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])
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
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
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
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
IX. Correlate miRNA signatures with cognitive failure in SCLC patients who received PCI and
X. Evaluate 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
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 HAPCI 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.
- 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
- 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 (see section 11.3 regarding axial T2/FLAIR sequence). 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. Sites may contact the Imaging Co-Chairs for further information or
assistance if needed.
- 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
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 PET/CT scan prior to initiating chemotherapy or thoracic
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
- 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; see Section 3.2.3 for details) 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
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
- Zubrod performance status 0-2
- Women of childbearing potential and male participants must practice adequate
- Women of childbearing potential must have a negative qualitative serum pregnancy test
=< 2 weeks prior to study entry
- Patients who are primary English or French speakers are eligible
- Patients must sign a study-specific informed consent prior to study entry
- 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 Dr.
Wefel. 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
- Patients must have a baseline raw score greater than 2 on the HVLT-R delayed recall
- Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in
overlap of radiation fields
- Radiographic evidence of CNS metastases
- Radiographic evidence of hydrocephalus or other architectural distortion of the
ventricular system, including placement of external ventricular drain or
- Planned concurrent chemotherapy or anti-tumor agent 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
- Contraindication to MR imaging, such as implanted metal devices or foreign bodies or
- 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
- 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