Case-Based Review

Small Cell Lung Cancer

2018 September/October;13(5):5-17

References

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ROLE OF RADIOTHERAPY

A subset of patients with extensive-stage SCLC may benefit from consolidative thoracic radiotherapy after completion of platinum-based chemotherapy. A randomized trial that enrolled patients who achieved complete or near complete response after 3 cycles of cisplatin plus etoposide compared thoracic radiotherapy in combination with continued chemotherapy versus chemotherapy alone.⁸⁵ The median OS was longer with the addition of thoracic radiotherapy compared to chemotherapy alone. Another phase 3 trial did not show improvement in 1-year OS with consolidative thoracic radiotherapy, but 2-year OS and 6-month PFS were longer.⁸⁶ In general, consolidative thoracic radiotherapy benefits patients who have residual thoracic disease and low-bulk extrathoracic disease that has responded to systemic therapy.⁸⁷ In addition, patients who initially presented with bulky symptomatic thoracic disease should also be considered for consolidative radiation.

Similar to other solid tumors, radiotherapy should be utilized for palliative purposes in patients with painful bone metastasis, spinal cord compression, or brain metastasis. Surgery is generally not recommended for spinal cord compression given the short life expectancy of patients with extensive-stage disease. Whole brain radiotherapy is preferred over stereotactic radiosurgery because micrometastasis is frequently present even in the setting of 1 or 2 radiographically evident brain metastasis.

NOVEL THERAPIES

The very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and high recurrence rate; however, at the same time this complexity can form the basis for effective targeted therapy for the disease. One of the major factors hindering the development of targeted therapies in SCLC is limited availability of tissue due to small tissue samples and the frequent presence of significant necrosis in the samples. In recent years, several different therapeutic strategies and targeted agents have been investigated for their potential role in SCLC. Several of them, including EGFR tyrosine kinase inhibitors (TKIs), BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors, have not been shown to provide a survival advantage in this disease. Several others, including PARP inhibitors, cellular developmental pathway inhibitors, and antibody-drug conjugates, are being tested. A phase 1 study of veliparib combined with cisplatin and etoposide in patients with previously untreated extensive-stage SCLC demonstrated a complete response in 14.3%, a partial response in 57.1%, and stable disease in 28.6% of patients with an acceptable safety profile.⁸⁸ So far, none of these agents are approved for use in SCLC, and the majority are in early- phase clinical trials.⁸⁹

One of the emerging targets in the treatment of SCLC is delta-like protein 3 (DLL3). DLL3 is expressed on more than 80% of SCLC tumor cells and cancer stem cells. Rovalpituzumab tesirine is an antibody-drug conjugate consisting of humanized anti-DLL3 monoclonal antibody linked to SC-DR002, a DNA-crosslinking agent. A phase 1 trial of rovalpituzumab in patients with relapsed SCLC after 1 or 2 prior lines of therapy reported a response rate of 31% in patients with DLL3 expression of ≥ 50%. The median duration of response and median PFS were both 4.6 months.⁹⁰ Rovalpituzumab is currently in later phases of clinical trials and has a potential to serve as an option for patients with extensive-stage disease after disease progression on platinum-based therapy.

SUMMARY

Four to 6 cycles of carboplatin and etoposide remain the standard of care first-line treatment for patients with extensive stage SCLC. The only FDA-approved second-line treatment option is topotecan. Re-treatment with the original platinum doublet is a reasonable option for patients who have disease progression 6 months or longer after completion of platinum-based therapy. The immune checkpoint inhibitors pembrolizumab and combination nivolumab and ipilimumab have shown promising results in the second-line setting and beyond. The role of PCI has become more controversial in recent years, and periodic brain MRI in lieu of PCI is now an acceptable approach.