Overview
SCLC is classified as a high-grade pulmonary neuroendocrine tumor (NET).19,20 It is among the 20% of lung tumors that exhibit neuroendocrine differentiation.19,20
- SCLC accounts for approximately 13% of all lung cancers.21
- Large cell neuroendocrine carcinoma (LCNEC) accounts for 3% of all lung cancers.
The most aggressive form of lung cancer, SCLC has an overall 5-year survival rate of <7%.21
Mechanism of Disease (SCLC)
Normal adult lung epithelium contains several distinct progenitor and stem cell populations.22 High-grade pulmonary neuroendocrine tumors (NETs) are believed to develop from neuroendocrine progenitor cells that have acquired mutations.22
- These most often develop from exposure to carcinogens in cigarette smoke.22
- High-grade NETs are characterized by a rapid doubling time, high growth fraction, and early development of metastases.23,25
SCLC has one of the highest mutation rates compared to other tumor types, per comprehensive sequencing studies.24
- SCLC tumor cells overexpress transcription factors critical for normal primary neuroendocrine cell development.22
- ASCL1, NEUROD1, SOX2, TTF1, Myc family
- Expression of ASCL1 and NEUROD1 are mutually exclusive in SCLC cell lines.22
- PARP1 and EZH2 were the most overexpressed proteins in SCLC in a study comparing significant differences in signaling pathways between SCLC and NSCLC.22
Tumor suppressors TP53 and RB1 (loss of function) and proto-oncogene Myc family members (upregulation) appear mutated in nearly all SCLC tumors.22,25
- Inactivating mutations in NOTCH family genes have been observed in 25% of human SCLC.22,25 Studies have shown DLL3, a NOTCH ligand, may be associated with the neuroendocrine phenotype and contribute to neuroendocrine tumorigenesis.22
- High DLL3 protein expression was found in approximately two-thirds of SCLC patients and was associated with long lasting stable disease.22
- KRAS mutations are rare or non-existent.22
Diagnosis & Staging
TNM system for staging SCLC is used in clinical trials. Veterans Administration Lung Study Group's (VALG) system of limited stage (LS) vs. extensive stage (ES) is most commonly used for clinical decision-making.26,27
- LS-SCLC: disease confined to the ipsilateral hemithorax (can be safely encompassed within a radiation field)
- ES-SCLC: disease spread beyond the ipsilateral hemithorax and cannot be included in a single radiation field
- Approximately two-thirds of patients present with ES-SCLC
- ES-SCLC is an aggressive, rapidly progressing disease with a poor prognosis
Accurate staging is critical to provide important prognostic information and determine appropriate treatment approach.26,27
Treatment Challenges
Overall, the 5-year relative survival for patients with SCLC is only 6.4%.21
Most patients present with ES-SCLC at diagnosis.27,28
- Median survival for ES-SCLC: 8 to 13 months
- Median survival for LS-SCLC: 15 to 20 months
First-line therapeutic options have remained largely unchanged for more than 40 years.27,29
- The 2-year survival rate for ES-SCLC has only improved by 2.2% (from 3.4% to 5.6%) between 1973 and 2002.30
Although SCLC is characterized by a high mutation rate, typically it harbors loss of function mutations or deletions in tumor suppressor genes and is not susceptible to selective targeted inhibition.22,25
Most patients develop chemoresistance and will suffer relapse within months of completing platinum-based chemotherapy.19,29 For patients who relapse <3 months after first-line therapy, treatment options are usually limited to palliative care.30,31
- Median survival for these patients is only 4 to 5 months after treatment.