Surgery With or Without Chemotherapy and Radiation Therapy in Treating Patients With Cancer of the Esophagus

A Prospective Randomized Phase III Trial Comparing Trimodality Therapy (Cisplatin, 5-FU, Radiotherapy, and Surgery) to Surgery Alone for Esophageal Cancer

RATIONALE: Drugs used in chemotherapy use 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. It is not yet known whether surgery is more effective with or without chemotherapy and radiation therapy for cancer of the esophagus.

PURPOSE: Randomized phase III trial to compare the effectiveness of surgery with or without combination chemotherapy and radiation therapy in treating patients who have cancer of the esophagus that can be surgically removed.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer
• Intervention / Treatment: Drug: fluorouracil; Radiation: radiation therapy; Drug: cisplatin; Procedure: surgical procedure

Detailed Description

OBJECTIVES: I. Compare overall five-year survival rates and treatment failures in patients receiving neoadjuvant cisplatin (CDDP) plus fluorouracil (5-FU) with concomitant radiotherapy followed by surgical resection versus patients receiving surgery alone. II. Assess and compare the toxicities of each approach. III. Compare the incidence and pattern of local (gastric or esophageal bed or regional lymph nodes) and distant (supraclavicular lymph node, liver, peritoneal carcinomatosis, or lung, brain, etc.) recurrence. IV. Evaluate the prognostic ability of noninvasive and minimally invasive pretreatment staging with regard to survival and recurrence. V. Evaluate the ability of preresection adjuvant chemotherapy with concomitant radiation therapy to render tumors to lower stages. VI. Evaluate the impact of lymph nodes on survival and recurrence.

OUTLINE: This a two arm, randomized study. Patients are stratified by: cell type of cancer (squamous cell vs adenocarcinoma); lymph nodes (positive vs negative); and stage (invasive vs noninvasive). Patients in arm I undergo chemotherapy and radiotherapy within 24 hours of each other. Chemotherapy consists of cisplatin (CDDP) by bolus IV infusion over 30 minutes on day 1 and again on day 29. Fluorouracil (5-FU) is administered by continuous IV infusion for 4 days (on days 1-4 and 29-32) after completion of cisplatin. Radiotherapy is administered on days 1-5, 8-12, 15-19, 22-26, and 29-33, with a boost on days 36-38. If there is no disease progression or unresectable disease, surgery is performed within 3-8 weeks following completion of therapy. Patients in arm II undergo surgery alone no later than 6 weeks postrandomization. Patients are followed at least every 3 months for two years, then every 6 months for the next two years, and annually thereafter.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093-0658
      • University of California San Diego Cancer Center
    • San Francisco, California, United States, 94115-0128
      • UCSF Cancer Center and Cancer Research Institute
  • Delaware
    • Wilmington, Delaware, United States, 19899
      • CCOP - Christiana Care Health Services
  • District of Columbia
    • Washington, District of Columbia, United States, 20307-5000
      • Walter Reed Army Medical Center
  • Florida
    • Miami Beach, Florida, United States, 33140
      • CCOP - Mount Sinai Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago Health Sciences Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Marlene & Stewart Greenebaum Cancer Center, University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Cancer Center
  • Missouri
    • Columbia, Missouri, United States, 65203
      • Ellis Fischel Cancer Center - Columbia
    • Saint Louis, Missouri, United States, 63110
      • Barnes-Jewish Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198-3330
      • University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • CCOP - Southern Nevada Cancer Research Foundation
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Norris Cotton Cancer Center
  • New Jersey
    • Mount Holly, New Jersey, United States, 08060
      • Fox Chase Cancer Center at Virtua-Memorial Hospital Burlington County
    • Paterson, New Jersey, United States, 07503
      • St. Joseph's Hospital and Medical Center
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • Manhasset, New York, United States, 11030
      • CCOP - North Shore University Hospital
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital - Cornell Campus
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center, NY
    • Rochester, New York, United States, 14642
      • University of Rochester Cancer Center
    • Syracuse, New York, United States, 13210
      • State University of New York - Upstate Medical University
    • Syracuse, New York, United States, 13210
      • CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center, UNC
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
    • Winston-Salem, North Carolina, United States, 27104-4241
      • CCOP - Southeast Cancer Control Consortium
    • Winston-Salem, North Carolina, United States, 27157-1082
      • Comprehensive Cancer Center of Wake Forest University Baptist Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19102-1192
      • Hahnemann University Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425-0721
      • Medical University of South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • University of Tennessee, Memphis Cancer Center
  • Vermont
    • Burlington, Vermont, United States, 05401-3498
      • Vermont Cancer Center
  • Virginia
    • Richmond, Virginia, United States, 23298-0037
      • MBCCOP - Massey Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

1. Patients with histologically documented untreated squamous cell carcinoma or adenocarcinoma of the thoracic esophagus (below 20 cm) or gastro-esophageal junction and with less than 2 cm distal spread into the gastric cardia were eligible.
2. No evidence of distant metastatic disease by history and physical examination
3. Upper endoscopy with biopsy, computed tomography (CT) of the chest and upper abdomen, and pulmonary function studies are required.
4. Bone scan is required for alkaline phosphatase more than 3X the institutional normal value.
5. Bronchoscopy is required if the primary tumor was adjacent to the trachea or left main stem bronchus.

6. Patients are required to have:

   • granulocyte counts ≥1,800/mL
   • platelet count ≥ 100,000/mL
   • creatinine clearance ≥ 50 mL/min
7. Esophageal ultrasound (EUS) and preresection staging by thoracoscopy (ts) and laparoscopy/minilaparotomy (ls), including biopsy of celiac axis and lesser curvature are recommended
8. Tumors must be considered surgically resectable (T1-3, NX), including regional thoracic lymph node (N1) metastases.
9. Patients with supraclavicular lymph nodes measuring ≤ 1.5 cm by CT (not palpable) are eligible.
10. Patients with lymph node metastases to levels 15 to 20 (predominantly celiac axis and paracardial nodes) ≤1.5 cm by CT.
11. Patients may not have previously received chemotherapy or radiation therapy for this tumor or any radiation therapy that would overlap the radiation fields required for this malignancy.
12. Patients with previous malignancies are eligible if more than 5 years had elapsed from diagnosis without evidence of tumor recurrence.
13. There can be no other serious illness that would limit survival to less than 2 years, or psychiatric condition that would prevent compliance with treatment or informed consent. Patients with uncontrolled or severe cardio- vascular disease,pulmonary disease, oractive infections are excluded.
14. Pregnant patients are excluded.
15. Informed consent is required for all patients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Surgery	Procedure: surgical procedure
Experimental: Chemotherapy + Radiation + Surgery	Drug: fluorouracil; Radiation: radiation therapy; Drug: cisplatin; Procedure: surgical procedure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival	up to 5 years

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Mark Krasna, MD, Jersey Shore University Medical Center

Publications and helpful links

General Publications

• Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, Kiel K, Willett C, Sugarbaker D, Mayer R. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008 Mar 1;26(7):1086-92. doi: 10.1200/JCO.2007.12.9593.
• Krasna M, Tepper JE, Niedzwiecki D, et al.: Trimodality therapy is superior to surgery alone in esophageal cancer: results of CALGB 9781. [Abstract] American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, 26-28 January 2006, San Francisco, California. A-4, 2006.
• Tepper JE, Krasna M, Niedzwiecki D, et al.: Superiority of trimodality therapy to surgery alone in esophageal cancer: results of CALGB 9781. [Abstract] J Clin Oncol 24 (Suppl 18): A-4012, 2006.

Study record dates

Study Major Dates

• Study Start: October 1, 1997
• Primary Completion (Actual): March 1, 2000
• Study Completion (Actual): March 1, 2000

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: May 18, 2004
• First Posted (Estimate): May 19, 2004

Study Record Updates

• Last Update Posted (Estimate): July 4, 2016
• Last Update Submitted That Met QC Criteria: July 1, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: stage II esophageal cancer; stage III esophageal cancer; squamous cell carcinoma of the esophagus; adenocarcinoma of the esophagus; stage I esophageal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Esophageal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Fluorouracil
• Other Study ID Numbers: CALGB-9781; U10CA031946 (U.S. NIH Grant/Contract); CLB-C9781; E-C9781; NCCTG-C9781; RTOG-9716; CDR0000065873 (Registry Identifier: NCI Physician Desk Reference)