Treatment of refractory and relapsed small cell lung cancer
- Karen Kelly, MD
Karen Kelly, MD
- Professor of Medicine
- University of California Davis Cancer Center
Small cell lung cancer (SCLC) represents 15 percent of all lung cancers and occurs almost exclusively in smokers. It is distinguished from non-small cell lung cancer by its rapid doubling time, high growth fraction, and the early development of widespread metastases. Although considered highly responsive to chemotherapy and radiotherapy, SCLC usually recurs within 14 to 15 months for patients with limited-stage SCLC and five to six months for patients with extensive-stage SCLC. Many of these patients are candidates for additional systemic treatment.
The median survival of patients with relapsed SCLC ranges from two to six months. The most important factors affecting prognosis are performance status, tumor extent (ie, limited versus extensive), and time to relapse after first-line therapy . Similarly, the likelihood of an objective response to second-line therapy depends upon the time from last therapy to relapse, the response to initial treatment, and the performance status.
The treatment of relapsed and refractory SCLC will be reviewed here. The initial management of SCLC and experimental approaches to treatment are considered separately. (See "Extensive stage small cell lung cancer: Initial management" and "Limited stage small cell lung cancer: Initial management" and "Experimental approaches to treatment for small cell lung cancer".)
GOALS AND EFFICACY OF CHEMOTHERAPY
Second-line chemotherapy generally is less effective than the initial treatment, but it can provide significant palliation for many patients. Symptom control and improved quality of life are the primary goals of treatment, and these must be clear to both patients and their families. While chemotherapy has been associated with improved quality of life outcomes , prolonged survival, increased time to tumor progression, and a reduction in tumor burden may also be achieved in some patients.
Single-agent chemotherapy generally is preferred because combination chemotherapy is associated with greater toxicity without an efficacy benefit . An exception to this approach is the use of the initial platinum-based combination chemotherapy for patients with a late relapse (>6 months). (See 'Sensitive disease (relapse after 90 days)' below.)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Albain KS, Crowley JJ, Livingston RB. Long-term survival and toxicity in small cell lung cancer. Expanded Southwest Oncology Group experience. Chest 1991; 99:1425.
- O'Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 2006; 24:5441.
- Nair BS, Bhanderi V, Jafri SH. Current and emerging pharmacotherapies for the treatment of relapsed small cell lung cancer. Clin Med Insights Oncol 2011; 5:223.
- Ciuleanu T, Samarzjia M, Demidchik Y, et AL. Randomized phase III study (SPEAR) of picoplatin plus best supportive care (BSC) or BSC alone in patients (pts) with SCLC refractory or progressive within 6 months after first-line platinum-based chemotherapy. J Clin Oncol 2010; 28:515s.
- NCCN guidelines v1.2016 https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf (Accessed on June 21, 2016).
- von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999; 17:658.
- von Pawel J, Gatzemeier U, Pujol JL, et al. Phase ii comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol 2001; 19:1743.
- Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol 2007; 25:2086.
- Garst J, Buller R, Lane S, Crawford J. Topotecan in the treatment of elderly patients with relapsed small-cell lung cancer. Clin Lung Cancer 2005; 7:190.
- Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 1992; 10:1225.
- LeChevalier T, Ibrahim N, Chomy P, et al. A phase II study of irinotecan in patients with small cell lung cancer progressing after initial response to first line chemotherapy (abstract). Proc Am Soc Clin Oncol 1997; 16:450a.
- DeVore R, Blanke C, Denham C, et al. Phase II study of irinotecan in patients with previously treated small cell lung cancer (abstract). Proc Am Soc Clin Oncol 1998; 17:451a.
- Sehouli J, Stengel D, Harter P, et al. Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer: a randomized multicenter phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J Clin Oncol 2011; 29:242.
- Allen JW, Moon J, Redman M, et al. Southwest Oncology Group S0802: a randomized, phase II trial of weekly topotecan with and without ziv-aflibercept in patients with platinum-treated small-cell lung cancer. J Clin Oncol 2014; 32:2463.
- Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer. Br J Cancer 1998; 77:347.
- Yamamoto N, Tsurutani J, Yoshimura N, et al. Phase II study of weekly paclitaxel for relapsed and refractory small cell lung cancer. Anticancer Res 2006; 26:777.
- Masters GA, Declerck L, Blanke C, et al. Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597. J Clin Oncol 2003; 21:1550.
- Hoang T, Kim K, Jaslowski A, et al. Phase II study of second-line gemcitabine in sensitive or refractory small cell lung cancer. Lung Cancer 2003; 42:97.
- Pietanza MC, Kadota K, Huberman K, et al. Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker. Clin Cancer Res 2012; 18:1138.
- Furuse K, Kubota K, Kawahara M, et al. Phase II study of vinorelbine in heavily previously treated small cell lung cancer. Japan Lung Cancer Vinorelbine Study Group. Oncology 1996; 53:169.
- Jotte R, Von Pawel J, Spigel DR, et al. Randomized phase III trial of amrubicin versus topotecan (Topo) as second-line treatment for small cell lung cancer (SCLC) (abstract #7000). J Clin Oncol 2011.
- Garassino MC, Torri V, Michetti G, et al. Outcomes of small-cell lung cancer patients treated with second-line chemotherapy: a multi-institutional retrospective analysis. Lung Cancer 2011; 72:378.
- Goto K, Ohe Y, Shibata T, et al. Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2016; 17:1147.
- Spigel DR, Socinski MA. Rationale for chemotherapy, immunotherapy, and checkpoint blockade in SCLC: beyond traditional treatment approaches. J Thorac Oncol 2013; 8:587.
- Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016; 17:883.
- Ott PA, Elez E, Hiret S, et al. Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. J Clin Oncol 2017; 35:3823.
- Reck M, Luft A, Szczesna A, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol 2016.
- Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol 2013; 24:75.
- GOALS AND EFFICACY OF CHEMOTHERAPY
- REGIMEN SELECTION BY LENGTH OF RELAPSE-FREE SURVIVAL
- Refractory disease (no response)
- Resistant disease (relapse within 90 days)
- Sensitive disease (relapse after 90 days)
- Efficacy of therapies
- - Topotecan and irinotecan
- - Other agents
- Treatment duration and further lines of therapy
- SPECIAL CONSIDERATIONS
- Late relapses (after six months)
- Poor performance status
- Brain metastases
- INVESTIGATIONAL APPROACHES
- - Checkpoint inhibition
- Anti-PD-1 antibodies
- Other experimental options
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS