Faculty Publications

Colorectal cancer is the second leading cause of cancer death in the United States. The nihilism that previously often characterized the treatment of patients with this disease has been replaced by a measure of excitement, given recent therapeutic advances. These advances have been stimulated in part through identification of cellular processes characteristic of colorectal cancers that permit therapeutic targeting with favorable therapeutic index. Inhibition of the epidermal growth factor receptor in the clinic has provided proof of principle that interruption of signal transduction cascades in patients with colorectal cancer has therapeutic potential. This experience has also taught us that resistance to such rationally developed targeted therapeutic strategies is common. In this article, we review the role of signal transduction in colorectal cancer, introduce promising molecular targets, and outline therapeutic approaches under development. We will describe the barriers t o success, and highlight paradigms to facilitate rapid and successful evaluation of new agents, in a clinical context that has (by virtue of recent clinical successes) become a somewhat crowded playing field.

Background. Patients with local recurrences or new head and neck primary tumors in previously irradiated tissues have few options for salvage treatment. One option for select patients is to undergo reirradiation with concurrent chemotherapy. The purpose of this study is to report the initial clinical results of the Fox Chase phase I and II prospective reirradiation and chemotherapy studies. Methods. Between July 1996 and January 2002, 38 patients with locally recurrent unresectable squamous cell carcinoma of the head and neck were treated with concurrent chemotherapy and reirradiation on two prospective trials. All patients had received prior radiation therapy to the head and neck region (median dose, 64.2 Gy). Patients received cisplatin and paclitaxel along with hyperfractionated external beam radiation therapy to the site of recurrence. Results. The median follow-up was 10 months. The median survival was 12.4 months, with actuarial rates of overall survival of 50% and 35% at 1 and 2 years, respectively. During follow-up, 63% of patients experienced local progression of disease, all in the irradiated field. Actuarial progression-free survival at 1 year was 33%, with a median time to progression of 7.3 months. Acute grade 3 to 4 toxicity included neutropenia, nausea, emesis, and mucositis. Conclusions. Hyperfractionated split-course reirradiation and concurrent cisplatin and paclitaxel chemotherapy demonstrates durable locoregional control in select patients, although late toxicity may occasionally be significant. Only sites of disease recurrence need to be covered in the reirradiation fields. © 2005 Wiley Periodicals, Inc.

BACKGROUND: Paclitaxel (24-h infusion) has yielded activity in advanced squamous cell carcinoma of the head and neck (SCCHN). Protracted exposure to paclitaxel may overcome resistance obsd. by using shorter infusions. Therefore we sought to evaluate paclitaxel by 96-h infusion in both treatment-naive and previously treated patients with SCCHN. MATERIALS AND METHODS: Eligibility stipulated bidimensionally measurable, biopsy-documented, incurable SCCHN, Eastern Cooperative Oncol. Group performance status (PS) 0-1, and adequate physiol. indexes. Patients were divided into three cohorts: (1) chemotherapy-naive; (2) chemotherapy-exposed, paclitaxel-naive; and (3) chemotherapy and paclitaxel exposed. Paclitaxel was dosed at 140 mg/m2 (96-h infusion) every 3 wk in treatment-naive patients and at 120 mg/m2 (96 h) every 3 wk in previously treated patients. RESULTS: Fifty patients were accrued between Feb. 1997 and July 2000. The study was terminated because of low response rate. Eighty percent of patients were male, 75% PS 1. Nearly half the patients had oropharyngeal or hypopharyngeal primary sites. There was one treatment-related death due to neutropenic fever/pneumonia. Grade 4 toxicities included granulocytopenia in eight patients (20%), thrombocytopenia, and stomatitis in one patient each. Grade 3 or greater anemia occurred in 10 patients. There was no grade 2 or 3 peripheral sensory neuropathy. In 15 chemotherapy-naive patients, two responses (13%) were obsd. There were no responses in treatment-exposed patients. The overall median survival was 5.5 mo, and 1-yr survival rate 10%. Treatment-naive patients had a median survival of 8.2 mo and 1-yr survival rate of 20%. CONCLUSIONS: Paclitaxel by 96-h infusion at a dose of 120-140 mg/m2/96 h is only marginally active in the treatment of SCCHN. This dose and schedule cannot be recommended for further evaluation. [on SciFinder (R)]