Cisplatin dose intensity in non-small cell lung cancer: phase II results of a day 1 and day 8 high-dose regimen.

Between October 1985 and March 1987, 92 patients were registered on a phase II study of the Northern California Oncology Group investigating the importance of dose intensity in the treatment of advanced non-small cell lung cancer (NSCLC). Treatment consisted of high-dose cisplatin in hypertonic saline (200 mg/m2 on a 28-day cycle) given in a divided day 1 and day 8 schedule. The response rate among 76 assessable patients was 36% (27/76), with complete response (CR) in 8% (6/76) and partial response (PR) in 28% (21/76). If all patients receiving any drug therapy were considered, the overall response rate was 31% (27/87), with CR in 7% (6/87) and PR in 24% (21/87). Median survival times for all assessable patients and all patients receiving any therapy were 37 and 35 weeks, respectively. With the use of a protocol design specifying dose delays rather than dose reduction for toxicity, the mean dose intensity delivered was 47.2 mg/m2 per week, or 94% of projected. Compared with other dose-intensive regimens of cisplatin, this day 1 and day 8 schedule was relatively well tolerated, with peripheral neuropathy as the dose-limiting toxicity. The data on response and median survival times among patients receiving this single-agent therapy are encouraging. They support the potential importance of cisplatin dose intensity in the treatment of NSCLC. Whether these results represent a positive dose-response effect in NSCLC will be tested in a randomized comparative trial of high-dose versus standard-dose cisplatin therapy.

Cisplatin chemoprotection and rescue: pharmacologic modulation of toxicity.

Although cisplatin is one of the most important antitumor agents yet developed, associated toxicities continue to limit its potential usefulness. Depending on the cisplatin dose and method of administration, limiting toxicities may include nephropathy, ototoxicity, peripheral neuropathy, or even myelosuppression. Recent therapeutic strategies such as hypertonic saline have proven successful in reducing the incidence of renal insufficiency, thus allowing cisplatin dose escalation to the level of 200 mg/m2 per 28-day cycle. Unfortunately, ototoxicity and a cumulative dose-related peripheral neuropathy have recently emerged as additional dose-limiting toxicities. One method of optimizing the therapeutic index of cisplatin is the concurrent administration of chemoprotective or rescue therapy. Ideally, an effective rescue agent would selectively reduce cisplatin-related side effects without reversing its antitumor activity. Three chemoprotective agents currently undergoing evaluation--WR-2721 (ethiofos), DDTC (diethyldithiocarbamate), and ORG-2766--have demonstrated preclinical efficacy. Clinical trials now in progress suggest that each agent may offer unique advantages, but many questions remain regarding the optimal use of these agents.