Clinical trial NCT00861094: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Esophageal Cancer
Keywords: adenocarcinoma of the esophagus
squamous cell carcinoma of the esophagus
stage IIA esophageal cancer
stage IIB esophageal cancer
stage IIIA esophageal cancer
stage IIIB esophageal cancer
stage IIIC esophageal cancer
stage IV esophageal cancer
Lead sponsor: UNICANCER
Sponsor class: OTHER
First posted: 2009-03-13
Enrollment: 266
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage of patients who complete the full study treatment (Phase II)
timeFrame: 12 weeks
measure: Endoscopic complete response rate (Phase II)
timeFrame: 12 weeks
measure: Progression-free survival (Phase III)
timeFrame: Until progression
Secondary outcomes:
measure: Safety profile as assessed by NCI CTC v2.0 (Phase II)
timeFrame: Total duration of the trial
measure: Overall survival (Phase III)
timeFrame: Total duration of the trial
measure: Complete response rate (Phase III)
timeFrame: Total duration of the trial
measure: Time to treatment failure (Phase III)
timeFrame: Total duration of the trial
measure: Incidence of grade 3-4 toxicities (Phase III)
timeFrame: Total duration of the trial
measure: Quality of life as assessed by EORTC QLQ-C30 (version 3) and EORTC QLQ-OES18 (Phase III)
timeFrame: Total duration of the trial
Other outcomes:
Locations:
city: Besancon
country: France
facility: CHR de Besancon - Hopital Saint-Jacques
city: Bordeaux
country: France
facility: Hopital Saint Andre
city: Bordeaux
country: France
facility: Institut Bergonie
city: Boulogne-Billancourt
country: France
facility: Hopital Ambroise Pare
city: Caen
country: France
facility: Polyclinique Du Parc
city: Caen
country: France
facility: Centre Regional Francois Baclesse
city: Dijon
country: France
facility: Hopital Du Bocage
city: Dijon
country: France
facility: Centre de Lutte Contre le Cancer Georges-Francois Leclerc
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: Centre Hospital Regional Universitaire de Limoges
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: CHU de la Timone
city: Montpellier
country: France
facility: Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hopital Europeen Georges Pompidou
city: Paris
country: France
facility: Hopital Saint-Louis
city: Paris
country: France
facility: Hopital Tenon
city: Poitiers
country: France
facility: CHU Poitiers
city: Reims
country: France
facility: Institut Jean Godinot
city: Reims
country: France
facility: CHU - Robert Debre
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Rouen
country: France
facility: Hopital Charles Nicolle
city: Saint Brieuc
country: France
facility: Clinique Armoricaine De Radiologie
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Toulouse
country: France
facility: Clinique Du Parc
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Alexis Vautrin
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Centre Alexis Vautrin
name: Thierry Conroy, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.