Gemcitabine Plus Cisplatin in Non-Small Cell Lung Cancer
Gemcitabine Plus Cisplatin in Non-Small Cell Lung Cancer
ABSTRACT & COMMENTARY
Synopsis: In a phase II study in 27 evaluable patients treated with gemcitabine and cisplatin, nine patients experienced a partial response. Grade 4 hematologic toxicity occurred in 20% of patients. Median survival was 8.4 months, and one-year survival was 37%. This is a regimen that deserves to be evaluated in phase III studies as a primary treatment for advanced non-small cell lung cancer.
Source: Sandler AB, et al. Cancer Therapeutics 1998; 1:158-163.
Lung cancer remains the number one cause of cancer deaths in the United States. In 1998, it is estimated that 171,500 people will get lung cancer and that 160,100 people will die from it. The vast majority of patients present with locally advanced disease that cannot be cured by surgery or surgery plus radiation therapy. Chemotherapy is not terribly effective; however, a number of the newer antineoplastic agents appear to have some activity. Agents that are commonly used in combination regimens include cisplatin, vinblastine, etoposide, mitomycin C, paclitaxel, vinorelbine, and the camptothecins.
Gemcitabine is a cytosine analogue that is activated by deoxycytidine kinase to difluorodeoxycytidine triphosphate, which is incorporated into newly synthesized DNA in place of cytidylate, and results in chain termination. Gemcitabine is also capable of inhibiting ribonucleotide reductase, an enzyme that is rate-limiting for DNA synthesis because it is essential for the generation of deoxynucleotide DNA precursors. Inhibition of ribonucleotide reductase may also inhibit DNA repair. Thus, the use of ribonucleotide reductase inhibitors together with DNA damaging agents like radiation therapy, alkylating agents, and cisplatin, can potentiate tumor cell kill.
Gemcitabine has been used as a single agent in lung cancer with overall responses of about 21% in a number of phase II studies using different doses and schedules. Cisplatin has a similar rate of single agent response. Sandler and colleagues at the University of Indiana Walther Cancer Institute and the Hoosier Oncology Group conducted a phase II study of gemcitabine 1000 mg/m2 by 30-minute IV infusion on days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m2 given after gemcitabine on day 1 at an infusion rate of 1 mg/min with vigorous hydration. Thirty patients were entered into the study. The median age was 62 years (range, 37-74); 40% had adenocarcinoma, 30% had squamous cell carcinoma, and 26.7% had large cell carcinoma. Baseline Karnofsky performance status was 80 in 17 patients, 90 in 10, and 100 in three. No patient had received prior chemotherapy.
Nine of 27 evaluable patients (33%) had a partial response to treatment. No complete responses were noted. The median number of cycles given was four. The median survival was 8.4 months, and the one-year survival was 37%. Median time to response was 1.9 months and the median duration of response was 10.3 months. The primary toxicity was bone marrow suppression, with thrombocytopenia as the most common manifestation. Grade 3 toxicity was seen in nine (30%) and grade 4 toxicity in six (20%). No episodes of bleeding occurred. While grade 4 neutropenia was seen in four patients (13.3%), no episodes of febrile neutropenia were noted. Nonhematologic toxicity was mild.
COMMENTARY
Other studies of gemcitabine and cisplatin have been reported in non-small cell lung cancer.1-3 The regimens differed on the day of the cycle that cisplatin was given and the reports differed in the fraction of treated patients who had local vs. metastatic disease. Response rates of 38-54% and one-year survival rates as high as 61% have been seen. It remains unclear whether response and toxicity are influenced by the day on which cisplatin is given, but the question could certainly benefit from more careful examination. Until the unanswered questions are addressed in clinical trials, this regimen of cisplatin and gemcitabine is worth considering as a palliative regimen for advanced lung cancer.
References
1. Crino L, et al. J Clin Oncol 1997;15:297-303.
2. Steward WP, et al. Proc Am Soc Clin Oncol 1995; 14:351.
3. Abratt RB, et al. J Clin Oncol 1997;15:744-749.
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