Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Treating Patients With Limited Stage or Extensive Stage Small Cell Lung Cancer

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.

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 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.

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

- Patients must have a three-dimensional (3D), T1-weighted, spoiled gradient (SPGR),
magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) MRI
scan without and with gadolinium contrast-enhanced T1-weighted axial, coronal, and
sagittal sequence acquisitions and standard T2-weighted axial and coronal fluid
attenuation inversion recovery (FLAIR) sequence acquisitions within 28 days of Step 1
registration; to yield acceptable image quality, the pre-contrast-enhanced should have
a resolution of 1 x 1 x 1.2 mm and should follow the protocols established by the
Alzheimer's Disease Neuroimaging Initiative (ADNI); performance of this sequence at a
3 Tesla field strength is recommended; sites may contact the Imaging Co-Chair, Dr.
Tammie Benzinger, for further information or assistance if needed; to yield acceptable
image quality, the gadolinium contrast-enhanced T1-weighted scan should use the
smallest possible axial slice thickness not exceeding 1.5 mm; the associated coronal
and sagittal sequences can be up to 2.5 mm in slice thickness; this imaging is
considered standard of care

- Note: The MRI study as part of response assessment following chemotherapy can be used
for this purpose, but the appropriate sequences must be obtained; this sequence cannot
be obtained prior to chemotherapy and is mandatory irrespective of randomization to
the experimental or control arm of this study

- 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 within 14 days
prior to Step 2 registration: HVLT-R, TMT, and COWA; the neurocognitive assessments
will be uploaded into the National Surgical Adjuvant Breast and Bowel Project,
Radiation Therapy Oncology Group, and Gynecologic Oncology Group (NRG) Oncology RAVE
system for evaluation by Dr. Wefel; once the upload is complete, a notification will
be sent to the site to proceed to Step 2; note: completed baseline neurocognitive
assessments can be uploaded at the time of Step 1 registration

- Patients must have a baseline raw score greater than 2 on the HVLT-R delayed recall

- Prior to chemotherapy or thoracic radiotherapy, patients must be defined as
limited-stage or extensive-stage SCLC after clinical staging evaluation involving the
following:

- History/physical examination;

- Computed tomography (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
within 8 weeks prior to initiating chemotherapy or thoracic radiotherapy)

- MRI of the brain

- For patients without evidence of extensive-stage SCLC on chest and abdomen CT and
brain MRI, a PET/CT or bone scan is required to confirm limited-stage SCLC

- Patients must be registered on study no earlier than 1 week and no later than 8 weeks
after completing chemotherapy (+/- thoracic radiotherapy)

- After chemotherapy, patients must be restaged using the same diagnostic work-up as
required pre-chemotherapy; repeat PET/CT or bone scan is not required; patients must
have:

- No central nervous system (CNS) metastases

- Radiographic partial or complete response to chemotherapy in at least one disease
site using Response Evaluation Criteria in Solid Tumors (RECIST) criteria

- No progression in any site

- Zubrod performance status 0-2

- Women of childbearing potential and male participants must practice adequate
contraception

- 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

Exclusion Criteria:

- 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

- Planned concurrent chemotherapy or anti-tumor agent during PCI

- 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

- Women of childbearing potential and male participants who are sexually active and not
willing/able to use medically acceptable forms of contraception