Brief Summary
This randomized phase II/III trial studies how well whole-brain radiation therapy works and compares it with or without hippocampal avoidance in treating patients with small cell lung cancer that is found in one lung, the tissues between the lungs, and nearby lymph nodes only (limited stage) or has spread outside of the lung in which it began or to other parts of the body (extensive stage). Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. The hippocampus is part of the brain that is important for memory. Avoiding the hippocampus during whole-brain radiation could decrease the chance of side effects on memory and thinking. It is not yet known whether giving whole-brain radiation therapy is more effective with or without hippocampal avoidance in treating patients with small cell lung cancer.
Brief Title
Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Limited Stage or Extensive Stage Small Cell Lung Cancer
Detailed Description
PRIMARY OBJECTIVES:
I. Determine whether the 12-month intracranial relapse rate following hippocampal avoidance (HA)-prophylactic cranial irradiation (PCI) is non-inferior compared to the rate following PCI for patients with small cell lung cancer (SCLC). (Randomized Phase II Component \[Non-Inferiority\]) II. Determine whether HA-PCI reduces the likelihood of 6-month deterioration from baseline in Hopkins Verbal Learning Test (HVLT)-Revised (R) delayed recall compared to PCI for patients with SCLC. (Phase III Component \[Efficacy\])
SECONDARY OBJECTIVES:
I. Compare time to cognitive failure, as measured by a battery of tests (HVLT-R, Controlled Oral Word Association (COWA) test, and Trail Making Test (TMT) parts A and B), after PCI versus HA-PCI in SCLC.
II. Compare time to cognitive failure as separately measured by each test (HVLT-R for Total Recall and Delayed Recognition, COWA test, and TMT parts A and B), after PCI versus HA-PCI for SCLC.
III. Compare patient-reported cognitive functioning and other quality of life domains (assessed by the European Organization for Research and Treatment of Cancer \[EORTC\] Quality of Life Questionnaire (QLQ)-Core \[C\]30 and BN20) between PCI versus HA-PCI for patients with SCLC.
IV. Compare overall survival after PCI versus HA-PCI for patients with SCLC.
V. Compare 12-month intracranial relapse rate (at completion of phase III) and time to intracranial relapse after PCI versus HA-PCI for patients with SCLC.
VI. Evaluate adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) criteria.
VII. Correlate changes in health-related quality of life (HRQOL) domains with changes in cognitive testing outcomes following PCI versus HA-PCI for patients with SCLC.
VIII. Assess cost-effectiveness of HA-PCI (intensity modulated radiation therapy \[IMRT\]) and PCI (3-dimensional conformal radiation therapy \[3DCRT\]) using the EuroQual (EQ)-5-Dimensions (5D)-5L.
IX. Correlate miRNA signatures with cognitive failure in SCLC patients who received PCI and HA-PCI.
X. Evaluate Apolipoprotein E (APOE) genotyping as potential predictor of neurocognitive decline, hippocampal atrophy after brain irradiation and/or differential benefit from hippocampal avoidance.
XI. Evaluate baseline MR imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from HA-PCI as compared to PCI.
TERTIARY OBJECTIVES:
I. Collect serum, whole blood, and urine for future translational research analyses.
II. Evaluate baseline magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from HA-PCI as compared to PCI.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients undergo PCI using 3DCRT daily for 2 weeks.
ARM II: Patients undergo PCI with HA using IMRT daily for 2 weeks.
After completion of study treatment, patients are followed every 3 months for 1 year, then every 6 months until 3 years and then annually until death.
I. Determine whether the 12-month intracranial relapse rate following hippocampal avoidance (HA)-prophylactic cranial irradiation (PCI) is non-inferior compared to the rate following PCI for patients with small cell lung cancer (SCLC). (Randomized Phase II Component \[Non-Inferiority\]) II. Determine whether HA-PCI reduces the likelihood of 6-month deterioration from baseline in Hopkins Verbal Learning Test (HVLT)-Revised (R) delayed recall compared to PCI for patients with SCLC. (Phase III Component \[Efficacy\])
SECONDARY OBJECTIVES:
I. Compare time to cognitive failure, as measured by a battery of tests (HVLT-R, Controlled Oral Word Association (COWA) test, and Trail Making Test (TMT) parts A and B), after PCI versus HA-PCI in SCLC.
II. Compare time to cognitive failure as separately measured by each test (HVLT-R for Total Recall and Delayed Recognition, COWA test, and TMT parts A and B), after PCI versus HA-PCI for SCLC.
III. Compare patient-reported cognitive functioning and other quality of life domains (assessed by the European Organization for Research and Treatment of Cancer \[EORTC\] Quality of Life Questionnaire (QLQ)-Core \[C\]30 and BN20) between PCI versus HA-PCI for patients with SCLC.
IV. Compare overall survival after PCI versus HA-PCI for patients with SCLC.
V. Compare 12-month intracranial relapse rate (at completion of phase III) and time to intracranial relapse after PCI versus HA-PCI for patients with SCLC.
VI. Evaluate adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) criteria.
VII. Correlate changes in health-related quality of life (HRQOL) domains with changes in cognitive testing outcomes following PCI versus HA-PCI for patients with SCLC.
VIII. Assess cost-effectiveness of HA-PCI (intensity modulated radiation therapy \[IMRT\]) and PCI (3-dimensional conformal radiation therapy \[3DCRT\]) using the EuroQual (EQ)-5-Dimensions (5D)-5L.
IX. Correlate miRNA signatures with cognitive failure in SCLC patients who received PCI and HA-PCI.
X. Evaluate Apolipoprotein E (APOE) genotyping as potential predictor of neurocognitive decline, hippocampal atrophy after brain irradiation and/or differential benefit from hippocampal avoidance.
XI. Evaluate baseline MR imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from HA-PCI as compared to PCI.
TERTIARY OBJECTIVES:
I. Collect serum, whole blood, and urine for future translational research analyses.
II. Evaluate baseline magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from HA-PCI as compared to PCI.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients undergo PCI using 3DCRT daily for 2 weeks.
ARM II: Patients undergo PCI with HA using IMRT daily for 2 weeks.
After completion of study treatment, patients are followed every 3 months for 1 year, then every 6 months until 3 years and then annually until death.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Extensive Stage Small Cell Lung Carcinoma
Limited Stage Small Cell Lung Carcinoma
Eligibility Criteria
Inclusion Criteria \[prior to Step 1 registration\]:
* Histologic proof or unequivocal cytologic proof (fine needle aspiration, biopsy or two positive sputa) of SCLC within 250 days prior to Step 1 registration
* High-grade neuroendocrine carcinoma or combined SCLC and NSCLC is permitted.
* Patients must have received chemotherapy and be registered to Step 1 registration no earlier than 7 days and no later than 56 days after completing chemotherapy. Note:
* Post-chemotherapy restaging imaging must be completed no more than 56 days prior to Step 1 registration.
* For patients with extensive-stage small cell lung cancer who are being considered for consolidative thoracic radiotherapy after chemotherapy, concomitant administration of consolidative thoracic radiotherapy and protocol-specified prophylactic cranial irradiation with or without hippocampal avoidance is permitted.
* Patients must have a gadolinium contrast-enhanced three-dimensional (3D), spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) MRI scan. To yield acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, MP-RAGE or TFE axial MRI scan must use the smallest possible axial slice thickness not exceeding 1.5 mm.
* This MRI must be obtained within 56 days prior to Step 1 registration. Note: The MRI study is mandatory irrespective of randomization to the experimental or control arm of this study.
* Prior to chemotherapy +/- thoracic radiotherapy, patients must be defined as limited-stage or extensive-stage SCLC after clinical staging evaluation involving the following:
1. History/physical examination;
2. CT of the chest and abdomen with contrast (does not have to be done if the patient has had a positron emission tomography (PET) / CT scan prior to initiating chemotherapy or thoracic radiotherapy);
3. MRI of the brain with contrast or diagnostic head CT with contrast;
4. For patients without evidence of extensive-stage SCLC on chest and abdomen CT and brain MRI or head CT, a PET/CT or bone scan is required to confirm limited-stage SCLC.
* After chemotherapy, patients must be restaged prior to Step 1 registration using the same diagnostic work-up as required pre-chemotherapy. Repeat PET/CT or bone scan is not required. Patients must have:
* History/physical examination within 30 days of Step 1 registration;
* No CNS metastases (Repeat MRI required) within 56 days prior to Step 1 registration;
* No progression in any site;
* Radiographic partial or complete response to chemotherapy in at least one disease site within 56 days prior to Step 1 registration.
1. If PET/CT was obtained prior to chemotherapy, either a repeat PET/CT or CT of the chest and abdomen with contrast can be obtained for response assessment.
2. Patients who underwent resection for limited-stage SCLC prior to chemotherapy and have no radiographically evident disease for response assessment remain eligible if post-chemotherapy imaging demonstrates no progression.
* Zubrod performance status 0-2 within 30 days prior to Step 1 registration.
* Women of childbearing potential must have a negative qualitative serum pregnancy test =\< 14 days prior to Step 1 registration.
* Patients who are primary English or French speakers are eligible
* Patients must sign a study-specific informed consent prior to study entry
Inclusion Criteria \[prior to Step 2 registration\]:
* The following baseline neurocognitive assessments must be completed and uploaded within 10 calendar days after or at the time of Step 1 registration: HVLT-R (recall, delayed recall, and recognition), TMT (Parts A and B), and COWA. The neurocognitive assessments will be uploaded into the NRG Oncology Rave System for evaluation by Neurocognitive Co-Chair. Once the upload is complete, within 3 business days, a notification email will be sent to the site to proceed to Step 2 registration. At minimum, the HVLT-R delayed recall must be able to be scored (i.e. completed without error) in order to be eligible.
* Patients must have a baseline raw score greater than 2 on the HVLT-R delayed recall as determined by central assessment by the Neurocognitive Co-Chair.
Exclusion Criteria:
* Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields
* Radiographic evidence of central nervous system (CNS) metastases
* Radiographic evidence of hydrocephalus or other architectural distortion of the ventricular system, including placement of external ventricular drain or ventriculoperitoneal shunt
* Planned concurrent chemotherapy during PCI
* Concurrent atezolizumab permitted
* Concomitant invasive malignancy or invasive malignancy within the past five years other than non-melanomatous skin cancer; history of in situ carcinoma (e.g. ductal carcinoma in situ of breast, in situ carcinoma of the cervix, vulva or larynx) is permitted
* Contraindication to MR imaging, such as implanted metal devices or foreign bodies or severe claustrophobia
* Severe, active comorbidity, defined as follows:
* Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
* Transmural myocardial infarction within the last 6 months
* Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
* Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
* Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
* Uncontrolled, clinically significant cardiac arrhythmias
* HIV positive with CD4 count \< 200 cells/microliter;
1. Note: Patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to Step 1 registration.
2. Note: HIV testing is not required for eligibility for this protocol.
* Pregnant or lactating women or women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic.
* Histologic proof or unequivocal cytologic proof (fine needle aspiration, biopsy or two positive sputa) of SCLC within 250 days prior to Step 1 registration
* High-grade neuroendocrine carcinoma or combined SCLC and NSCLC is permitted.
* Patients must have received chemotherapy and be registered to Step 1 registration no earlier than 7 days and no later than 56 days after completing chemotherapy. Note:
* Post-chemotherapy restaging imaging must be completed no more than 56 days prior to Step 1 registration.
* For patients with extensive-stage small cell lung cancer who are being considered for consolidative thoracic radiotherapy after chemotherapy, concomitant administration of consolidative thoracic radiotherapy and protocol-specified prophylactic cranial irradiation with or without hippocampal avoidance is permitted.
* Patients must have a gadolinium contrast-enhanced three-dimensional (3D), spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) MRI scan. To yield acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, MP-RAGE or TFE axial MRI scan must use the smallest possible axial slice thickness not exceeding 1.5 mm.
* This MRI must be obtained within 56 days prior to Step 1 registration. Note: The MRI study is mandatory irrespective of randomization to the experimental or control arm of this study.
* Prior to chemotherapy +/- thoracic radiotherapy, patients must be defined as limited-stage or extensive-stage SCLC after clinical staging evaluation involving the following:
1. History/physical examination;
2. CT of the chest and abdomen with contrast (does not have to be done if the patient has had a positron emission tomography (PET) / CT scan prior to initiating chemotherapy or thoracic radiotherapy);
3. MRI of the brain with contrast or diagnostic head CT with contrast;
4. For patients without evidence of extensive-stage SCLC on chest and abdomen CT and brain MRI or head CT, a PET/CT or bone scan is required to confirm limited-stage SCLC.
* After chemotherapy, patients must be restaged prior to Step 1 registration using the same diagnostic work-up as required pre-chemotherapy. Repeat PET/CT or bone scan is not required. Patients must have:
* History/physical examination within 30 days of Step 1 registration;
* No CNS metastases (Repeat MRI required) within 56 days prior to Step 1 registration;
* No progression in any site;
* Radiographic partial or complete response to chemotherapy in at least one disease site within 56 days prior to Step 1 registration.
1. If PET/CT was obtained prior to chemotherapy, either a repeat PET/CT or CT of the chest and abdomen with contrast can be obtained for response assessment.
2. Patients who underwent resection for limited-stage SCLC prior to chemotherapy and have no radiographically evident disease for response assessment remain eligible if post-chemotherapy imaging demonstrates no progression.
* Zubrod performance status 0-2 within 30 days prior to Step 1 registration.
* Women of childbearing potential must have a negative qualitative serum pregnancy test =\< 14 days prior to Step 1 registration.
* Patients who are primary English or French speakers are eligible
* Patients must sign a study-specific informed consent prior to study entry
Inclusion Criteria \[prior to Step 2 registration\]:
* The following baseline neurocognitive assessments must be completed and uploaded within 10 calendar days after or at the time of Step 1 registration: HVLT-R (recall, delayed recall, and recognition), TMT (Parts A and B), and COWA. The neurocognitive assessments will be uploaded into the NRG Oncology Rave System for evaluation by Neurocognitive Co-Chair. Once the upload is complete, within 3 business days, a notification email will be sent to the site to proceed to Step 2 registration. At minimum, the HVLT-R delayed recall must be able to be scored (i.e. completed without error) in order to be eligible.
* Patients must have a baseline raw score greater than 2 on the HVLT-R delayed recall as determined by central assessment by the Neurocognitive Co-Chair.
Exclusion Criteria:
* Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields
* Radiographic evidence of central nervous system (CNS) metastases
* Radiographic evidence of hydrocephalus or other architectural distortion of the ventricular system, including placement of external ventricular drain or ventriculoperitoneal shunt
* Planned concurrent chemotherapy during PCI
* Concurrent atezolizumab permitted
* Concomitant invasive malignancy or invasive malignancy within the past five years other than non-melanomatous skin cancer; history of in situ carcinoma (e.g. ductal carcinoma in situ of breast, in situ carcinoma of the cervix, vulva or larynx) is permitted
* Contraindication to MR imaging, such as implanted metal devices or foreign bodies or severe claustrophobia
* Severe, active comorbidity, defined as follows:
* Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
* Transmural myocardial infarction within the last 6 months
* Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
* Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
* Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
* Uncontrolled, clinically significant cardiac arrhythmias
* HIV positive with CD4 count \< 200 cells/microliter;
1. Note: Patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to Step 1 registration.
2. Note: HIV testing is not required for eligibility for this protocol.
* Pregnant or lactating women or women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic.
Inclusion Criteria
Inclusion Criteria \[prior to Step 1 registration\]:
* Histologic proof or unequivocal cytologic proof (fine needle aspiration, biopsy or two positive sputa) of SCLC within 250 days prior to Step 1 registration
* High-grade neuroendocrine carcinoma or combined SCLC and NSCLC is permitted.
* Patients must have received chemotherapy and be registered to Step 1 registration no earlier than 7 days and no later than 56 days after completing chemotherapy. Note:
* Post-chemotherapy restaging imaging must be completed no more than 56 days prior to Step 1 registration.
* For patients with extensive-stage small cell lung cancer who are being considered for consolidative thoracic radiotherapy after chemotherapy, concomitant administration of consolidative thoracic radiotherapy and protocol-specified prophylactic cranial irradiation with or without hippocampal avoidance is permitted.
* Patients must have a gadolinium contrast-enhanced three-dimensional (3D), spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) MRI scan. To yield acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, MP-RAGE or TFE axial MRI scan must use the smallest possible axial slice thickness not exceeding 1.5 mm.
* This MRI must be obtained within 56 days prior to Step 1 registration. Note: The MRI study is mandatory irrespective of randomization to the experimental or control arm of this study.
* Prior to chemotherapy +/- thoracic radiotherapy, patients must be defined as limited-stage or extensive-stage SCLC after clinical staging evaluation involving the following:
1. History/physical examination;
2. CT of the chest and abdomen with contrast (does not have to be done if the patient has had a positron emission tomography (PET) / CT scan prior to initiating chemotherapy or thoracic radiotherapy);
3. MRI of the brain with contrast or diagnostic head CT with contrast;
4. For patients without evidence of extensive-stage SCLC on chest and abdomen CT and brain MRI or head CT, a PET/CT or bone scan is required to confirm limited-stage SCLC.
* After chemotherapy, patients must be restaged prior to Step 1 registration using the same diagnostic work-up as required pre-chemotherapy. Repeat PET/CT or bone scan is not required. Patients must have:
* History/physical examination within 30 days of Step 1 registration;
* No CNS metastases (Repeat MRI required) within 56 days prior to Step 1 registration;
* No progression in any site;
* Radiographic partial or complete response to chemotherapy in at least one disease site within 56 days prior to Step 1 registration.
1. If PET/CT was obtained prior to chemotherapy, either a repeat PET/CT or CT of the chest and abdomen with contrast can be obtained for response assessment.
2. Patients who underwent resection for limited-stage SCLC prior to chemotherapy and have no radiographically evident disease for response assessment remain eligible if post-chemotherapy imaging demonstrates no progression.
* Zubrod performance status 0-2 within 30 days prior to Step 1 registration.
* Women of childbearing potential must have a negative qualitative serum pregnancy test =\< 14 days prior to Step 1 registration.
* Patients who are primary English or French speakers are eligible
* Patients must sign a study-specific informed consent prior to study entry
Inclusion Criteria \[prior to Step 2 registration\]:
* The following baseline neurocognitive assessments must be completed and uploaded within 10 calendar days after or at the time of Step 1 registration: HVLT-R (recall, delayed recall, and recognition), TMT (Parts A and B), and COWA. The neurocognitive assessments will be uploaded into the NRG Oncology Rave System for evaluation by Neurocognitive Co-Chair. Once the upload is complete, within 3 business days, a notification email will be sent to the site to proceed to Step 2 registration. At minimum, the HVLT-R delayed recall must be able to be scored (i.e. completed without error) in order to be eligible.
* Patients must have a baseline raw score greater than 2 on the HVLT-R delayed recall as determined by central assessment by the Neurocognitive Co-Chair.
* Histologic proof or unequivocal cytologic proof (fine needle aspiration, biopsy or two positive sputa) of SCLC within 250 days prior to Step 1 registration
* High-grade neuroendocrine carcinoma or combined SCLC and NSCLC is permitted.
* Patients must have received chemotherapy and be registered to Step 1 registration no earlier than 7 days and no later than 56 days after completing chemotherapy. Note:
* Post-chemotherapy restaging imaging must be completed no more than 56 days prior to Step 1 registration.
* For patients with extensive-stage small cell lung cancer who are being considered for consolidative thoracic radiotherapy after chemotherapy, concomitant administration of consolidative thoracic radiotherapy and protocol-specified prophylactic cranial irradiation with or without hippocampal avoidance is permitted.
* Patients must have a gadolinium contrast-enhanced three-dimensional (3D), spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) MRI scan. To yield acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, MP-RAGE or TFE axial MRI scan must use the smallest possible axial slice thickness not exceeding 1.5 mm.
* This MRI must be obtained within 56 days prior to Step 1 registration. Note: The MRI study is mandatory irrespective of randomization to the experimental or control arm of this study.
* Prior to chemotherapy +/- thoracic radiotherapy, patients must be defined as limited-stage or extensive-stage SCLC after clinical staging evaluation involving the following:
1. History/physical examination;
2. CT of the chest and abdomen with contrast (does not have to be done if the patient has had a positron emission tomography (PET) / CT scan prior to initiating chemotherapy or thoracic radiotherapy);
3. MRI of the brain with contrast or diagnostic head CT with contrast;
4. For patients without evidence of extensive-stage SCLC on chest and abdomen CT and brain MRI or head CT, a PET/CT or bone scan is required to confirm limited-stage SCLC.
* After chemotherapy, patients must be restaged prior to Step 1 registration using the same diagnostic work-up as required pre-chemotherapy. Repeat PET/CT or bone scan is not required. Patients must have:
* History/physical examination within 30 days of Step 1 registration;
* No CNS metastases (Repeat MRI required) within 56 days prior to Step 1 registration;
* No progression in any site;
* Radiographic partial or complete response to chemotherapy in at least one disease site within 56 days prior to Step 1 registration.
1. If PET/CT was obtained prior to chemotherapy, either a repeat PET/CT or CT of the chest and abdomen with contrast can be obtained for response assessment.
2. Patients who underwent resection for limited-stage SCLC prior to chemotherapy and have no radiographically evident disease for response assessment remain eligible if post-chemotherapy imaging demonstrates no progression.
* Zubrod performance status 0-2 within 30 days prior to Step 1 registration.
* Women of childbearing potential must have a negative qualitative serum pregnancy test =\< 14 days prior to Step 1 registration.
* Patients who are primary English or French speakers are eligible
* Patients must sign a study-specific informed consent prior to study entry
Inclusion Criteria \[prior to Step 2 registration\]:
* The following baseline neurocognitive assessments must be completed and uploaded within 10 calendar days after or at the time of Step 1 registration: HVLT-R (recall, delayed recall, and recognition), TMT (Parts A and B), and COWA. The neurocognitive assessments will be uploaded into the NRG Oncology Rave System for evaluation by Neurocognitive Co-Chair. Once the upload is complete, within 3 business days, a notification email will be sent to the site to proceed to Step 2 registration. At minimum, the HVLT-R delayed recall must be able to be scored (i.e. completed without error) in order to be eligible.
* Patients must have a baseline raw score greater than 2 on the HVLT-R delayed recall as determined by central assessment by the Neurocognitive Co-Chair.
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02635009
Org Class
Other
Org Full Name
NRG Oncology
Org Study Id
NRG-CC003
Overall Status
Active, not recruiting
Phases
Phase 2
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Randomized Phase II/III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small Cell Lung Cancer
Primary Outcomes
Outcome Description
The HVLT-R delayed recall test assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials to recall after a 20-minute delay. The score is the sum of the number of words correctly recalled and ranges from 0 to 36, with a higher score indicating better functioning. Deterioration is defined a decrease from baseline of at least 3 points.
Outcome Measure
Number of Participants With Deterioration in HVLT-R Delayed Recall Score at Six Months (Phase III)
Outcome Time Frame
Baseline and six months
Outcome Description
Intracranial relapse, defined as the development of a new brain metastasis as documented on brain MRI with contrast or head CT with contrast.
Outcome Measure
Number of Participants With Intracranial Relapse at 12 Months (Phase II)
Outcome Time Frame
From baseline to 12 months
Secondary Ids
Secondary Id
NCI-2015-01548
Secondary Id
NRG-CC003
Secondary Id
NRG-CC003
Secondary Id
UG1CA189867
Secondary Outcomes
Outcome Description
Neurocognitive failure is defined as the first instance of neurocognitive decline in any of six assessments, as determined my reliable change index: Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Trail Making Test (TMT) part A, TMT part B, and Controlled Oral Word Association (COWA). Failure time is defined as time from randomization to failure, death (competing event), or last follow-up (censored). Neurocognitive failure rates are estimated using the cumulative incidence method. The distributions of failure times are compared, which is reported in the statistical analysis results. Six-month rates are reported here. Analysis occurred after all patients had been on study for at least six months.
Outcome Time Frame
Randomization to date of failure, death, or last known follow-up whichever occurred first. Maximum follow-up at time of analysis was 7.2 years.
Outcome Measure
Percentage of Participants With Neurocognitive Failure (Phase III)
Outcome Description
The HVLT-R Total Recall score assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials. Raw score is the sum of the number of targets correctly recalled, ranging from 0 to 36. Higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 5 points.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in HVLT-R Total Recall Score (Phase III)
Outcome Description
he HVLT-R Total Recall score assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials. Raw score is the sum of the number of targets correctly recalled, ranging from 0 to 36. Higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 5 points.
Outcome Time Frame
Baseline,18, 24 months.
Outcome Measure
Number of Participants With Deterioration in HVLT-R Total Recall Score (Phase III)
Outcome Description
The HVLT-R Delayed Recall test assesses verbal learning and memory. After memorizing a list of 12 nouns for 3 consecutive trials, this test requires recalling the 12 targets after a 20-minute delay. Raw scores are sum of the number of targets correctly recalled. The score ranges from 0 to 12. A higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 3 points. Six-month results are reported as the primary endpoint.
Outcome Time Frame
Baseline, 3, 12 months.
Outcome Measure
Number of Participants With Deterioration in HVLT-R Delayed Recall Score (Phase III)
Outcome Description
The HVLT-R Delayed Recall test assesses verbal learning and memory. After memorizing a list of 12 nouns for 3 consecutive trials, this test requires recalling the 12 targets after a 20-minute delay. Raw scores are sum of the number of targets correctly recalled. The score ranges from 0 to 12. A higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 3 points.
Outcome Time Frame
Baseline, 18, 24 months.
Outcome Measure
Number of Participants With Deterioration in HVLT-R Delayed Recall Score (Phase III)
Outcome Description
The HVLT-R Delayed Recognition assesses verbal learning and memory. After memorizing a list of 12 nouns for 3 consecutive trials and recalling the 12 targets after a 20-minute delay, the test involves then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are the sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified. The score ranges from -12 to 12 for recognition. A higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 2 points.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in HVLT-R Delayed Recognition Score (Phase III)
Outcome Description
The HVLT-R Delayed Recognition assesses verbal learning and memory. After memorizing a list of 12 nouns for 3 consecutive trials and recalling the 12 targets after a 20-minute delay, the test involves then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are the sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified. The score ranges from -12 to 12 for recognition. A higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 2 points.
Outcome Time Frame
Baseline, 18, 24 months.
Outcome Measure
Number of Participants With Deterioration in HVLT-R Delayed Recognition Score (Phase III)
Outcome Description
The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A, reported here), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order. The score is the amount of time, in seconds, that it takes the patient to complete the maze. The range for Part A is 0 to 180 (3 minutes). Lower scores indicate better functioning. Deterioration is defined an increase from baseline of at least 12 seconds.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in Trail Making Test (TMT) Part A (Phase III)
Outcome Description
The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A, reported here), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order. The score is the amount of time, in seconds, that it takes the patient to complete the maze. The range for Part A is 0 to 180 (3 minutes). Lower scores indicate better functioning. Deterioration is defined an increase from baseline of at least 12 seconds.
Outcome Time Frame
Baseline, 18, 24 months.
Outcome Measure
Number of Participants With Deterioration in Trail Making Test (TMT) Part A (Phase III)
Outcome Description
The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the second part (Part B, reported here), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete the maze. The score range for Part B is 0 to 300 (5 minutes). Lower scores indicate better functioning. Deterioration is defined an increase from baseline of at least 26 seconds.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in TMT Part B Score (Phase III)
Outcome Description
The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the second part (Part B, reported here), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete the maze. The score range for Part B is 0 to 300 (5 minutes). Lower scores indicate better functioning. Deterioration is defined an increase from baseline of at least 26 seconds.
If reporting a score on a scale, please include the unabbreviated scale title, the minimum and maximum values, and whether higher scores mean a better or worse outcome.
If reporting a score on a scale, please include the unabbreviated scale title, the minimum and maximum values, and whether higher scores mean a better or worse outcome.
Outcome Time Frame
Baseline, 18, 24 months.
Outcome Measure
Number of Participants With Deterioration in TMT Part B Score (Phase III)
Outcome Description
The COWA is a verbal fluency test that measures spontaneous production of words belonging to the same category or beginning with some designated letter. Patients are given 1 minute to name as many words as possible beginning with the designated letter. The procedure is then repeated for the remaining two letters. Two alternate forms of the COWA are employed to minimize practice effects. The score is the sum of the correct responses with a range of 0 to infinity. A higher score indicates better functioning. Deterioration is defined an increase from baseline of at least 12 words.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in Controlled Oral Word Association (COWA) Score (Phase III)
Outcome Description
The COWA is a verbal fluency test that measures spontaneous production of words belonging to the same category or beginning with some designated letter. Patients are given 1 minute to name as many words as possible beginning with the designated letter. The procedure is then repeated for the remaining two letters. Two alternate forms of the COWA are employed to minimize practice effects. The score is the sum of the correct responses with a range of 0 to infinity. A higher score indicates better functioning. Deterioration is defined an increase from baseline of at least 12 words.
Outcome Time Frame
Baseline,18, 24 months.
Outcome Measure
Number of Participants With Deterioration in Controlled Oral Word Association (COWA) Score (Phase III)
Outcome Description
Common Terminology Criteria for Adverse Events (version 5) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Outcome Time Frame
From start of treatment to last known follow-up . Maximum follow-up time was 7.2 years.
Outcome Measure
Number of Participants by Highest Grade Adverse Event Reported (Phase III)
Outcome Description
The QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life (QOL) of cancer patients participating in international clinical trials. Global Health Status is considered a measure of overall quality of life and is calculated from two questions whose raw scores are averaged and then transformed to a range of 0 (worst) to 100 (best). Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30) Global Health Status (Phase III)
Outcome Description
The QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life (QOL) of cancer patients participating in international clinical trials. Global Health Status is considered a measure of overall quality of life and is calculated from two questions whose raw scores are averaged and then transformed to a range of 0 (worst) to 100 (best). Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline,18, 24 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-C30 Global Health Status (Phase III)
Outcome Description
The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-C30 Physical Functioning Score (Phase III)
Outcome Description
The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline,18, 24 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-C30 Physical Functioning Score (Phase III)
Outcome Description
The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life (QOL) of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-C30 Role Functioning Score (Phase III)
Outcome Description
The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life (QOL) of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline,18, 24 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-C30 Role Functioning Score (Phase III)
Outcome Description
The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-C30 Emotional Functioning Score (Phase III)
Outcome Description
The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline,18, 24 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-C30 Emotional Functioning Score (Phase III)
Outcome Description
The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life (QOL) of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-C30 Social Functioning Score (Phase III)
Outcome Description
The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life (QOL) of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline,18, 24 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-C30 Social Functioning Score (Phase III)
Outcome Description
The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life (QOL) of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-C30 Cognitive Functioning Score (Phase III)
Outcome Description
The EORTC QLQ-C30 is a 30-item self-report questionnaire used to assess the health-related quality of life (QOL) of cancer patients participating in international clinical trials. A functional scale raw score is transformed to a range of 0 (worst) to 100 (best) in which a high score represents a healthy level of functioning. Deterioration is defined a reduction of 10% from baseline.
Outcome Time Frame
Baseline,18, 24 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-C30 Cognitive Functioning Score (Phase III)
Outcome Description
The EORTC QLQ-BN20 is a 20-item self-report questionnaire supplement to the QLQ-C30 for patients used to assess the health-related quality of life of brain cancer patients. A symptom scale raw score is transformed to a range of 0 (best) to 100 (worst) in which a high score represents a high level of symptomatology/problems. For patients with a baseline score of 0, a follow-up score of ≥ 10 is considered as a deterioration. Otherwise, a 10% increase is considered as a deterioration.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in EORTC Quality of Life Questionnaire BN-20 (QLQ-BN20) Motor Dysfunction Score (Phase III)
Outcome Description
The EORTC QLQ-BN20 is a 20-item self-report questionnaire supplement to the QLQ-C30 for patients used to assess the health-related quality of life of brain cancer patients. A symptom scale raw score is transformed to a range of 0 (best) to 100 (worst) in which a high score represents a high level of symptomatology/problems. For patients with a baseline score of 0, a follow-up score of ≥ 10 is considered as a deterioration. Otherwise, a 10% increase is considered as a deterioration.
Outcome Time Frame
Baseline,18, 24 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-BN20 Motor Dysfunction Score (Phase III)
Outcome Description
The QLQ-BN20 is a 20-item self-report questionnaire supplement to the QLQ-C30 for patients used to assess the health-related quality of life of brain cancer patients. A symptom scale raw score is transformed to a range of 0 (best) to 100 (worst) in which a high score represents a high level of symptomatology/problems. For patients with a baseline score of 0, a follow-up score of ≥ 10 is considered as a deterioration. Otherwise, a 10% increase is considered as a deterioration.
Outcome Time Frame
Baseline, 3, 6, 12 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-BN20 Communication Deficit Score (Phase III)
Outcome Description
The QLQ-BN20 is a 20-item self-report questionnaire supplement to the QLQ-C30 for patients used to assess the health-related quality of life of brain cancer patients. A symptom scale raw score is transformed to a range of 0 (best) to 100 (worst) in which a high score represents a high level of symptomatology/problems. For patients with a baseline score of 0, a follow-up score of ≥ 10 is considered as a deterioration. Otherwise, a 10% increase is considered as a deterioration.
Outcome Time Frame
Baseline,18, 24 months.
Outcome Measure
Number of Participants With Deterioration in EORTC QLQ-BN20 Communication Deficit Score (Phase III)
Outcome Description
The Pearson correlation coefficient was calculated for EORTC QLQ-C30 (physical, role, emotional, cognitive, and social functioning domains and global health status) and QLQ-BN20 (motor dysfunction and communication deficit) versus the standardized neurocognitive function (HVLT-R total recall, HVLT-R delayed recall, HVLT-R delayed recognition, COWA, TMT parts A and B) and the Clinical Trial Battery Composite (CTB Comp) score (mean of the z-scores for the six NCF scores) for all patients, treatment arms combined. The Pearson correlation coefficient is computed for each pair of measurements, resulting in 48 correlation coefficients. Possible values range from -1 (negatively correlated) to 1(positively correlated), with 0 indicating no correlation. A correlation with a value in range -0.35 to 0.35 is considered weak and is indicated by "0" in the table. Because of the large number of comparisons, only individual correlation coefficients outside that range are listed here.
Outcome Time Frame
6 months
Outcome Measure
Correlation of Quality of Life and Neurocognitive Function (NCF) Measures at 6 Months
Outcome Description
The incremental cost per quality-adjusted life year (QALY) ratio will be calculated as total cost of the PCI with HA using IMRT arm (Arm 2) minus total cost of the PCI using 3DCRT arm (Arm 1), divided by the quality adjusted survival of the Arm 1 patients minus the quality adjusted survival of Arm 2 patients.
Outcome Time Frame
Baseline to two years
Outcome Measure
Incremental Cost-per Quality-adjusted Life Year (QALY) (Cost-effectiveness as Measured by the EQ-5D (Phase III)
Outcome Description
Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. Analysis occurred after all patients had been on study for at least 8 months.
Outcome Time Frame
From the date of randomization to the date of death or last follow-up. Maximum follow-up time at time of analysis was 7.2 years.
Outcome Measure
Overall Survival (Phase III)
Outcome Description
Intracranial relapse is defined as the development of a new brain metastasis as documented on brain MRI with contrast or head CT with contrast. Time to intracranial relapse is defined as time from randomization to the date of first intracranial relapse, last known follow-up (censored), or death without intracranial relapse (competing risk), whichever occurred first. Intracranial relapse rates are estimated using the cumulative incidence method. The distributions of intracranial relapse times are compared between the arms, which is reported in the statistical analysis results. One-year rates are provided here. Analysis occurred at time of the phase III primary analysis.
Outcome Time Frame
From date of randomization to date of intracranial relapse, death, or last known follow-up, whichever occurred first. Maximum follow-up at time of analysis was 7.2 years.
Outcome Measure
Intracranial Relapse Rate (Phase III)
Outcome Description
Pearson correlation coefficients will be used to assess the effect of hippocampal volume and FLAIR volume change on baseline neurocognitive function, as measured by the HVLT-R, COWA, and TMT, separately for each arm.
Outcome Time Frame
Baseline to 6 months
Outcome Measure
White Matter Injury and Hippocampal Volume on Neurocognitive Function (Phase III)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
William Bodner
Investigator Email
wbodner@montefiore.org