Phase I trial of docetaxel and vinorelbine in patients with advanced nonsmall cell lung carcinoma.

BACKGROUND: With preclinical evidence of synergy, this dose-finding trial examining the combination of docetaxel and vinorelbine given with prophylactic filgrastim for the treatment of patients with nonsmall cell lung carcinoma was undertaken. METHODS: Twenty-seven patients with advanced nonsmall cell lung carcinoma received vinorelbine as an intravenous push immediately followed by docetaxel as a 1-hour intravenous infusion once every 2 weeks at 1 of 7 different dose levels. Vinorelbine was escalated from 15 mg/m(2) (Level I) to 45 mg/m(2) (Level VII) and docetaxel was increased from 50 mg/m(2) (Level I) to 60 mg/m(2) (Level VII). Prophylactic corticosteroids and filgrastim were employed prospectively. RESULTS: After completion of dose Level VII, accrual was terminated because Phase II dose intensity of both agents had been reached and further escalation was believed to be unsafe. At dose Level VII, one episode of first-cycle febrile neutropenia and a death after three treatment cycles due to Haemophilus influenzae sepsis (Grade 5 toxicity according to the Common Toxicity Criteria of the National Cancer Institute) without neutropenia were noted. In all, 209 treatment cycles were administered and febrile neutropenia was observed in only 4 of these treatments (1.9%). Bacteremia occurred in three patients (four episodes) in the absence of neutropenia. Symptomatic onycholysis was observed in three patients. Clinically significant peripheral neuropathy and fluid retention were rare. Confirmed partial responses were noted in 10 patients for a response rate of 37% (95% confidence interval, 20-57%). CONCLUSIONS: Docetaxel at a dose of 60 mg/m(2) and vinorelbine at a dose of 45 mg/m(2), both given every 2 weeks, can be combined safely to achieve Phase II dose intensity of both agents. An ongoing Phase II trial will define the activity of this treatment combination.

Phase II trial of docetaxel and vinorelbine in patients with advanced non-small-cell lung cancer.

PURPOSE: Docetaxel and vinorelbine are active agents in advanced non-small-cell lung cancer (NSCLC) and demonstrate preclinical synergism perhaps, in part, through their inactivation of the proto-oncogene bcl-2. We show that docetaxel (60 mg/m(2)) and vinorelbine (45 mg/m(2)) can be safely combined when given on an every 2-week schedule with filgrastim, with encouraging antitumor activity observed. PATIENTS AND METHODS: Thirty-five chemotherapy naïve patients with advanced NSCLC received vinorelbine as an intravenous push immediately followed by docetaxel as a 1-hour intravenous infusion once every 2 weeks. Prophylactic corticosteroids, ciprofloxacin, and filgrastim were used. RESULTS: We delivered median doses of 450 mg/m(2) of vinorelbine and 600 mg/m(2) of docetaxel. The major objective response rate was 51% (95% confidence interval [CI], 34% to 68%). With a median follow-up of 14 months, the predicted median survival time was 14 months, and the 1-year survival rate was 60% (95% CI, 44% to 80%). Febrile neutropenia occurred in five patients and five (1.3%) of 384 treatments. No dose-limiting neurotoxicity occurred. Symptomatic onycholysis and excessive lacrimation were observed after several months or more of therapy. CONCLUSION: Docetaxel 60 mg/m(2) and vinorelbine 45 mg/m(2), both given every 2 weeks, is a highly active combination for the treatment of advanced NSCLC. Filgrastim largely obviates neutropenic fever and allows for the single-agent dose-intensity of both drugs to be delivered. The occurrence of certain late toxicities can limit use in some cases and suggests that the combination could also be beneficial in settings requiring briefer, fixed periods of treatment, such as in induction or postoperative therapy.

Oral cisapride for the control of delayed vomiting following high-dose cisplatin.

Although combination antiemetics prevent vomiting during the initial 24 h after high-dose (> or =100 mg/m2) cisplatin, many patients experience delayed emesis 24-120 h afterwards despite receiving prophylactic dexamethasone and metoclopramide during this time. Cisapride is a prokinetic agent, which stimulates propulsive motility throughout the gastrointestinal tract without causing extrapyramidal effects. In this phase II trial, we tested the ability of cisapride to prevent delayed emesis following cisplatin. Twenty patients receiving initial cisplatin >100 mg/m2 were entered. All patients received intravenous dexamethasone with either metoclopramide or ondansetron to prevent acute emesis 0-24 h after receiving cisplatin. Patients who had experienced two or fewer acute vomiting episodes then received cisapride 20 mg orally four times daily for 4 days (24-120 h after cisplatin). Cisapride prevented delayed emesis in 2 patients (10%) during the entire 4-day period (95% confidence interval, 1-32%). Abdominal cramping and pain occurred in 35%. At the dose and schedule tested, oral cisapride prevented delayed emesis in only 10% of patients receiving cisplatin >100 mg/m2 and caused abdominal cramping in 35%. Since in prior trials among similar patients, placebo prevented delayed emesis in 11%, further study of cisapride and dose escalation for this indication are not recommended.

Assuring the optimal use of serotonin antagonist antiemetics: the process for development and implementation of institutional antiemetic guidelines at Memorial Sloan-Kettering Cancer Center.

PURPOSE: The need to foster the appropriate and cost-effective use of serotonin-antagonist antiemetic drugs spurred the creation of guidelines. The process by which institution-wide guidelines at Sloan-Kettering were developed, implemented, assessed, and modified is described. METHODS: A multidisciplinary group working with disease-specific management teams assigned the emetic potential of chemotherapy programs to one of five categories. Antiemetic regimens, including a specified dose and schedule of a serotonin-antagonist and dexamethasone, were assigned to each emetic category. The information was collated by disease site and chemotherapy program into hospital-wide antiemetic regimen recommendations. Quality assessment was conducted initially and repeated each time the guidelines were modified. RESULTS: Patient surveys demonstrated a high level of satisfaction with emetic control, which was similar to reported results. Data from the latest survey showed zero emetic episodes in 93% and 87% of participants given moderate and highly emetogenic chemotherapy, respectively. Compliance with the guidelines, initially in 73%, has been improved using a standardized chemotherapy order "check box" labeled, "Antiemetics as per Guidelines." Antiemetic drug expenditures decreased from a projected $2.8 million to $1.3 million annually. CONCLUSION: The guidelines became an educational tool that ensured the delivery of optimal antiemetic therapy chosen by professionals with the greatest knowledge of both the particular chemotherapy regimen and cancer site. Implementation of the guidelines resulted in substantial savings while treating more patients. The guidelines were easily modified as new chemotherapeutic agents and antiemetic drugs became available.

Prevention of acute emesis in cancer patients following high-dose cisplatin with the combination of oral dolasetron and dexamethasone.

PURPOSE: Dolasetron is a 5-HT3 antagonist antiemetic with active oral and intravenous formulations. The effects of this class are enhanced when combined with dexamethasone. This study tested the ability of the combination of oral dolasetron 200 mg and oral dexamethasone 20 mg to prevent acute emesis in cancer patients receiving initial cisplatin at doses > or = 70 mg/m2. Additionally, patients were randomly assigned to receive a second dosage of the regimen 16 hours later to improve control of acute symptoms. PATIENTS AND METHODS: A total of 75 patients were entered, with 38 randomized to the two-dose regimen. Thirty-five percent were women and 77% had lung cancer. RESULTS: Overall, the regimen prevented acute vomiting in 76% (95% confidence interval, 65% to 85%), including 74% of 35 patients who received cisplatin at doses > or = 100 mg/m2. There was no observed difference in emesis prevention between the one-dose (76%) and two-dose (76%) regimens (95% confidence interval for the difference, -20% to 19%). The median time to the onset of emesis was 19 hours for the one-dose regimen and 17 hours for the two-dose regimen in those patients with emesis. Headache occurred in 11% who received one dose and 16% who received two doses. CONCLUSION: The combination of oral dolasetron 200 mg and dexamethasone 20 mg given only once prevented acute emesis in 76% of patients who received cisplatin > or = 70 mg/m2. Administration of a second dose of the regimen did not improve the observed prevention rate or delay the time to emesis. This one-dose oral regimen has comparable or better effectiveness than reported results of intravenous combination regimens in preventing cisplatin-induced vomiting and merits further study and use.

Phase II study of the combination of the novel bioreductive agent, tirapazamine, with cisplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: Tirapazamine is a bioreductive compound synergistic with cisplatin in preclinical testing. This phase II study was conducted to evaluate the efficacy and toxicity of tirapazamine with cisplatin in patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS: Twenty patients with unresectable stage III-B and IV non-small-cell lung cancer who had not received prior chemotherapy were given tirapazamine (390 mg/m2) intravenously (i.v.) over two hours followed one hour later by cisplatin (75 mg/m2) i.v. over one hour every 21 days. RESULTS: Five of 20 patients (25%) had major objective responses (95% confidence interval, 11%-50%). Median duration of response was eight months with a one-year survival of 40%. Toxicities included temporary hearing loss (25%), muscle cramping, diarrhea, skin rash and nausea/vomiting. No grade 3 or 4 hematologic or renal toxicity was observed. CONCLUSIONS: The combination of tirapazamine plus cisplatin appears to be safe and active in the treatment of advanced non-small lung cancer without a substantial increase in toxicity compared to cisplatin alone. A phase III randomized study compared the combination to cisplatin alone has completed accrual. Further evaluation of tirapazamine with other active agents and in multi-modality therapy is warranted.