Laurie L. Herscher

A pilot study of longitudinal serum cytokine and angiogenesis factor levels as markers of therapeutic response and survival in patients with head and neck squamous cell carcinoma

Head and neck squamous cell carcinomas (HNSCCs) were previously shown to express a repertoire of cytokines and angiogenesis factors that contribute to malignant pathogenesis and are detectable in serum. Pretreatment and posttreatment serum levels of cytokines and angiogenesis factors were evaluated as markers for outcome in patients with HNSCC.

Concurrent Paclitaxel and Radiation in the Treatment of Locally Advanced Head and Neck Cancer

PURPOSE To determine the feasibility of an organ preservation regimen consisting of infusional paclitaxel administered concurrently with radiotherapy to patients with locally advanced head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS Thirty-three previously untreated patients with stage III or IV tumors were enrolled onto the study. Paclitaxel was administered as a 120-hour continuous infusion every 3 weeks during the course of radiation therapy. Sixteen patients received a paclitaxel dose of 105 mg/m(2), and 17 patients received 120 mg/m(2). Radiation was delivered in a standard format at 1.8 Gy/d to a total dose of 70.2 to 72 Gy. RESULTS Three months after therapy, a 76% complete response (CR) at the primary site and a 70% overall CR was achieved. At 36 months, locoregional control was 55.7%, overall survival was 57.8%, and disease-free survival was 51.1%. The median survival duration for all 33 patients was greater than 50 months at the time of this report. Local toxicities including mucositis, dysphagia, and skin reactions were severe but tolerable. All patients retained functional speech, and all but four patients were swallowing food 3 months after treatment. Steady-state plasma concentrations for paclitaxel were not achieved during a 120-hour infusion, suggesting a nonlinear process. Tumor volume quantified by pretreatment computerized tomography imaging was associated with likelihood of response and survival. CONCLUSION Paclitaxel administered as a 120-hour continuous infusion in combination with radiotherapy is a feasible and promising treatment for patients with advanced HNSCC.

Radiation Dose to Otologic Structures During Head and Neck Cancer Radiation Therapy

Background: Otologic structures are often contained within head and neck cancer radiation treatment ports. The dosimetry to otologic structures has not been routinely analyzed and radiation treatment planning does not currently attempt to specifically avoid the inner ear structures when dosimetry is calculated. Recent studies demonstrate that up to 30% of patients experience sensorineural hearing loss on multimodality therapy with cisplatin and radiation.

NATIONAL CANCER INSTITUTE (PHASE II) STUDY OF HIGH-GRADE GLIOMA TREATED WITH ACCELERATED HYPERFRACTIONATED RADIATION AND IODODEOXYURIDINE: RESULTS IN ANAPLASTIC ASTROCYTOMA

PURPOSE We report the outcome of a Phase II study of a cohort of patients with high-grade glioma treated with accelerated hyperfractionated radiation and the radiation sensitizer, iododeoxyuridine (IdUrd). METHODS AND MATERIALS Between January 1988 and December 1990, 39 consecutive patients with high-grade glioma were enrolled and treated on a Phase II protocol including hyperfractionated radiation and IdUrd. Thirty-two patients were male and seven were female. Age range was 19 to 71 years with a median age of 38 years. IdUrd (1000 mg/m2 per day) was administered in two separate 14-day courses, the first during the initial radiation field and the second during the final cone-down field. All patients were treated consistently with partial brain technique and received 1.5 Gy/fraction twice daily to a mean total dose of 71.25 Gy (range 66-72 Gy excluding one patient who did not complete treatment). The initial field was treated to 45 Gy followed by a cone-down field covering the tumor volume plus a 1-cm margin to the final dose. Patients were assessed for acute and long-term morbidity and followed for outcome. Two patients had biopsies during the course of treatment. Flow cytometry and high performance liquid chromatography was used to evaluate the labeling index and the percent replacement of IdUrd in the biopsy specimen. RESULTS Thirty-eight of 39 patients completed therapy. One patient died on treatment at 48 Gy and is included in the survival analysis. No patient was lost to follow-up. Twenty-one patients had Grade 3 (anaplastic astrocytoma) tumors and 18 patients had Grade 4 (glioblastoma multiforme). Median survival for the entire cohort was 23 months. For the glioblastoma multiforme patients, median survival was 15 months. The median survival of the anaplastic astrocytoma patients has not yet been reached. In the patients assessed, the range of IdUrd tumor cell incorporation was only 0-2.4%. CONCLUSION Accelerated hyperfractionated radiation therapy with IdUrd was administered with acceptable acute toxicity. The major acute side effects of mucositis and thrombocytopenia were related to IdUrd infusion and were dose-dependent. There were no unacceptable acute toxicities referable to the radiation as delivered. With a median potential follow-up of 51 months, the actuarial median survival of the glioblastoma multiforme patients is comparable with the best previously published reports. The outcome of patients with anaplastic astrocytoma compares very favorably with even the most aggressive multi-modality approaches in the recent literature with a minimum of acute morbidity.

Phase I study of weekly gemcitabine as a radiation sensitizer for unresectable pancreatic cancer.

PURPOSE To determine the maximal tolerated dose and dose-limiting toxicities (DLTs) of weekly gemcitabine with concurrent radiotherapy (RT) in patients with unresectable adenocarcinoma of the pancreas. METHODS AND MATERIALS Patients who had locally advanced or recurrent unresectable pancreatic cancer were eligible. Gemcitabine was administered as a 30-min infusion once weekly for a total of five cycles during the course of RT. The starting dose of gemcitabine was 350 mg/m(2)/wk. Doses were escalated by increments of 25% in successive cohorts of 3-6 patients. RT was delivered at 180 cGy/d to a total dose of 5400-5580 cGy to the gross tumor volume. RESULTS Nineteen patients were entered in this study through three dose levels (350-550 mg/m(2)/wk). The maximal tolerated dose was determined to be 440 mg/m(2)/wk. The DLTs were neutropenia, thrombocytopenia, and failure to receive all five cycles of gemcitabine. Other non-DLTs included 16 Grade III toxicities, which consisted of thrombosis, infection, nausea, vomiting, hypotension, constipation, diarrhea, and fatigue. One patient at each gemcitabine dose level experienced Grade IV vomiting, and the patient at the 550 mg/m(2) dose developed Grade IV anorexia. CONCLUSION The maximal tolerated dose of gemcitabine when administered as a 30-min infusion once weekly during RT for unresectable pancreatic cancer was found to be 440 mg/m(2)/wk. The DLTs were neutropenia, thrombocytopenia, and failure to receive all five cycles of chemotherapy. Concurrent gemcitabine and RT is reasonably well tolerated and deserves additional evaluation against the current standard of care.

Phase I study of paclitaxel as a radiation sensitizer in the treatment of mesothelioma and non-small-cell lung cancer.

PURPOSE To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of paclitaxel with concurrent thoracic irradiation in patients with malignant pleural mesothelioma and locally advanced non-small-cell lung cancer (NSCLC) using a 120-hour continuous infusion regimen. A secondary objective was to assess the effect of paclitaxel on the cell cycle through serial tumor biopsies. PATIENTS AND METHODS Paclitaxel was administered as a 120-hour (5-day) continuous infusion repeated every 3 weeks during the course of radiation therapy. The starting dose of paclitaxel was 90 mg/m2. Doses were escalated at 15-mg/m2 increments in successive cohorts of three patients. In NSCLC patients, radiation was delivered to the primary tumor and regional lymph nodes for a total tumor dose of 6,120 cGy. In mesothelioma patients, hemithoracic irradiation was delivered as the initial treatment field with a conedown to the tumor volume for a total dose of 5,760 to 6,300 cGy. Tumor biopsies were obtained, if possible, before and during paclitaxel treatment. RESULTS Thirty patients were entered onto this study through three dose levels (from 90 mg/m2 to 120 mg/m2). The MTD was determined to be 105 mg/m2. The dose-limiting toxicity was grade 4 neutropenia (two patients). Grade 2 gastrointestinal (GI) toxicity (nausea and vomiting) was also observed at 120 mg/m2. Three of 30 patients developed a hypersensitivity reaction. Six patients had grade 2 lung injury manifested by a persistent cough that required antitussives. Five patients underwent tumor biopsies. None of the patients showed a significant block of cells in mitosis (G2/M) after paclitaxel infusion. CONCLUSION The MTD of paclitaxel, when administered as a 120-hour continuous infusion with concurrent radiotherapy, was determined to be 105 mg/m2. The dose-limiting toxicity was neutropenia. Continuous infusion paclitaxel administered with large field irradiation of the lung is well tolerated and deserves continued evaluation.

Taxanes as radiosensitizers for head and neck cancer.

Combinations of paclitaxel and radiation therapy or paclitaxel with other chemotherapy agents and radiation have been tested with variable results in patient populations. To date, three phase I trials have been conducted using paclitaxel alone in combination with radiotherapy for the treatment of patients with head and neck cancer. Dose-limiting toxicity in the 1-hour infusion was mucositis, whereas in the 24-h/wk infusion, fever was the dose-limiting toxicity. In the long-term infusion (24 h/d, 7 d/wk), no dose-limiting toxicity was seen at the doses of paclitaxel given. In two of the protocols in which biopsies were obtained, a G2/M block was observed. A phase I protocol using paclitaxel in combination with fluorouracil and hydroxyurea with radiation and a phase II protocol using paclitaxel with cisplatin in operable head and neck cancers have been reported. Preliminary results suggest that paclitaxel in combination with radiotherapy is a reasonable experimental treatment that deserves further study in patients with stage III and IV squamous cell carcinomas of the head and neck.

Intraperitoneal gemcitabine therapy for advanced adenocarcinoma of the pancreas

S: PLENARY and PARALLEL SESSIONS ciated with reduced risk of pancreatic leak. Conclusion: Neo-CRT does not increase the mortality or morbidity of PD. In contrast, neo-CRT was associated with a marked reduction in the incidence of pancreatic leak as well as leakassociated morbidity. 17 Complete Response to Neoadjuvant Chemoradiation Therapy for Esophageal Cancer Does Not Confer a Survival Advantage C.R. Schmidt, l* J.L. Tarpley, 2 J.R. Roberts, i A.S. Pearson l M.C. Kelley, 1 M. Ninan,lj .D. Berlin, 1 A.B. Chakravarthy, i R.D. Beauchamp, I N.B. Merchant. 1 1. Vanderbilt Universi.ty Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN; 2. Nashville Veterans Administration Hospital, Nashville, TN. INTRODUCTION: Randomized trials ofneoadjuvant chemoradiation therapy for esophageal cancer (Neo) have yielded conflicting results. It has been suggested that a complete response following Neo for esophageal cancer confers a survival advantage. The purpose of our study is to determine if patients with complete response (CR) after Neo for esophageal cancer have improved overall survival (OS), disease-specific survival (DSS) or disease-free survival (DFS) compared to those who do not have a CR (No CR). METHODS: 147 consecutive patients who underwent surgical resection for esophageal cancer were retrospectively reviewed. CR was defined as pathologic stage 0 at resection after chemoradiation therapy. Patients with stage IV disease were excluded. Median follow-up time was 21 months overall and 26 months for survivors. Thirty day operative mortality for all patients was 3.4% (n=5). 118 patients received Neo and 29 underwent resection alone. 41 patients had a squamous cell carcinoma (SCC) and 106 had an adenocarcinoma (AC). Survival analysis was performed using the Kaplan-Meier method and statistical significance determined by the log rank test. RESULTS: Of the 118 patients that received Neo followed by surgical resection, 38 (32%) had a CR while 80 (68%) had No CR. There was no statistically significant difference in OS, DSS or DFS between those who had a CR versus No CR (P=0.42, 0.21, 0.23, respectively). Stratifying for AC versus SCC did not influence survival outcomes. There was no significant difference in 30-day mortality between those who had Neo followed by resection vs. those who underwent resection alone (n=3 vs. 2 respectively, P=0.256, Fishers Exact Test) nor was there any difference in overall complications (n=34 vs. 9 respectively, P-0.503, Chi-square). CONCLUSION: CR to Neo followed by surgical resection does not confer a survival advantage compared to those with No CR. We must continue to explore other avenues of therapy for patients with locally advanced esophageal cancer.