Radiotherapy and concomitant weekly 1-hour infusion of paclitaxel in the treatment of head and neck cancer--results from a Phase I trial.

PURPOSE: To define the maximum tolerated dose (MTD) by describing the dose-limiting toxicity (DLT) of weekly paclitaxel (PAC) given as a 1-h I.V. infusion in patients with head and neck cancer concomitant to irradiation. METHODS AND MATERIALS: Patients with unresectable or incompletely resected head and neck cancer were enrolled into a prospective, dose-escalating Phase I study. Toxicity was graded according to the WHO toxicity score. MTD dose was defined when two out of six patients developed DLT. The starting dose of PAC was 20 mg/m2 once weekly I.V. over 60 min, with a subsequent dose escalation of 10 mg/m2 in cohorts of three new patients. Radiation therapy was administered in three field technique over 6-7 weeks in 2.0 Gy/daily fractions for 5 consecutive days/week up to total doses of 60-70 Gy. RESULTS: From 1994-1996, 18 patients completing three dose levels were included into the study. Altogether, 101 courses of chemotherapy were evaluable for toxicity. On the second dose level (30 mg/m2) one of three patients experienced DLT with Grade IV mucositis. On the next dose level with 40 mg/m2 PAC weekly one patient experienced DLT being prolonged Grade III mucositis. From the following three patients required, two patients showed no DLT. The third patient showed mucositis of WHO Grade 4 and died from hemorrhage caused by a rupture of the a pharyngeal wall. Dose level 2 (30 mg/m2) was repeated and one of the three newly treated patients again suffered from mucositis WHO Grade 4. CONCLUSION: When PAC is given weekly as a 1-h infusion concomitant to radiotherapy, MTD is 30 mg/m2 with mucositis being DLT; hematological and further nonhematological toxicity is mild.

Phase I/II study of the combination of carboplatin and paclitaxel as first-line chemotherapy in patients with advanced epithelial ovarian cancer.

PURPOSE: We performed a phase I/II study evaluating the combination of paclitaxel and carboplatin as first-line chemotherapy in patients with advanced ovarian cancer. The aim of this study was to define a feasible and safe combination regimen that could be recommended for future phase III studies. DESIGN: This study was a parallel two-arm, non-randomized, open trial. In a first step, carboplatin was administered at a fixed dose of AUC 5 and paclitaxel was escalated in 25 mg/ m2 steps starting at 135 mg/m2. Paclitaxel was given as a three-hour infusion. Carboplatin was administered on day 1 following paclitaxel in one study arm and 24 hours after paclitaxel infusion on day 2 in the other study arm. Carboplatin was escalated to AUC 6 and AUC 7.5 after the MTD for paclitaxel had been defined. Treatment was repeated every three weeks. PATIENTS: Sixty-one patients with untreated histologically confirmed epithelial ovarian cancer were recruited of whom 59 were found eligible and evaluable for toxicity. Thirty-three patients with bidimensionally measurable disease were evaluable for tumor response. RESULTS: We could not detect any advantage of the two-day schedule compared with the more convenient one-day schedule. Dose limiting toxicities were neutropenia, thrombocytopenia, and neurotoxicity. Except for two patients, toxicity was acceptable and clinically managable. One patient died of neutropenic sepsis and one further patient developed grade III peripheral neurotoxicity that did not resolve within two months after chemotherapy had been terminated. Overall objective response rate was 70%. The MTD for paclitaxel was 185 mg/m2 and AUC 6 for carboplatin, respectively. Secondary prophylaxis with G-CSF did not allow further dose escalation and therefore is not generally recommended. CONCLUSIONS: Paclitaxel 185 mg/m2 given as three-hour infusion followed by carboplatin AUC 6 is a feasible and safe regimen and can be recommended for phase III trials. Observed response rates justify further evaluation of this combination. A randomized phase III trial comparing a three-hour infusion of paclitaxel 185 mg/m2 combined with either carboplatin AUC 6 or cisplatin 75 mg/m2 as first-line chemotherapy of advanced ovarian cancer has recently been initiated by our group.

Extended phase II study of paclitaxel as a 3-h infusion in patients with ovarian cancer previously treated with plantinum.

An extended phase II study was performed to evaluate single-agent paclitaxel as salvage chemotherapy for ovarian cancer. The aim of this study was to evaluate the 3-h infusion schedule of paclitaxel in terms of toxicity and antitumour efficacy. Furthermore, we analysed the impact on response and survival of the extent of prior chemotherapy and status of resistance against platinum. This study was an open, non-randomised, multicentre trial. The dose of paclitaxel used was 175 mg/m2 in patients who had received one or two prior therapies, and 135 mg/m2 in patients who had received three prior therapies. Paclitaxel was given as a 3-h infusion. Courses were repeated every 3 weeks. 114 patients with platinum-pretreated epithelial ovarian cancer were recruited of whom 112 were found eligible and evaluable for toxicity. 104 patients with bidimensionally measurable disease who received more than one course of chemotherapy were evaluable for response, progression-free (PFS) and survival. Toxicity was generally manageable. Main toxicities were non-cumulative neutropenia with 22.3% of courses with WHO grade 3/4 and peripheral neuropathy which occurred in more than half of the courses and was of WHO grade 2 and 3 in 20.1 and 1.3% of the courses, respectively. Neuropathy was associated with the higher dose per course and with cumulative paclitaxel dose. Objective responses were reported in 20% (21/104) of the patients (95% CI 13-29%) with a median response duration of 36.7 weeks. Survival and PFS for the whole group were 45.9 and 15.1 weeks, respectively. Performance status, number of tumour lesions and extent of prior chemotherapy were found to be prognostic factors for survival. Extent of prior chemotherapy was the only prognostic factor for PFS. Platinum resistance did not predict response to treatment. Paclitaxel 175 mg/m2 given as a 3-h infusion is an appropriate treatment for patients with platinum-resistant ovarian cancer who have not previously received more than two chemotherapy regimens. Paclitaxel did not show results superior to historical data for platinum retreatment in patients with platinum-sensitive, recurrent ovarian cancer.

Paclitaxel combined with carboplatin in the first-line treatment of advanced ovarian cancer: a phase I trial.

Recently, a randomized study conducted by the Gynecologic Oncology Group (GOG 111) demonstrated that, given by a 24-hour infusion, the combination of cisplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is superior to combination cisplatin/cyclophosphamide in previously untreated patients with advanced ovarian cancer. This combination, however, necessitates hospitalization. Combination paclitaxel/carboplatin would be expected to induce fewer nonhematologic side effects but may be more myelotoxic. Thus, we started a phase I dose-escalation study to determine the maximal tolerated dose of paclitaxel given as a 3-hour infusion in combination with carboplatin, both drugs administered every 21 days. The paclitaxel dose was escalated by increments of 25 mg/m2, starting at 135 mg/m2 (level 1), 160 mg/m2 (level 2), 185 mg/m2 (level 3), and 210 mg/m2 (level 4). Carboplatin was administered to achieve an area under the concentration-time curve of 5, using the Calvert formula For study levels 5 and 6, the carboplatin dose was targeted at area under the concentration-time curves of 6 and 7.5, respectively, and was combined with a fixed paclitaxel dose of 185 mg/m2. Thirty previously untreated patients with stage IIC to IV ovarian cancer were enrolled. Nonhematologic toxicity, including nausea/vomiting and arthralgia/myalgia, was mild. Across all dose levels, a total of 16 patients developed peripheral neurotoxicity (World Health Organization grades 1 and 2). At dose level 5, one patient experienced reversible grade 4 neurotoxicity. Neutropenia was the principal dose-limiting hematologic toxicity. During 33 (31%) of 106 courses, World Health Organization grade 4 neutropenia was observed. Granulocyte colony-stimulating factor was required in only 7.6% of courses. Thrombocytopenia was less than that expected when carboplatin is given alone. Clinical responses were observed in eight of 14 patients, for an overall response rate of 57%. The combination of carboplatin plus paclitaxel was found to be an active regimen. This trial demonstrates that carboplatin dosed by the Calvert equation and 3-hour paclitaxel can be combined safely at full therapeutic doses for six or more courses in patients with advanced epithelial ovarian cancer.

Paclitaxel in simultaneous radiochemotherapy of head and neck cancer: preclinical and clinical results.

Several studies have presented evidence that paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) displays a radiation-sensitizing effect. We therefore analyzed the influence of paclitaxel and concomitant radiation on the proliferation kinetics of head and neck tumor cells and normal fibroblasts. Our data clearly support the notion that paclitaxel given with radiation exerts an additive effect on the clonogenic survival of squamous cell carcinoma cells and normal fibroblasts. Since concomitant radiochemotherapy has proven to be beneficial for the treatment of locally advanced head and neck cancer, we are testing the feasibility of simultaneous paclitaxel plus radiotherapy. Paclitaxel is given on a one-time weekly basis. Up to now, 13 evaluable patients have been treated, and the maximum tolerable dose has not been reached at 40 mg/m2. Mucositis is expected to be the dose-limiting toxicity.

Clinical course and management of paclitaxel extravasation.

Four case reports describing our experience with clinical course and management of paclitaxel extravasation are presented. Local reactions included swelling, mild pain, erythema, induration and hyperpigmentation, but no ulceration. Two patients were treated with cooling only while two further patients received additional hyaluronidase injections subcutaneously. The latter patients suffered longer from symptoms. Local reaction resolved within two weeks and paclitaxel treatment was continued in 3 of 4 patients without further complications. Overall, paclitaxel extravasation induced only mild soft tissue reaction and cooling should be considered standard treatment.

Paclitaxel combined with carboplatin in the first-line treatment of advanced ovarian cancer.

In a phase I study to determine the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given as a 3-hour infusion in combination with carboplatin administered every 21 days to women with advanced ovarian cancer, paclitaxel doses were escalated as follows: level 1, 135 mg/m2; level 2, 160 mg/m2; level 3, 185 mg/m2; and level 4,210 mg/m2. The fixed dose of carboplatin at levels 1 through 4 was given to achieve an area under the concentration-time curve (AUC) of 5 using the Calvert formula. In levels 5 and 6 the carboplatin dose was targeted at AUCs of 6 and 7.5, respectively, combined with a fixed paclitaxel dose of 185 mg/m2. To date, 30 previously untreated patients, all with a good performance status (Eastern Cooperative Oncology Group 0 to 2) have been entered into this ongoing study. The dose-limiting toxicity of the combination was myelosuppression (leukopenia, granulocytopenia, and thrombocytopenia). Neurotoxicity was largely moderate. So far, 14 patients are evaluable for response; of these, eight (57%) showed objective (complete or partial) response and disease stabilized in six patients. No patient had disease progression. We conclude that the combination of paclitaxel 185 mg/m2 administered as a 3-hour infusion followed immediately by a 1-hour infusion of carboplatin at an AUC of 6 can be administered safely in a 21-day schedule in the outpatient setting. The recommended dose for phase III studies is paclitaxel 185 mg/m2 and carboplatin AUC 6.

Clinical phase I study of paclitaxel followed by cisplatin in advanced head and neck squamous cell carcinoma.

We performed a clinical phase I trial of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck, using a 3-hour infusion of paclitaxel followed by a 1-hour infusion of cisplatin. Treatment with this combination was repeated every 21 days. Patients who had received prior treatment with platinum-containing regimens were excluded. However, patients who had received two or fewer courses of radiochemotherapy not including platinum compounds were eligible. At present, 21 patients have been entered into this ongoing study. Doses ranged from paclitaxel 135 mg/m2 plus cisplatin 75 mg/m2 to paclitaxel 250 mg/m2 plus cisplatin 100 mg/m2. The maximum tolerated dose was reached at paclitaxel 250 mg/m2 and cisplatin 100 mg/m2. The dose-limiting toxicity of this regimen was myelosuppression (leukopenia, granulocytopenia). Clinically, neurosensory toxicity was moderate. However, preliminary analyses of threshold electrotonus studies indicate the presence of subclinical neurotoxicity in most patients. One patient receiving paclitaxel 200 mg/m2 plus cisplatin 100 mg/m2 developed grade 3 motor neurotoxicity. Profound orthostatic hypotension was observed in five patients receiving paclitaxel 200 mg/m2 plus cisplatin 100 mg/m2 or higher. Neurotoxicity was of delayed onset and slowly reversible, and its severity appeared to be dose related. Twelve patients are currently evaluable for response. Of these, three partial remissions were observed (6, 6+, and 3+ months). Five additional patients had stable disease. We conclude that the combination of paclitaxel administered as a 3-hour infusion followed by cisplatin is an active regimen in advanced head and neck cancer. In addition to myelosuppression, orthostatic hypotension may be a potentially significant clinical toxicity. Clinical phase II studies have been initiated, using a dose of paclitaxel 200 mg/m2 and cisplatin 100 mg/m2.

Neoadjuvant therapy for squamous cell esophageal carcinoma.

A number of studies have demonstrated that preoperative chemotherapy (CTx) and combination radiochemotherapy (RTx/CTx) in patients with potentially resectable and locally advanced squamous cell esophageal carcinoma is feasible. In patients with potentially resectable tumors, neoadjuvant therapy followed by surgical resection has, however, so far not shown an increase in the resection rate, rate of complete macroscopic and microscopic tumor resections, i.e. R0-resections according to the UICC, or survival time as compared to patients who had surgical resection alone. In this situation a survival benefit, if at all, can be expected only in those who respond to preoperative therapy. At the present time preoperative CTx or RTx/CTx in patients with potentially resectable esophageal carcinoma must therefore be considered investigational and should not be performed outside the context of clinical trials. In patients with locally advanced esophageal carcinoma, neoadjuvant therapy markedly increases the rate of R0-resections and appears to prolong survival. Combined modality therapy in this context is, however, associated with a substantial perioperative mortality and morbidity. Open questions that have to be addressed by randomized studies include the role, extent and timing of surgical resection in the combined modality approach to patients with locally advanced squamous cell esophageal carcinoma. Research has to focus on preoperative staging modalities and the development of more effective and less toxic preoperative therapy regimen to improve identification of patients that might benefit from combined modality therapy and to more effectively combat systemic recurrences.