Adenocarcinoma of the Lower Rectum
Conditions
Brief summary
The investigators' data from a phase I study of short course radiation therapy followed by chemotherapy showed 74% complete clinical response (cCR). Given the promising response rate, the investigators are evaluating short course radiation therapy (SCRT) followed by chemotherapy in a multi-institution phase II trial to validate the cCR rate of this treatment paradigm. SCRT has not been prospectively evaluated in non-operative management for patients with non-metastatic rectal adenocarcinoma.
Interventions
RADIATIONRadiation therapy
-Monday-Friday treatment is strongly recommended
DRUGFOLFOX regimen
-CAPOX can be given as alternative
DRUGCAPOX regimen
Given as an alternative to FOLFOX
Sponsors
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of biopsy proven stage I-IIIB (cT1-3, N0-2a, M0) adenocarcinoma of the rectum; staging must also be based on multidisciplinary evaluation including MRI * Tumor ≤ 12 cm from anal verge as determined by MRI or endoscopy * Clinically detectable (MR, endoscopy, or DRE) tumor present * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * At least 18 years of age * Adequate bone marrow function defined as: * Absolute neutrophil count (ANC) \> 1,500 cells/mm3 * Hemoglobin\> 8 g/dl * Platelets \>100,000 cells/mm3 * Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * Able to understand and willing to sign an Institutional Review Board (IRB)-approved written informed consent document.
Exclusion criteria
* Prior radiation therapy, chemotherapy or extirpative surgery for rectal cancer. * Prior oxaliplatin or capecitabine use for any malignancy * No prior radiation therapy to the pelvis. * A history of other malignancy (except non-melanomatous skin cancers) with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease. * Currently receiving any investigational agents. * A history of allergic reaction attributed to compounds of similar chemical or biologic composition to capecitabine, 5FU, oxaliplatin, or leucovorin. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study entry. * Patients with HIV are eligible unless their CD4+ T-cell counts are \< 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective antiretroviral therapy (ART) according to Department of Health and Human Services (DHHS) treatment guidelines is recommended. HIV testing for patients without a history of HIV is not a protocol requirement.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Complete Response Rate | Completion of treatment (estimated to be 22 weeks) | \- Criteria for clinical complete response: * No residual gross tumor at procto/sigmoidoscopy; or only erythematous scar or ulcer * No palpable tumor on DRE * No radiographic evidence of tumor on MRI * No suspicious mesorectal lymph nodes on MRI * Negative biopsy from scar, ulcer, or former tumor site (if necessary according to surgeon's judgment) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | At 2 years | * Criteria for progressive disease: * Increase in the size of primary tumor by RECIST criteria (increase of at least 20% from nadir in the sum of the target lesion, with an absolute increase of at least 5 mm) * New metastatic disease * PFS is defined as the time from date of treatment to death or progression, which occurs first. The alive patients without progression are censored as the last date follow-up. |
| Incidence of Any Grade 3 or Higher Toxicity During Treatment | From start of treatment through the completion of treatment (estimated to be 22 weeks) | \- The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. |
| Incidence of Post Chemoradiotherapy Grade 3 or Higher Toxicity | At 1 year after the start of radiation | \- The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. |
| Quality of Anorectal Function as Measured by the FACT-C Questionnaire (Physical Well-Being) | Baseline, Completion of chemo (up to 16 weeks), and 10-14 months after radiation therapy | * Physical Well-Being section of the FACT-C questionnaire consists of 7 questions. * Answers to the questions range from 0=not at all to 4=very much. The higher the total score the lower quality of life. * The total score for this section ranges from 0-28. |
| Quality of Anorectal Function as Measured by the FACT-C Questionnaire (Social/Family Well-Being) | Baseline, Completion of chemo (up to 16 weeks), and 10-14 months after radiation therapy | * Social/Family Well-Being section of the FACT-C questionnaire consists of 7 questions. * Answers to the questions range from 0=not at all to 4=very much. The higher the total score the lower quality of life. * The total score for this section ranges from 0-28. |
| Quality of Anorectal Function as Measured by the FACT-C Questionnaire (Emotional Well-Being) | Baseline, Completion of chemo (up to 16 weeks), and 10-14 months after radiation therapy | * Emotional Well-Being section of the FACT-C questionnaire consists of 6 questions. * Answers to the questions range from 0=not at all to 4=very much. The higher the total score the lower quality of life. * The total score for this section ranges from 0-24. |
| Quality of Anorectal Function as Measured by the FACT-C Questionnaire (Functional Well-Being) | Baseline, Completion of chemo (up to 16 weeks), and 10-14 months after radiation therapy | * Functional Well-Being section of the FACT-C questionnaire consists of 7 questions. * Answers to the questions range from 0=not at all to 4=very much. The higher the total score the lower quality of life. * The total score for this section ranges from 0-28. |
| Quality of Anorectal Function as Measured by the FACT-C Questionnaire (Colorectal Cancer Subscale) | Baseline, Completion of chemo (up to 16 weeks), and 10-14 months after radiation therapy | * Colorectal Cancer Subscale section of the FACT-C questionnaire consists of 7 scored questions. * Answers to the questions range from 0=not at all to 4=very much. The higher the total score the lower quality of life. * The total score for this section ranges from 0-28. |
| Quality of Anorectal Function as Measured by the FACT-C Questionnaire (FACT-G Total Score) | Baseline, Completion of chemo (up to 16 weeks), and 10-14 months after radiation therapy | * The FACT-G total score is calculated by adding the Physical Well Being subscale score, Social/Family Well Being subscale score, Emotional Well Being subscale score, and Functional Well Being subscale score * Answers to the questions comprising the subscales range from 0=not at all to 4=very much. The higher the total score the lower quality of life. * The total score ranges from 0-108. |
| Quality of Anorectal Function as Measured by the FACT-C Questionnaire (FACT-C-TOI Total Score) | Baseline, Completion of chemo (up to 16 weeks), and 10-14 months after radiation therapy | * The FACT-C-Trial Outcome Index (TOI) total score is calculated by adding the Physical Well Being subscale score, Functional Well Being subscale score, and the Colorectal Cancer subscale score * Answers to the questions comprising the subscales range from 0=not at all to 4=very much. The higher the total score the lower quality of life. * The total score ranges from 0-84. |
| Quality of Anorectal Function as Measured by the FACT-C Questionnaire (FACT-C Total Score) | Baseline, Completion of chemo (up to 16 weeks), and 10-14 months after radiation therapy | * The FACT-C total score is calculated by adding the Physical Well Being subscale score, Social/Family Well Being subscale score, Emotional Well Being subscale score, Functional Well Being subscale score, and the Colorectal Cancer subscale score * Answers to the questions comprising the subscales range from 0=not at all to 4=very much. The higher the total score the lower quality of life. * The total score ranges from 0-136. |
| Organ Preservation Rate | At 1 year | — |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMichael Waters, M.D., Ph.D.
Washington University School of Medicine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Radiation + FOLFOX * Pelvic radiotherapy 5GY x 5 fractions once daily
* Radiation to extra-mesorectal node 7 Gy x 5 fractions once daily
* FOLFOX should begin 2-4 weeks after completion of radiotherapy and will consist of FOLFOX x 8 cycles (16 weeks).
* Oxaliplatin day 1 every 14 days
* Leucovorin day 1 every 14 days. Levoleucovorin may be substituted if leucovorin is not available.
* 5-FU bolus day 1 every 14 days
* 5-FU infusion day 1 every 14 days over 46 hours
* An optional simultaneous integrated boost of 30 Gy in 5 fractions to the primary tumor is permitted | 55 |
| Radiation + CAPOX * Pelvic radiotherapy 5GY x 5 fractions once daily
* Radiation to extra-mesorectal node 7 Gy x 5 fractions once daily
* CAPOX should begin 2-4 weeks after completion of radiotherapy and will consist of CAPOX x 5 cycles (15 weeks).
* Capecitabine 1000 mg/m\^2 by mouth twice per day on days 1-14 of every 21 day cycle
* Oxaliplatin 130 mg/m\^2 intravenous on day 1 of each 21 day cycle
* An optional simultaneous integrated boost of 30 Gy in 5 fractions to the primary tumor is permitted | 8 |
| Total | 63 |
Baseline characteristics
| Characteristic | Radiation + FOLFOX | Total | Radiation + CAPOX |
|---|---|---|---|
| Age, Continuous | 61 years | 61 years | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 55 Participants | 63 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 7 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 49 Participants | 56 Participants | 7 Participants |
| Region of Enrollment United States | 55 participants | 63 participants | 8 participants |
| Sex: Female, Male Female | 17 Participants | 19 Participants | 2 Participants |
| Sex: Female, Male Male | 38 Participants | 44 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 55 | 0 / 8 |
| other Total, other adverse events | 31 / 55 | 4 / 8 |
| serious Total, serious adverse events | 21 / 55 | 2 / 8 |
Outcome results
Primary
Clinical Complete Response Rate
\- Criteria for clinical complete response: * No residual gross tumor at procto/sigmoidoscopy; or only erythematous scar or ulcer * No palpable tumor on DRE * No radiographic evidence of tumor on MRI * No suspicious mesorectal lymph nodes on MRI * Negative biopsy from scar, ulcer, or former tumor site (if necessary according to surgeon's judgment)
Time frame: Completion of treatment (estimated to be 22 weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radiation + FOLFOX | Clinical Complete Response Rate | 36 Participants |
| Radiation + CAPOX | Clinical Complete Response Rate | 2 Participants |
Secondary
Incidence of Any Grade 3 or Higher Toxicity During Treatment
\- The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.
Time frame: From start of treatment through the completion of treatment (estimated to be 22 weeks)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hypertension | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Alanine aminotransferase increased | 2 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hypoalbuminemia | 0 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Delirium | 0 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hypocalcemia | 0 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Anorexia | 0 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hypokalemia | 2 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Depression | 0 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hyponatremia | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Acidosis | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Infection - cellulitis | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Diarrhea | 5 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Neutrophil count decreased | 22 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Anal pain | 0 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Platelet count decreased | 0 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Fall | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Proctitis | 2 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Aspartate aminotransferase increased | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Rectal hemorrhage | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Fatigue | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Rectal pain | 0 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Anxiety | 0 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Skin infection | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Febrile neutropenia | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Superior vena cava syndrome | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Congestive heart failure | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Thromboembolic event | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Generalized muscle weakness | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Vomiting | 0 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Weight loss | 0 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Anemia | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | White blood cell decreased | 7 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hyperglycemia | 3 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Peripheral sensory neuropathy | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Dehydration | 1 Participants |
| Radiation + FOLFOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Abdominal pain | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Vomiting | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Abdominal pain | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Acidosis | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Alanine aminotransferase increased | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Anal pain | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Anemia | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Anorexia | 2 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Anxiety | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Aspartate aminotransferase increased | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Congestive heart failure | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Dehydration | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Delirium | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Depression | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Diarrhea | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Fall | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Fatigue | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Febrile neutropenia | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Generalized muscle weakness | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hyperglycemia | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hypertension | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hypoalbuminemia | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hypocalcemia | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hypokalemia | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Hyponatremia | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Infection - cellulitis | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Neutrophil count decreased | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Platelet count decreased | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Proctitis | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Rectal hemorrhage | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Rectal pain | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Skin infection | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Superior vena cava syndrome | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Thromboembolic event | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Weight loss | 1 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | White blood cell decreased | 0 Participants |
| Radiation + CAPOX | Incidence of Any Grade 3 or Higher Toxicity During Treatment | Peripheral sensory neuropathy | 1 Participants |
Secondary
Incidence of Post Chemoradiotherapy Grade 3 or Higher Toxicity
\- The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.
Time frame: At 1 year after the start of radiation
Secondary
Organ Preservation Rate
Time frame: At 1 year
Secondary
Organ Preservation Rate
Time frame: At 2 years
Secondary
Progression-free Survival (PFS)
* Criteria for progressive disease: * Increase in the size of primary tumor by RECIST criteria (increase of at least 20% from nadir in the sum of the target lesion, with an absolute increase of at least 5 mm) * New metastatic disease * PFS is defined as the time from date of treatment to death or progression, which occurs first. The alive patients without progression are censored as the last date follow-up.
Time frame: At 2 years
Secondary
Quality of Anorectal Function as Measured by the FACT-C Questionnaire
* Questionnaire with 5 sections (physical well-being, social/family well being, emotional well-being, functional well-being, and additional concerns) * Answers to the questions range from 0=not at all to 4=very much. The higher the total score the lower quality of life.
Time frame: 10-14 months after radiation therapy