There is a paucity of randomized trial data on the management of small cell lung cancer (SCLC) brain metastases. Current guidelines from the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) offer somewhat different recommendations on the use of prophylactic cranial irradiation (PCI) in stage I-III disease.
“The data on PCI in limited stage SCLC are old and generally did not include MRI,” said Inga S. Grills, MD, professor and head of thoracic oncology, Oakland University William Beaumont School of Medicine, Auburn Hills, Michigan. “We know PCI affects quality of life as well as brain function. PCI is typically offered for limited stage (LS) disease with discussions about quality of life and neurocognition. For patients who decline PCI, MRI surveillance is appropriate. And I personally recommend surveillance in extensive stage (ES) disease.”
During WCLC 2022, Dr. Grills opened a symposium on “Optimizing the Management of SCLC and Neuroendocrine Tumors.” The good news, she said, is there are many ongoing international trials comparing PCI to surveillance in both limited stage and extensive stage SCLC.
Current data suggest that low-dose PCI is associated with less neurologic deterioration and better overall survival compared to high-dose PCI. Trials of standard PCI versus hippocampal avoidance PCI produced conflicting results. Results from a recent trial, NRG-CC003, may provide more guidance.
Watch On-Demand: Optimizing the Management of SCLC and Neuroendocrine Tumors
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Recent data comparing first line stereotactic radiosurgery (SRS) versus whole-brain radiotherapy (WBRT) show a survival advantage for SRS as well as improved quality of life and cognition. The data are similar for non-small cell lung cancer (NSCLC) and brain metastases from other body sites.
Patients with ES-SCLC will likely benefit from a combination of immunotherapy plus chemotherapy. The phase III Impower133 study compared atezolizumab plus carboplatin/etoposide versus carboplatin/etoposide alone to show a significant improvement in overall survival (22.0% vs 16.8% at 24 months) and longer time to intracranial progression (20.2 months vs. 10.5 months). Durvalumab has also been approved for first line ES-SCLC in combination with chemotherapy.
Most data on immune checkpoint inhibition (ICI) in managing brain metastases is largely from NSCLC. Concurrent ICI plus SRS is the standard approach for NSCLC, melanoma, and renal cell carcinoma, Dr. Grills said, suggesting potential benefit in SCLC.
Patients with recurrent SCLC have few approved options—topotecan for Stage I-III or lurbinectedin for Stage IV. Lurbinectedin has a conditional approval from the US Food and Drug Administration contingent on future confirmatory trials, but has a more favorable toxicity profile than topotecan.
Better understanding of the biology has the potential to raise the tail of the survival curve for SCLC, said Alvaro Quintanal-Villalonga, PhD, head of thoracic oncology, Memorial Sloan Kettering Cancer Center, New York. Recent findings have identified at least five SCLC subtypes, each with its own molecular characteristics and potential targets.
“We have a number of new strategies and novel targets,” Dr. Quintanal-Villalonga said “Immunotherapy, DNA damage response, epigenetic targets, signaling pathways, and a novel transporter, Exportin1, are all being actively pursued.”
Large-cell neuroendocrine carcinoma (LCNEC) accounts for about 3% of all lung cancers and has two distinctive sets of molecular characteristics. Type I has an NSCLC-like genomic profile and NE-like transcriptional profile. Type II has an SCLC-like genomic and a non-NE-like transcriptional profile, said Andrea Ardizzone, MD, Professor of Medical Oncology, IRCCS University Hospital, University of Bologna, Bologna, Italy.
These distinct characteristics may partially explain why in the clinic we see such different results between patients.
About 25% of LCNECs are stage I-IIIA at diagnosis. About 40% can be cured by surgery, with lobectomy the most effective surgical approach, Dr. Ardizzone continued. Adjuvant chemotherapy can improve 5-year survival and SCLC-like regimens generally have better outcomes versus NSCLC-like regimens. Adjuvant chest RT is generally not helpful.
Chemoradiation is the treatment of choice for locally advanced disease, preferably platinum-etoposide. Early data suggest that PCI may be beneficial.
“Unfortunately, half of LCNEC cases are metastatic at diagnosis,” Dr. Ardizzone said. “SCLC-based regimens usually give better response and survival than NSCLC-based approaches. But not always.”
Mutational studies can help. Patients with RB1 loss of expression mutation have a worse prognosis and do better with an SCLC regimen. Patients with wild type RB1 and intact expression have a better prognosis and do better with NSCLC-based regimens.
“There are suggestions that immunotherapy may help and several ongoing trials,” Dr. Ardizzone added. “When possible, referral of this rare, aggressive, and heterogenous disease to specialized centers for clinical studies is encouraged.”