Radiation Therapy + Combination Chemotherapy as 1st-Line Therapy for Patients With Inoperable Esophageal Cancer

Phase II-III Study Comparing Radiochemotherapy With the FOLFOX Regimen Versus Radiochemotherapy With 5FU-cisplatin (Herskovic Regimen) in First Line Treatment of Patients With Inoperable Oesophageal Cancer.

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as oxaliplatin, fluorouracil, leucovorin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) together with radiation therapy may kill more tumor cells.

PURPOSE: This randomized phase II/III trial is studying radiation therapy and two different combination chemotherapy regimens to compare how well they work as first-line therapy in treating patients with esophageal cancer that cannot be removed by surgery.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer
• Intervention / Treatment: Radiation: radiation therapy; Drug: oxaliplatin; Drug: cisplatin; Drug: 5-FU; Drug: Folinic Acid

Detailed Description

OBJECTIVES:

Primary

• To assess the feasibility of radiochemotherapy comprising oxaliplatin, fluorouracil, and leucovorin calcium (FOLFOX regimen) vs fluorouracil and cisplatin (Herskovic regimen) in patients with inoperable esophageal cancer. (Phase II)
• To assess the endoscopic complete response rate in patients treated with these regimens. (Phase II)
• To compare the event-free survival of patients treated with these regimens. (Phase III)

Secondary

• To assess the toxicity profile of these regimens using the NCI CTC v2.0 criteria. (Phase II)
• To compare the overall survival, endoscopic complete response rate, incidence of grade 3-4 toxicities, and time to treatment failure in patients treated with these regimens. (Phase III)
• To evaluate the quality of life of these patients using EORTC QLQ-C30 (version 3) and a validated disease-specific module EORTC QLQ-OES18. (Phase III)

OUTLINE: This is a multicenter study. Patients are stratified according to histological type (adenocarcinoma or adenosquamous carcinoma vs squamous cell carcinoma), pretreatment weight loss within the past 6 months (grade 1 [< 10%] vs grade 2 [≥ 10%]), ECOG performance status (0 vs 1 vs 2), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I (modified FOLFOX 4 regimen): Patients undergo radiotherapy 5 days a week for 5 weeks. Beginning concurrently with radiotherapy, patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment with chemotherapy repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.
• Arm II (Herskovic regimen): Patients undergo radiotherapy as in arm I. Patients also receive cisplatin IV continuously over 24 hours on day 1 and fluorouracil IV continuously over 96 hours on days 1-4 of weeks 1, 5, 8, and 11 in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, periodically during study therapy, and then every 6 months for 1 year and annually for 3 years after completion of study therapy.

After completion of study therapy, patients are followed at 4 weeks and then every 3-6 months until disease progression.

PROJECTED ACCRUAL: A total of 97 patients will be accrued for the phase II portion of the study. A total of 169 patients will be accrued for the phase III portion of the study.

• Study Type: Interventional
• Enrollment (Actual): 266
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Besancon, France, 25030
    • CHR de Besancon - Hopital Saint-Jacques
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Bordeaux, France, 33075
    • Hopital Saint André
  • Boulogne-Billancourt, France, F-92104
    • Hopital Ambroise Pare
  • Caen, France, 14076
    • Centre Regional Francois Baclesse
  • Caen, France, 14052
    • Polyclinique du Parc
  • Dijon, France, 21034
    • Hopital Du Bocage
  • Dijon, France, 21079
    • Centre de Lutte Contre le Cancer Georges-Francois Leclerc
  • Lille, France, 59020
    • Centre OSCAR LAMBRET
  • Limoges, France, 87042
    • Centre Hospital Regional Universitaire de Limoges
  • Lyon, France, 69373
    • Centre LEON BERARD
  • Marseille, France, 13385
    • CHU de la Timone
  • Montpellier, France, 34298
    • Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
  • Nice, France, 06189
    • Centre Antoine Lacassagne
  • Paris, France, 75015
    • Hopital Europeen Georges Pompidou
  • Paris, France, 75970
    • Hopital Tenon
  • Paris, France, 75475
    • Hôpital Saint-Louis
  • Poitiers, France, 86021
    • CHU Poitiers
  • Reims, France, 51092
    • CHU - Robert Debre
  • Reims, France, 51056
    • Institut Jean Godinot
  • Rennes, France, 35042
    • Centre Eugene Marquis
  • Rouen, France, 76031
    • Hopital Charles Nicolle
  • Saint Brieuc, France, F-22015
    • Clinique Armoricaine de Radiologie
  • Strasbourg, France, 67065
    • Centre Paul Strauss
  • Toulouse, France, 31052
    • Institut Claudius Regaud
  • Toulouse, France, 31078
    • Clinique du Parc
  • Vandoeuvre-les-Nancy, France, 54511
    • Centre Alexis Vautrin
  • Villejuif, France, F-94805
    • Institut Gustave Roussy

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

DISEASE CHARACTERISTICS:

• Histologically proven adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma of the esophagus

  • Locally advanced disease (any T, N0 or N1, M0 or M1a)

    • No metastatic disease, except for tumor involvement of the upper third of the esophagus or cervical esophageal tumor with regional nodes, or tumor involvement of the lower third of the esophagus with celiac nodes (M1a)

      • Cervical primary tumor with positive supraclavicular or cervical lymph nodes (defined as N1) allowed
      • No radiographic evidence of enlarged (≥ 1.5 cm) celiac lymph nodes by CT scan or echography
  • No small cell or undifferentiated carcinoma of the esophagus
  • No multiple carcinomas of the esophagus (i.e., > 1 esophageal tumor)

  • No cardia tumor (Siewert II) or gastric tumor extension to the esophagus (Siewert III)

    • Esophageal tumor extension to the cardia (Siewert I) (center of the tumor lying > 1 cm-5 cm above gastroesophageal junction) allowed
• Inoperable disease OR surgery is contraindicated
• No tracheo-esophageal fistula or invasion of the tracheo-bronchial tree

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Life expectancy ≥ 3 months
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 10 g/dL (transfusion allowed)
• Creatinine < 15 mg/L
• Total bilirubin < 1.5 times upper limit of normal (ULN)
• ALT and AST < 2.5 times ULN
• Prothrombin time ≥ 60%
• Not pregnant or nursing
• Fertile patients must use effective contraception
• Caloric intake sufficient (i.e., > 1,000 Kcal/m²/day) (orally or with gastrostomy)
• No weight loss > 20% normal body weight within the past 3 months
• No complete dysphagia
• No exclusive requirement for parenteral nutrition

• No peripheral neuropathy > grade 1

  • No sensitive peripheral neuropathy with functional impairment
• No auditory disorders
• No other prior malignancies except curatively treated nonmelanoma skin cancer or carcinoma in situ of the cervix or stage I or II node-negative head and neck cancer that was curatively treated > 3 years ago

• No myocardial infarction within the past 6 months

  • Patients who have had a myocardial infarction > 6 months ago are eligible provided there is no transient ischemia by thallium myocardial scintigraphy and patient is able to undergo chemotherapy , as determined by a cardiologist
• No other serious illness or medical condition (e.g., symptomatic coronary disease, left ventricular failure, or uncontrolled infection)
• No stage II-IV arterial disease, according to the DE LERICHE and FONTAINE classification
• No geographical, social, or psychological circumstances preventing regular follow-up

PRIOR CONCURRENT THERAPY:

• No prior treatment for esophageal cancer (e.g., surgery, chemotherapy, or radiotherapy)
• No prior cervical, thoracic, or abdominal radiotherapy with field overlapping the proposed esophageal radiotherapy field
• More than 30 days since prior experimental drugs or participation in another clinical trial
• No other concurrent anticancer therapy
• No concurrent phenytoin or yellow fever vaccine
• No concurrent high-dose, long-term corticosteroids
• No concurrent calcium gluconate/magnesium sulfate infusions
• No concurrent hematopoietic growth factors
• No concurrent esophageal dilatation

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
Experimental: FOLFOX and radiotherapy; Oxaliplatin (85mg/m2); Folinic Acid (200mg/m2); 5-FU (400mg/m2-Bolus and 1600mg/m2 over 46h)- once every two weeks for six cycles	Radiation: radiation therapy; Drug: oxaliplatin; Drug: 5-FU; Other Names: 5-Fluorouracil; Drug: Folinic Acid
Experimental: 5-FU / cisplatin and radiotherapy; 5-FU (100mg/m2); Cisplatin (75mg/m2)	Radiation: radiation therapy; Drug: cisplatin; Drug: 5-FU; Other Names: 5-Fluorouracil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of patients who complete the full study treatment (Phase II)	12 weeks
Endoscopic complete response rate (Phase II)	12 weeks
Progression-free survival (Phase III)	Until progression

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety profile as assessed by NCI CTC v2.0 (Phase II)	Total duration of the trial
Overall survival (Phase III)	Total duration of the trial
Complete response rate (Phase III)	Total duration of the trial
Time to treatment failure (Phase III)	Total duration of the trial
Incidence of grade 3-4 toxicities (Phase III)	Total duration of the trial
Quality of life as assessed by EORTC QLQ-C30 (version 3) and EORTC QLQ-OES18 (Phase III)	Total duration of the trial

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Principal Investigator: Thierry Conroy, MD, Centre Alexis Vautrin

Publications and helpful links

General Publications

• Winter A, Cuer B, Conroy T, Juzyna B, Gourgou S, Mollevi C, Touraine C. Flexible modeling of longitudinal health-related quality of life data accounting for informative dropout in a cancer clinical trial. Qual Life Res. 2022 Sep 17. doi: 10.1007/s11136-022-03252-6. Online ahead of print.
• Cuer B, Conroy T, Juzyna B, Gourgou S, Mollevi C, Touraine C. Joint modelling with competing risks of dropout for longitudinal analysis of health-related quality of life in cancer clinical trials. Qual Life Res. 2022 May;31(5):1359-1370. doi: 10.1007/s11136-021-03040-8. Epub 2021 Nov 24.
• Cuer B, Mollevi C, Anota A, Charton E, Juzyna B, Conroy T, Touraine C. Handling informative dropout in longitudinal analysis of health-related quality of life: application of three approaches to data from the esophageal cancer clinical trial PRODIGE 5/ACCORD 17. BMC Med Res Methodol. 2020 Sep 3;20(1):223. doi: 10.1186/s12874-020-01104-w.
• Conroy T, Galais MP, Raoul JL, Bouche O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, Francois E, Crehange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Federation Francophone de Cancerologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. doi: 10.1016/S1470-2045(14)70028-2. Epub 2014 Feb 18. Erratum In: Lancet Oncol. 2014 Dec;15(13):e587. Lancet Oncol. 2014 Dec;15(13):e587.

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: March 12, 2009
• First Submitted That Met QC Criteria: March 12, 2009
• First Posted (Estimate): March 13, 2009

Study Record Updates

• Last Update Posted (Estimate): December 18, 2015
• Last Update Submitted That Met QC Criteria: December 17, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: squamous cell carcinoma of the esophagus; adenocarcinoma of the esophagus; stage IIB esophageal cancer; stage IIIA esophageal cancer; stage IIIB esophageal cancer; stage IIIC esophageal cancer; stage IV esophageal cancer; stage IIA 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; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Oxaliplatin; Leucovorin; Levoleucovorin; Folic Acid
• Other Study ID Numbers: CDR0000595050; FRE-FNCLCC- ACCORD-17-0707; EU-20848