S0124: Cisplatin Combined With Either Irinotecan or Etoposide in Treating Patients With Extensive-Stage Small Cell Lung Cancer

• Objective response rate [ Time Frame: 0-3 years or until death ] [ Designated as safety issue: No ]
• Toxicity [ Time Frame: Arm 1: every 28 days Arm 2: every 21 days ] [ Designated as safety issue: Yes ]
• Time to tumor progression [ Time Frame: From date of registration until date of progression or date of death from any cause, whichever came first, assessed up to 3 years ] [ Designated as safety issue: No ]

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known whether cisplatin combined with irinotecan is more effective than cisplatin combined with etoposide in treating extensive-stage small cell lung cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of cisplatin combined with either irinotecan or etoposide in treating patients who have extensive-stage small cell lung cancer.

OBJECTIVES:

• Compare the survival of patients with extensive stage small cell lung cancer treated with cisplatin and irinotecan vs cisplatin and etoposide.
• Compare the objective response rate and progression-free survival of patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.
• Determine the association between UGT1A1 polymorphisms and irinotecan-associated toxic effects in these patients.
• Determine the association between ERCC-1 and XRCC-1 polymorphisms and non-response of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number of metastatic sites (single vs multiple), lactic dehydrogenase (no greater than upper limit of normal (ULN) vs greater than ULN), and weight loss in the past 6 months (5% or less vs more than 5%). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive irinotecan IV over 90 minutes on days 1, 8, and 15 and cisplatin IV over 30-60 minutes on day 1. Courses repeat every 4 weeks.
• Arm II: Patients receive etoposide IV over 30-60 minutes on days 1-3 and cisplatin IV over 30-60 minutes on day 1. Courses repeat every 3 weeks.

Treatment in both arms continues for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 1 year and then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 620 patients (310 per treatment arm) will be accrued for this study within 4 years.

• Drug: cisplatin

  Arm 1: 60 mg/m2 IV (over 30-60 min) on Day 1, Q 4 weeks x 4 Cycles

  Arm 2: 80 mg/m2 IV (over 30-60 min) on Day 1, Q 4 weeks x 4 Cycles

• Drug: etoposide
  100 mg/m2 IV (over 30-60 min) on Days 1 , 2 & 3. Q 3 weeks x 4 Cycles
• Drug: irinotecan hydrochloride
  60 mg/m2 IV (over 90 min)on Days 1, 8 & 15. Q 4 weeks x 4 Cycles

• Active Comparator: 1
  Interventions:

  • Drug: cisplatin
  • Drug: irinotecan hydrochloride
• Active Comparator: 2
  Interventions:

  • Drug: cisplatin
  • Drug: etoposide

• Lara PN Jr, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, Jett J, Langer CJ, Kuebler JP, Dakhil SR, Chansky K, Gandara DR. Phase III Trial of Irinotecan/Cisplatin Compared With Etoposide/Cisplatin in Extensive-Stage Small-Cell Lung Cancer: Clinical and Pharmacogenomic Results From SWOG S0124. J Clin Oncol. 2009 Apr 6; [Epub ahead of print]
• Natale RB, Lara PN, Chansky K, et al.: S0124: A randomized phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients (pts) with previously untreated extensive stage small cell lung cancer (E-SCLC). [Abstract] J Clin Oncol 26 (Suppl 15): A-7512, 2008.
• Hanna N, Bunn PA Jr, Langer C, Einhorn L, Guthrie T Jr, Beck T, Ansari R, Ellis P, Byrne M, Morrison M, Hariharan S, Wang B, Sandler A. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006 May 1;24(13):2038-43.
• Lara P, Chansky K, Shibata T, et al.: Cisplatin + irinotecan versus cisplatin + etoposide in extensive stage small cell lung cancer (E-SCLC): Final "common arm": comparative outcomes analysis of JCOG 9511 and SWOG 0124. [Abstract] J Clin Oncol 27 (Suppl 15): A-8027, 2009.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed extensive stage small cell lung cancer (SCLC)
• Measurable or evaluable disease by CT scan, MRI, x-ray, physical exam, or nuclear exam
• Brain metastases allowed if previously treated with radiotherapy and/or surgery and are neurologically stable (i.e., no progressing symptoms and off steroids and anticonvulsants)

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Zubrod 0-1

Life expectancy

• Not specified

Hematopoietic

• WBC at least 3,000/mm^3
• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST or ALT no greater than 2.5 times ULN

Renal

• Creatinine normal
• Creatinine clearance at least 50 mL/min

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• HIV negative
• No concurrent AIDS-related illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior biologic therapy for SCLC
• No filgrastim (G-CSF) within 24 hours of chemotherapy

Chemotherapy

• No prior systemic chemotherapy for SCLC

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• See Disease Characteristics
• At least 21 days since prior brain radiotherapy and recovered
• No other prior radiotherapy for SCLC

Surgery

• See Disease Characteristics
• At least 21 days since prior thoracic or other major surgery and recovered

Other

• No concurrent enzyme inducing antiepileptic drugs (phenytoin, phenobarbital, oxcarboxepine, or carbamazepine)

• National Cancer Institute (NCI)
• North Central Cancer Treatment Group
• Cancer and Leukemia Group B