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

Last Updated: 2024-07-17

Study Results

Results available

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Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

PHASE2/PHASE3

Total Enrollment

418 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-12-22

Study Completion Date

2027-04-30

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Extensive Stage Small Cell Lung Carcinoma Limited Stage Small Cell Lung Carcinoma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

SUPPORTIVE_CARE

Blinding Strategy

NONE

Study Groups

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PCI using 3DCRT

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

Group Type ACTIVE_COMPARATOR

Three-Dimensional Conformal Radiation Therapy

Intervention Type RADIATION

daily fractions

PCI with HA using IMRT

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

Group Type EXPERIMENTAL

Intensity-Modulated Radiation Therapy

Intervention Type RADIATION

daily fractions

Interventions

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Three-Dimensional Conformal Radiation Therapy

daily fractions

Intervention Type RADIATION

Intensity-Modulated Radiation Therapy

daily fractions

Intervention Type RADIATION

Other Intervention Names

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3-dimensional conformal radiation therapy 3-dimensional radiation therapy 3D-CRT Conformal Therapy Radiation Conformal Therapy 3DCRT IMRT Intensity Modulated RT Intensity-Modulated Radiotherapy

Eligibility Criteria

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Inclusion Criteria

* 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

* 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.

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Vinai Gondi

Role: PRINCIPAL_INVESTIGATOR

NRG Oncology

Locations

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University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, United States

Site Status

Lewis and Faye Manderson Cancer Center

Tuscaloosa, Alabama, United States

Site Status

Banner University Medical Center - Tucson

Tucson, Arizona, United States

Site Status

Marin General Hospital

Greenbrae, California, United States

Site Status

Los Angeles General Medical Center

Los Angeles, California, United States

Site Status

USC / Norris Comprehensive Cancer Center

Los Angeles, California, United States

Site Status

Mercy UC Davis Cancer Center

Merced, California, United States

Site Status

Kaiser Permanente Oakland-Broadway

Oakland, California, United States

Site Status

Saint Joseph Hospital - Orange

Orange, California, United States

Site Status

Kaiser Permanente-Rancho Cordova Cancer Center

Rancho Cordova, California, United States

Site Status

Sutter Cancer Centers Radiation Oncology Services-Roseville

Roseville, California, United States

Site Status

The Permanente Medical Group-Roseville Radiation Oncology

Roseville, California, United States

Site Status

Sutter Medical Center Sacramento

Sacramento, California, United States

Site Status

University of California Davis Comprehensive Cancer Center

Sacramento, California, United States

Site Status

California Pacific Medical Center-Pacific Campus

San Francisco, California, United States

Site Status

Kaiser Permanente Medical Center - Santa Clara

Santa Clara, California, United States

Site Status

Gene Upshaw Memorial Tahoe Forest Cancer Center

Truckee, California, United States

Site Status

Sutter Solano Medical Center/Cancer Center

Vallejo, California, United States

Site Status

Swedish Medical Center

Englewood, Colorado, United States

Site Status

Poudre Valley Hospital

Fort Collins, Colorado, United States

Site Status

Hartford HealthCare - Saint Vincent's Medical Center

Bridgeport, Connecticut, United States

Site Status

Yale University

New Haven, Connecticut, United States

Site Status

Helen F Graham Cancer Center

Newark, Delaware, United States

Site Status

Christiana Care Health System-Christiana Hospital

Newark, Delaware, United States

Site Status

Boca Raton Regional Hospital

Boca Raton, Florida, United States

Site Status

UM Sylvester Comprehensive Cancer Center at Coral Gables

Coral Gables, Florida, United States

Site Status

Broward Health Medical Center

Fort Lauderdale, Florida, United States

Site Status

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, United States

Site Status

Miami Cancer Institute

Miami, Florida, United States

Site Status

Orlando Health Cancer Institute

Orlando, Florida, United States

Site Status

Moffitt Cancer Center

Tampa, Florida, United States

Site Status

Grady Health System

Atlanta, Georgia, United States

Site Status

Emory University Hospital Midtown

Atlanta, Georgia, United States

Site Status

Piedmont Hospital

Atlanta, Georgia, United States

Site Status

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, United States

Site Status

Northside Hospital

Atlanta, Georgia, United States

Site Status

Northside Hospital-Forsyth

Cumming, Georgia, United States

Site Status

Memorial Health University Medical Center

Savannah, Georgia, United States

Site Status

Lewis Cancer and Research Pavilion at Saint Joseph's/Candler

Savannah, Georgia, United States

Site Status

Queen's Medical Center

Honolulu, Hawaii, United States

Site Status

The Cancer Center of Hawaii-Liliha

Honolulu, Hawaii, United States

Site Status

The Cancer Center of Hawaii-Pali Momi

‘Aiea, Hawaii, United States

Site Status

Saint Alphonsus Cancer Care Center-Boise

Boise, Idaho, United States

Site Status

Saint Luke's Cancer Institute - Boise

Boise, Idaho, United States

Site Status

Saint Alphonsus Cancer Care Center-Caldwell

Caldwell, Idaho, United States

Site Status

Saint Luke's Cancer Institute - Meridian

Meridian, Idaho, United States

Site Status

Saint Luke's Cancer Institute - Nampa

Nampa, Idaho, United States

Site Status

Saint Alphonsus Cancer Care Center-Nampa

Nampa, Idaho, United States

Site Status

Saint Luke's Cancer Institute - Twin Falls

Twin Falls, Idaho, United States

Site Status

Northwestern University

Chicago, Illinois, United States

Site Status

John H Stroger Jr Hospital of Cook County

Chicago, Illinois, United States

Site Status

Rush University Medical Center

Chicago, Illinois, United States

Site Status

Decatur Memorial Hospital

Decatur, Illinois, United States

Site Status

Crossroads Cancer Center

Effingham, Illinois, United States

Site Status

Northwestern Medicine Cancer Center Delnor

Geneva, Illinois, United States

Site Status

Edward Hines Jr VA Hospital

Hines, Illinois, United States

Site Status

Condell Memorial Hospital

Libertyville, Illinois, United States

Site Status

Loyola University Medical Center

Maywood, Illinois, United States

Site Status

Illinois CancerCare-Peoria

Peoria, Illinois, United States

Site Status

Methodist Medical Center of Illinois

Peoria, Illinois, United States

Site Status

OSF Saint Francis Medical Center

Peoria, Illinois, United States

Site Status

Memorial Medical Center

Springfield, Illinois, United States

Site Status

Carle Cancer Center

Urbana, Illinois, United States

Site Status

Northwestern Medicine Cancer Center Warrenville

Warrenville, Illinois, United States

Site Status

Ascension Saint Vincent Anderson

Anderson, Indiana, United States

Site Status

Parkview Hospital Randallia

Fort Wayne, Indiana, United States

Site Status

Parkview Regional Medical Center

Fort Wayne, Indiana, United States

Site Status

Goshen Center for Cancer Care

Goshen, Indiana, United States

Site Status

IU Health Ball Memorial Hospital

Muncie, Indiana, United States

Site Status

Saint Luke's Hospital

Cedar Rapids, Iowa, United States

Site Status

Mercy Hospital

Cedar Rapids, Iowa, United States

Site Status

Iowa Methodist Medical Center

Des Moines, Iowa, United States

Site Status

University of Kansas Cancer Center

Kansas City, Kansas, United States

Site Status

Lawrence Memorial Hospital

Lawrence, Kansas, United States

Site Status

University of Kansas Cancer Center-Overland Park

Overland Park, Kansas, United States

Site Status

Ascension Via Christi Hospitals Wichita

Wichita, Kansas, United States

Site Status

Wesley Medical Center

Wichita, Kansas, United States

Site Status

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, United States

Site Status

Tulane University School of Medicine

New Orleans, Louisiana, United States

Site Status