Glenn S. Kroog

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.

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.

Flutamide withdrawal plus hydrocortisone resulted in clinical complete response in a patient with prostate carcinoma

Combined androgen blockade (CAB) (medical or surgical castration plus antiandrogen therapy) is considered by many to be the optimal endocrine maneuver for patients with metastatic prostate carcinoma. When progression occurs after CAB, the discontinuation of the antiandrogen is recommended. The authors present a patient that had a clinical complete response to flutamide withdrawal plus hydrocortisone that, at last follow‐up, had been maintained for more than 46 months.

Acute arterial thrombosis in a patient with breast cancer after chemotherapy with 5-fluorouracil, doxorubicin, leucovorin, cyclophosphamide, and interleukin-3

Background. Interleukin‐3 (IL‐3) is an experimental agent used to ameliorate neutropenia in patients receiving chemotherapy. Arterial thrombotic episodes after use of IL‐3 have not been reported previously.

In Vitro Analysis of Bombesin/Gastrin-Releasing Peptide Receptor (bb2) Ligand Binding and G-Protein Coupling

Bombesin/gastrin releasing peptide receptors (GRP-R, or bb2) mediate a broad spectrum of biological responses including secretion of other peptide hormones, gastric acid secretion, smooth muscle contraction, modulation of neuron firing rate, and growth regulation of both normal and neoplastic cells. Of particular interest, bombesin and its receptor have been shown to promote the growth of some human lung carcinoma cells by an autocrine mechanism, a phenomenon that is thought to play a pivotal role in the pathogenesis and progression of these tumors. These observations make the bb2 receptor a potentially important target for early intervention and prevention strategies. To develop these strategies, it is essential to understand the initial events in receptor mediated signal transduction: ligand binding and activation of Gq, a cognate heterotrimeric G protein for this receptor. We have developed in vitro assays for both ligand binding and G protein activation, which allow a quantitative analysis of the molecular pharmacology of both processes. In addition to providing important insights into the pharmacology of bb2, these in vitro assays provide a means to evaluate the utility and efficacy of compounds or drugs which may interfere with ligand binding and/or receptor/G-protein coupling.