Five Fractions of Radiotherapy Followed by Full Dose FOLFOX Chemotherapy as Preoperative Treatment for Rectal Cancer

Phase 2

Completed

Conditions: Rectal Neoplasms

Interventions: Radiation: External beam radiation
Drug: Oxaliplatin
Drug: Leucovorin
Drug: 5-FU
Drug: Capecitabine

Registration Number: NCT01060007

Lead Sponsor: Washington University School of Medicine

Brief Summary: To determine if short course radiotherapy followed by chemotherapy can maintain morbidity at or below levels reported with concurrent 5FU, oxaliplatin, and radiotherapy, while maintaining response rates comparable to what would be expected with radiotherapy and concurrent chemotherapy.

Detailed Description: Our principal objectives in this trial will be to determine if short course radiotherapy followed by chemotherapy can maintain morbidity at or below levels reported with concurrent 5FU (oral capecitabine if 5FU is unavailable), oxaliplatin, and radiotherapy, while maintaining response rates comparable to what would be expected with radiotherapy and concurrent chemotherapy. If we can establish a T stage downstaging rate that is significantly better than 50% and if acute tolerance is acceptable, then we would consider this study as having provided sufficient pilot data to support including this approach as an arm in a multi-institution phase III trial. The long-term goal is improved overall control of disease by delivering better chemotherapy earlier.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 80

Inclusion Criteria

Biopsy proven adenocarcinoma of the rectum
Patient evaluated by surgeon and found to be a potential surgical candidate. Since the primary objectives are response to chemoradiation and acute toxicity, lesions which are initially unresectable are eligible-provided the surgeon feels that, if there is sufficient response, surgery could become feasible.
Clinical evidence of T3 or T4 disease. This can be by imaging studies (see or by physical findings (tethering on palpation for T3 lesions or invasion of a neighboring organ for T4 lesions)
Karnofsky Performance Status at >60
Laboratory criteria:
Absolute neutrophil count >= 1.5 K
Platelets >= 100 K
Total Bilirubin <= 2.0;
SGOT and Alkaline Phosphatase <= 2 x upper limit of normal
Creatinine < 2.0
Hemoglobin >= 8.0
Informed consent signed
Tumor measurable in at least one dimension. This may be, e.g. length and/or width measured endoscopically or on digital rectal examination, and maximum rectal wall thickness determined by imaging studies.
Estimated longevity at least 12 months
Patients with distant metastatic disease will be eligible if they satisfy all other conditions

Exclusion Criteria

Pregnant women, children < 18 years, or patients unable to give informed consent
Patients with a past history of pelvic radiotherapy.
Patients with any other malignancy within the past 5 years except: skin cancer or in-situ cervical cancer
Patients with known allergy/intolerance to 5FU, Leucovorin, Oxaliplatin, Capecitabine
Prior chemotherapy for colorectal cancer.
Grade >= 2 peripheral neuropathy
Any condition which, in the opinion of the treating medical oncologist, renders the patient unfit for 5FU (oral capecitabine if 5FU is unavailable), Leucovorin, Oxaliplatin chemotherapy

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Neoadjuvant radiation followed by FOLFOX	External beam radiation	Radiation - 20 Gy in 5 fractions to regional nodes. 25 Gy in the same 5 fractions to macroscopic disease. This is given over 1 week. FOLFOX Chemotherapy - after two weeks rest - oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 IV/2 hours followed sequentially by 5FU 400 mg/m2 IV push and 5FU 2400 mg/m2 over 46 hour CIVI. Repeat ever other week for a total of 4 courses (this equals 6 weeks). If 5-FU is unavailable -- oral capecitabine can be given as 1000 mg/m2 BID on days 1-7 every 14 days.
Neoadjuvant radiation followed by FOLFOX	Oxaliplatin	Radiation - 20 Gy in 5 fractions to regional nodes. 25 Gy in the same 5 fractions to macroscopic disease. This is given over 1 week. FOLFOX Chemotherapy - after two weeks rest - oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 IV/2 hours followed sequentially by 5FU 400 mg/m2 IV push and 5FU 2400 mg/m2 over 46 hour CIVI. Repeat ever other week for a total of 4 courses (this equals 6 weeks). If 5-FU is unavailable -- oral capecitabine can be given as 1000 mg/m2 BID on days 1-7 every 14 days.
Neoadjuvant radiation followed by FOLFOX	Leucovorin	Radiation - 20 Gy in 5 fractions to regional nodes. 25 Gy in the same 5 fractions to macroscopic disease. This is given over 1 week. FOLFOX Chemotherapy - after two weeks rest - oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 IV/2 hours followed sequentially by 5FU 400 mg/m2 IV push and 5FU 2400 mg/m2 over 46 hour CIVI. Repeat ever other week for a total of 4 courses (this equals 6 weeks). If 5-FU is unavailable -- oral capecitabine can be given as 1000 mg/m2 BID on days 1-7 every 14 days.
Neoadjuvant radiation followed by FOLFOX	5-FU	Radiation - 20 Gy in 5 fractions to regional nodes. 25 Gy in the same 5 fractions to macroscopic disease. This is given over 1 week. FOLFOX Chemotherapy - after two weeks rest - oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 IV/2 hours followed sequentially by 5FU 400 mg/m2 IV push and 5FU 2400 mg/m2 over 46 hour CIVI. Repeat ever other week for a total of 4 courses (this equals 6 weeks). If 5-FU is unavailable -- oral capecitabine can be given as 1000 mg/m2 BID on days 1-7 every 14 days.
Neoadjuvant radiation followed by FOLFOX	Capecitabine	Radiation - 20 Gy in 5 fractions to regional nodes. 25 Gy in the same 5 fractions to macroscopic disease. This is given over 1 week. FOLFOX Chemotherapy - after two weeks rest - oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 IV/2 hours followed sequentially by 5FU 400 mg/m2 IV push and 5FU 2400 mg/m2 over 46 hour CIVI. Repeat ever other week for a total of 4 courses (this equals 6 weeks). If 5-FU is unavailable -- oral capecitabine can be given as 1000 mg/m2 BID on days 1-7 every 14 days.

Primary Outcome Measures

Name	Time	Method
Rate of T Stage Downstaging	Mean number of weeks before surgery 17.3 (SD +/- 2.9 weeks)	T stage downstaging is defined as clinical pretreatment American Joint Committee on Cancer T stage (cT) being greater than pathologic T stage at surgery (ypT).
Preoperative Gastrointestinal Morbidity	Mean number of weeks before surgery 17.3 (SD +/- 2.9 weeks)	As measured by participants who experience grade 3 or higher gastrointestinal morbidity

Secondary Outcome Measures

Name	Time	Method
Rate of Locoregional Control	1 year
Freedom From Disease Relapse	30 months	Kaplan-Meier projections.
Determine Quality of Anorectal Function	Up to 1 year	Anorectal function was measured by the participant's response to the FACT-C questionnaire question "I have control of my bowels". The answers ranged from 0=not at all to 4=very much.
Incidence of Post Chemoradiotherapy Grade 3 or Higher Morbidity	1 year (completion of all treatment)
Rate of Overall Control	1 year
Incidence of Any Late Grade 3 or Higher Morbidity	Preoperative (mean time from start of radiation to surgery 17.3 weeks (SD +/- 2.9 weeks)
Local Control	30 months	* Kaplan-Meier projections * Local control = control of primary tumor