Three Different Radiation Therapy Regimens in Treating Patients With Limited-Stage Small Cell Lung Cancer Receiving Cisplatin and Etoposide

• Toxicity [ Designated as safety issue: Yes ]
• Complete and partial response rates [ Designated as safety issue: No ]
• Failure-free survival [ Designated as safety issue: No ]
• Local tumor progression according to RECIST criteria [ Designated as safety issue: No ]
• Rates of distant metastases and intracranial metastases [ Designated as safety issue: No ]

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as etoposide and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known which radiation therapy regimen is more effective when given together with chemotherapy in treating patients with limited-stage small cell lung cancer.

PURPOSE: This randomized phase III trial is comparing two different chest radiation therapy regimens to see how well they work in treating patients with limited-stage small cell lung cancer.

OBJECTIVES:

Primary

• To determine whether administering high-dose thoracic radiotherapy, 70 Gy (2 Gy once daily over 7 weeks) or 61.2 Gy (1.8 Gy once daily for 16 days followed by 1.8 Gy twice daily for 9 days), will improve median and 2-year survival compared with 45 Gy (1.5 Gy twice daily over 3 weeks) in patients with limited-stage small cell lung cancer.

Secondary

• To compare treatment-related toxic effects of thoracic radiotherapy regimens in patients with limited-stage small cell lung cancer.
• To compare response rates, failure-free survival, and toxicity of thoracic radiotherapy regimens in patients with limited-stage small cell lung cancer.
• To compare rates of local relapse, distant metastases, and brain metastases with these regimens.
• To describe the patterns of use of thoracic intensity-modulated radiotherapy (IMRT) in patients with limited-stage small cell lung cancer.

OUTLINE: This is a 2-part, multicenter, randomized study. Patients are stratified according to gender, weight loss 6 months prior to study entry (≤ 5% of body weight vs > 5% of body weight), ECOG performance status (0 vs 1 vs 2), radiotherapy technique (intensity-modulated radiotherapy vs 3-dimensional conformal radiotherapy), and radiotherapy start time (at first course of protocol chemotherapy, after one course of prior non-protocol chemotherapy vs at first course of protocol chemotherapy, without prior non-protocol chemotherapy vs at second course of protocol chemotherapy, without prior non-protocol chemotherapy).

• Part 1: Patients are randomized to 1 of 3 treatment arms.

  • Arm I: Patients undergo standard-dose (45 Gy given in 30 treatments) thoracic radiotherapy twice daily, 5 days a week, for 3 weeks. Patients also receive cisplatin IV on day 1 and etoposide IV on days 1, 2, and 3.
  • Arm II: Patients undergo higher-dose (70 Gy given in 35 treatments) thoracic radiotherapy once daily, 5 days a week, for 7 weeks. Patients also receive cisplatin and etoposide as in arm I.
  • Arm III: (discontinued as of 01/15/13) Patients undergo higher-dose (61.2 Gy given in 34 treatments) thoracic radiotherapy once daily, 5 days a week, during the initial 16 days (approximately 3 weeks) of treatment and then twice daily, 5 days a week, for the final 9 days (approximately 2 weeks) of treatment. Patients also receive cisplatin and etoposide as in arm I.

In all arms, treatment with cisplatin and etoposide repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

• Part 2: An interim analysis, conducted after accrual of 30 patients per arm, will select one experimental arm based upon a comparison of treatment-related toxicity. The most toxic experimental arm will be discontinued, and the trial will continue comparing standard therapy (arm I) to the selected experimental regimen (arm II) as in part 1.

Prophylactic radiotherapy: Within 3-6 weeks after completion of chemotherapy, patients with responding disease are eligible to undergo prophylactic radiotherapy to the brain once a day, 5 days a week, for 2 weeks.

After completion of study treatment, patients are followed up at least every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years or until disease progression. At disease progression, patients are followed up every 6 months.

• Radiation: 3-dimensional conformal radiation therapy
  Given at 1 of 2 doses on one of two different schedules (Arm III discontinued as of 01/15/13)
• Radiation: intensity-modulated radiation therapy
  Given at 1 of 2 doses on one of two different schedules (Arm III discontinued as of 01/15/13)

• Active Comparator: Arm I
  Patients undergo standard-dose (45 Gy given in 30 treatments) thoracic radiotherapy twice daily, 5 days a week, for 3 weeks.
  Interventions:

  • Radiation: 3-dimensional conformal radiation therapy
  • Radiation: intensity-modulated radiation therapy
• Experimental: Arm II
  Patients undergo higher-dose (70 Gy given in 35 treatments) thoracic radiotherapy once daily, 5 days a week, for 7 weeks.
  Interventions:

  • Radiation: 3-dimensional conformal radiation therapy
  • Radiation: intensity-modulated radiation therapy
• Experimental: Arm III
  (discontinued as of 01/15/13) Patients undergo higher-dose (61.2 Gy given in 34 treatments) thoracic radiotherapy once daily, 5 days a week, during the initial 16 days (approximately 3 weeks) of treatment and then twice daily, 5 days a week, for the final 9 days (approximately 2 weeks) of treatment.
  Interventions:

  • Radiation: 3-dimensional conformal radiation therapy
  • Radiation: intensity-modulated radiation therapy

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed small cell lung cancer (SCLC)

  • Limited-stage disease

    • Disease restricted to one hemithorax with regional lymph node metastases, including ipsilateral hilar, ipsilateral and contralateral mediastinal, and ipsilateral supraclavicular lymph nodes

• The following patients are not eligible:

  • Patients with disease involvement of the contralateral hilar or supraclavicular lymph nodes
  • Patients with pleural effusions that are visible on plain chest radiographs, whether cytologically positive or not
  • Patients with cytologically positive pleural or pericardial fluid, regardless of the appearance on plain x-ray
• Measurable disease, defined as at least one unidimensionally measurable lesion ≥ 2 cm by conventional techniques OR ≥ 1 cm by spiral CT scan

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Granulocytes ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST ≤ 2.0 times ULN
• Serum creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 70 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• Patients may have received one and only one course of chemotherapy prior to enrolling on CALGB 30610, which must have included cisplatin and etoposide

  • If a patient has had one course of cisplatin/etoposide prior to registration, the patient must have had all of the prior-to-registration tests prior to starting their first course of chemotherapy
  • Registration to CALGB-30610 must take place within 14-21 days after the start of the non-protocol therapy; failing to do all of the above will make the patient NOT eligible for CALGB-30610
• No prior radiotherapy or chemotherapy (except for the chemotherapy described above) for SCLC
• No prior mediastinal or thoracic radiotherapy
• No prior complete surgical resection of SCLC
• No concurrent treatment with hormones or other chemotherapeutic agents except for steroids given for adrenal failure; hormones administered for non-disease-related conditions (e.g., insulin for diabetes); and intermittent use of dexamethasone as an antiemetic

• National Cancer Institute (NCI)
• Radiation Therapy Oncology Group