Phase I trial of liposomal encapsulated doxorubicin (Myocet; D-99) and weekly docetaxel in advanced breast cancer patients.

BACKGROUND: We conducted a phase I trial to determine the safety and maximum tolerated dose (MTD) of non-pegylated liposome-encapsulated doxorubicin (Myocet; D-99) administered with weekly docetaxel in metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: Twenty-one patients with no prior chemotherapy for MBC received D-99 (60 or 50 mg/m2) intravenously (i.v.) on day 1 and escalating doses of docetaxel (25, 30 and 35 mg/m2 i.v. on days 1 and 8 in cohorts of three to six patients. Treatment cycles were repeated every 21 days for a maximum of six cycles. RESULTS: The maximum tolerated dose (MTD) was 50 mg/m2 of D-99 in combination with 25 mg/m2 of weekly docetaxel. The most common grade 4 toxicity was neutropenia that occurred in 42 (41%) of treatment cycles, with 10 hospitalizations for febrile neutropenia. Serious protocol-defined cardiac events occurred in three (14%) patients, with two (10%; 95% confidence interval [CI] 1% to 30%) developing congestive heart failure (CHF) after a total cumulative anthracycline dose (adjuvant doxorubicin + D-99) of 540 mg/m2. CONCLUSIONS: D-99 in combination with weekly docetaxel, at the doses and schedule as administered in this trial, is not recommended for phase II testing. Additional trials, using different doses and schedules, are required to evaluate the potential side-effects and efficacy of D-99 and docetaxel.

Long-term follow-up on an intensified treatment regimen for advanced resectable head and neck squamous cell carcinomas.

From February 1993 through July 1994, 37 patients with stage III-IV squamous cell carcinomas of the oral cavity, oropharynx, or hypopharynx (stage II-IV) were registered to a treatment regimen consisting of preoperative continuous infusion cisplatin (80 mg/m2/80 hours) with hyperfractionated external beam radiotherapy (9.1 Gy/7 fractions of 1.3 Gy BID), surgical resection, intraoperative radiotherapy (7.5 Gy), and postoperative radiotherapy (40 Gy) with concurrent cisplatin (100 mg/m2 x 2 courses). The objectives of the regimen were to improve patient compliance while also increasing treatment intensity. The purpose of this article is to report the local, regional (nodal), and distant disease control of these patients after an extended time at risk (median 40 months). Overall compliance (73%), local control at primary site (97%), and regional nodal control (95%) were excellent. The rate of distant metastasis was 19%. Absolute survival at 48 months was 45.9%.

Induction paclitaxel in previously untreated, resectable, advanced squamous cell carcinomas of head and neck.

BACKGROUND: Previous Phase II trials evaluating paclitaxel as a single agent have produced objective response rates of 38-40%. However, in these studies patients had recurrent disease and had received previous treatment with chemotherapy, radiation, surgery, or some combination of the same. To the authors' knowledge, the study reported here is the first to examine the role of paclitaxel in affecting objective antitumor response, as a single agent, in a previously untreated patient population. METHODS: Patients with untreated, resectable, advanced squamous cell carcinoma of the head and neck were eligible for this Phase II trial. The treatment plan included paclitaxel 250 mg/m(2) administered by 24-hour intravenous infusion every 21 days for a total of 3 courses and primary prophylaxis with colony stimulating factor during each course of chemotherapy. Surgical resection was performed after recovery from the final course of chemotherapy. After adequate wound healing, patients received external beam radiotherapy (median dose to primary site, 55.8 Gray [Gy]; median dose to neck sites, 50.4 Gy). RESULTS: Forty-five patients were registered. Thirty-eight patients completed the planned chemotherapy, 41 patients underwent surgical resection, and 37 patients completed the intended radiotherapy. The objective response rate was 50% (10% complete response; 40% partial response). Severe or life-threatening (Grade 3 or higher) granulocytopenia or thrombocytopenia occurred in 78% and 27% of patients, respectively. Two patients died of sepsis. Seventy-one percent, 67%, and 91% of patients were free of local, lymph node, and distant recurrence, respectively, with a median follow-up of 37 months. The 4-year overall survival and disease-related survival rates were 44.4% and 52.9%, respectively. CONCLUSION: The authors conclude that paclitaxel is an active agent in patients with advanced head and neck carcinoma. However, the overall disease control, achieved by using paclitaxel as induction therapy, did not appear to be better than that achieved with standard treatment methods. Combined modality regimens with concurrent chemotherapy and radiotherapy have demonstrated more promise.

Intensification regimen 2 for advanced head and neck squamous cell carcinomas.

OBJECTIVE: To determine the feasibility, toxicity, and compliance of an intense treatment regimen for patients with advanced, previously untreated, resectable head and neck squamous cell carcinomas. DESIGN: Prospective, nonrandomized, controlled (phase 1 or 2) clinical trial; median time at risk, 25 months (range, 7 days to 36 months). SETTING: Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus. PATIENTS: Forty-three patients (median age, 59 years; range, 32-76 years) with resectable, previously untreated stage III or IV squamous cell carcinomas of the oral cavity, oropharynx, or hypopharynx or stage II squamous cell carcinomas of the hypopharynx (referred sample of patients). INTERVENTIONS: Days 1 to 4, perioperative, slightly accelerated, hyperfractionated radiotherapy (9.1 Gy) to off cord fields; days 1 to 3, cisplatin, 30 mg/m2 per day; day 4, surgical resection and intraoperative radiotherapy boost (7.5 Gy); days 45 to 52, postoperative radiotherapy (40 Gy to the primary site and upper neck and 45 Gy to the supraclavicular areas); days 24, 45, and 66, paclitaxel, 135 mg/m2 per 24 hours, with routine granulocyte colony-stimulating factor support; and days 25 and 46, cisplatin, 100 mg/m2. MAIN OUTCOME MEASURES: Toxicity, compliance, local control, and distant metastatic rates. RESULTS: Patient compliance was 91% (39 of 43 patients), but protocol compliance was only 58% (25 of 43 patients), reflecting increased toxicity of the systemic regimen (2 [5%] of the 43 patients experienced grade 5 hematologic toxicity due to the regimen; 16 [37%], grade 4; and 10 [23%], grade 3). Local-regional control was 92% (23 of 25 patients), and the distant metastatic rate was 8% (2 of 25) in patients completing treatment per protocol. One patient had surgical salvage of a second primary tumor. CONCLUSIONS: Local control and patient compliance were encouraging, but systemic toxicity was unacceptable. Thus, the paclitaxel was changed to a weekly regimen.