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Suramin is a new experimental polyanionic compound that has shown evidence of antitumor activity in patients with hormone refractory prostate cancer. After a few years of Phase I and Phase II testing, much of the drug's toxicity pattern has been carefully characterized. Similarly, pharmacologic studies have defined many of the drug's complex pharmacologic properties to the extent that simple outpatient methods of drug administration can be easily accomplished. A pharmacologically derived, fixed outpatient schedule has been shown to be safe and effective and is currently in active Phase III development in prostate cancer and will provide more definitive data regarding the role of suramin in the treatment of this disease. Despite these accomplishments, a number of questions require further study, such as definition of pharmacodynamic correlations, effects on the hypothalamic-pituitary-adrenal and gonadal axis, and the nature of its most common dose-limiting toxicity, which is a syndrome of malaise and fatigue. Cancer 1995 ; 75 :1927-34.

In a previous study, we reported a 72% response rate (CR = 52%) in patients with unresectable head and neck (HN) carcinomas treated with simultaneous carboplatin (CBDCA) and radiotherapy (RT). Bleomycin (Bleo), a known radiosensitizing agent, has been shown to increase response rates when given together with RT in similar patients. To explore the nonoverlapping toxicities of these two agents, we combined i.v. CBDCA (100 mg/m2/week), Bleo (5 units on day 1 and 4/weekly) and standard doses of RT in patients with unresectable HN carcinomas. Chemotherapy (CT) was continued until completion of RT. Twenty-three (13 males, 10 females) previously untreated patients with stage IV squamous cell carcinoma of the HN were treated at the University of Maryland Medical Center: 61% had oropharyngeal cancers; 26%, hypopharynx; 9%, oral cavity; and 4%, an unknown primary. Moderate to severe mucositis developed in 90%, which required RT interruptions of up to 3 weeks. After a median follow-up (FU) of 18 months, 35% achieved a complete response (CR) and 65% died from progressive disease. These preliminary data suggest that the addition of Bleo increases mucosal toxicity substantially and, while a moderate response rate was observed, it is unlikely that the CR rate will be higher than CBDCA/RT, which was also better tolerated and hence more suitable to multimodal approaches.

Fifteen patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck received a 5 day continuous I.V. infusion of 6-thioguanine repeated every five weeks. Dose limiting toxicity was primarily hematological with grade III/IV leucopenia and thrombocytopenia seen in seven patients. Nausea and vomiting was moderate and well controlled with antiemetics. No complete or partial responses were observed, with a median time to progression of 58 days and a median survival of 227+ days for the entire group. Based on these results we do not recommend I.V. 6-thioguanine for the treatment of this disease.

Patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) were stratified by performance status, extent of disease, and prior radiotherapy and subsequently randomized to receive carboplatin (CBDCA; Bristol-Myers, Wallingford, CT) administered intravenously (IV) monthly, initially at doses of 400 mg/m2 in combination with methotrexate (MTX) given IV weekly at doses of 40 mg/m2 or MTX alone at the same dose/schedule. Significant dose-limiting myelosuppression required CBDCA dose reductions to 300 mg/m2 and, subsequently, 200 mg/m2. Nonhematological toxicities were not significant. Our study objective was to determine whether CBDCA plus MTX produce a substantial improvement in response rate over single-agent MTX. A response rate of 50% (complete [CR] plus partial response [PR]) for CBDCA plus MTX compared with 25% for MTX was specified as the difference to be detected. We employed a two-stage study design for randomized trials that allowed for early termination of studies involving relatively ineffective treatment regimens. With this design, the study could be closed after the first stage (20 patients entered onto each treatment arm) if the number of responders to CBDCA plus MTX were not superior to MTX. Five of 20 patients responded to treatment in each arm, and we were able to conclude that the addition of CBDCA to MTX is unlikely to result in a twofold increase in response rate compared with MTX alone in this group of patients. This two-stage design represents a simple and efficient method of testing the relative efficacy of new combinations containing at least one active agent against a suitable control arm in this disease. It addresses scientific and ethical issues of continuing testing with relatively ineffective treatments, and at the same time provides a reliable method for identifying very active regimens likely to represent significant therapeutic advances.

The prognosis of patients with squamous cell carcinoma (SQC) of the head and neck (HN) depends on the primary site and anatomical extent of the disease. Recurrence rates after conventional surgery (S) and/or radiotherapy (RT) remain low for localized tumors, whereas in advanced loco-regional disease they occur in over 60% of all cases. Several combinations of treatment modalities have been attempted in order to improve local control in Stages III and IV. Unfortunately, the recurrence rate remains high with added morbidity when conventional surgery is combined with pre or post-operative radiotherapy. Induction chemotherapy (CT) with Cisplatinum and Bleomycin has resulted in severe toxicities when combined with radiotherapy. To evaluate the toxicity of Carboplatin (CBDCA), a second generation platinum analog, when given simultaneously with conventional doses of radiotherapy, 26 patients with Stage IV SQC of the head and neck were treated at the University of Maryland Medical Systems. There were 23 males and 3 females; median age was 59 years and median Karnofski performance status was 60. Twenty patients had received no prior therapy; six had surgical exploration and excision with measurable residual disease. Anatomically, six patients had tumors of the oral cavity, twelve in the pharynx, one in the nasopharynx, four in the larynx, one in the hypopharynx, one in the maxillary antrum, and one was an unknown primary. These patients were treated as out-patients with weekly injections of Carboplatin. The dose was escalated: two patients received 60 mg/M2, seven received 75 mg/M2, thirteen were treated with 100 mg/M2, and four with 400 mg/M2. The radiotherapy was given daily with conventional fractions of 180 cGy and total tumor doses of 60-75 Gy. Toxicities were mainly hematological with median nadirs decreasing with increasing doses of Carboplatin. Mucositis was seen in over 80% of the patients, but interestingly enough, it has never been more severe than that observed with radiotherapy alone. So far, there has not been any kidney, ear, or neurotoxicities. Of 25 evaluable patients, 19 (76%) responded with 13 (52%) showing complete response. The overall median survival time is 266+ days (324+ for responders and 179+ for non-responders). The follow-up is still short, 10-14 months, but 9 of 13 patients with complete response have not yet progressed.