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Lack of Efficacy of Topotecan in the Treatment of Metastatic or Recurrent Squamous Carcinoma of the Head and Neck

An Eastern Cooperative Oncology Group Trial (E3393)

Murphy, Barbara A., M.D.; Leong, Traci, M.S.; Burkey, Brian, M.D.; Langer, Corey, M.D.; Forastiere, and Arlene, M.D.

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American Journal of Clinical Oncology: February 2001 - Volume 24 - Issue 1 - p 64-66
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Metastatic and recurrent squamous carcinoma of the head and neck is a moderately chemosensitive tumor. A number of single agents have been identified that have a response rate of 15% to 40%. 1,2 Combination chemotherapy results in a significantly increased response rate (30–70%); however, no statistically significant improvement in survival has been demonstrated. 3 Because of the relatively high rate of comorbid disease and suboptimal social support systems available to many of these patients, toxicity associated with combination chemotherapy regimens can be excessive. New effective agents with a more tolerable toxicity profile are needed for the treatment of this disease process.

Topoisomerases are nuclear enzymes involved in DNA replication, transcription, and recombination. 4 As such, they are important targets for antineoplastic agents. Camptothecin, the first in a novel class of topoisomerase I inhibitors, was associated with excess toxicity. 5 Further development of this agent was abandoned. Several subsequently developed camptothecin analogs demonstrated significant clinical activity in a number of solid tumors. Topotecan, a potent, water-soluble camptothecin analog, is active in recurrent ovarian and small-cell lung carcinoma. Dose-limiting toxicity of single-agent topotecan is myelosuppression with neutropenia and thrombocytopenia predominating. 6

The preliminary results of a single institution phase II study of topotecan for the treatment of advanced squamous carcinoma of the head and neck were reported in 1994. 7 Topotecan was administered as a daily 30-minute infusion for 5 consecutive days at a dose of 1.5 mg/m2 per day cycled every 21 days. The major response rate was 24% (4 partial remissions of 17 evaluable patients). Given their promising preliminary results, the Eastern Cooperative Oncology Group initiated a phase II trial of weekly infusional topotecan in patients with metastatic or locally recurrent squamous carcinoma of the head and neck. This report details the response, toxicity, and survival results for the 32 patients accrued to this trial.


Patient Selection

Thirty-two patients were enrolled on study between June 16, 1995 and February 2, 1996. All patients had histologically confirmed bidimensionally measurable squamous carcinoma of the head and neck that was considered to be incurable with surgery or radiation therapy. Patients with nasopharyngeal primaries were excluded. Patients were stratified in two cohorts based on extent of previous treatment. Chemonaive patients were defined as having had no prior therapy for recurrent or metastatic disease. Patients who had received neoadjuvant, concomitant, or adjuvant therapy as part of primary therapy were considered chemonaive if treatment had been completed a minimum of 6 months before study entry. Patients who did not respond to one regimen for recurrent or metastatic disease were termed chemofailures. Patients were required to have measurable disease and an Eastern Cooperative Oncology Group performance status of 0 to 2. Other eligibility requirements included: absolute neutrophil count 1,500/mm3 or greater, platelet more than 100,000 mm3, serum bilirubin less than 1.5 mg/dl, and serum creatinine 1.5 mg/dl or less or creatinine clearance of 60 ml/min or more. Informed consent was obtained from all patients in accordance with institutional guidelines.


Patients received topotecan 1.5 mg/m2 as a 24-hour continuous infusion. Treatment was repeated weekly for 4 weeks followed by a 1-week rest. Cycles were repeated every 5 weeks. Therapy was given either on an inpatient or outpatient basis at the discretion of the treating physician. A complete blood count with differential was obtained before each treatment for dose modification.

All toxicities were evaluated using the Common Toxicity Criteria. Dose modifications were made for grade II neutropenia or thrombocytopenia and any clinically significant nonhematologic grade III or IV toxicities. In patients experiencing grade II neutropenia or thrombocytopenia, treatment was continued with a permanent 25% dose reduction. Treatment was withheld in patients experiencing any clinically significant grade III or IV toxicity until symptoms had reduced to grade I. Treatment was then resumed with a permanent 25% dose reduction. Two subsequent 25% dose reductions were allowed for patients with recurring toxicity. Patients who experienced a grade III or IV toxicity at 25% of the original dose were removed from study.

Response and Survival Assessment

Response was assessed using standard response criteria. Patients were encouraged to complete a minimum of one cycle before discontinuing therapy. A complete response consisted of complete disappearance of all clinically detectable disease for at least 4 weeks without any new sites of disease. A partial response consisted of a decrease of 50% or more in tumor size for at least 4 weeks without any new sites of disease. Stable disease was defined as no significant change in measurable disease for 4 weeks and no new sites of disease. Progression was defined as any new lesions, or an increase in the area of any malignant lesions more than 2 cm2 of 25% or greater, or an increase in the area of any malignant lesion less than or equal to 2 cm2 of 50% or greater, or a 25% or greater increase in the sum of the products of individual lesions. Survival was measured from the date of study entry.


Patients were stratified in two cohorts based on previous therapy for metastatic or recurrent disease. A standard two-stage design with early stopping rules was applied to each cohort of patients. At least one response was required in the first 15 eligible patients for accrual to continue to a total of 33 per group. Overall survival curves were estimated with the Kaplan-Meier method. 8


A total of 32 patients were entered on study: 16 chemonaive and 16 chemotherapy failures. All 32 patients were evaluable for toxicity. Two patients (one in each cohort) were ineligible: one patient had a nasopharyngeal carcinoma and one patient received treatment 6 days before study registration. Of the 30 eligible patients, 2 patients were not evaluable for response because of lack of repeat tumor measurements. Patient characteristics are listed in Table 1. Of note, 23% of patients had a performance status of 2 and 27% of patients had a weight loss of 4.5 kg or more in the previous 6 months.

Table 1
Table 1:
Selected baseline patient characteristics

Toxicity was generally mild. No treatment-related deaths were reported in either cohort. The predominant toxicity was myelosuppression, with 16% (5/32) of patients experiencing grade III or IV neutropenia. Three patients experienced grade III infection and six patients experienced grade III and IV anemia (Table 2). Grade III thrombocytopenia was reported in one patient. Nonhematologic toxicity was minimal.

Table 2
Table 2:
Grade III and IV toxicity incidence (N = 32)

No responses were noted in either treatment arm. Median survivals were 4.6 and 3.2 months in the chemonaive and previously treated arm, respectively. One-year survival was 33% for chemonaive patients and 13% for previously treated patients (Table 3).

Table 3
Table 3:
Best response by treatment


We reported the results of a phase II trial of topotecan 1.5 mg/m2 by 24 hours continuous infusion weekly for 4 weeks followed by a 1-week rest. Toxicity was modest, with hematologic toxicity predominating. Using this dose and schedule, topotecan failed to demonstrate efficacy in patients with head and neck cancer who were either chemonaive or chemofailures.

Since this trial was initiated, the investigators in Birmingham have published the final results of their phase II trial of topotecan 1.5 mg/m2 for 5 days, repeated every 3 weeks. 9 Twenty-six patients were enrolled on the study, 23 were evaluable for toxicity, and 22 were evaluable for response. Toxicity in this trial was moderate, with neutropenia occurring in 42% of cycles and 9 patients requiring blood transfusions. The overall response rate was 13%, with 1 complete remission and 2 partial remissions. Although the response rate was modest, the authors were encouraged by the results of their trial. Using the same dose and schedule, the Southwest Oncology Group conducted a phase II trial of topotecan in metastatic and recurrent squamous carcinoma of the head and neck . 10 The toxicity profile was similar to those reported by the Birmingham investigators. Of 29 patients entered on trial, 21 were eligible for response. No responses were noted.

Three phase II trials evaluating the efficacy of two different schedules of topotecan in the treatment of RMSCHN have now been completed. The cumulative results of these trials reveal that topotecan has minimal activity in the treatment of squamous cell carcinoma of the head and neck. Further studies of this agent are not planned.


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Squamous carcinoma; Head and neck cancer; Topotecan; Metastatic disease; Treatment

© 2001 Lippincott Williams & Wilkins, Inc.