Clinical, toxicological and pharmacological aspects of gemcitabine

Gemcitabine is a new pyrimidine antimetabolite which inhibits DNA synthesis after being phosphorylated intracellularly to its triphosphate. The drug is usually administered as a 30-min intravenous infusion weekly for 3 weeks followed by 1 week of rest, this constituting one cycle. The dose-limiting toxicity is myelosuppression, with thrombocytopenia and anaemia quantitatively more important than granulocytopenia. Non-haematological toxicity, including nausea, vomiting and malaise, are mild. Flu-like symptoms, including transient febrile episodes or fever, responding to acetaminophen, and transient rises in hepatic transaminases and serum creatinine, alopecia, confusion, somnolence, oedema and generalized erythematous rash may also occur. In non-small cell lung cancer (NSCLC), gemcitabine gives a partial response rate of 19-26% with a median duration of 7-13 months. Complete responses are rare. Currently available single agents for advanced NSCLC have demonstrated a maximum response rate of 15%, whereas combination chemotherapy can yield response rates of up to 40% in selected patients. Other novel chemotherapeutic agents for NSCLC such as irinotecan, topotecan, paclitaxel, docetaxel, vinorelbine and edatrexate might have comparable efficacy. Combination therapy of gemicitabine and cisplatin show promising antitumour activity with response rates of 36-59% and warrants further investigation. However, prospective direct comparisons with these regimens have not yet been studied. The response rate in advanced small cell lung cancer, advanced ovarian cancer, squamous cell carcinoma of the head and neck, bladder cancer, and renal cell carcinoma is 27, 20, 13, 56 and 6%, respectively, albeit without responses. Gemcitabine has been tested in other malignancies advanced gastric cancer, metastatic malignant melanoma, and advanced colorectal adenocarcinoma, but antitumour activity has not been found. In conclusion, due to its relatively good partial response rate and acceptable toxicity profile, gemcitabine is a promising drug in the palliative treatment of NSCLC. Its ultimate place in other malignancies awaits further investigation.