Charles E. Riggs

ADULT HEAD AND NECK SOFT TISSUE SARCOMAS

The purpose was to determine the optimal treatment for adult patients with head and neck soft tissue sarcomas.

Altered fractionation and/or adjuvant chemotherapy in definitive irradiation of squamous cell carcinoma of the head and neck

Objective To review the roles of altered fractionation and adjuvant chemotherapy in the treatment of patients with squamous cell carcinomas of the head and neck.

Sinonasal undifferentiated carcinoma.

Purpose:The purpose of this paper is to discuss the treatment and outcomes for patients with sinonasal undifferentiated carcinoma. Methods:Review of the pertinent literature. Results:Most series contain a limited number of patients treated with various combinations of surgery, radiotherapy (RT), and chemotherapy. Follow-up periods for disease-free patients are sometimes relatively short. The majority of patients present with locally advanced tumors; 10% to 30% have clinically positive regional nodes. The risk of local–regional recurrence after treatment is probably 20% to 30% or higher, depending on the extent of disease. The likelihood of distant dissemination is approximately 25% to 30% and the cure rate varies from roughly 20% to 50%. Better outcomes are observed in patients treated with craniofacial resection combined with pre- or postoperative RT alone or with adjuvant chemotherapy. This is probably due, in part, to selection bias. Patients with incompletely resectable tumors are best treated with definitive RT and adjuvant chemotherapy. Conclusion:The optimal treatment is craniofacial resection combined with adjuvant RT alone or with chemotherapy. The risk of relapse is relatively high and the probability of cure is modest. Patients with incompletely resectable tumors may sometimes be cured with definitive chemoradiation.

Adjunctive therapy (whole body hyperthermia versus lonidamine) to total body irradiation for the treatment of favorable b-cell neoplasms: a report of two pilot clinical trials and laboratory investigations

Based on earlier clinical and preclinical investigations, we designed two different pilot trials for patients with nodular lymphoma or chronic lymphocytic leukemia. These studies evaluated the use of either 41.8 degrees C whole body hyperthermia (WBH), or the nonmyelosuppressive chemotherapeutic drug, lonidamine (LON), as an adjunct to total body irradiation (TBI) (12.5 cGy twice a week, every other week for a planned total dose of 150 cGy). Whole body hyperthermia was initiated approximately 10 min after total body irradiation; lonidamine was administered orally (420 mg/m2) on a daily basis. Although entry to the studies was nonrandomized, the two patient populations were accrued during the same time frame and were comparable in terms of histology, stage of disease, performance status, and prior therapy. Of 8 patients entered on the TBI/WBH study, we observed 3 complete responses (CR), 4 partial responses (PR), and 1 improvement (i.e., a 48% decrease in tumor burden). Of 10 patients entered in the TBI/LON study, there was 1 CR and 4 PR. For the TBI/WBH study, myelosuppression was not treatment-limiting; there were no instances of infection or bleeding and platelet support was never required. The median survival time for the TBI/WBH study is 52.5 months based on Kaplan Meir estimates. Two patients remain in a CR. The median time to treatment failure (MTTF) is 9.4 months (90% confidence interval = 7-15.4 months). In the TBI/LON study, 50% of patients receiving TBI required treatment modification due to platelet-count depression during therapy, but there were no instances of infection or bleeding. Frequently observed LON-related toxicities included myalgias, testicular pain, photophobia and ototoxicity. For the TBI/LON study, median survival is 7.6 months; MTTF was 2.4 months. In analyzing the results of these pilot studies, our subjective clinical impressions lead to the hypothesis that WBH protected against TBI-induced thrombocytopenia during therapy, whereas LON had no effect on TBI-induced myelosuppression. This speculation was tested and confirmed in a series of in vitro and in vivo experiments.

Combination chemotherapy with adriamycin and streptozotocin; II. Clinicopharmacologic correlation of augmented adriamycin toxicity caused by streptozotocin

Plasma pharmacokinetics were compared in patients with advanced sarcomas receiving adriamycin, 60 mg/m2 intravenously (iv) on day 1 every 3 wk in combination with streptozotocin, 500 mg/m2/day iv on days 1 to 5 every 3 wk, and patients receiving adriamycin alone in the same dose and schedule. The combination‐treated group had greater adriamycin drug exposure (concentration × time) when serial plasma levels were analyzed by fluorescence assay and by radioimmunoassay (RlA). The plasma t½ of adriamycin equivalents measured by fluorescence assay was also significantly prolonged in the combination‐treated group. These changes correlated welt with an increase in adriamycin‐related toxicity—mucositis and myelosuppression—seen in the patients who received the combination drug therapy. Plasma streptozotocin kinetics and the incidence of streptozotocin‐related side effects—hepatic and renal function abnormalities—were those published for streptozotocin alone. Evidence is presented to support the hypothesis that the increased incidence of adriamycin side effects is due to streptozotocin‐related hepatic dysfunction, affecting both the detoxification and excretion of adriamycin. Combination of other drugs with adriamycin should take into account their potential for inducing hepatic dysfunction which may affect the therapeutic index of adriamycin.

Racial disparity in oral and pharyngeal cancer in Florida in 1991-2008: mixed trends in stage of diagnosis.

OBJECTIVES To explore changes in distribution of stage at diagnosis among individuals with oral and pharyngeal cancers over the past two decades and whether the changes differ by race. METHODS We obtained 1991-2008 cancer incidence data for nine anatomic sites of the oral and pharyngeal structure from the Florida Cancer Data System. These cancers were grouped into oral squamous cell carcinoma (SCC), pharyngeal SCC, and other head and neck cancers. Annual percent change was calculated for each group to characterize trends in age-adjusted cancer incidence over time by race and stage at diagnosis. RESULTS During 1991-2008, the overall age-adjusted oral SCC incidence was decreasing for both races, with a greater decline observed among Blacks. There was a large drop in incidence of regional-stage diagnoses among Blacks. For pharyngeal SCC, the age-adjusted incidence of localized- and regional-stage diagnoses was increasing for Whites during 1991-2008, with the largest increase in the incidence of regional-stage diagnoses. The percentage of localized-stage diagnoses was increasing for both races for oral SCC. A slight increase in percentage of localized-stage diagnoses was observed for Blacks for pharyngeal SCC, whereas no obvious change was observed among Whites. CONCLUSIONS Blacks continued to have lower percentages of localized-stage diagnoses than Whites for nearly all sites, but an increasing percentage of localized-stage diagnoses was observed for oral SCC among Blacks. For pharyngeal SCC, the increase in incidence among Whites was accompanied by an increasing percentage of late-stage diagnoses. Coordinated public health approaches with a special emphasis on screening underserved populations are needed.

Initial Observations on the Effects of Δ9-Tetrahydrocannabinol on the Plasma Pharmacokinetics of Cyclophosphamide and Doxorubicin

Abstract: We studied the effect of THC upon the pharmacokinetics of cyclophosphamide (CTX) and doxorubicin (ADR). Plasma THC was determined by RIA. Plasma concentrations of CTX and ADR were measured by GLC and fluorescence, respectively. RIA confirmed plasma levels of THC >20 ng/ml for patients who received THC. CTX half‐life was not significantly changed with use of THC (7.7 ± 3.6 hours without versus 5.25 ± 2.6 hours with THC). ADR half‐life with THC was greater than without THC (175 ± 197 hours versus 92 ± 92 hours, respectively). Total drug exposure as determined by areas under the curves were similar (12.4 ± 6 μM · hr without versus 13.8 ± 4 μM · hr with THC). These preliminary data suggest that RIA is reliable for assessing THC plasma concentrations. THC induces no apparent alterations of CTX or ADR pharmacokinetics.

Definitive altered fractionation radiotherapy and concomitant weekly cisplatin for locally advanced head and neck cancer.

Background:The purpose of this study was to determine the efficacy and toxicities of single-agent weekly cisplatin for patients with squamous cell carcinoma of the head and neck treated definitively with radiation therapy (RT). Methods:Thirty-five patients with American Joint Committee of Cancer stage II (3%), stage III (14%), or stage IV (83%) squamous cell carcinoma of the oropharynx, larynx, or hypopharynx treated from June 2000 to November 2003 at the University of Florida were retrospectively reviewed. Subjects received radiation therapy (RT; median, 74.4 Gy) and cisplatin, 30 mg/m2/wk. Altered fractionation was used in 34 of 35 (97%) patients. The endpoints were best response, percentage of grade III or IV toxicities, local-regional control, disease-free survival, cause-specific survival, and overall survival. Results:The median number of cycles of cisplatin administered was 6. Grade III or IV toxicities were: anemia, 11%; thrombocytopenia, 6%; leukopenia, 26%; and mucositis, 23%. No patients had renal failure and 1 patient (3%) died because of therapy-related complications. Responses to therapy included 71% complete response, 17% partial response, and 6% stable disease. Median follow-up for all patients was 1.8 years (range, 0.1–7.8 years); median follow-up for living patients was 4.4 years (range, 2.6–7.8 years). The 3-year outcomes were: local-regional control, 85%; disease-free survival, 56%; cause-specific survival, 59%; and overall survival, 40%. Conclusion:Concomitant weekly CDDP with definitive RT is feasible, tolerable, highly active, and comparable with more complex, costly, and toxic regimens. Intercurrent disease was a significant contributor to mortality in our population. Our regimen is an attractive alternative to sequential chemoradiotherapy programs.

Continuous infusion, intravesical doxorubicin for the treatment of regionally advanced bladder cancer : A phase I-II trial

Patients with regionally advanced bladder cancer not considered candidates for definitive surgical intervention underwent continuous antegrade infusion of doxorubicin by percutaneous nephrostomy tube. Doxorubicin was administered for 7 consecutive days at a rate designed to achieve target urinary concentrations (range 5-80 micrograms/ml). Urine and serum concentrations of doxorubicin were monitored daily. Toxicity was assessed by serial renal scans, antegrade nephrostograms, blood counts, and serum chemistries. Patients were restaged after three cycles of therapy. In all, 23 cycles, constituting 156 days of therapy, were administered to 10 patients. Target urinary drug levels were achieved during all cycles. Total doxorubicin dose ranged from 125 to 2,500 mg. No systemic (neutropenia or myocardial dysfunction) or regional toxicity (extravasation, sepsis, stricture) was noted. Five of 10 patients tolerated the planned three treatment cycles. Poor performance status (PS, Eastern Cooperative Oncology Group: ECOG 3) strongly correlated with treatment intolerance and early death from disease. After three cycles of therapy, 2 of 5 evaluable patients had stable disease, I had radiographic partial response (PR) with a biopsy demonstrating extensive tumor necrosis, I had no identifiable tumor at the time of restaging transurethral resection of bladder tumor (TURBT), and a final patient with upper and lower tract carcinoma in situ (CIS) was cytologically staged NED. (no evidence of disease). These findings demonstrate the feasibility and low toxicity of this approach.

Phase II trial of edatrexate in patients with metastatic colorectal cancer.

SummaryEdatrexate is an analog of methotrexate whichin vitro demonstrated activity against human colon cancer xenografts grown in nude mice. In a phase II trial, 12 patients with metastatic colorectal cancer and no prior chemotherapy were treated with Edatrexate 80 mg/m2/week for an initial period of 8 weeks. No objective responses were observed. Edatrexate is inactive against colon cancer at the dose and schedule used in this trial.