Neoadjuvant Chemoradiotherapy and Adjuvant Chemotherapy in Treating Patients Who Are Undergoing Surgical Resection for Locally Advanced Rectal Cancer

NCT00081289 | Completed Phase 2 Results DMC

• 2 other identifiers: RTOG-0247CDR0000350136
• Study Type: interventional
• Target: 146
• Locations: 1 country
• Sites: 5

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Chemoradiotherapy (combining chemotherapy with radiation therapy) before surgery may shrink the tumor so that it can be removed. Giving chemotherapy after surgery may kill any remaining tumor cells. PURPOSE: This randomized phase II trial is studying two different regimens of neoadjuvant chemoradiotherapy and adjuvant chemotherapy and comparing how well they work in treating patients who are undergoing surgical resection for locally advanced rectal cancer.

Conditions

Colorectal Cancer

Keywords

stage III rectal cancer; adenocarcinoma of the rectum; stage II rectal cancer

Outcome Measures

Primary Outcomes (1)

• Pathologic Complete Response Rate

  A pathologic complete response (pCR) was defined as no evidence of residual cancer histologically; disease progression or death before surgery was considered less than pCR (even without surgical specimen). All cases were reviewed by the study's surgical oncology co-chair for the determination of pCR. Each arm was first analyzed alone. If the arm had 9 or more pCRs in 48 evaluable pts, then the null hypothesis (H0) of 10% pCR rate would be rejected in favor of the alternative hypothesis of 25%, providing 90% power with a two-sided 10% type I error rate. If both arms reject H0, then statistical selection theory would be used to choose the arm for further study in a phase III trial. If only one arm has acceptable pCR rate, then that arm would be pursued in a phase III trial.

  After protocol surgery, approximately 10-16 weeks from randomization based on surgery occurring 4-8 weeks after chemoradiation

Secondary Outcomes (18)

• Survival Rate at 4 Years

  From randomization to four years

• Local-regional Failure Rate at 4 Years

  From randomization to four years

• Distant Failure Rate at 4 Years

  From randomization to four years

• Second Primary Rate at 4 Years

  From randomization to four years

• Disease-free Survival Rate at 4 Years

  From randomization to four years

Study Arms (2)

Neoadjuvant chemoradiation with irinotecan

EXPERIMENTAL

Patients receive neoadjuvant therapy comprising 45 Gy (1.8 Gy/fx) + 5.4 Gy boost (1.8 Gy/fx) radiation therapy (RT), oral capecitabine 1200mg/m\^2/day 5 days/week during RT, and irinotecan 50 mg/m\^2 IV for 1 hour days 1, 8, 22, 29. Surgery 4-8 weeks after RT. Postoperative chemotherapy beginning Day 1 postoperatively for nine 14-day cycles(folinic acid 400 mg/m\^2 over 2 hours Day 1; 5-fluorouracil bolus 400 mg/m\^2 IV push Day 1 plus 2400 mg/m\^2 IV continuous infusion over 46 hours, beginning Day 1; and oxaliplatin 85 mg/m\^2 IV over 2 hours Day 1) .

Radiation: Radiation Therapy; Drug: Capecitabine 1200 mg/m^2/day; Drug: Irinotecan; Procedure: Surgery; Drug: Folinic Acid; Drug: Fluorouracil; Drug: Oxaliplatin

Neoadjuvant chemoradiation with oxaliplatin

EXPERIMENTAL

Patients receive neoadjuvant therapy comprising 45 Gy (1.8 Gy/fx) + 5.4 Gy boost (1.8 Gy/fx) radiation therapy (RT), oral capecitabine 1650mg/m\^2/day 5 days/week during RT, and oxaliplatin 50 mg/m\^2 IV for 2 hours days 1, 8, 15, 22, 29. Surgery 4-8 weeks after RT. Postoperative chemotherapy beginning Day 1 postoperatively for nine 14-day cycles(folinic acid 400 mg/m\^2 over 2 hours Day 1; 5-fluorouracil bolus 400 mg/m\^2 IV push Day 1 plus 2400 mg/m\^2 IV continuous infusion over 46 hours, beginning Day 1; and oxaliplatin 85 mg/m\^2 IV over 2 hours Day 1) .

Radiation: Radiation Therapy; Drug: Capecitabine 1650 mg/m^2/day; Drug: Oxaliplatin; Procedure: Surgery; Drug: Folinic Acid; Drug: Fluorouracil

Interventions

Radiation Therapy RADIATION

Pelvic radiation therapy given once daily 5 days a week for 6 weeks, 45 Gy in 25 fractions + boost of 5.4 Gy in 3 fractions for a total dose of 50.4 Gy.

Neoadjuvant chemoradiation with irinotecan; Neoadjuvant chemoradiation with oxaliplatin

Capecitabine 1650 mg/m^2/day DRUG

825 mg/m\^2 q12 hours (1650 mg/m\^2/day) orally 5 days per week during radiotherapy.

Neoadjuvant chemoradiation with oxaliplatin

Capecitabine 1200 mg/m^2/day DRUG

600 mg/m\^2 q12 hours(1200 mg/m\^2/day) orally 5 days per week during radiotherapy.

Neoadjuvant chemoradiation with irinotecan

Irinotecan DRUG

50mg/m\^2 IV over 1 hour on days 1, 8, 22, and 29

Also known as: Irinotecan Hydrochloride

Neoadjuvant chemoradiation with irinotecan

Oxaliplatin DRUG

50mg/m\^2 IV over 2 hours on days 1, 8, 15, 22, and 29

Neoadjuvant chemoradiation with oxaliplatin

Surgery PROCEDURE

All patients will undergo surgery four to eight weeks following the completion of radiation therapy. The choice of procedure abdominoperineal resection (APR), low anterior resection (LAR), or LAR/coloanal anastomosis is at the discretion of the surgeon.

Neoadjuvant chemoradiation with irinotecan; Neoadjuvant chemoradiation with oxaliplatin

Folinic Acid DRUG

400 mg/m\^2 IV over 2 hours Day 1 (postoperatively) ,every 14 days, for nine 14-day cycles.

Also known as: Leucovorin

Neoadjuvant chemoradiation with irinotecan; Neoadjuvant chemoradiation with oxaliplatin

Fluorouracil DRUG

5-fluorouracil bolus 400 mg/m\^2 IV push Day 1 (postoperatively), every 14 days, for nine 14-day cycles. 5-fluorouracil infusion 2400 mg/m\^2 IV continuous infusion over 46 hours, beginning day 1, every 14 days, for nine 14-day cycles.

Also known as: 5-FU

Neoadjuvant chemoradiation with irinotecan; Neoadjuvant chemoradiation with oxaliplatin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adenocarcinoma of the rectum originating at or below 12 cm from the anal verge without evidence of distant metastases
• Patient must be 18 years of age or greater.
• Potentially resectable en bloc based upon surgeon evaluation
• Clinical stages T3 or T4, based upon endorectal ultrasound, or physical examination (only acceptable for T4 lesions).
• Absolute neutrophil count of \> 1500 per microliter and platelet count \> 100,000 per microliter; aspartate aminotransferase (AST) and alkaline phosphatase \< 2.5 X upper limit of normal (ULN), bilirubin \< = 1.5 ULN, calculated creatinine clearance \> 50 ml/min using Cockcroft-Gault formula:
• CrCl male = (140 - age) x (wt. in kg) / (Serum Cr) x 72
• CrCl female = 0.85 x (CrCl male)
• Zubrod performance status 0-2
• No history of other malignancies within 5 years, except non-melanoma skin cancer, in situ carcinoma of the cervix, or ductal carcinoma in situ of the breast. Previous invasive cancer permitted if disease free at least 5 years.
• Signed study-specific informed consent prior to randomization

You may not qualify if:

• Any evidence of distant metastasis
• Synchronous primary colon carcinomas, except T1 lesions (full colonoscopy not required for enrollment)
• Extension of malignant disease to the anal canal
• Prior radiation therapy to the pelvis
• Prior chemotherapy for malignancies
• Serious, uncontrolled, concurrent infection(s).
• Participation in any investigational drug study within 4 weeks preceding the start of study treatment.
• Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 12 months.
• Evidence of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake.
• Other serious uncontrolled medical conditions that the investigator feels might compromise study participation.
• Major surgery within 4 weeks of the study treatment.
• Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome.
• Known, existing uncontrolled coagulopathy.
• No concurrent cimetidine allowed.

Sponsors & Collaborators

• Radiation Therapy Oncology Group: lead
• National Cancer Institute (NCI): collaborator

Study Sites (5)

University of California Davis Cancer Center

Sacramento, California, 95817, United States

Location

Baptist-South Miami Regional Cancer Program

Miami, Florida, 33176, United States

Location

Ingalls Cancer Care Center at Ingalls Memorial Hospital

Harvey, Illinois, 60426, United States

Location

Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton

Marlton, New Jersey, 08053, United States

Location

Northeast Radiation Oncology Center

Dunmore, Pennsylvania, 18512, United States

Location

Related Publications (2)

• Wong SJ, Winter K, Meropol NJ, Anne PR, Kachnic L, Rashid A, Watson JC, Mitchell E, Pollock J, Lee RJ, Haddock M, Erickson BA, Willett CG. Radiation Therapy Oncology Group 0247: a randomized Phase II study of neoadjuvant capecitabine and irinotecan or capecitabine and oxaliplatin with concurrent radiotherapy for patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2012 Mar 15;82(4):1367-75. doi: 10.1016/j.ijrobp.2011.05.027. Epub 2011 Jul 19.

  PMID: 21775070 RESULT

• Wong SJ, Moughan J, Meropol NJ, et al.: Efficacy endpoints of RTOG 0247: A randomized phase II study of neoadjuvant capecitabine (C) and irinotecan (I) or C and oxaliplatin (O) with concurrent radiation therapy (RT) for locally advanced rectal cancer. [Abstract] J Clin Oncol 29 (Suppl 15): A-3517, 2011.

  RESULT

MeSH Terms

Conditions

Colorectal Neoplasms; Rectal Neoplasms

Interventions

Radiotherapy; Capecitabine; Irinotecan; Oxaliplatin; Surgical Procedures, Operative; Leucovorin; Fluorouracil

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Camptothecin; Alkaloids; Coordination Complexes; Organic Chemicals; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes

Limitations and Caveats

Due to excessive GI adverse events in the first 35 patients, chemotherapy dosage was modified and the protocol was amended (treatment descriptions reflect the revision). Therefore the first 35 patients are not included in outcome measure results.

Results Point of Contact

• Title: Wendy Seiferheld
• Organization: NRG Oncology

seiferheldw@nrgoncology.org

Study Officials

• Neal J. Meropol, MD

  Fox Chase Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 7, 2004
• First Posted: April 8, 2004
• Study Start: March 1, 2004
• Primary Completion: May 1, 2011
• Study Completion: December 1, 2016
• Last Updated: February 27, 2020
• Results First Posted: November 25, 2013

Record last verified: 2020-02

Locations

US (5)