Use of gemcitabine in non-small-cell lung cancer

Question: What is the role of gemcitabine (Gemzar®), alone or in combination, in the treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC)? Perspectives: Evidence was selected and reviewed by one member of the Lung Cancer Disease Site Group (Lung DSG) of the Cancer Care Ontario Practice Guidelines Initiative (CCOPGI) and by methodologists. The present practice guideline report has been reviewed and approved by the Lung DSG, which comprises medical and radiation oncologists, surgeons, a medical sociologist, and two community representatives. External review by Ontario practitioners was obtained through a mailed survey. Final approval of the practice guideline report was obtained from the Practice Guidelines Coordinating Committee. The Cancer Care Ontario Practice Guidelines Initiative has a formal standardised process to ensure the currency of each guideline report. The process consists of periodic review and evaluation of the scientific literature and, where appropriate, integration of that literature with the original guideline information. Methodology: A systematic search of the MEDLINE (1966 through June 2002), CANCERLIT (1975 through June 2002), and Cochrane Library (Issue 2, 2002) databases, and of abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology (1998 through 2001) was undertaken, seeking evidence relevant to the present practice guideline report. Randomised clinical trials of gemcitabine as first-line chemotherapy, alone or in combination with other chemotherapy agents, compared with best supportive care (BSC) or another chemotherapy regimen, and randomised or phase II trials of gemcitabine alone or in combination as second-line chemotherapy were eligible for inclusion in the present report. Results: Literature Search Results: The DSG located 30 randomised clinical trials (14 reported in abstract form) involving gemcitabine alone or in combination with other chemotherapy agents as first-line chemotherapy for locally advanced or metastatic NSCLC. Among the randomised trials, 4 compared singleagent gemcitabine with BSC or another chemotherapy regimen; 13 compared a gemcitabine/platinum combination with another chemotherapy regimen; 2 compared different doses or schedules of cisplatin combined with gemcitabine; 7 involved triplet regimens containing gemcitabine and a platinum agent; and 4 compared a non-platinum-based gemcitabine combination with another chemotherapy regimen. The DSG also found 13 fully published phase II trials of gemcitabine alone or in combination as secondline chemotherapy. Key Evidence: In the ten clinical trials that compared cisplatin/gemcitabine with other chemotherapy regimens (most commonly cisplatin/vinorelbine or a platinum/taxane combination), the response rates for the cisplatin/gemcitabine regimen varied from 22% to 67%, with a range in median survival from 8.1 months to 9.8 months. Among those ten trials, three of the largest trials (including two reported in abstract form) detected similar response rates and survival for cisplatin/gemcitabine as compared with cisplatin/ vinorelbine, cisplatin/paclitaxel, carboplatin/ paclitaxel, and cisplatin/docetaxel. The cisplatin/ gemcitabine combination had a longer time-to-progression as compared with cisplatin/paclitaxel in one of those studies (4.2 months vs. 3.4 months, p = 0.001), but that finding was not associated with improvement in median survival (8.1 months vs. 7.8 months) or 1-year survival (36% vs. 31%). Seven randomised trials included gemcitabine as part of a three-drug, first-line chemotherapy regimen. Two of three trials by the Southern Italy Cooperative Oncology Group (which may include some of the same data) detected improved response rates and survival for cisplatin with gemcitabine and either vinorelbine or paclitaxel as compared with two drug combinations. Three additional large randomised trials published in abstract form showed no benefit from three-drug combinations as compared with two-drug combinations. One small randomised trial, also published in abstract form, detected a higher response rate for a triplet regimen of gemcitabine/carboplatin/ paclitaxel as compared with a doublet regimen of carboplatin/paclitaxel (61% vs. 28%, p = 0.017). Thirteen phase II trials of gemcitabine alone or in combination as second-line chemotherapy showed response rates of 3%-33% and a median survival of 3.9-11 months. Harms: The toxicity of cisplatin/gemcitabine varied in comparison with other regimens. Grades 3 or 4 thrombocytopoenia and anaemia generally occurred more often with cisplatin/gemcitabine. The difference was reported as significant for thrombocytopoenia when compared with cisplatin/etoposide (55% vs. 13%, p = 0.0457), mitomycin/ifosfamide/cisplatin (38% vs. 12%, p < 0.001), cisplatin/vinorelbine (16% vs. < 1%, p < 0.05), and cisplatin/paclitaxel (50% vs. 6%, p < 0.05), and for anaemia when compared with cisplatin/paclitaxel (28% vs. 13%, p < 0.05). The frequency of neutropoenia was more variable, although it was more common with cisplatin/etoposide (76% vs. 64%, p = 0.0009) and cisplatin/vinorelbine (44% vs. 16%, p < 0.05) than with cisplatin/gemcitabine. Practice Guideline: These recommendations apply to adult patients with locally advanced or metastatic NSCLC who are considered candidates for first-line or second-line chemotherapy. Cisplatin/gemcitabine can be recommended as one of several options for a first-line chemotherapy regimen in patients with locally advanced or metastatic NSCLC. Evidence is insufficient to recommend adding a third drug to a gemcitabine/platinum combination. Evidence is insufficient to recommend routinely substituting carboplatin for cisplatin in combination with gemcitabine. At present, evidence is insufficient to recommend gemcitabine combined with a taxane as first-line therapy for NSCLC. There is currently no evidence from randomised clinical trials that second-line chemotherapy with gemcitabine is associated with any improvement in survival.