The initial single-agent trials of paclitaxel were conducted in patients with one or fewer prior chemotherapy regimes. Responses were seen in 56 percent and 62 percent of women with paclitaxel given at 200-250 mg/m2. A subsequent randomized trial used the 3-hour infusion schedule and compared 135 mg/m2 to175 mg/m2. Responsed were uniformly lower at 22 percent and 29 percent, respectively. All but one of the trials in patients with two or more prior chemotherapy regimes used the 24 hour infusion schedule with or without G-CSF. Responses were lower in patients who had received more extensive therapy and thrombocytopenia occured. One study, which used a 96-hour infusion schedule and treated patients with anthracyclin-resistant disease, had 48 percent objective responses. Mucositis was dose-limiting. Two thirds of the patients received G-CSF but G-CSF did not affect the incidence of febrile neutropenia or mucositis. Combination trials with doxorubicin and cisplatin have been reported. The initial phase I combination trials used paclitaxel by 24-or 72-hour infusion, and all used G-CSF. Dose limiting toxicity proved to be schedule dependednt. In the 72-hour infusion schedule, typhlitis(neutropenic enterocolitis) in addition to mucositis was dose-limiting. In both the bolus and the 24-hour infusion schedules, clinical observation and later pharmacokinetic studies showed that the sequence of administration of paclitaxel and doxorubicin affected the toxicity. When paclitaxel, given by 24-hour infusion, precedes doxorubicin, doxorubicin plasma levels at the end of the infusion were an average of 70 percent higher than in these phase I trials were similar to standard combination chemotherapy studies, but only in the 3-hour infusion schedule was the incidence of complete remissions high. Other promising combinations include cisplatin, and monoclonal antibodies to epidermal growth factor. The issue of efficacy in patients with anthracycline resistance is discussed. Important questions for future studies of paclitaxel are discussed.

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Lung cancer is one of the most common cancers in the world and the leading cause of cancer death in the United States. It is comprised of non small cell(NSCLC) and small cell lung cancer (SCLC). Chemotherapy has been used frequently in patients with stage IV NSCLC. Paclitaxel is a novel anti-microtubular chemotherapeutic agent with a unique mechanism of action. The preclinical evaluation of paclitaxel revealed a broad spectrum of antitumor activity against various tumors including lung cancer cell lines.

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Paclitaxel is among the most promising agents developed in the past 15 years for the treatment of solid tumors. Two phase II trials have shown that paclitaxel has significant single-agent activity in patients with head and neck cancer. Preclinical data suggest that alterations in dose and schedule may have a significant influence on clinical response; studies are underway, therefore, to determine the best schedule for administering paclitaxel. Furthermore, studies to define the most effective method of combining paclitaxel with other fagents such as cisplatin, 5-FU, methotrexate, edatrexate and ifosfamide are being completed. Finally, efforts are under way to define the role of paclitaxel in combination with radiotherapy in patients with head and neck cancer. Our hope is that the addition of this active new agent to current therapeutic approaches will lead to an improvement in the overall survival of patients with squamous cell carcinoma of the head and neck.

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Metastatic or local-regional unresectable carcinoma of the esophagus or gastroesophageal junction results in a dismal prognosis. Most patients, succumb to either locally advancing disease or progressive widespread metastases. Chemotherapeutic agents given as single agent or in combination often result in either no benefit or only transient palliation. New active agents are needed to improve the outcome of these patients. A phase II NCI-sponsored study of Paclitaxel was conducted at UT M.D. Anderson Cancer Center, Houston, Texas and Memorial Sloan-Kettering Cancer Center, New York, simultaneously. Eligible patients included those with unresectable local-regional or metastatic carcinoma of the esophagus or gastroesophageal junction. The purpose of the study was to evaluate response rate, duration of response, and toxicity. Prior chemotherapy or biologic therapy was not alllowed. Patients with either squamous cell carcinoma or adenocarcinoma were eligible for this study. The starting dose of Paclitaxel was 250 mg/m2 administered by a 24-hour IV infusion repeated every 21 days. All patients were premedicated with dexamethasone, cimetidine, and diphenhydramine hydrochloride. In addition, all patients received granulocyte-colony stimulating factor(G-CSF; 5 mug/Kg)s.c. daily 24 hours after the completion of Paclitaxel to reduce the duration and severity of granulocytopenia. Fifty-three patients were registered. Two patients were inevaluable since they did not receive Paclitaxel. Fifty-one patients were assessable for response and response duration. Thirty-three patients had adenocarcinoma and 18 had squamous cell carcinoma. Forty-four patients were men and 6 were women. The median age was 57 years(range, 36 to 77 years). The median Zubrod PS was 1(range, 1 to 2). The median no. of courses was 4(range, 1-14+; total courses 229). The dose was reduced in 53 courses and increased in 15. Sixteen(32 percent) patients achieved a response(one complete and 15 partial) and eleven(22 percent) achieved a minor response. Among 33 patients with adenocarcinoma, 12(36 percent; 95 percent Confidence Interval, 14 percent to 58 percent) achieved either a complete(one patient)or partial resposne(11 patients) and 6 patients had a minor response. Four(22 percent; 95 percent Confidence Interval, 3 percent to 41 percent) of 18 patients with squamous cell carcinoma had a partial response and 4 (22 percent) had a minor response. The median duration of partial response was 17 weeks(range, 7 to 58 weeks). At a median follow up of 12+ months, 28 patients remain alive with an actuarial median survival duration of 10.2 months (range, 2 months to 20+ months). Paclitaxel was well tolerated. Granulocytopenia was frequent resulting in 11 hospitalizations in 9 patients in 9 patients. Grade 3 neuropathy was observed in three patients. Our data suggest that Paclitaxel is an active agent against adenocarcinoma as well as squamous cell carcinoma of the esophagus. Plans to study Paclitaxel in combination with cisplatin and 5-fluorouracil in this group of patients are underway.

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Paclitaxel has been evaluatied for efficacy and toxicity in relapsed and refractoryy patients with ovarian cancer. A total of thirty patients have been treated with Paclitaxel 135 mg/m2 continous infusion over 24 hours repeated every 21 days. All patients were premedicated with Dexamethasone, Promethazine HCl and Ranitidine or Cimetidine. Seventeen patients were stage III while 13 had stage IV disease. All patients had previously received platinum based regimes. Sixteen(53 percent)out of 30 patients showed objective response while complete response was observed in 3(10 percent) patients. Hypersensitivity reaction was not encountered. Grade III to IV myelosuppression and neutropenia were seen in more than 50 percent of courses. However, these were frequently transient. Neuropathy and myalgia were rarely noticed. Alopecia was uniformly observed in all patients. The present data indicate the efficacy of Paclitaxel in ovarian cancer. The efficacy and toxicity profile in Indian Patients appears to resemble the data from the West.

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Because many obstacles were encountered during the early development of paclitaxel, disease directed phase II trials were initially performed in a limited number of tumor types. However, the results with paclitaxel in ovarian and breast cancers produced a high level of enthusiasm for the further development of the taxanes, and broad phase II investigations are underway. Thus ar, paclitaxel has demonstrated significant activity in several types of genitourinary cancers, particularly carcinomas of the urothelium and testes. The preliminary results with paclitaxel in these and other tumor types are reviewed in this report. Similar to the situation in breast and ovarian cancers, subsequent evaluations in other sensitive tumors will need to be directed at defining the optimal use of paclitaxel in combination chemotherapy regimes, as well as optimal scheduling and dosing. Such studies are necessary so that the agent can be utilized optimally in evaluations of its utility in the primary or adjuvant treatment setting where new active agents are likely to have their greatest impact on survival.

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