Josephine L. Feliciano, MD
Although small cell lung cancer (SCLC) accounts for 15% of the overall population of lung cancer, the majority of these patients will die of their disease, according to Josephine L. Feliciano, MD.
"SCLC is a very aggressive neuroendocrine tumor (NET) with high proliferation index, high Ki-67, and early metastatic behavior—so it is rarely a surgical disease," said Feliciano. "It is very responsive to chemotherapy and radiotherapy, but unfortunately the majority—if not all—will recur after initial response."
This histology is strongly correlated with cigarette smoking, and is rarely seen in nonsmokers. However, Feliciano explained that it is important to remember that patients with EGFR
-positive non–small cell lung cancer (NSCLC) or genomic variants can transition histologies. These patients should be rebiopsied to look for a change in histology. Extrapulmonary small cell carcinoma is treated along a similar paradigm to SCLC.
In a presentation during the 2018 OncLive®
State of the Science Summit™ on Advanced Non–Small Cell Lung Cancer, Feliciano, an assistant professor of Oncology at Johns Hopkins Medicine, discussed the role of immunotherapy and the potential of targeted agents in SCLC.
SCLC is defined as a malignant epithelial tumor consisting of small cells with scant cytoplasm, ill-defined borders, finely granular nuclear chromatin, and inconspicuous nucleoli. World Health Organization (WHO) criteria states that these cells are small in size, have a high mitotic rate, and often have extensive necrosis.
Diagnostically, tissue is very important. Tissue can be taken by either a transthoracic or bronchoscopic biopsy of the metastatic site. Necrosis or crush artifact can be found in these tumors, so it is sometimes a challenge to immediately determine whether it is SCLC, Feliciano explained.
"In general, what we are looking for is the Ki-67, mitotic rate, and certain markers, such as chromogranin and synaptophysin, which can help us with the diagnosis," she said.
Patients with SCLC are categorized as either having limited- or extensive-stage disease. Limited-stage disease can be safely treated with definitive radiation therapy in the first-line setting, while the volume of extensive-stage disease is often too large to be encompassed in a tolerable radiotherapy plan.
The standard of care for patients with limited-stage disease is concurrent chemoradiotherapy with platinum-based therapy and etoposide. In patients who have responsive disease, prophylactic cranial irradiation is often associated with improved mortality. The median overall response rate (ORR) for these patients is anywhere from 70% to 90%, but more than 75% of these patients will recur.
The first-line standard therapy for extensive-stage disease, also categorized as distant metastatic disease, is platinum-based therapy and etoposide. These patients can respond quickly and drastically, Feliciano said, but nearly all will recur. The median overall survival (OS) in chemotherapy-treated patients with extensive-stage disease is 8 to 10 months.
Up until August 2018, topotecan was the sole FDA-approved option for patients with chemotherapy-sensitive disease who relapsed after first-line therapy. The FDA approved single-agent nivolumab (Opdivo) for the treatment of patients with SCLC with disease progression following platinum-based chemotherapy and 1 other line of therapy, based on data from the phase I/II CheckMate-032 trial.
There are currently no FDA-approved regimens for patients who are refractory to chemotherapy, but off-label options include temozolomide, taxanes, irinotecan, gemcitabine, and bendamustine.
"Sadly, there has not been much movement forward with efficacy for SCLC in decades, said Feliciano. “There are tens of thousands of patients who have been enrolled in studies, and there really has not been much change in improvement in survival.”
Investigators are interested in utilizing checkpoint inhibitors for SCLC. Feliciano explained that SCLC is associated with paraneoplastic syndromes, and it appears that patients with autoimmune paraneoplastic syndromes may experience improved outcomes and better survival with immunotherapy. Additionally, since SCLC tends to be most associated with smoking, these patients might have higher tumor mutational burden (TMB).
The 2 main types of checkpoint inhibitors that have been evaluated in SCLC are CTLA-4 inhibitors, such as ipilimumab (Yervoy) and tremelimumab, and anti–PD-1 agents, such as nivolumab and pembrolizumab (Keytruda).
"The management of SCLC has not changed significantly in the past decades, but because checkpoint inhibitors have been reported to have some durable responses, there are ongoing studies,” she added. “An immune therapy has been approved, and a combination has made it onto NCCN guidelines.”