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

Unicancer

Status and phase: Completed; Phase 3; Phase 2

Conditions: Esophageal Cancer

Treatments: Drug: oxaliplatin; Drug: cisplatin; Drug: Folinic Acid; Drug: 5-FU; Radiation: radiation therapy

Study type: Interventional

Funder types: Other

Identifiers

NCT00861094

FRE-FNCLCC- ACCORD-17-0707

EU-20848

CDR0000595050

Details and patient eligibility

About

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.

Full 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.

Enrollment: 266 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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266 participants in 2 patient groups

FOLFOX and radiotherapy

Experimental group

Description:

Oxaliplatin (85mg/m2); Folinic Acid (200mg/m2); 5-FU (400mg/m2-Bolus and 1600mg/m2 over 46h)- once every two weeks for six cycles

Treatment:

Radiation: radiation therapy

Drug: 5-FU

Drug: oxaliplatin

Drug: Folinic Acid

5-FU / cisplatin and radiotherapy

Experimental group

Description:

5-FU (100mg/m2); Cisplatin (75mg/m2)

Treatment:

Radiation: radiation therapy

Drug: 5-FU

Drug: cisplatin