When patients with small cell lung cancer (SCLC) progress, as is common with such an aggressive malignancy, brain metastasis is a known possibility. As such, guidelines have recommended prophylactic cranial irradiation for patients with SCLC who respond well to first-line therapy to decrease the risk of brain metastases.1,2 Prophylactic cranial irradiation typically comprises whole-brain radiotherapy, which has been the standard of care for many years, even though it is associated with neurocognitive toxicity and neurocognitive function decline.3
In recent years, several studies have challenged the use of prophylactic whole-brain radiotherapy, demonstrating that the approach may not be as beneficial as previously believed.4
Meta-analyses have shown that patients with SCLC receiving prophylactic cranial irradiation achieved longer survival (hazard ratio [HR] = 0.59; 95% confidence interval [CI] = 0.55–0.63; P < .001). However, further analysis showed that the survival benefit did not persist when focused only on patients without brain metastases, as confirmed by MRI (HR = 0.74; 95% CI = 0.52–1.05; P = .08). This suggests that the survival benefit may only relate to patients who already had brain metastases.5
A phase III Japanese study similarly did not show improved survival for prophylactic cranial irradiation compared with observation in patients with extensive-stage SCLC who were confirmed by MRI not to have any brain metastases (11.6 vs 13.7 months, respectively; HR = 1.27; 95% CI = 0.96–1.68; P = .094).6 This study instead led to recommendations for close surveillance with brain MRIs in patients with extensive-stage SCLC, and additional studies continue to add to the pool of information moving clinicians further away from prophylactic brain irradiation.
Recently, in the Journal of Clinical Oncology, two studies were published that seek to move further away from the use of prophylactic whole-brain radiotherapy and towards more modern targeted radiation approaches for patients with SCLC.
Stereotactic Radiosurgery for Brain Metastases
Prior studies of focal approaches to brain radiotherapy for patients with brain metastases have typically excluded patients with SCLC due to concerns of new brain metastasis development and neurologic death. Recent retrospective data have suggested the potential viability of stereotactic brain radiation for patients with SCLC and brain metastases.
A multi-institutional, prospective, single-arm phase II trial explored the use of stereotactic radiation rather than whole-brain radiotherapy in patients with SCLC who had 1 to 10 brain metastases to assess neurologic death rates compared with that of whole-brain radiotherapy.7
Participants were allowed to have received prior neurosurgical resection and systemic therapy, but no prior brain-directed radiation; patients with leptomeningeal disease, unresected tumors greater than 5 cm, stage IV/V chronic kidney disease, end-stage renal disease, or an inability to undergo brain MRI with contrast were excluded. In the study, patients received brain-directed stereotactic brain radiation therapy using volumetric-modulated arc therapy on a linear accelerator. Radiation dose and fractions were determined by the size of the tumor.
The primary endpoint was neurologic death, or radiographic progression in the brain and corresponding neurologic symptomatology or systemic symptoms of a life-threatening nature, as determined by two radiation oncologists. Secondary endpoints included overall survival; the incidence and time to detection of new brain metastases, leptomeningeal disease, salvage neurosurgical resection, or salvage brain-directed radiation; systemic disease progression; and seizures.
The trial cohort included 100 participants who were compared with 35 historical control patients. Of the trial participants, 64% underwent stereotactic radiosurgery, 22% received stereotactic radiotherapy, and 12% had a combination of both.
Twenty patients had neurologic death and 64 had non-neurologic death. The two radiologists only disagreed in 2% of cases requiring a tie-breaking vote. At 1 year, the rate of neurologic death was 11% (95% confidence interval [CI] = 5.8%‒18.1%); at 2 years, it was 20.3% (95% CI = 12.7%‒29.1%). The rates of non-neurologic death were 48.0% (95% CI = 37.9%‒57.4%) and 61.7% (95% CI = 50.8%‒70.8%) at 1 and 2 years, respectively. Median overall survival was 10.2 months (95% CI = 8.5‒12.2).
In terms of historical controls, the rates of neurologic death with whole-brain radiotherapy were 17.5% at 1 year and 35.2% at 2 years. The one-sided P value for noninferiority was .001.
Univariable analyses did not find factors associated with neurologic death, "suggesting that our results may apply to most patients who were eligible for the study," according to Ayal A. Aizer, MD, MHS, of the Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, and colleagues.
Sixty-one percent of patients developed new brain metastases, 9% developed leptomeningeal disease, and 65% had systemic disease progression. Thirty-nine percent of patients received at least one course of salvage stereotactic brain radiation, and 22% received salvage whole-brain radiotherapy. A total of 78% of patients were able to avoid whole-brain radiotherapy for their entire clinical course.
At least one local recurrence following on-study treatment was observed in 13% of patients. Nine percent experienced radiographic necrosis, and 5% had symptomatic necrosis.
Five patients achieved durable, long-term tumor control without recurrence for over 18 months without subsequent systemic or local therapy.
Radiation therapy was considered tolerable without many severe toxicities. No grade 5 events were reported that were related to study treatment.
Aizer et al concluded that their "study suggests the utility of SRS/SRT in the management of patients with SCLC and a limited number of brain metastases. It appears that WBRT is not necessary for such patients, provided that frequent MRI-based surveillance of the brain is used."
Commenting on the study in an editorial, Benjamin T. Cooper, MD, and Douglas Kondziolka, MD, both of NYU Langone Medical Center, noted that the historical control focused on an era before immunotherapy was used for patients with SCLC and that frequent MRI scans allowed the researchers to detect new brain metastases early and offer prompt treatment to favorably impact neurologic death rates. However, they did highlight that using stereotactic radiosurgery allows whole-brain radiotherapy to be saved for later, as it can only be done safely once at full therapeutic doses, and stereotactic radiosurgery also lessens the amount of time that systemic therapy is held.3
"This treatment strategy relies on frequent MRI surveillance and brings the management of SCLC into the modern era where maximal brain sparing is prioritized when possible," Drs. Cooper and Kondziolka concluded.
Hippocampal Avoidance Without Brain Metastases
Randomized trials have shown that hippocampal avoidance techniques during therapeutic whole-brain radiotherapy for patients with brain metastases have prevented neurologic symptoms,8 making it a standard of care for brain metastasis management.
The multicenter seamless randomized phase II/III NRG-CC003 trial was conducted to look at the use of hippocampal avoidance during prophylactic cranial irradiation in patients with SCLC and no brain metastases to reduce radiation-induced neurocognitive function toxicity without compromising the benefit of whole-brain radiotherapy. 9
All patients in the study had achieved a response to chemotherapy treatment, with or without thoracic radiotherapy.
Participants (n = 393) were randomly assigned to undergo prophylactic cranial irradiation with or without hippocampal avoidance. The prescribed dose of irradiation was 25 Gy in 10 fractions. Memantine use was optional.
The primary endpoints were 12-month intracranial relapse rate and 6-month learning and memory-delayed recall failure. Secondary endpoints included first and any failure of a neurocognitive function test, health-related quality of life, overall survival, and toxicity.
Prophylactic cranial irradiation led to a noninferior 12-month intracranial relapse rate of 14.7% with hippocampal avoidance vs 14.8% without (P < .0001).
Six-month deterioration in learning and memory-delayed recall was not significantly different between the two arms at 30% and 25.5% for standard prophylactic cranial irradiation and hippocampal avoidance, respectively (P = .28).
Median overall survival in the hippocampal avoidance arm was 20.7 months (95% CI = 17.0‒34.7 months) compared with 24.9 months (95% CI = 17.8‒36.4 months) in the standard prophylactic cranial irradiation arm.
After adjustment for stratification factors, the risk of failing a neurocognitive function test was much lower in the hippocampal avoidance arm (adjusted hazard ratio [HR] = 0.78; 95% CI = 0.61‒0.99; P = .039). The majority of first neurocognitive failures in both arms were due to learning and memory and processing speed.
The study authors, led by Vinai Gondi, MD, of Northwestern University Feinberg School of Medicine, concluded that "although NRG-CC003 did not meet its primary endpoint of delayed recall preservation, the use of hippocampal avoidance during prophylactic cranial irradiation reduces the risk of overall neurocognitive failure, which has been a practice-changing endpoint in previous neurocognitive toxicity risk-reduction trials for brain metastases."
Research Next Steps
Going forward, researchers are continuing to explore more modern approaches to targeted radiation for patients with SCLC. One such randomized study is exploring the use of stereotactic radiotherapy as compared with hippocampal-sparing whole-brain radiotherapy for patients with SCLC and 1 to 10 brain metastases to determine which approach is superior for this patient population.
Additionally, the phase III NRG-CC009 trial is investigating the use of high-dose stereotactic radiosurgery vs memantine and whole-brain radiation with hippocampal avoidance in patients with SCLC and brain metastases. This study, which is led by Dr. Gondi as the principal investigator, is nearing completion and is expected to provide level I evidence on the appropriate use of stereotactic radiosurgery for brain metastases from SCLC.
DISCLOSURE: Dr. Aizer has received research funding from Varian and NH TherAguix. For full disclosures of the study authors, visit ascopubs.org.
REFERENCES
1. Aupérin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341:476-484, 1999.
2. Ganti AKP, Loo BW, Badiyan S, et al: NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer, Version 2.2026. Available at https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed September 18, 2025.
3. Cooper BT, Kondziolka D: Modern targeted radiation in patients with brain metastases from small cell lung cancer. J Clin Oncol 43:2958-2960, 2025.
4. Edelman MJ: Prophylactic cranial irradiation for small-cell lung cancer: time for a reassessment. Am Soc Clin Oncol Educ Book 40:24-28, 2020.
5. Gaebe K, Erickson AW, Li AY, et al: Re-examining prophylactic cranial irradiation in small cell lung cancer: a systematic review and meta-analysis. EClinicalMedicine 67:102396, 2024.
6. Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in patients with extensive-stage small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 18:663-671, 2017.
7. Aizer AA, Tanguturi SK, Shi DD, et al: Stereotactic radiosurgery in patients with small cell lung cancer and 1-10 brain metastases: a multi-institutional, phase II, prospective clinical trial. J Clin Oncol 43:2986-2997, 2025.
8. Brown PD, Gondi V, Pugh S, et al: Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: phase III trial NRG Oncology CC001. J Clin Oncol 38:1019-1029, 2020.
9. Gondi V, Pugh SL, Mehta MP, et al: Hippocampal avoidance during prophylactic cranial irradiation for patients with small cell lung cancer: randomized phase II/III trial NRG-CC003. J Clin Oncol. August 11, 2025 (early release online).
EXPERT POINT OF VIEW
Progress in the Treatment of Brain Disease in Small Cell Lung Cancer
Martin J. Edelman, MD, FACP, FASCO, Professor and Chair, Department of Hematology/Oncology; Associate Director for Clinical Research Integration; and G. Morris Dorrance Chair in Medical Oncology, Fox Chase Cancer Center, as well as the Chair of the Department of Medical Oncology, Lewis Katz School of Medicine, Temple University, provided the following commentary about how and why these two studies are significant advances for the treatment of brain disease for patients with small cell lung cancer (SCLC), and stresses consideration of the sequencing of therapies for these patients and the triggers for the initiation of such treatments.
"Central nervous system (CNS) disease in small cell cancer (both with pulmonary and extrapulmonary primaries) is frequent and perhaps almost a universal aspect of these diseases. Both the CNS disease and its treatment have the potential for devastating consequences in what is frequently an elderly population with significant comorbidities. The prior standard of care for treatment of CNS disease was whole-brain radiotherapy (WBRT), with the assumption that the presence of a single lesion implied the more diffuse involvement. Additionally, the frequency and severity of CNS disease led to the adoption of WBRT as prophylactic cranial irradiation (PCI) for patients who had obtained excellent responses to treatment for limited SCLC, and then in extensive SCLC. WBRT (whether to treat established disease or prevent it) subjects the patient to a time-consuming, and potentially toxic, treatment. The two recent studies, from the NRG and a Dana Farber–led consortium, represent significant advances in supporting a “less is more” strategy., The first by demonstrating that hippocampal avoidance during PCI reduces the toxicity of WBRT, and the second by demonstrating that stereotactic radiotherapy (SRS) produces excellent control in the brain when there are a few metastatic lesions.
While hippocampal avoidance decreases the toxicity of PCI, it is important to note that the role of PCI in SCLC is controversial. Many of the trials justifying the use of PCI that are included in meta-analyses were done prior to the routine use of MRI and/or PET scanning. Additionally, variability in the use of systemic therapies may have strongly influenced the outcomes. The current MAVERICK trial (Southwest Oncology Group trial 1827) will hopefully answer the question as to the utility of PCI in general.
The trial of SRS demonstrates that the treatment of established disease does not require WBRT. However, unanswered is the appropriate sequencing of treatments. In this study, only 50% of patients received systemic therapy prior to SRS. Patients had a median of two (range = two to four) metastatic lesions. The median size of the largest of the lesions was 2 cm, and only 32% had neurologic symptoms. It does not appear that any of these patients required urgent/emergent treatment of the CNS disease. SCLC is a systemic disease. There is an overwhelming literature, dating back decades, that SCLC brain metastases respond to systemic therapy. As most patients on the Aizer trial (58%) ultimately experienced systemic progression (which was clearly the primary cause of death), it is reasonable to ask if the priority for treatment should be systemic in an essentially asymptomatic population. Radiotherapy is then reserved for salvage and/or consolidation of response. It is important to note that this does require close follow-up of patients (eg, frequent CNS imaging) and should not require symptomatic deterioration before institution of treatment.
The focus on CNS disease has frequently resulted in the requirement that brain disease be “controlled” either with surgery or radiotherapy before patient entry onto clinical trials. In a disease in which the CNS is almost inevitably involved, this seems unreasonable. The results in other lung cancer entities, most notably ALK-translocated disease, clearly indicate that systemic therapy can result in long-term control of alldisease sites, including the brain. Recent guidance by the U.S. Food and Drug Administration has recognized that a critical aspect for the assessment of new agents is activity in the brain, with recommendations regarding the inclusion of such patients on early phase studies.
Recent advances in therapeutics and a growing understanding of the biologic complexity of SCLC bring new urgency to the rapid accrual and completion of studies testing novel approaches. CNS involvement, including its treatment and toxicity reduction, are one aspect of this care, but not necessarily the priority. Upfront, interdisciplinary involvement is critical if we are to make progress with the disease."
DISCLOSURE: Dr. Edelman reported research support from Novartis and MBrace; membership on Data Safety Monitoring Boards for AstraZeneca, BMS, GSK, Pfizer, AnHeart, Sana, Seagen, Nuvation; consultant/scientific advisory board member for Amgen, Jazz, Boehringer-Ingelheim, Catalyst, Coherus, Harpoon, Auron, Cardinal Health, Lantheus, MJH Healthcare.
