Concurrent Once Daily Versus Twice Daily Radiotherapy for Limited Stage Small Cell Lung Cancer

OBJECTIVES:

Primary

• Compare overall survival of patients with limited stage small cell lung cancer treated with chemoradiotherapy comprising cisplatin, etoposide, and once vs twice daily radiotherapy.

Secondary

• Compare local progression-free survival of patients treated with these regimens.
• Compare metastasis-free survival of patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.
• Compare response rates in patients treated with these regimens.
• Compare the cytotoxic dose intensity of these regimens in these patients.
• Compare the dose intensity of two different schedules of radiotherapy in these patients.

OUTLINE: This is a multicenter, randomized, controlled study. Patients are stratified according to participating center, ECOG performance status (0-1 vs 2), and lactic dehydrogenase, sodium, and alkaline phosphatase levels. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive cisplatin IV over 2 hours on days 1-3 OR on day 1 only and etoposide IV over 45-90 minutes on days 1-3. Treatment repeats every 21 days for up to 6 courses. During course 2, patients undergo concurrent radiotherapy once daily 5 days a week for 6½ weeks (total of 33 fractions).
• Arm II: Patients receive cisplatin and etoposide as in arm I. During courses 2 and 3, patients undergo concurrent radiotherapy twice daily 5 days a week for 3 weeks (total of 30 fractions).

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Beginning 3-4 weeks after completion of chemoradiotherapy, patients in both arms achieving a complete or partial response with no evidence of brain metastasis undergo prophylactic cranial irradiation once daily 5 days a week for 2 weeks (total of 10 fractions).

After completion of study treatment, patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 532 patients will be accrued for this study.

Inclusion/exclusion criteria:

• Either sex, age ≥18 years
• Performance status ECOG grade 0-1. Patients with PS 2 whose general condition is explained by obstructive/bulky disease likely to improve after the first cycle of chemotherapy can be included at the discretion of the local investigator. Patients with PS 2 as a result of comorbid conditions will be excluded.
• Histologically or cytologically confirmed SCLC
• No patients with mixed small-cell and non-small-cell histologic features
• No history of previous malignancy in the last 5 years (except non melanomatous skin or in-situ cervix carcinoma). Patients with previous malignancies (except breast cancer) and in remission for at least 5 years can be included.
• Limited stage disease (Veterans Administration Lung Cancer Study Group) ie patients whose disease can be encompassed within a radical radiation portal.
• No pleural or pericardial effusions proven to be malignant
• RT target volume acceptable by the local radiotherapist
• Pulmonary function

• FEV1 >1 litre or 40% predicted value
• KCO (DLCO/VA) >40%predicted
• Maximum of one of the following adverse biochemical factors:

• Serum alkaline phosphatase more than >1.5 times the upper limit of normal (ULN)
• Serum sodium < Lower limit of Normal
• Serum LDH > ULN
• Normal serum creatinine and calculated creatinine clearance >50 ml/min. If calculated creatinine clearance is <50 ml/mn according to the Cockroft and Gault formula, an EDTA clearance should be performed
• Adequate haematological function

• Neutrophils >1.5 x 109/l
• Platelets >100 x 109/l
• Adequate liver function: ALT & AST <= 2.5 x ULN
• No other previous or concomitant illness or treatment which in the opinion of the clinician will interfere with the trial treatments or comparisons
• No prior surgical resection of the primary tumour, no prior radiotherapy for lung cancer
• Considered fit to receive any of the trial regimens
• Female patients must satisfy the investigator that they are not pregnant, or are not of child-bearing potential, or are using adequate contraception. Men must also use adequate contraception, as etoposide is clastogenic.
• Patients must not be breastfeeding
• Patient has read the patient information sheet and has signed the consent form.
• Patients available for follow-up