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

NRG Oncology

Status and phase: Active, not recruiting; Phase 3; Phase 2

Conditions: Limited Stage Small Cell Lung Carcinoma; Extensive Stage Small Cell Lung Carcinoma

Treatments: Radiation: Three-Dimensional Conformal Radiation Therapy; Radiation: Intensity-Modulated Radiation Therapy

Study type: Interventional

Funder types: Other; NETWORK; NIH

Identifiers

NCT02635009

NRG-CC003 (Other Identifier)

UG1CA189867 (U.S. NIH Grant/Contract)

NCI-2015-01548 (Registry Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 418 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Supportive Care

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

418 participants in 2 patient groups

PCI using 3DCRT

Active Comparator group

Description:

Prophylactic cranial irradiation (PCI) using three-dimensional conformal radiation therapy (3DCRT) for 2 weeks, 5 fractions/week.

Treatment:

Radiation: Three-Dimensional Conformal Radiation Therapy

PCI with HA using IMRT

Experimental group

Description:

PCI with hippocampal avoidance (HA) using intensity-modulated radiation therapy (IMRT) for 2 weeks, 5 fractions/week.

Treatment:

Radiation: Intensity-Modulated Radiation Therapy