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

• ClinicalTrials.gov Identifier: NCT00861094
• Recruitment Status: Completed
• First Posted: March 13, 2009
• Last Update Posted: December 18, 2015
• Sponsor: UNICANCER
• Information provided by (Responsible Party): UNICANCER

Tracking Information

• First Submitted Date: March 12, 2009
• First Posted Date: March 13, 2009
• Last Update Posted Date: December 18, 2015
• Study Start Date: March 2008
• Actual Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 15, 2013)

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

Original Primary Outcome Measures (submitted: March 12, 2009)

• Percentage of patients who complete the full study treatment (Phase II)
• Endoscopic complete response rate (Phase II)
• Event-free survival (Phase III)

Current Secondary Outcome Measures (submitted: May 15, 2013)

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

Original Secondary Outcome Measures (submitted: March 12, 2009)

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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Radiation Therapy + Combination Chemotherapy as 1st-Line Therapy for Patients With Inoperable Esophageal Cancer
• Official Title: 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.

Brief Summary

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.

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
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Esophageal Cancer

Intervention

• Drug: cisplatin
• Drug: 5-FU
  Other Name: 5-Fluorouracil
• Drug: oxaliplatin
• Radiation: radiation therapy
• Drug: Folinic Acid

Study Arms

• 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
  Interventions:

  • Drug: 5-FU
  • Drug: oxaliplatin
  • Radiation: radiation therapy
  • Drug: Folinic Acid
• Experimental: 5-FU / cisplatin and radiotherapy
  5-FU (100mg/m2); Cisplatin (75mg/m2)
  Interventions:

  • Drug: cisplatin
  • Drug: 5-FU
  • Radiation: radiation therapy

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. 2023 Mar;32(3):669-679. doi: 10.1007/s11136-022-03252-6. Epub 2022 Sep 17.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 12, 2009): 266
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: December 2012
• Actual Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT00861094
• Other Study ID Numbers: CDR0000595050; FRE-FNCLCC- ACCORD-17-0707; EU-20848
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: UNICANCER
• Original Responsible Party: Not Provided
• Current Study Sponsor: UNICANCER
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Thierry Conroy, MD; Centre Alexis Vautrin

• PRS Account: UNICANCER
• Verification Date: December 2015