculated creatinine clearance of ≥ 50 ml/min. * Clearance to be calculated using Cockcroft formula: Males: 1.23 x (140 - age) x weight (kg) - serum creatinine (μmol/l) ; Females: 1.05 x (140 - age) x weight (kg) - serum creatinine (μmol/l) * The patient must have an ECOG performance status of 0, 1. * Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life and health utility questionnaires. * Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate. * Must be accessible for treatment and follow up. Patients registered on this trial must be treated with chemotherapy and followed at the enrolling centre. * Protocol treatment is to begin within 5 working days of patient enrollment. * Women/men of childbearing potential must have agreed to use a highly effective contraceptive method during and for 6 months after completion of chemotherapy.
Exclusion criteria
* Patient has pathologic high risk factors on either the initial biopsy specimen report or follow-up biopsy (if done): high histologic grade, mucinous histology, lymphatic or vascular invasion. * History of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years. * Synchronous cancer. * Prior treatment for rectal cancer. * Previous pelvic radiation for any reason. * Patients with known dihydropyrimidine dehydrogenase deficiency * Treatment with other investigational drugs or anti-cancer therapy within 28 days prior to enrolment. * Clinically significant (i.e. active) cardiovascular disease for example cerebro vascular accidents (\< 6 months prior to enrolment), myocardial infarction (\< 6 months prior to enrolment), unstable angina, New York Heart Association (NYHA) grade II or higher, congestive heart failure, serious cardiac arrhythmia requiring medication. * Any contra-indications to undergo MRI imaging.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Organ Preservation | 3 years | Defined as the percentage of patients with tumour downstaging to ypT0/T1good N0 and who avoid radical surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Locoregional Relapses at 3 Years | 3 years | Locoregional relapse is defined as reappearance of a tumour within the rectum or pelvis. The percentage of loco-reginal relapse at 3 years was estimated by Kaplan-Meier method for the survival function of the loco-regional relapse free survival, defined as the time from enrollment to the first date of definitive evidence (clinical, radiological or pathological) of locoregional relapses with patients who developed distant relapse only, died, loss to follow up, or were alive at clinical cut-off censored at respectively at last date of distant relapses, date of death, date of lost to follow-up, or last disease assessment date. |
| Percentage of Distant Relapse at 3 Years | 3 years | Distant relapse is defined as appearance of rectal cancer disease at sites remote from the rectum. The percentage of distant relapse at 3 years was estimated also by Kaplan-Meier method for the survival function of the distant free survival, defined as the time from enrollment to the first date of definitive evidence (clinical, radiological or pathological) of distant relapses with patients who died, loss to follow up, or were alive at clinical cut-off censored at respectively: date of death, date of lost to follow-up, and last disease assessment date. |
| Percentage of Disease Free at 3 Years | 3 years | Percentage of disease free at 3 years was estimated by Kaplan-Meier method for the survival function of Disease-Free Survival (DFS), which is defined as the interval from date of enrollment to the first date of the events defined below: * Locoregional relapse * Distant relapse * Non-protocol radiotherapy, chemotherapy, or biologic therapy without documentation of the site of failure * Death due to any other reason. Patients who were alive without locoregional or distant relapse or receiving non-protocol radiotherapy, chemotherapy, or biologic therapy without documentation of the site of failure at the clinical data cutoff date were censored at their last disease assessment date. 3 year disease free survival was estimated by Kaplan-Meier method. |
| Rate of Intraoperative Complications | 1 day | Percentage of patients with at least one intraoperative injury |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Chemotherapy (FOLFOX or CAPOX) Followed by Tumour Excision FOLFOX infusion on a 14 day cycle (IV oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 over 2 hours on day 1 and bolus fluorouracil 400 mg/m2 over 5 - 15 minutes and continuous infusion of fluorouracil 2400 mg/m2 over 46 to 48 hours on days 1-2) for a total of 6 cycles or CAPOX on a 21 day cycle (IV oxaliplatin 130 mg/m2 over 2 hours on day 1 and 1000 mg/m2 capecitabine orally twice daily for 14 days from day 1) for a total of 4 cycles. | 58 |
| Total | 58 |
Baseline characteristics
| Characteristic | Chemotherapy (FOLFOX or CAPOX) Followed by Tumour Excision |
|---|---|
| Age, Continuous | 66.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 48 Participants |
| Region of Enrollment Canada | 54 participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 58 |
| other Total, other adverse events | 58 / 58 |
| serious Total, serious adverse events | 1 / 58 |
Outcome results
Primary
Percentage of Organ Preservation
Defined as the percentage of patients with tumour downstaging to ypT0/T1good N0 and who avoid radical surgery.
Time frame: 3 years
Population: All participants who had chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy (FOLFOX or CAPOX) Followed by Tumour Excision | Percentage of Organ Preservation | 57 percentage of participants |
Secondary
Percentage of Disease Free at 3 Years
Percentage of disease free at 3 years was estimated by Kaplan-Meier method for the survival function of Disease-Free Survival (DFS), which is defined as the interval from date of enrollment to the first date of the events defined below: * Locoregional relapse * Distant relapse * Non-protocol radiotherapy, chemotherapy, or biologic therapy without documentation of the site of failure * Death due to any other reason. Patients who were alive without locoregional or distant relapse or receiving non-protocol radiotherapy, chemotherapy, or biologic therapy without documentation of the site of failure at the clinical data cutoff date were censored at their last disease assessment date. 3 year disease free survival was estimated by Kaplan-Meier method.
Time frame: 3 years
Population: All participants enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy (FOLFOX or CAPOX) Followed by Tumour Excision | Percentage of Disease Free at 3 Years | 84.3 percentage of participants |
Secondary
Percentage of Distant Relapse at 3 Years
Distant relapse is defined as appearance of rectal cancer disease at sites remote from the rectum. The percentage of distant relapse at 3 years was estimated also by Kaplan-Meier method for the survival function of the distant free survival, defined as the time from enrollment to the first date of definitive evidence (clinical, radiological or pathological) of distant relapses with patients who died, loss to follow up, or were alive at clinical cut-off censored at respectively: date of death, date of lost to follow-up, and last disease assessment date.
Time frame: 3 years
Population: All participants enrolled
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy (FOLFOX or CAPOX) Followed by Tumour Excision | Percentage of Distant Relapse at 3 Years | 5.3 percentage of participants |
Secondary
Percentage of Locoregional Relapses at 3 Years
Locoregional relapse is defined as reappearance of a tumour within the rectum or pelvis. The percentage of loco-reginal relapse at 3 years was estimated by Kaplan-Meier method for the survival function of the loco-regional relapse free survival, defined as the time from enrollment to the first date of definitive evidence (clinical, radiological or pathological) of locoregional relapses with patients who developed distant relapse only, died, loss to follow up, or were alive at clinical cut-off censored at respectively at last date of distant relapses, date of death, date of lost to follow-up, or last disease assessment date.
Time frame: 3 years
Population: All patients enrolled
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy (FOLFOX or CAPOX) Followed by Tumour Excision | Percentage of Locoregional Relapses at 3 Years | 7.1 percentage of participants |
Secondary
Rate of Intraoperative Complications
Percentage of patients with at least one intraoperative injury
Time frame: 1 day
Population: Patients who had BOTH chemotherapy and tumor excision with transanal endoscopic microsurgery (TEM) or transanal minimally invasive surgery (TAMIS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy (FOLFOX or CAPOX) Followed by Tumour Excision | Rate of Intraoperative Complications | 1.89 percentage of participants |