NCT02635009

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

Completed Phase 2, PHASE3 Results posted Last updated 2 March 2026

What this trial tests

Phase 2, PHASE3 trial testing Three-Dimensional Conformal Radiation Therapy in Extensive Stage Small Cell Lung Carcinoma in 418 participants. Completed in 4 September 2025.

Timeline

22 December 2015

Primary endpoint
18 May 2023

4 September 2025

Quick facts

Lead sponsor	NRG Oncology
Phase	Phase 2, PHASE3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	supportive care
Enrollment	418
Start date	22 December 2015
Primary completion	18 May 2023
Estimated completion	4 September 2025
Sites	285 locations across Canada, United States

Drugs / interventions tested

• Three-Dimensional Conformal Radiation Therapy
• Intensity-Modulated Radiation Therapy

Conditions studied

• Extensive Stage Small Cell Lung Carcinoma — all drugs for Extensive Stage Small Cell Lung Carcinoma →
• Limited Stage Small Cell Lung Carcinoma — all drugs for Limited Stage Small Cell Lung Carcinoma →

Sponsor

NRG Oncology — full company profile →

Who can join

18 and older, any sex, with Extensive Stage Small Cell Lung Carcinoma or Limited Stage Small Cell Lung Carcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With Deterioration in HVLT-R Delayed Recall Score at Six Months (Phase III) Primary · Baseline and six months

The HVLT-R delayed recall test assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials to recall after a 20-minute delay. The score is the sum of the number of words correctly recalled and ranges from 0 to 36, with a higher score indicating better functioning. Deterioration is defined a decrease from baseline of at least 3 points.

Group	Value	95% CI
PCI Using 3DCRT (Arm 1)	33
PCI With HA Using IMRT (Arm 2)	27

Number of Participants With Intracranial Relapse at 12 Months (Phase II) Primary · From baseline to 12 months

Intracranial relapse, defined as the development of a new brain metastasis as documented on brain MRI with contrast or head CT with contrast.

Group	Value	95% CI
PCI Using 3DCRT (Arm 1)	16
PCI With HA Using IMRT (Arm 2)	12

Percentage of Participants With Neurocognitive Failure (Phase III) Secondary · Randomization to date of failure, death, or last known follow-up whichever occurred first. Maximum follow-up at time of analysis was 7.2 years.

Neurocognitive failure is defined as the first instance of neurocognitive decline in any of six assessments, as determined my reliable change index: Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Trail Making Test (TMT) part A, TMT part B, and Controlled Oral Word Association (COWA). Failure time is defined as time from randomization to failure, death (competing event), or last follow-up (censored). Neurocognitive failure rates are estimated using the cumulative incidence method. The distributions of failure times are compared, wh

Group	Value	95% CI
PCI Using 3DCRT	57.0	49.6 – 63.8
PCI With HA Using IMRT	52.7	45.3 – 59.5

Number of Participants With Deterioration in HVLT-R Total Recall Score (Phase III) Secondary · Baseline, 3, 6, 12 months.

The HVLT-R Total Recall score assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials. Raw score is the sum of the number of targets correctly recalled, ranging from 0 to 36. Higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 5 points.

3 months

Group	Value	95% CI
PCI Using 3DCRT	47
PCI With HA Using IMRT	47

6 months

Group	Value	95% CI
PCI Using 3DCRT	33
PCI With HA Using IMRT	35

12 months

Group	Value	95% CI
PCI Using 3DCRT	20
PCI With HA Using IMRT	17

Number of Participants With Deterioration in HVLT-R Total Recall Score (Phase III) Secondary · Baseline,18, 24 months.

he HVLT-R Total Recall score assesses verbal learning and memory. The test involves memorizing a list of 12 nouns for 3 consecutive trials. Raw score is the sum of the number of targets correctly recalled, ranging from 0 to 36. Higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 5 points.

18 months

Group	Value	95% CI
PCI Using 3DCRT (Arm 1)	21
PCI With HA Using IMRT (Arm 2)	22

24 months

Group	Value	95% CI
PCI Using 3DCRT (Arm 1)	14
PCI With HA Using IMRT (Arm 2)	15

Number of Participants With Deterioration in HVLT-R Delayed Recall Score (Phase III) Secondary · Baseline, 3, 12 months.

The HVLT-R Delayed Recall test assesses verbal learning and memory. After memorizing a list of 12 nouns for 3 consecutive trials, this test requires recalling the 12 targets after a 20-minute delay. Raw scores are sum of the number of targets correctly recalled. The score ranges from 0 to 12. A higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 3 points. Six-month results are reported as the primary endpoint.

3 months

Group	Value	95% CI
PCI Using 3DCRT	40
PCI With HA Using IMRT	34

12 months

Group	Value	95% CI
PCI Using 3DCRT	23
PCI With HA Using IMRT	19

Number of Participants With Deterioration in HVLT-R Delayed Recall Score (Phase III) Secondary · Baseline, 18, 24 months.

The HVLT-R Delayed Recall test assesses verbal learning and memory. After memorizing a list of 12 nouns for 3 consecutive trials, this test requires recalling the 12 targets after a 20-minute delay. Raw scores are sum of the number of targets correctly recalled. The score ranges from 0 to 12. A higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 3 points.

18 months

Group	Value	95% CI
PCI Using 3DCRT (Arm 1)	16
PCI With HA Using IMRT (Arm 2)	25

24 months

Group	Value	95% CI
PCI Using 3DCRT (Arm 1)	18
PCI With HA Using IMRT (Arm 2)	12

Number of Participants With Deterioration in HVLT-R Delayed Recognition Score (Phase III) Secondary · Baseline, 3, 6, 12 months.

The HVLT-R Delayed Recognition assesses verbal learning and memory. After memorizing a list of 12 nouns for 3 consecutive trials and recalling the 12 targets after a 20-minute delay, the test involves then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are the sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified. The score ranges from -12 to 12 for recognition. A higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 2 poi

3 months

Group	Value	95% CI
PCI Using 3DCRT	49
PCI With HA Using IMRT	45

6 months

Group	Value	95% CI
PCI Using 3DCRT	11
PCI With HA Using IMRT	11

12 months

Group	Value	95% CI
PCI Using 3DCRT	19
PCI With HA Using IMRT	22

Number of Participants With Deterioration in HVLT-R Delayed Recognition Score (Phase III) Secondary · Baseline, 18, 24 months.

The HVLT-R Delayed Recognition assesses verbal learning and memory. After memorizing a list of 12 nouns for 3 consecutive trials and recalling the 12 targets after a 20-minute delay, the test involves then identifying the 12 targets from a list of semantically related or unrelated items (delayed recognition). Raw scores are the sum of targets incorrectly identified subtracted from the sum of the number of targets correctly identified. The score ranges from -12 to 12 for recognition. A higher score indicates better functioning. Deterioration is defined a decrease from baseline of at least 2 poi

18 months

Group	Value	95% CI
PCI Using 3DCRT (Arm 1)	13
PCI With HA Using IMRT (Arm 2)	12

24 months

Group	Value	95% CI
PCI Using 3DCRT (Arm 1)	12
PCI With HA Using IMRT (Arm 2)	3

Number of Participants With Deterioration in Trail Making Test (TMT) Part A (Phase III) Secondary · Baseline, 3, 6, 12 months.

The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A, reported here), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order. The score is the amount of time, in seconds, that it takes the patient to complete the maze. The range for

3 months

Group	Value	95% CI
PCI Using 3DCRT	27
PCI With HA Using IMRT	30

6 months

Group	Value	95% CI
PCI Using 3DCRT	21
PCI With HA Using IMRT	26

12 months

Group	Value	95% CI
PCI Using 3DCRT	22
PCI With HA Using IMRT	14

Number of Participants With Deterioration in Trail Making Test (TMT) Part A (Phase III) Secondary · Baseline, 18, 24 months.

The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the first (Part A, reported here), the targets are all numbers (1, 2, 3, etc.) and the test taker needs to connect them in sequential order. The score is the amount of time, in seconds, that it takes the patient to complete the maze. The range for

18 months

Group	Value	95% CI
PCI Using 3DCRT (Arm 1)	15
PCI With HA Using IMRT (Arm 2)	13

24 months

Group	Value	95% CI
PCI Using 3DCRT (Arm 1)	15
PCI With HA Using IMRT (Arm 2)	9

Number of Participants With Deterioration in TMT Part B Score (Phase III) Secondary · Baseline, 3, 6, 12 months.

The TMT is a neuropsychological test of visual attention and task switching that can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning. Subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. There are two parts to the test: in the second part (Part B, reported here), the subject alternates between numbers and letters (1, A, 2, B, etc.). The score is the amount of time, in seconds, that it takes the patient to complete the maze. The score range for Part B is 0 to 300 (5

3 months

Group	Value	95% CI
PCI Using 3DCRT	43
PCI With HA Using IMRT	38

6 months

Group	Value	95% CI
PCI Using 3DCRT	26
PCI With HA Using IMRT	38

12 months

Group	Value	95% CI
PCI Using 3DCRT	22
PCI With HA Using IMRT	19

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline to last known follow-up or death. Maximum follow-up time was 7.2 years.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

PCI Using 3DCRT

Serious: 26/191 (14%)

Deaths: 118/196

PCI With HA Using IMRT

Serious: 17/189 (9%)

Deaths: 112/197

Serious adverse events (78 terms)

Reaction	System	PCI Using 3DCRT	PCI With HA Using IMRT
Lung infection	Infections and infestations	—	—
Anemia	Blood and lymphatic system disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Fatigue	General disorders and administration site conditions	—	—
Anorexia	Metabolism and nutrition disorders	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Blood and lymphatic system disorders - Other	Blood and lymphatic system disorders	—	—
Edema limbs	General disorders and administration site conditions	—	—
Gait disturbance	General disorders and administration site conditions	—	—
Infections and infestations - Other	Infections and infestations	—	—
Platelet count decreased	Investigations	—	—
Weight loss	Investigations	—	—
Dehydration	Metabolism and nutrition disorders	—	—
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	—	—
Confusion	Psychiatric disorders	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—
Hypertension	Vascular disorders	—	—
Thrombotic thrombocytopenic purpura	Blood and lymphatic system disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—

Other adverse events (38 terms — click to expand)

Reaction	System	PCI Using 3DCRT	PCI With HA Using IMRT
Fatigue	General disorders and administration site conditions	—	—
Headache	Nervous system disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—
Dizziness	Nervous system disorders	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—
Memory impairment	Nervous system disorders	—	—
Anorexia	Metabolism and nutrition disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Dermatitis radiation	Injury, poisoning and procedural complications	—	—
Weight loss	Investigations	—	—
Anemia	Blood and lymphatic system disorders	—	—
Hearing impaired	Ear and labyrinth disorders	—	—
Blurred vision	Eye disorders	—	—
Lymphocyte count decreased	Investigations	—	—
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	—	—
Dysgeusia	Nervous system disorders	—	—
Pain	General disorders and administration site conditions	—	—
Insomnia	Psychiatric disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Fall	Injury, poisoning and procedural complications	—	—
Dysphagia	Gastrointestinal disorders	—	—
Gait disturbance	General disorders and administration site conditions	—	—
Anxiety	Psychiatric disorders	—	—
Peripheral sensory neuropathy	Nervous system disorders	—	—
Platelet count decreased	Investigations	—	—
Depression	Psychiatric disorders	—	—
Tinnitus	Ear and labyrinth disorders	—	—
Dry mouth	Gastrointestinal disorders	—	—
Productive cough	Respiratory, thoracic and mediastinal disorders	—	—
Confusion	Psychiatric disorders	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Amnesia	Nervous system disorders	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—

Most-reported serious reactions: Lung infection, Anemia, Abdominal pain, Constipation, Nausea, Vomiting, Fatigue, Anorexia.

Data from ClinicalTrials.gov NCT02635009 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Whole-Brain Radiotherapy for Brain Metastases: Evolution or Revolution?
   Brown PD, Ahluwalia MS, Khan OH, Asher AL, et al · · 2018 · cited 160× · PMID 29272161 · DOI 10.1200/jco.2017.75.9589
2. Radiation and Systemic Therapy for Limited-Stage Small-Cell Lung Cancer.
   Bogart JA, Waqar SN, Mix MD. · · 2022 · cited 88× · PMID 34985935 · DOI 10.1200/jco.21.01639
3. Recent advances in managing brain metastasis.
   Kotecha R, Gondi V, Ahluwalia MS, Brastianos PK, et al · · 2018 · cited 67× · PMID 30473769 · DOI 10.12688/f1000research.15903.1
4. A prospective evaluation of hippocampal radiation dose volume effects and memory deficits following cranial irradiation.
   Ma TM, Grimm J, McIntyre R, Anderson-Keightly H, et al · · 2017 · cited 57× · PMID 29128167 · DOI 10.1016/j.radonc.2017.09.035
5. Prophylactic cranial irradiation after definitive chemoradiotherapy for limited-stage small cell lung cancer: Do all patients benefit?
   Farooqi AS, Holliday EB, Allen PK, Wei X, et al · · 2017 · cited 52× · PMID 28073578 · DOI 10.1016/j.radonc.2016.11.012
6. Management of brain metastases in lung cancer: evolving roles for radiation and systemic treatment in the era of targeted and immune therapies.
   Myall NJ, Yu H, Soltys SG, Wakelee HA, et al · · 2021 · cited 36× · PMID 34859233 · DOI 10.1093/noajnl/vdab106
7. What is the role of radiotherapy for extensive-stage small cell lung cancer in the immunotherapy era?
   Nesbit EG, Leal TA, Kruser TJ. · · 2019 · cited 31× · PMID 31673520 · DOI 10.21037/tlcr.2019.05.01
8. Prophylactic cranial irradiation in small-cell lung cancer: update on patient selection, efficacy and outcomes.
   Manapov F, Käsmann L, Roengvoraphoj O, Dantes M, et al · · 2018 · cited 27× · PMID 30323698 · DOI 10.2147/lctt.s137577