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Research insights: Managing neurologic events in ES-SCLC

MDlinx Apr 02, 2024

Metastases remain a concern following extensive-stage small-cell lung cancer (ES-SCLC) diagnosis, resulting in a 5-year overall survival rate of just 6.7%. ES-SCLC has a predilection for CNS in particular, note the authors of a study reported in Thoracic Cancer.

Shi X, Wang P, Li Y, et al. Using MRI radiomics to predict the efficacy of immunotherapy for brain metastasis in patients with small cell lung cancer. Thorac Cancer. 2024;15(9):738–748.

At diagnosis, 10% of patients have brain metastases, and 40%–60% eventually develop it. 


Emerging research provides a glimpse into the latest guidance and insights on treating brain metastases and other neurological events in ES-SCLC.



Brain metastases


According to the results of the IMpower133 trial, the presence of brain metastases was correlated with a lack of benefit from atezolizumab. Instead, other immune checkpoint inhibitors (ICIs) plus other agents may be more effective.

Authors of evidence-based guidelines for SCLC published in the Journal of Clinical Oncology expressed their views on the implications of their findings.

Khurshid H, Ismaila N, Bian J, et al. Systemic therapy for small-cell lung cancer: ASCO-Ontario Health (Cancer Care Ontario) Guideline. J Clin Oncol. 2023;41(35):5448–5472.


“While empiric chemotherapy and radiotherapy have had a major impact on the survival of patients with SCLC,” they wrote, “it is doubtful that these modalities will provide further significant improvements in outcomes." ICIs have provided new treatment alternatives and hope for SCLC patients for the first time in 30 years, but the number of patients benefitting from the treatment remains limited. "Recently, advances in our knowledge of SCLC biology, molecular subtypes, and therapeutic vulnerabilities have created a buzz in the field for the first time in several decades," the authors noted.


Ongoing efforts to translate these findings to the clinic will hopefully launch a golden age of SCLC research and improvements in survival.

Research into the use of nivolumab plus temozolomide, which is an oral cytotoxic agent with blood-brain barrier penetrance, might prove fruitful in combating brain metastases. Combinations of ICIs with CHK1 and PARP inhibitors have proven promising in preclinical models of SCLC, but trials of ICIs plus PARP inhibition in SCLC have fallen short (although hinting at potential biomarkers for enhanced patient selection).


Patient selection is an issue with testing the efficacy of agents vs brain metastases in SCLC. Clinical trials often involve only patients with good performance status.

Expanding clinical trials to include patients with marginal performance status (ie, ECOG PS 2) could help investigators further elucidate the risk-benefit ratio for ICIs and other novel therapies and improve outcomes for patients. In addition, for many trials, the presence of brain metastases—or at least uncontrolled brain metastases—is a criterion for exclusion, but this may be changing.

Most recently, investigators have been exploring the use of a radiomics nomogram model to predict the intracranial efficacy of ICIs in SCLC patients with brain metastases to better gauge personalized approaches to treatment. This research was reported in Thoracic Cancer. The current radiomic nomogram combines related radiomic features and clinical factors to predict intracranial efficacy. The approach was validated using MRI for intracranial efficacy prediction of ICIs in SCLC patients with brain metastases.

The authors summed up their work: “In conclusion, we developed and validated a radiomics nomogram prediction model for predicting the intracranial efficacy of ICIs in SCLC patients with [brain metastases]. This study can help tailor patient treatment schedules, improve clinical decision-making, and offer extensive potential  applications. A larger cohort of patients is still necessary for subsequent studies.”


Lambert-Eaton myasthenic syndrome


Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic neurologic syndrome (PNS). It is a neuromuscular disorder of autoimmune origin that involves proximal muscle weakness, decreased/absent tendon reflexes, and autonomic dysfunction.

As the authors of a case report published in Cureus explain, 47%–62% of LEMS patients have comorbid cancer, with SCLC most prevalent.

Yamazoe M, Hatakeyama T, Furukawa K, et al. Atezolizumab-induced Lambert-Eaton myasthenic syndrome in a patient with small-cell lung cancer. Cureus. 2023;15(1):e33557.

One hypothesis is that LEMS results from antibodies vs voltage-gated calcium channels (VGCCs) present on the presynaptic nerve terminal, thus decreasing acetylcholine release from the presynaptic membrane.


Although adding atezolizumab or durvalumab to chemotherapy in the first-line treatment of ES-SCLC has substantially improved OS than with chemo alone, ICIs can lead to various immune-related adverse events (irAEs), including neuromuscular disorders. Nevertheless, LEMS as a neurological irAE is uncommon.

“Without a validated diagnostic test, it is difficult to determine whether LEMS in SCLC patients on atezolizumab treatment is caused by a PNS of SCLC or an irAE induced by atezolizumab,” write the case report authors. 

LEMS as a PNS of SCLC is treated using chemotherapy, radiotherapy, or surgery. Symptomatic treatment includes 3,4-aminopyridine (DAP) or cholinesterase inhibitors.

If these agents fail, steroid and immunosuppressant therapies may offer benefit. When steroids and immunosuppressants fail, LEMS can be targeted with IVIg or plasmapheresis, with rituximab used in refractory cases.

“In general, the treatment for ICI-induced neurological irAEs depends on the severity of the symptoms. For all mild neurological symptoms attributed to ICIs, ICI therapy should be discontinued, and steroid therapy should be instituted. IVIg or plasmapheresis should be considered in cases of lack of response to steroid therapy,” note the authors.



Leptomeningeal lung cancer metastases


Although rare, leptomeningeal lung cancer metastases (LLM) present in about 10% of SCLC patients with solid tumors.

Nguyen A, Nguyen A, Dada OT, et al. Leptomeningeal metastasis: a review of the pathophysiology, diagnostic methodology, and therapeutic landscape. Curr Oncol. 2023;30(6):5906–5931.


Symptom alleviation and palliation due to the poor prognosis of LLM is a focus of treatment. Radiotherapy is a standard approach to LLM management. Craniospinal irradiation has recently been employed and augmented by modern-day techniques. For instance, proton beam therapy exhibits a decreased risk of iatrogenic toxicity. Standard of care is systemic chemotherapy plus intrathecal chemotherapy for non-nodular types of leptomeningeal metastases.


In particular, intrathecal strategies may someday prove useful in treating LLM.

Authors of a review in Neurotherapeutics recognize that further work is needed, but they state that retrospective studies, post hoc analyses, and small prospective trials during the last 20 years “provide a glimmer of hope for patients with leptomeningeal metastases, suggesting that several cancer-directed strategies are not only active in the intrathecal space but also improve survival against historical odds.”

Wilcox JA, Li MJ, Boire AA. Leptomeningeal metastases: new opportunities in the modern era. Neurotherapeutics. 2022;19(6):1782–1798.


“Discordant drug responses between the brain and leptomeningeal compartments should trigger further investigation, including dedicated clinical protocols designed for LM, pharmacokinetic monitoring to ensure adequate CSF penetration, and biomarker analysis for potential pathways of therapeutic resistance. Further characterizations of the leptomeningeal immune microenvironment and the molecular mechanisms that underlie LM progression have the potential to uncover novel treatments for this underserved patient population,” the authors added.

What this means for you

Various neurological adverse events result from SCLC or the treatment associated with the condition. Emerging research examines the use of ICIs to treat brain metastases and intrathecal strategies to treat LLM.


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