Colorectal Cancer
Conditions
Keywords
stage II rectal cancer, stage III rectal cancer, adenocarcinoma of the rectum
Brief summary
RATIONALE: 5FU based neoadjuvant chemoradiation (nCRT) is the standard of care for Stage II/III rectal cancer. Pathologic complete response (pCR) and downstaging have been associated with improved outcomes. The addition of oxaliplatin (OXA) to neoadjuvant therapy may reduce distant disease recurrence. Adjuvant treatment with OXA for rectal cancer has been motivated by benefits demonstrated in stage III colon cancer. Objective: To determine the feasibility, toxicity, and efficacy of preoperative OXA/5FU and RT followed by total mesorectal excision (TME) and adjuvant PURPOSE: This phase II trial is studying the side effects and how well giving neo-adjuvant combination chemotherapy with radiation works in treating patients undergoing surgery for rectal cancer.
Detailed description
OBJECTIVES: Primary * To assess the complete pathologic response rate in patients with rectal cancer treated with radiation, modified neoadjuvant FOLFOX 6 chemotherapy followed by total mesorectal excision and adjuvant modified FOLFOX 6 chemotherapy. Secondary * To observe the overall pathologic response rate in these patients. * To correlate pathologic staging with preoperative ultrasound and pelvic MRI staging. * To assess toxic side effects of these regimens in these patients. * To assess patterns of disease relapse, disease-free survival outcomes, and overall survival outcomes of these patients. OUTLINE: Patients with stage II/III rectal cancer were treated with OXA 60mg/m2 weekly continuous infusion 5FU of 225 mg/m2/d d1-5 with pelvic RT of 1.8Gy/d for 28 doses. Adjuvant therapy consisted of 6 cycles of biweekly FOLFOX6. Surgery: Patients undergo total mesorectal excision by anterior resection or an abdominal perineal resection within 4 weeks after completion of neoadjuvant therapy. Adjuvant therapy: Within 4 weeks after surgery, patients receive modified FOLFOX 6 chemotherapy comprising oxaliplatin and leucovorin calcium IV over 2 hours on day 1 and continuous fluorouracil IV over 46 hours on days 1-2. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients complete quality of life assessment questionnaires at baseline and at each follow-up visit. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and annually thereafter.
Interventions
DRUG5-FU
5-FU: continuous infusion via portable pump during all RT (approximately 33 days)
DRUGOxaliplatin
Oxaliplatin: 50mg/m2 weekly dosing during RT (Day 1)
DRUGleucovorin
Folinic Acid (Leucovorin): 400 mg/m2; 2-hour IV infusion simultaneously with oxaliplatin
PROCEDUREmesorectal excision
mesorectal excision
Sponsors
Beth Israel Medical Center
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
* Histologically proven adenocarcinoma of the rectum with no distant metastases. * T3-4N0M0, TanyN1-3M0 assessed by clinical exam, TRUS, MRI and CT * The distal border of the tumor must be at or below the peritoneal reflection, defined as within 12 centimeters of the anal verge by protoscopic examination. * No prior chemotherapy or pelvic irradiation. * ECOG performance status 0-1 * Age 18 to 70 years * ANC \>= 1500/mm3 and platelets \>= 100,000/mm3 * Serum creatinine \<= 1.5 x ULN; bilirubin \<= 1.5 x ULN; ALT\<= 2.5 x ULN
Exclusion criteria
* Pregnant or lactating females; patients not practicing active contraception while sexually active. * No other serious medical condition * A psychiatric disorder that would prohibit the subject from participating fully. * Peripheral neuropathy \> grade 1 * History within the past 5 years of a cancer diagnosis except for non-melanomatous skin cancers or in situ cervix carcinoma. * HIV positive patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Response and Complete Response | Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, an average of 3.5 months | Pathologic Response and Complete Response to preoperative therapy will be determined at the time of surgical resection. All grossly visible areas of ulceration and/or induration with be measured and submitted for histological evaluation. The unit of measure is the tumor response rate to preoperative chemoradiation. Pathologic complete response (pCR) is defined as no evidence of invasive tumor cells on pathologic examination of the primary rectal cancer. Tumor regression grade (TRG) will be quantitated into five grades: TRG 1 (complete regression) -absence of residual cancer and fibrosis extending from the site of original tumor through the layers of the rectal wall. TRG 2 characterized by the presence of rare residual cancer cells scattered through the fibrosis. TRG 3 characterized by an increase in the number of residual cancer cells, but fibrosis still predominant. TRG 4 -residual cancer outgrowing fibrosis. TRG 5 characterized by absence of regressive changes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Resectability Rates | Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, 3 months after beginning of chemoradiation treatment. | Complete resectability rates assessed by circumferential margin. |
| Local Regional Control | median follow-up 22 months post-TME | subjects were followed for median of 22 months post-surgery |
| Disease-free Survival | median 22 months follow-up | — |
| Treatment Toxicity | Weekly during chemoradiation treatment (3 months). Bi-weekly during adjuvant FOLFOX therapy (3.5 months). | Toxicity was assessed weekly during neoadjuvant chemotherapy and radiation therapy, bi-weekly during adjuvant FOLFOX therapy. |
| Patterns of Disease Failure, Including Local Recurrence and Distant Metastasis Assessed by CT Scan | median follow-up 22 months | — |
| Number of Participants With Comparison of Preoperative Stage With Post-treatment Pathologic Stage | Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, 3 months after beginning of chemoradiation treatment. | Thin-section high resolution pelvic MRI was used to image the tumor prior to chemoradiation and repeated prior to surgery, and then compared to post-treatment pathological stage. |
| Overall Survival | median follow-up 22 months | — |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from 2004-2009 from the oncology practice at Beth Israel and Roosevelt Hospitals.
Participants by arm
| Arm | Count |
|---|---|
| Chemoradiation,Surgery, Chemotherapy Preoperative Chemoradiation with oxaliplatin/5-FU followed by mesorectal excision and FOLFOX 6 | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 12 |
Baseline characteristics
| Characteristic | Chemoradiation,Surgery, Chemotherapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 11 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 60.3 years STANDARD_DEVIATION 10.5 |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 27 |
| serious Total, serious adverse events | 16 / 27 |
Outcome results
Primary
Pathologic Response and Complete Response
Pathologic Response and Complete Response to preoperative therapy will be determined at the time of surgical resection. All grossly visible areas of ulceration and/or induration with be measured and submitted for histological evaluation. The unit of measure is the tumor response rate to preoperative chemoradiation. Pathologic complete response (pCR) is defined as no evidence of invasive tumor cells on pathologic examination of the primary rectal cancer. Tumor regression grade (TRG) will be quantitated into five grades: TRG 1 (complete regression) -absence of residual cancer and fibrosis extending from the site of original tumor through the layers of the rectal wall. TRG 2 characterized by the presence of rare residual cancer cells scattered through the fibrosis. TRG 3 characterized by an increase in the number of residual cancer cells, but fibrosis still predominant. TRG 4 -residual cancer outgrowing fibrosis. TRG 5 characterized by absence of regressive changes.
Time frame: Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, an average of 3.5 months
Population: Number of subjects undergoing TME
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation,Surgery, Chemotherapy | Pathologic Response and Complete Response | 3 Participants |
Secondary
Complete Resectability Rates
Complete resectability rates assessed by circumferential margin.
Time frame: Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, 3 months after beginning of chemoradiation treatment.
Population: Out of the 27 patients enrolled, a total 23 underwent TME.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation,Surgery, Chemotherapy | Complete Resectability Rates | 3 patient |
Secondary
Disease-free Survival
Time frame: median 22 months follow-up
Population: Out of the 27 patients enrolled, a total 23 underwent TME and were assessed for disease-free survival.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation,Surgery, Chemotherapy | Disease-free Survival | 16 participants |
Secondary
Local Regional Control
subjects were followed for median of 22 months post-surgery
Time frame: median follow-up 22 months post-TME
Population: Out of the 27 patients enrolled, a total 23 underwent TME and were assessed for local regional control.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation,Surgery, Chemotherapy | Local Regional Control | 21 patient |
Secondary
Number of Participants With Comparison of Preoperative Stage With Post-treatment Pathologic Stage
Thin-section high resolution pelvic MRI was used to image the tumor prior to chemoradiation and repeated prior to surgery, and then compared to post-treatment pathological stage.
Time frame: Total mesorectal excision (TME) participants were evaluated at the time of surgical resection, 3 months after beginning of chemoradiation treatment.
Population: Out of the 27 patients enrolled, a total 23 underwent TME. These 23 patients were included for comparison of preoperative stage and post-treatment pathologic stage.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation,Surgery, Chemotherapy | Number of Participants With Comparison of Preoperative Stage With Post-treatment Pathologic Stage | 13 patient |
Secondary
Overall Survival
Time frame: median follow-up 22 months
Population: Patients who completed treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation,Surgery, Chemotherapy | Overall Survival | 21 participants |
Secondary
Patterns of Disease Failure, Including Local Recurrence and Distant Metastasis Assessed by CT Scan
Time frame: median follow-up 22 months
Population: Out of the 27 patients enrolled, a total 23 underwent TME and were assessed for patterns of disease failure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation,Surgery, Chemotherapy | Patterns of Disease Failure, Including Local Recurrence and Distant Metastasis Assessed by CT Scan | 2 patients |
Secondary
Treatment Toxicity
Toxicity was assessed weekly during neoadjuvant chemotherapy and radiation therapy, bi-weekly during adjuvant FOLFOX therapy.
Time frame: Weekly during chemoradiation treatment (3 months). Bi-weekly during adjuvant FOLFOX therapy (3.5 months).
Population: According to the citation J Clin Oncol 28,2010 (suppl; abstract e14128): acute grade 3-4 toxicities occurred in 16 patients, mainly hypersensitivity reactions and OXA associated peripheral neuropathy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiation,Surgery, Chemotherapy | Treatment Toxicity | 16 patients |