The effect of gemcitabine in non-small cell lung cancer

Abstract

Even though chemotherapy in non-resectable non-small cell lung cancer (NSCLC) lee& to a modest increase in survival, the therapeutic results of chemotherapy in this disease is far from satisfactory. More effective chemotherapy is needed and the development of new active cytostatic agents is a mean in achieving this goal. NSCLC is rather chemoresistant and only relatively few cytostatic drugs are active in this disease. Among the most active older drugs are ifosfamide, vindesine, vinblastine, mitomycinG and cisplatin; all with an average response rate of 20% when used as a single agents. Usually, only partial responses are seen in the patients treated and the duration of response is short; 3-5 months. Combination chemotherapy has improved the response rate with a significant impact on survival in metaanalyses. Identification on new drugs with significant activity against NSCLC is therefore sorely needed in order to improve the response rate, the fraction of complete responses and the duration of response with the ultimate aim of increasing the quality-of-life and survival of the patients treated. Among the most promising new agents are the taxanes (paclitaxel and docetaxel), topotecan, (Hycamtin) CPT-11 (irinotecan), vinorelbine and gemcitabine (gemzar). Gemcitabine (2’2’-difluorodeoxycitidine) is a new pyrimidine analog with both novel metabolic properties and mechanisms of action. Although it is structurally similar to the antimetabolite cytarabine (AraC), its cellular pharmacology and mechanism of action differ markedly, which may explain why gemcitabine has a much wider spectrum of antitumour activity against several solid tumours than AraC (1). Extensive data generated from early phase I trials demonstrated that the clinical toxicity profile of gemcitabine is schedule dependent. The current accepted best schedule from the phase I studies is once weekly x 3 i.v. every 28 days, which provides a combination of activity and acceptable tolerability with minimal non-haematologic toxicity and manageable neutropenia and thrombocytopenia. The non-haematologic toxicity includes mild nausea and vomiting, lethargy, reversible skin rash and occasional mild peripheral oedema. Alopecia and mucositis are rare events. In addition, elevation of hepatic transaminase as well as varying degrees of dyspnoea have been reported. Activity in gemcitabine in NSCLC was already noted in the initial phase I trials. It has since been confirmed in a number of phase II trials performed both in Europe, the US and South Africa (2). The selection of patients was quite similar in all the studies and included patients with inoperable TNM stage Illa, Illb, or IV, adeno-, squamousor large cell carcinoma with bidimensionally measured disease, and the World Health Organisation performance status 0 to 2. None of the patients had received prior chemotherapy. A majority of the trials applied a schedule of gemcitabine given i.v. day 1, 8 and 15 every 4 weeks with a dose of 800 mg/m* in the initial trials, later on increased to 1200-l 500 mg/m* in subsequent trials, when toxicity secundary to gemcitabine was observed to be very modest. Alltogether, 438 patients with NSCLC have been treated with gemcitabine using dosage between 800-1250 mg/m* giving an overall response rate of 21% (95% Cl, 16-25). The median response varies from study to study being 2549 weeks, while the medians survivals in the trials are between 26-46 weeks. In some of the studies more detailed data are available concerning changes in the clinical symptomatology. From Gatzemeier and al.‘s study (3) it is noteworthy that of 10 patients with performance status 2 on entry, 3 improved on performance status 1. 27% of the 65 eligible patients reduced their analgesic requirements. Of 83 eligible patients who experienced pain at study entry, these symptoms improved in 31%. Other disease-related symptom improvements included: cough (35%) dyspnoea (22%), and haemoptysis (68%). Similar results have also been reported by Thatcher et al. (4) With respect to response among the various histological cell types cumulated data show no significant difference when comparing squamous-, adeno-, and large cell carcinoma with the response rates being 16%, 19%, and 27%, respectively (2). In other phase II trials gemcitabine has been combined with various cytostatic compounds as doublets such as cisplatin, carboplatin, iphosphamide, etoposide, vindesine, taxol, and taxotere (5, 6, 7) and also in triplets using for instance gemcitabine together with cisplatin or carboplatin together with taxol or vinorelbine. The response rate has varied between 38-58% based on published abstracts with the majority being between 3552% thus achieving substantially higher response rate compaired to single-agent chemotherapy. Various phase Ill trials are at present ongoing comparing various 2-drug combinations including gemcitabine vs. combinations without gemcitabine. Noteworthy is in a European study that gemcitabine when compared to etoposide and cisplatin resulted in considerably less toxicity and similar survival (8). Other studies explore the combination of gemcitabine with radiotherapy in stage Ill non-small cell lung cancer (9).