Immunotherapy in Extensive-Stage Small Cell Lung Cancer

Small cell lung cancer (SCLC) remains a poorly understood disease with aggressive features, high relapse rates, and significant morbidity as well as mortality, yet persistently limited treatment options. For three decades, the treatment algorithm of SCLC has been stagnant despite multiple attempts to find alternative therapeutic options that could improve responses and increase survival rates. On the other hand, immunotherapy has been a thriving concept that revolutionized treatment options in multiple malignancies, rendering previously untreatable diseases potentially curable. In extensive stage SCLC, immunotherapy significantly altered the course of disease and is now part of the treatment algorithm in the first-line setting. Nevertheless, the important questions that arise are how best to implement immunotherapy, who would benefit the most, and finally, how to enhance responses.     

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer

IntruductionRadiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ESCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiotherapy (TRT) after induction chemotherapy for SCLC.MethodsPatients with ESCLC who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity in the 35 days following initiation of treatment.ResultsThirty-eight patients with ESCLC (median age 65 years, range: 37–79 years) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100 to 200 mg with no dose-limiting toxicity in the 35-day window. There were no grade 4-5 toxicities; 2 (6%) patients experienced grade 3 events (n = 1 rash, n = 1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range: 1–13 months); median progression-free and overall survival times were 6.1 months (95% confidence interval: 4.1–8.1) and 8.4 months (95% confidence interval: 6.7-10.1).ConclusionsConcurrent pembrolizumab-TRT was tolerated well with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g., enrolling progressors on induction chemotherapy). Although randomized studies have shown benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.     

Phase II Study of Maintenance Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer (SCLC)

Objective

The aim of this study was to assess the efficacy of maintenance pembrolizumab in patients with extensive-stage SCLC after treatment with platinum and etoposide.

Surgery for Small Cell Lung Cancer

Retrospective analyses have shown that, following surgical resection, patients with early-stage small cell lung cancer have a survival rate comparable to that seen with non-small cell lung cancer, especially if combined modality therapy is used. Surgery has been employed in three specific instances: primary surgery followed by postoperative chemotherapy and, when indicated, mediastinal irradiation for tumors presenting as peripheral nodules; multimodality therapy including induction chemotherapy followed by surgery; and radiotherapy in "resectable," very limited disease and "salvage surgery" for patients with limited disease previously treated, recurring at the primary site. The results of such surgery in very selected patients yields the best reported results in the treatment of small cell lung cancer. These approaches are worthy of further study.     

Real-World Treatment Patterns,Clinical Outcomes,and Health Care Resource Utilization in Extensive-Stage Small Cell Lung Cancer in Canada

The prognosis for extensive-stage small cell lung cancer (ES-SCLC) is poor. Real-world evidence can highlight the unmet clinical need within this population. We conducted a population-based cohort study of ES-SCLC patients diagnosed in a large Canadian province (2010–2018) using electronic medical records and administrative claims data. In all, 1941 ES-SCLC patients were included, of which 476 (25%) were recurrent cases. Median age at diagnosis was 70 years (range: 39–94) and 50.2% were men. Of the 1941 ES-SCLC patients, 29.5% received chemotherapy and radiotherapy, 17.0% chemotherapy alone, 8.7% radiotherapy alone, and 44.8% received best supportive care. Chemotherapy was initiated by 46.5%, 8.5%, and 1.4% of first-, second-, and third-line patients, with lower uptake for recurrent cases. Median survival from first-, second-, and third-line chemotherapy was 7.82 months (95% CI: 7.50–8.22), 5.72 months (95% CI: 4.90–6.87), and 3.83 months (95% CI: 2.99–4.60). Among patients who received first-line therapy, the 2-year and 5-year survival was 7.3% (95% CI: 5.7–9.2) and 2.9% (95% CI: 1.8–4.5). In conclusion, initiation of first-line treatment in ES-SCLC was low with significant attrition in subsequent lines. These results underscore the need for effective front-line treatments and highlight the potential for novel therapies to improve patient outcomes.     

小细胞肺癌与TNM分期

小细胞肺癌的临床侵袭性强，易于转移，因而长期以来认为手术疗效较差，治疗方法主要是放化疗，因此分期手段也以美国退伍军人肺癌协会的局限期和广泛期为主。随着肺癌分期手段的进步，分期的准确性进一步提高。大量回顾性的资料表明，早期小细胞肺癌的手术疗效不亚于非小细胞肺癌。而对拟手术的小细胞肺癌的分期也应采用现代更精确的TNM分期。     

Systemic Treatment of Small Cell Lung Cancer

Small cell lung cancer (SCLC) accounts for 20–25% of all lung cancer and is characterized by an aggressive clinical course with early dissemination and extremely high risk of recurrence. Chemotherapy has been the cornerstone of treatment, with high response rates including complete responses. Despite the sensitivity of this disease to cytotoxic drugs, the majority of patients will face recurrence and die of the disease within two years. For more than thirty years, investigators have conducted numerous trials using different drug regimens and schedules, as well as different therapeutic modalities. The combination of cyclophosphamide, doxorubicin (adriamycin) and vincristine (CAV) was one of the first widely accepted regimens for the treatment of SCLC. Later, CAV and its hybrids were replaced by the similarly effective but less toxic regimen of cisplatin and etoposide (PE). Clinical investigators have tried different approaches to improve the efficacy of these regimens, such as alternating CAV/PE; consolidation and maintenance therapy; intensive treatment with high-dose chemotherapy; increased frequency of drug administration; or high dose therapy with stem cell support — all with no definitive successes, leaving PE as the standard treatment for patients with SCLC. The recent arrival of new chemotherapy agents such as topotecan, irinotecan, and taxanes may represent a step forward in the treatment of this disease. The most promising regimen is the combination of irinotecan and cisplatin which, according to Japanese investigators, achieves a significantly better survival than standard PE. If validated by confirmatory trials, this combination could well become the new standard treatment for extensive chemotherapy-naïve SCLC. Biological agents are also being widely investigated, including vaccines, matrix metalloproteinase inhibitors, anti-sense therapy, and monoclonal antibodies. Advances in molecular biology will hopefully contribute to progress in the treatment of this lethal disease.     

Prognostic Factors in Small Cell Lung Cancer

Extent of disease and clinical performance status have been used traditionally for prognostic stratification of patients with small cell lung cancer. A plethora of other prognostic attributes reflecting host factors, tumor factors, and serological and hematological parameters have been described over the last decade. Attempts to assess the contribution of the latter attributes to prognostication in small cell lung cancer have lead to the formation of multivariate prognostic models. These models invariably describe prognostic groupings that are not identified by the conventional two-stage classification currently in use. Consensus for application of a new prognostic classification is evolving with analysis of prognostic data from diverse clinical centers.