Forty percent of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage IV disease. Treatment goals are to prolong survival and control disease-related symptoms. Treatment options include cytotoxic chemotherapy and targeted agents. Factors influencing treatment selection include comorbidity, performance status (PS), histology, and molecular genetic features of the cancer. Radiation therapy and surgery are generally used in selective cases for symptom palliation.
At the time of recurrence, many SCLC patients are potential candidates for further therapy.
Although second-line chemotherapy has been shown to produce tumor regression, responses are usually short lived; the median survival is rarely more than 12 months and usually less than 6 months after second-line therapy. Response to first-line chemotherapy predicts for subsequent response to second-line therapy.
As in other chemosensitive tumors (e.g., Hodgkin lymphoma and ovarian epithelial cancer), two main categories of patients receiving second-line chemotherapy have been described: sensitive and resistant. Sensitive patients have a first-line response that lasted more than 90 days after treatment was completed. These patients have the greatest benefit from second-line chemotherapy. Patients with sensitive disease respond to the same initial regimen in approximately 50% of cases; however, cumulative toxic effects may ensue. Resistant patients either did not respond to first-line chemotherapy or responded initially but relapsed within 90 days of completion of their primary therapy. Results from phase II studies of drugs such as topotecan, irinotecan, and gemcitabine indicate that response rates to agents vary depending on whether patients have sensitive, resistant, or refractory disease.[4,5,6,7,8][Level of evidence: 3iiiDii]
Topotecan is standard chemotherapy for recurrent SCLC. Patients with sensitive disease may achieve response to a number of agents including topotecan, irinotecan, taxanes, vinorelbine, paclitaxel, or gemcitabine.[4,5,6,7,8,9,10,11][Level of evidence: 3iiiDii] Response rates to combination agents are generally higher than those reported for single agents;[12,13] however, many studies do not report the patients with sensitive, resistant, or refractory disease.
A randomized comparison of second-line treatment with either cyclophosphamide, doxorubicin, and vincristine (CAV) or topotecan in patients with sensitive disease reported no significant difference in response rates or survival, but palliation of common lung cancer symptoms was better with topotecan.[Level of evidence: 1iiC]
A phase III trial comparing chemotherapy with best supportive care (BSC) in relapsed SCLC patients demonstrated that the addition of oral topotecan to BSC significantly increased overall survival and resulted in better symptom control compared with BSC alone.[Level of evidence: 1iiA] The study enrolled 141 patients with chemosensitive or chemoresistant relapsed SCLC who were unsuitable for further standard intravenous chemotherapy. The median survival times for patients receiving topotecan plus BSC were 25.9 weeks versus 13.9 weeks for BSC alone (P = .01).
A randomized, phase III trial (CWRU-SKF-1598) of 304 patients assessed the use of oral topotecan (2.3 mg/m2 /day for 5 days every 21 days) or intravenous topotecan (1.5 mg/m2 /day for 5 days every 21 days). Confirmed response rates were 18.3% and 21.9%, respectively.[Level of evidence: 1iiDii] Secondary endpoints of median survival and 1-year survival rates were also similar (33 weeks vs. 35 weeks and 33% vs. 29%, respectively). Patients receiving oral topotecan experienced less grade 4 neutropenia (47% vs. 64.2%) but more diarrhea of all grades (35.9% vs. 19.9%) than with intravenous topotecan. Quality-of-life (QOL) analysis (using a nonvalidated QOL questionnaire) demonstrated no significant difference between the two arms.