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

Inclusion Criteria [prior to Step 1 registration]:

• Histologic proof or unequivocal cytologic proof (fine needle aspiration, biopsy ortwo 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 noearlier than 7 days and no later than 56 days after completing chemotherapy. Note:

• Post-chemotherapy restaging imaging must be completed no more than 56 daysprior to Step 1 registration.

• For patients with extensive-stage small cell lung cancer who are beingconsidered for consolidative thoracic radiotherapy after chemotherapy,concomitant administration of consolidative thoracic radiotherapy andprotocol-specified prophylactic cranial irradiation with or without hippocampalavoidance is permitted.

• Patients must have a gadolinium contrast-enhanced three-dimensional (3D), spoiledgradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbofield echo (TFE) MRI scan. To yield acceptable image quality, the gadoliniumcontrast-enhanced three-dimensional SPGR, MP-RAGE or TFE axial MRI scan must use thesmallest 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 orcontrol arm of this study.

• Prior to chemotherapy +/- thoracic radiotherapy, patients must be defined aslimited-stage or extensive-stage SCLC after clinical staging evaluation involvingthe following:

1. History/physical examination;

2. CT of the chest and abdomen with contrast (does not have to be done if thepatient has had a positron emission tomography (PET) / CT scan prior toinitiating 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 CTand brain MRI or head CT, a PET/CT or bone scan is required to confirmlimited-stage SCLC.

• After chemotherapy, patients must be restaged prior to Step 1 registration using thesame diagnostic work-up as required pre-chemotherapy. Repeat PET/CT or bone scan isnot 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 1registration;

• No progression in any site;

• Radiographic partial or complete response to chemotherapy in at least onedisease site within 56 days prior to Step 1 registration.

1. If PET/CT was obtained prior to chemotherapy, either a repeat PET/CT or CTof the chest and abdomen with contrast can be obtained for responseassessment.
2. Patients who underwent resection for limited-stage SCLC prior tochemotherapy and have no radiographically evident disease for responseassessment remain eligible if post-chemotherapy imaging demonstrates noprogression.

• Zubrod performance status 0-2 within 30 days prior to Step 1 registration.

• Women of childbearing potential must have a negative qualitative serum pregnancytest =< 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 uploadedwithin 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 neurocognitiveassessments will be uploaded into the NRG Oncology Rave System for evaluation byNeurocognitive Co-Chair. Once the upload is complete, within 3 business days, anotification email will be sent to the site to proceed to Step 2 registration. Atminimum, the HVLT-R delayed recall must be able to be scored (i.e. completed withouterror) in order to be eligible.

• Patients must have a baseline raw score greater than 2 on the HVLT-R delayed recallas determined by central assessment by the Neurocognitive Co-Chair.

Exclusion Criteria:

• Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting inoverlap of radiation fields

• Radiographic evidence of central nervous system (CNS) metastases

• Radiographic evidence of hydrocephalus or other architectural distortion of theventricular system, including placement of external ventricular drain orventriculoperitoneal shunt

• Planned concurrent chemotherapy during PCI

• Concurrent atezolizumab permitted

• Concomitant invasive malignancy or invasive malignancy within the past five yearsother than non-melanomatous skin cancer; history of in situ carcinoma (e.g. ductalcarcinoma in situ of breast, in situ carcinoma of the cervix, vulva or larynx) ispermitted

• Contraindication to MR imaging, such as implanted metal devices or foreign bodies orsevere claustrophobia

• Severe, active comorbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalizationwithin the last 6 months

• Transmural myocardial infarction within the last 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of registration

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

• Chronic obstructive pulmonary disease exacerbation or other respiratory illnessrequiring hospitalization or precluding study therapy at the time ofregistration

• 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 undertreatment with highly active antiretroviral therapy (HAART) and have a CD4count ≥ 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 participantswho are sexually active and not willing/able to use medically acceptable forms ofcontraception; this exclusion is necessary because the radiation treatment involvedin this study may be significantly teratogenic.