Rectal Cancer
Conditions
Brief summary
The purpose of the research is to evaluate whether both chemotherapy and radiotherapy can lead to higher rates of clinical complete response leading to organ preservation in human subjects with cancer. The objective is to learn if this treatment approach may safely be used as an alternative to the standard treatment for rectal cancer and to know the quality-of-life in these patients.
Detailed description
Primary Objective: To assess clinical complete response of an organ preservation approach using short course radiation followed by intensified chemotherapy. Secondary Objective: To assess safety in all enrolled patients, local regrowth rate and other cancer specific outcomes (metastasis-free survival, colostomy-free survival and overall survival), longitudinal health-related quality of life of this organ preservation approach
Interventions
DRUGFOLFOXIRI
Chemotherapy regimen of Oxaliplatin 85mg/m2 , Leucovorin 400 mg/m2 , Irinotecan 165mg/m2 , 5-Fluorouracil
DRUGFOLFOX regimen
Chemotherapy regimen of Oxaliplatin 85mg/m2, Leucovorin 400 mg/m2, 5-Fluorouracil 2400mg/m2
DRUGXELOX
Chemotherapy regimen of Oxaliplatin 130 mg/m2, Capecitabine 1000mg/m2
RADIATIONIMRT
Radiotherapy (5 Gy x 5 fractions) with an additional boost fraction (5 Gy x 1 fraction) delivered sequentially
Sponsors
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. Pathologically (histologically or cytologically) proven diagnosis of adenocarcinoma of rectum requiring total mesorectal excision as deemed by multidisciplinary evaluation * 2.At least 18 years of age * 3.For women of childbearing potential or who are not postmenopausal (see Appendix B for Definition of Menopausal Status), a negative urine or serum pregnancy test must be done. Also, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for up to 4 weeks following the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * 4.ECOG 0, 1, or 2 * 5.Ability to understand and the willingness to personally sign the written IRB approved informed consent document. * 6.Patients must have acceptable organ and marrow function as defined below: * Absolute neutrophil count (ANC) \>1,500/uL * Hg \> 8.0 g/dL; if blood transfusion is performed for achieving adequate hemoglobin level, the level should stay above goal for at least 1 week after transfusion * Platelets \>100,000/uL * Total bilirubin \<1.5X normal institutional limits * aspartate aminotransferase (AST) (SGOT) / alanine aminotransferase (ALT)(SGPT) \< 3X upper limit of normal * Creatinine \<1.5X upper limit of normal or creatinine clearance (CrCL)\>50 by Cockcroft-Gault * 7 Clinical stage \>T2N0 or low T2N0 rectal cancer (AJCC, 8th ed.) including no metastases based on the following diagnostic workup: * General history and physical examination with DRE (if deemed appropriate by treating physician) within 45 days prior to enrollment * Sigmoidoscopy within 90 days prior to enrollment The following imaging studies are required within 45 days prior to enrollment: * CT chest/abdomen/pelvis * MRI Pelvis
Exclusion criteria
* 1.Prior pelvic RT or chemotherapy for rectal cancer. * 2.Upper T2N0 rectal cancers eligible for sphincter-preservation surgery * 3.Use of other investigational agents. * 4.Ongoing or active infections requiring systemic antibiotic treatment or uncontrolled intercurrent illness including but not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * 5.Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. Patients with any previous malignancy without evidence of disease for \>3 years will be allowed to enter the trial. * 6.Known hypersensitivity to 5-FU compounds. * 7.Pregnant and breastfeeding women are excluded. Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and for up to 4 weeks after the study are excluded. (This applies to women who have experienced menarche and have not undergone successful surgical sterilization or are not postmenopausal). Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, known HIV-positive patients with detectable viral loads and/or receiving combination anti-retroviral therapy are excluded from the study. \- 8.Primary unresectable rectal cancer (tumor invading adjacent organs and en bloc resection will not achieve negative margins).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Complete Response (cCR) | 8 (+/-4 ) weeks following completion of RT and chemotherapy, an average of 9 months | Proportion of patients who achieve a clinical complete response following therapy, expressed as a number and proportion without dispersion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Toxicity | 8 (+/- 4) weeks following completion of RT and chemotherapy, an average of 3 months | Toxicity defined as non-hematologic grade 4 adverse events using CTCAE v5 or higher toxicity at least possibly related to treatment, and assessed up to 3 months after completion of radiotherapy (RT) and chemotherapy. |
| Local Regrowth Rate | 22 (+/- 2) months following completion of RT and chemotherapy, an average of 24 months (2 years) | Local regrowth is defined as the presence of adenocarcinoma within the rectal wall or within the mesorectum confirmed by pathology, expressed as a percentage with its 95% confidence interval. |
| Disease Free Survival (DFS) | 22 (+/- 2) months following completion of RT and chemotherapy, an average of 24 months (2 years) | DFS defined as the time from the start date of RT to the date of the first documented progression or death due to any cause assessed up to 2 years after completion of chemotherapy. Patients will be censored at the last date of follow-up if lost to follow-up prior to two years, expressed as a median with interquartile range. |
| Colostomy-free Survival | 22 (+/- 2) months following completion of RT and chemotherapy, an average of 24 months (2 years) | Colostomy-free survival defined as the time from the start date of RT to the date of colostomy or death due to any cause assessed up to 2 years after completion of chemotherapy, expressed as a median with interquartile range. Patients will be censored at the last date of follow-up if lost to follow-up prior to two years. |
| Overall Survival (OS) | 27 (+/- 4) months following completion of RT and chemotherapy, an average of 2.25 years | OS defined as death from any cause from start date of RT until death, study completion, or loss to follow-up, whichever occurs first. This will be reported as median survival time with interquartile range. |
Countries
United States
Participant flow
Pre-assignment details
38 patients were enrolled, but 1 withdrew prior to treatment start and was thus replaced. We had 37 patients initiate treatment on study and be evaluable for primary outcome.
Participants by arm
| Arm | Count |
|---|---|
| Radiation/FOLFOXIRI Treatment comprised of 6 daily fractions of radiotherapy at 5 Gy per fraction followed by 4 months of FOLFOXIRI. | 37 |
| Total | 37 |
Baseline characteristics
| Characteristic | Radiation/FOLFOXIRI |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 26 Participants |
| Region of Enrollment United States | 37 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 37 |
| other Total, other adverse events | 37 / 37 |
| serious Total, serious adverse events | 25 / 37 |
Outcome results
Primary
Clinical Complete Response (cCR)
Proportion of patients who achieve a clinical complete response following therapy, expressed as a number and proportion without dispersion.
Time frame: 8 (+/-4 ) weeks following completion of RT and chemotherapy, an average of 9 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiation/FOLFOXIRI | Clinical Complete Response (cCR) | 0.24 Proportion of Participants |
Secondary
Colostomy-free Survival
Colostomy-free survival defined as the time from the start date of RT to the date of colostomy or death due to any cause assessed up to 2 years after completion of chemotherapy, expressed as a median with interquartile range. Patients will be censored at the last date of follow-up if lost to follow-up prior to two years.
Time frame: 22 (+/- 2) months following completion of RT and chemotherapy, an average of 24 months (2 years)
Population: All participants who initiated the RT and chemotherapy regimen (intent-to-treat population) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiation/FOLFOXIRI | Colostomy-free Survival | 11 months |
Secondary
Disease Free Survival (DFS)
DFS defined as the time from the start date of RT to the date of the first documented progression or death due to any cause assessed up to 2 years after completion of chemotherapy. Patients will be censored at the last date of follow-up if lost to follow-up prior to two years, expressed as a median with interquartile range.
Time frame: 22 (+/- 2) months following completion of RT and chemotherapy, an average of 24 months (2 years)
Population: All participants who initiated the RT and chemotherapy regimen (intent-to-treat population) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiation/FOLFOXIRI | Disease Free Survival (DFS) | 22 months |
Secondary
Local Regrowth Rate
Local regrowth is defined as the presence of adenocarcinoma within the rectal wall or within the mesorectum confirmed by pathology, expressed as a percentage with its 95% confidence interval.
Time frame: 22 (+/- 2) months following completion of RT and chemotherapy, an average of 24 months (2 years)
Population: All patients managed with an organ preservation approach.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiation/FOLFOXIRI | Local Regrowth Rate | 50 Percentage of participants |
Secondary
Number of Participants With Toxicity
Toxicity defined as non-hematologic grade 4 adverse events using CTCAE v5 or higher toxicity at least possibly related to treatment, and assessed up to 3 months after completion of radiotherapy (RT) and chemotherapy.
Time frame: 8 (+/- 4) weeks following completion of RT and chemotherapy, an average of 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Radiation/FOLFOXIRI | Number of Participants With Toxicity | 0 proportion of participants |
Secondary
Overall Survival (OS)
OS defined as death from any cause from start date of RT until death, study completion, or loss to follow-up, whichever occurs first. This will be reported as median survival time with interquartile range.
Time frame: 27 (+/- 4) months following completion of RT and chemotherapy, an average of 2.25 years
Population: All participants who initiated the RT and chemotherapy regimen (intent-to-treat population) were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiation/FOLFOXIRI | Overall Survival (OS) | 27 months |