Lung Cancer Health Center

Standard Treatment Options for Recurrent NSCLC

Standard treatment options for recurrent NSCLC include the following:

1. Radiation therapy (for palliation).[1]
2. Chemotherapy alone, including the following for patients who have previously received platinum chemotherapy:
   1. Docetaxel.[2,3]
   2. Pemetrexed.[3]
   3. Erlotinib after failure of both platinum-based and docetaxel chemotherapies.[4]
   4. Gefitinib.[5]
3. Surgical resection of isolated cerebral metastasis (for highly selected patients).[6]
4. Laser therapy or interstitial radiation therapy (for endobronchial lesions).[7]
5. Stereotactic radiation surgery (for highly selected patients).[8,9]

Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[10][Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.[11,12] Informed patients with good performance status (PS) and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered.

Evidence:

1. Two prospective randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;[2,13] however, criteria for the selection of appropriate patients for second-line treatment are not well defined.[14]
2. A meta-analysis of five trials of 865 patients assessing the efficacy and safety of docetaxel administered weekly or every 3 weeks has been reported.[15] In that analysis the following was shown:
   1. Median survival was 27.4 weeks for patients treated every 3 weeks and 26.1 weeks for patients treated weekly (P = .24, log-rank test).
   2. Significantly less severe neutropenia and febrile neutropenia were reported with weekly docetaxel (P < .001 for both), whereas no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxic effects.
3. A randomized phase III trial of 571 patients designed to demonstrate the noninferiority of pemetrexed compared with docetaxel showed no difference in response rates, progression-free survival (PFS), or overall survival (OS).[3][Level of evidence: 1iiA] Of note, patients with squamous histology benefited from docetaxel and those with nonsquamous histologies appeared to benefit more from pemetrexed.[16]
4. A report of a randomized placebo-controlled trial indicated that erlotinib prolongs survival and time to deterioration in symptoms in NSCLC patients after first-line or second-line chemotherapy compared with placebo.[17,18] In this trial of 731 patients, 49% had received two prior chemotherapy regimens, and 93% had received platinum-based chemotherapy.
   1. OS was 6.7 months among those who had received two prior chemotherapy regimens and 4.7 months among those who had received platinum-based chemotherapy. The hazard ratio (HR) was 0.70 (P < .001), in favor of erlotinib.[17][Level of evidence: 1iiA]
5. Other studies have evaluated the use of erlotinib in combination with other agents.[19,20] These studies reported the following:
   1. When used in combination with carboplatin and paclitaxel[19] or cisplatin and gemcitabine,[20] erlotinib was not found to improve response rates, disease-free survival (DFS), or OS in previously untreated patients with advanced or metastatic NSCLC.[19,20][Level of evidence: 1iiA]
6. A randomized phase III trial evaluating gefitinib versus placebo in 1,692 previously treated NSCLC patients showed the following:
   1. Gefitinib does not improve OS.
   2. Median survival did not differ significantly between the groups in the overall population (5.6 mo for gefitinib and 5.1 mo for placebo; HR = 0.89; 95% confidence interval [CI], 0.77-1.02; P = .087) or among the 812 patients with adenocarcinoma (6.3 mo vs. 5.4 mo; HR = 0.84; CI, 0.68-1.03; P = .089).
   3. Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than in the placebo group for never-smokers (n = 375; 95% CI, 0.67 [0.49-0.92]; P = .012; median survival 8.9 mo vs. 6.1 mo) and for patients of Asian origin (n = 342; 95% CI, 0.66 [0.48-0.91]; P = .01; median survival 9.5 mo vs. 5.5 mo).[21][Level of evidence: 1iiA]
7. In two randomized trials comparing the addition of gefitinib with standard platinum combination chemotherapy, no improvement in response rates, PFS, or OS was shown.[22,23][Level of evidence: 1iiA]
8. In a large randomized trial, gefitinib was compared with docetaxel in patients with locally advanced or metastatic NSCLC who had been pretreated with platinum-based chemotherapy.[5] The primary objective was to compare OS between the groups with coprimary analyses to assess noninferiority in the overall population and superiority in patients with high epidermal growth factor receptor (EGFR) gene copy number in the intention-to-treat population. The 1,466 patients were randomly assigned to receive gefitinib (250 mg per day orally; n = 733) or docetaxel (75 mg/m² intravenously every 3 weeks; n = 733).
   1. Noninferiority of gefitinib compared with docetaxel was confirmed for OS (HR = 1.020; 95% CI, 0.905-1.150). However, superiority of gefitinib in patients with high EGFR gene copy number (85 patients vs. 89 patients) was not proven (HR = 1.09; 95% CI, 0.78-1.51; P = 0.62).
   2. In the gefitinib group, the most common adverse events were rash or acne (49% vs. 10%) and diarrhea (35% vs. 25%). In the docetaxel group, neutropenia (5% vs. 74%), asthenia (25% vs. 47%), and alopecia (3% vs. 36%) were most common.
   3. This INTEREST trial established noninferior survival of patients treated with gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced NSCLC.