Case-Based Review

Small-Cell Lung Cancer




The role of immune checkpoint inhibitors in the treatment of SCLC is evolving and currently there are no FDA-approved immunotherapy agents in SCLC. A recently conducted phase I/II trial (CheckMate 032) of anti-PD-1 antibody nivolumab with or without anti-CTLA-1 antibody ipilimumab in patients with relapsed SCLC reported a response rate of 10% with nivolumab 3 mg/kg and 21% with nivolumab 1 mg/kg + ipilimumab 3 mg/kg. The 2-year OS was 26% with the combination and 14% with single agent nivolumab [56,57]. Only 18% of patients had PD-L1 expression of ≥ 1% and the response rate did not correlate with PD-L1 status. The rate of grade 3 or 4 adverse events was approximately 20% and only 10% of patients discontinued treatment because of toxicity. Based on these data, nivolumab plus ipilimumab is now included in the NCCN guidelines as one of the options for patients with SCLC who experience disease relapse within 6 months of receiving platinum-based therapy; however, it is questionable whether routine use of this combination is justified based on currently available data. However the evidence for the combination of nivolumab and ipilimumab remains limited. This efficacy and toxicity data of both randomized and nonrandomized cohorts were presented together making it hard to interpret the results.

Another phase Ib study (KEYNOTE-028) utilizing anti-PD-1 antibody pembrolizumab 10 mg/kg IV every 2 weeks in patients with relapsed SCLC after receiving one or more prior lines of therapy and PD-L1 expression of ≥ 1% showed a response rate of 33% with median duration of response of 19 months and 1-year OS of 38% [58]. Although only 28% of screened patients had PD-L1 expression of ≥ 1% , these results indicated that at least a subset of SCLC patients are able to achieve durable responses with immune checkpoint inhibition. A number of clinical trials utilizing immune checkpoint inhibitors in various combinations and settings are currently underway.

Role of Prophylactic Cranial Irradiation

The role of PCI in extensive-stage SCLC is not clearly defined. A randomized phase III trial conducted by EORTC comparing PCI with no PCI in patients with extensive-stage SCLC who had attained partial or complete response to initial platinum-based chemotherapy showed decrease in the incidence of symptomatic brain metastasis and improvement in 1-year OS with PCI. However, this trial did not require mandatory brain imaging prior to PCI and therefore it is unclear if some patients in the PCI group had asymptomatic brain metastasis prior to enrollment and therefore received therapeutic benefit from brain radiation. Additionally, the dose and fractionation of PCI was not standardized across patient groups. A more recent phase III study conducted in Japan that compared PCI (25Gy in 10 fractions) with no PCI reported no difference in survival between the two groups. As opposed to EORTC study, the Japanese study did require baseline brain imaging to confirm absence of brain metastasis prior to enrollment. In addition, the patients in the control arm underwent periodic brain MRI to allow early detection of brain metastasis [59]. Given the emergence of the new data, the impact of PCI on survival in patients with extensive-stage SCLC is unproven and PCI likely has a role in a highly select small group of patients with extensive-stage SCLC. PCI is not recommended for patients with poor performance status (ECOG PS 3–4) or underlying neurocognitive disorders [33,60]. NMDA receptor antagonist memantine can be used in patients undergoing PCI to delay the occurrence of cognitive dysfunction [61]. Memantine 20 mg daily delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed compared to placebo in patients receiving whole brain radiation [61].

Role of Radiation

A subset of patients with extensive-stage SCLC may benefit from consolidative thoracic radiation after completion of platinum-based chemotherapy. A randomized trial including patients who achieved complete or near complete response after 3 cycles of cisplatin plus etoposide compared thoracic radiation in combination with continued chemotherapy versus chemotherapy alone [62]. The median OS was longer with the addition of thoracic radiation compared to chemotherapy alone. Another phase III trial did not show improvement in 1-year OS with consolidative thoracic radiation, but 2-year OS and 6-month PFS were longer [63]. In general, consolidative thoracic radiation benefits patients who have residual thoracic disease and low-bulk extrathoracic disease that has responded to systemic therapy [64]. In addition, patients who initially presented with bulky symptomatic thoracic disease should also be considered for consolidative radiation.

Similar to other solid tumors, radiation should be utilized for palliative purposes in patients with painful bone metastasis, spine cord compression, or brain metastasis. Surgery is generally not recommended for spinal cord compression given the short life expectancy with extensive stage disease. Whole brain radiotherapy is preferred over SRS because of frequent presence of micrometastasis even in the setting of one or two radiographically evident brain metastasis.

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