Lung Cancer
Conditions
Keywords
extensive stage small cell lung cancer
Brief summary
RATIONALE: Radiation therapy uses high energy x-rays to kill tumor cells. This may be an effective treatment for extensive stage small cell lung cancer. PURPOSE: This randomized phase II trial is comparing how well radiation therapy to the brain works when given with or without radiation therapy to other areas of the body in treating patients with extensive stage small cell lung cancer.
Detailed description
OBJECTIVES: Primary * To compare the 1-year overall median survival rate in patients with extensive stage small cell lung cancer treated with prophylactic cranial irradiation with vs without consolidative extracranial radiotherapy following platinum-based chemotherapy. Secondary * To compare treatment-related adverse events in these patients. * To evaluate patterns of failure in these patients. * To compare the time to first failure in these patients. * To evaluate the percentage of the planned radiotherapy dose given to each site. OUTLINE: This is a multicenter study. Patients are stratified according to response to prior treatment (complete response vs partial response) and number of metastatic lesions (1 vs 2-3). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients undergo prophylactic cranial irradiation 5 days per week for 2 weeks. * Arm II: Patients undergo prophylactic cranial irradiation as in arm I. Patients also undergo consolidative extracranial radiotherapy to locoregional and residual metastatic disease 5 days per week for 2-3 weeks. After completion of study treatment, patients are followed up at 2 weeks; at 1, 2, 6, 9, and 12 months; every 6 months for 2 years; and then annually thereafter.
Interventions
RADIATIONProphylactic Cranial Irradiation
Prophylactic Cranial Irradiation (PCI) to the brain in ten once-daily fractions of 2.5 Gy, five days per week, for a total of 25 Gy.
RADIATIONRadiation Therapy
Radiation Therapy (RT) to locoregional and residual metastatic disease in 15 once daily fractions of 3.0 Gy, 5 days per week, for a total of 45 Gy
Sponsors
National Cancer Institute (NCI)
NRG Oncology
Radiation Therapy Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed extensive stage small cell lung cancer (SCLC) diagnosed within the past 6 months\* * Has 1-4 extracranial metastatic lesions NOTE: \*Diagnosis made before treatment with chemotherapy * Has completed 4-6 courses of platinum-based chemotherapy within the past 8 weeks AND meets the following criteria: * Radiographic partial or complete response to chemotherapy in ≥ 1 site of disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (if radiotherapy has been delivered to primary disease with chemotherapy, there must be complete or partial response in ≥ 1 of the sites that has not been treated with radiotherapy) * No progression in any site * No limited stage SCLC, even if disease progressed * No brain or central nervous system (CNS) metastases PATIENT CHARACTERISTICS: * Zubrod performance status 0-2 * Absolute neutrophil count (ANC) ≥ 1,000/mm\^3 * Platelets ≥ 75,000/mm\^3 * Hemoglobin ≥ 8.0 g/dL (the use of transfusion or other intervention is allowed) * Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) (for patients who will receive radiotherapy to the liver) * Serum bilirubin \< 1.5 times ULN (for patients who will receive radiotherapy to the liver) * Serum creatinine \< 1.5 times ULN (for patients who will receive radiotherapy to the kidneys) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No severe, active co-morbidity, defined as any of the following: * Acute bacterial or fungal infection requiring IV antibiotics at the time of study registration * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of study registration PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Recovered from prior chemotherapy (i.e., toxicities ≤ grade 1 \[except for neuropathy and alopecia\]) * Thoracic radiotherapy administered concurrently with or before chemotherapy for the current diagnosis allowed (these patients will not receive mediastinal radiotherapy per protocol) * No prior radiotherapy to the region of this cancer that would result in overlap of radiotherapy fields * No concurrent chemotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (12-month Rate Reported) | From randomization to last follow-up. Analysis occurred after all patients had been potentially followed for at least 12 months. Maximum follow-up at time of analysis was 46.0 months. | Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. This analysis was planned to occur when all patients had been potentially followed for at least 12 months. The 12-month rate is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Experiencing a Grade 3 or Higher Adverse Event | From randomization to last follow-up. Analysis occurred after all patients had been potentially followed for at least 12 months. Maximum follow-up at time of analysis was 46.0 months. | Adverse events (AE) are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. |
| Patterns of Failure - Number of Patients With Failure by Site | From randomization to last follow-up. Analysis occurred after all patients had been potentially followed for at least 12 months. Maximum follow-up at time of analysis was 46.0 months. | Failure was defined as progressive disease in areas treated with radiation development of measurable disease at sites that had achieved a complete response either with chemotherapy prior to study entry or following radiation, or development of new disease characteristic of small-cell lung cancer dissemination as determined by imaging \[per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1\] and physical examination. A patient could be counted in more than one category. |
| First Failure (12-month Rate Reported) | From randomization to last follow-up. Analysis occurred after all patients had been potentially followed for at least 12 months. Maximum follow-up at time of analysis was 46.0 months. | Failure was defined as progressive disease in areas treated with radiation development of measurable disease at sites that had achieved a complete response either with chemotherapy prior to study entry or following radiation, or development of new disease characteristic of small-cell lung cancer dissemination as determined by imaging \[per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1\] and physical examination. Time to first failure is defined as time from randomization to the date of first failure, last known follow-up (censored), or death (competing risk). First failure rates are estimated using the cumulative incidence method. |
| Percentage of Planned Radiotherapy Dose (All Sites) That Was Delivered | From start to end of radiation therapy; up to 32 days for Prophylactic Cranial Irradiation arm, up to 68 days for Prophylactic Cranial Irradiation + Consolidation Radiotherapy arm. | Total dose to the brain was to be 25 Gy for all patients. For patients on PCI+consolidative RT, patients were to get 45 Gy at 3 Gy per fraction to the locoregional area as well as to residual metastatic disease. Alternatively, these regions could have received 30-40 Gy in 10 fractions. The total planned dose was determined, and a percentage was calculated based for each patient as total delivered dose / total planned dose. |
Countries
Canada, Israel, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prophylactic Cranial Irradiation Prophylactic Cranial Irradiation (PCI) | 42 |
| Prophylactic Cranial Irradiation + Consolidation Radiotherapy Prophylactic Cranial Irradiation (PCI) plus consolidative radiation therapy (RT) to locoregional and residual metastatic disease | 44 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 7 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Prophylactic Cranial Irradiation | Prophylactic Cranial Irradiation + Consolidation Radiotherapy | Total |
|---|---|---|---|
| Age, Continuous | 61 years | 66 years | 63 years |
| Sex: Female, Male Female | 24 Participants | 23 Participants | 47 Participants |
| Sex: Female, Male Male | 18 Participants | 21 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 42 | 36 / 44 |
| serious Total, serious adverse events | 1 / 42 | 6 / 44 |
Outcome results
Primary
Overall Survival (12-month Rate Reported)
Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. This analysis was planned to occur when all patients had been potentially followed for at least 12 months. The 12-month rate is reported.
Time frame: From randomization to last follow-up. Analysis occurred after all patients had been potentially followed for at least 12 months. Maximum follow-up at time of analysis was 46.0 months.
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylactic Cranial Irradiation | Overall Survival (12-month Rate Reported) | 60.1 percentage of participants |
| Prophylactic Cranial Irradiation + Consolidation Radiotherapy | Overall Survival (12-month Rate Reported) | 50.8 percentage of participants |
Comparison: The null hypothesis (H0) was that PCI + RT is not effective versus the alternative hypothesis (H1) that PCI + RT is effective. Assumptions were that PCI alone would have hazard rate λc of 1.204 and PCI + RT a hazard rate λc of 0.799 (hazard ratio λt/λc = 0.663). At each planned analysis, the p-value from the log-rank test statistic assessing overall survival was compared to the nominal significance level. The final targeted accrual was 154.p-value: 0.210395% CI: [0.82, 2.53]Log Rank
Secondary
First Failure (12-month Rate Reported)
Failure was defined as progressive disease in areas treated with radiation development of measurable disease at sites that had achieved a complete response either with chemotherapy prior to study entry or following radiation, or development of new disease characteristic of small-cell lung cancer dissemination as determined by imaging \[per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1\] and physical examination. Time to first failure is defined as time from randomization to the date of first failure, last known follow-up (censored), or death (competing risk). First failure rates are estimated using the cumulative incidence method.
Time frame: From randomization to last follow-up. Analysis occurred after all patients had been potentially followed for at least 12 months. Maximum follow-up at time of analysis was 46.0 months.
Population: All eligible patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylactic Cranial Irradiation | First Failure (12-month Rate Reported) | 79.6 percentage of participants |
| Prophylactic Cranial Irradiation + Consolidation Radiotherapy | First Failure (12-month Rate Reported) | 75.0 percentage of participants |
p-value: 0.0102Log Rank
Secondary
Patterns of Failure - Number of Patients With Failure by Site
Failure was defined as progressive disease in areas treated with radiation development of measurable disease at sites that had achieved a complete response either with chemotherapy prior to study entry or following radiation, or development of new disease characteristic of small-cell lung cancer dissemination as determined by imaging \[per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1\] and physical examination. A patient could be counted in more than one category.
Time frame: From randomization to last follow-up. Analysis occurred after all patients had been potentially followed for at least 12 months. Maximum follow-up at time of analysis was 46.0 months.
Population: All eligible patients who had a failure
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prophylactic Cranial Irradiation | Patterns of Failure - Number of Patients With Failure by Site | 1st failure site = diagnosis site | 25 Participants |
| Prophylactic Cranial Irradiation | Patterns of Failure - Number of Patients With Failure by Site | 1st failure site = brain | 0 Participants |
| Prophylactic Cranial Irradiation | Patterns of Failure - Number of Patients With Failure by Site | Failure at any time at new site | 10 Participants |
| Prophylactic Cranial Irradiation | Patterns of Failure - Number of Patients With Failure by Site | 1st failure site = locoregional disease | 20 Participants |
| Prophylactic Cranial Irradiation + Consolidation Radiotherapy | Patterns of Failure - Number of Patients With Failure by Site | Failure at any time at new site | 19 Participants |
| Prophylactic Cranial Irradiation + Consolidation Radiotherapy | Patterns of Failure - Number of Patients With Failure by Site | 1st failure site = diagnosis site | 13 Participants |
| Prophylactic Cranial Irradiation + Consolidation Radiotherapy | Patterns of Failure - Number of Patients With Failure by Site | 1st failure site = locoregional disease | 8 Participants |
| Prophylactic Cranial Irradiation + Consolidation Radiotherapy | Patterns of Failure - Number of Patients With Failure by Site | 1st failure site = brain | 6 Participants |
Secondary
Percentage of Patients Experiencing a Grade 3 or Higher Adverse Event
Adverse events (AE) are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time frame: From randomization to last follow-up. Analysis occurred after all patients had been potentially followed for at least 12 months. Maximum follow-up at time of analysis was 46.0 months.
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylactic Cranial Irradiation | Percentage of Patients Experiencing a Grade 3 or Higher Adverse Event | 24 percentage of participants |
| Prophylactic Cranial Irradiation + Consolidation Radiotherapy | Percentage of Patients Experiencing a Grade 3 or Higher Adverse Event | 36 percentage of participants |
p-value: 0.24Fisher Exact
Secondary
Percentage of Planned Radiotherapy Dose (All Sites) That Was Delivered
Total dose to the brain was to be 25 Gy for all patients. For patients on PCI+consolidative RT, patients were to get 45 Gy at 3 Gy per fraction to the locoregional area as well as to residual metastatic disease. Alternatively, these regions could have received 30-40 Gy in 10 fractions. The total planned dose was determined, and a percentage was calculated based for each patient as total delivered dose / total planned dose.
Time frame: From start to end of radiation therapy; up to 32 days for Prophylactic Cranial Irradiation arm, up to 68 days for Prophylactic Cranial Irradiation + Consolidation Radiotherapy arm.
Population: All eligible patients who started study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prophylactic Cranial Irradiation | Percentage of Planned Radiotherapy Dose (All Sites) That Was Delivered | 100 percentage of planned dose delivered |
| Prophylactic Cranial Irradiation + Consolidation Radiotherapy | Percentage of Planned Radiotherapy Dose (All Sites) That Was Delivered | 100 percentage of planned dose delivered |