Epidermal growth factor receptor blockade potentiates apoptosis mediated by Paclitaxel and leads to prolonged survival in a murine model of oral cancer.

PURPOSE: Because survival for patients with oral cancer has not improved over the past 25 years, new approaches for treatment are needed. Targeted molecular therapy against epidermal growth factor receptor (EGFR) has shown promise as an adjuvant therapy in preliminary studies in several solid tumors, including head and neck cancer. The objective of this study was to determine the efficacy of paclitaxel and PKI166, a novel inhibitor of EGFR, against oral cavity cancer. EXPERIMENTAL DESIGN AND RESULTS: JMAR human oral cancer cells were pretreated for 1 h with PKI166 and then stimulated with epidermal growth factor. EGFR-specific tyrosine kinase autophosphorylation measured by Western immunoblotting was inhibited by PKI166 in a dose-dependent fashion at all doses tested (0.01-1 micro M). Next, the induction of apoptosis in JMAR cells treated with paclitaxel (0.001 to 0.1 micro M) with or without PKI166 (0, 1, or 2 micro M) was determined using a propidium iodide assay. The addition of 2.0 micro M PKI166 significantly increased tumor cell death, shifting the amount of paclitaxel needed to induce apoptosis in 50% of cells from 0.1 to 0.001 micro M. These in vitro findings were confirmed using an orthotopic model of oral cancer. JMAR oral cancer cells were implanted into the tongues of nude mice. After lingual tumors developed, mice were randomized into four groups (n = 10): (a) oral PKI166 (100 mg/kg); (b) i.p. paclitaxel (200 micro g/wk); (c) PKI166 and paclitaxel; or (d) placebo. Mice treated with PKI166/paclitaxel demonstrated a significant increase in survival (P = 0.028). After necropsy, all tongue tumors were evaluated for apoptosis by the terminal deoxynucleotidyl transferase-mediated nick end labeling assay. A greater apoptotic fraction of tumor cells was found in tumors of mice treated with paclitaxel and PKI166 as compared with the other treatment groups (136.4 versus 37.8; P = 0.016). CONCLUSIONS: Combination therapy with paclitaxel and PKI166 prolongs survival in an orthotopic preclinical model of tongue cancer by increasing programmed cell death of oral cancer.

Facial nerve monitoring in chronic ear surgery: US practice patterns.

OBJECTIVE: The use of intraoperative facial nerve monitoring (IOFNM) improves facial nerve outcomes in acoustic neuroma surgery, but the role of IOFNM in chronic ear surgery (CES) is poorly defined. This study was performed to identify IOFNM practice patterns in the United States for CES. METHODS: A 10-item survey was mailed to a random sample of 500 active members of the American Academy of Otolaryngology-Head and Neck Surgery. RESULTS: The overall response rate was 45.2%. Of the respondents, 75% had access to IOFNM, and of this group, 66% used IOFNM at least some of the time. Otolaryngologists trained in the 1990s (P < 0.0001), those in an academic setting (P = 0.02), and those who perform more otologic than other types of surgery (P = 0.004) were more likely to use IOFNM. Although most respondents had access to IOFNM, only 32% thought that IOFNM should be required for CES. CONCLUSIONS: The majority of otolaryngologists who perform CES have access to IOFNM and will use it at least some of the time. IOFNM use is especially prevalent in otolaryngologists who have trained recently and in more experienced otologic surgeons. However, there are strong feelings against requiring IOFNM for CES.

Disparity in pathologic and clinical lymph node staging in oral tongue carcinoma. Implication for therapeutic decision making.

BACKGROUND: Regional lymph node metastasis is the most reliable predictor of treatment outcomes for patients with squamous cell carcinoma of the oral tongue (SCCOT). A recent American Joint Committee on Cancer staging update of malignant melanoma has incorporated pathologic lymph node staging. The authors hypothesized that pathologic lymph node staging (pN) would be a more reliable predictor of treatment outcomes than clinical lymph node staging (cN). METHODS: The authors retrospectively reviewed 266 patients who received primary surgical treatment for SCCOT, including a neck dissection, from January 1980 to December 1995. Overall and disease-specific survival and disease-free interval were compared with respect to clinical and pathologic lymph node stages. RESULTS: Statistically significant survival differences were identified for both clinical (cN0-cN2) and pathologic lymph node stages (pN0-pN2). However, survival and disease-free interval differences for pathologic lymph node staging reached higher statistical significance (P < 0.0001) than for clinical lymph node staging (P < 0.002). This disparity can be explained by stage migration (i.e., patients with cN0-1 disease have a more advanced lymph node stage at the time of pathologic review compared with patients without cN0-1 disease). The authors found a 34% rate of occult lymph node disease in the cN0 group (19% of occult lymph nodes had extracapsular spread [ECS]). Similarly, 43% of cN1 patients had a higher stage than pN2b disease and 50% had ECS. CONCLUSIONS: Pathologic lymph node staging, based on a staging or therapeutic neck dissection, should be considered for patients treated for SCCOT to identify high-risk patients who may benefit from additional adjuvant therapy. Prospective studies are essential to validate these findings before pathologic lymph node staging is included in standard staging criteria.

Extent of extracapsular spread: a critical prognosticator in oral tongue cancer.

BACKGROUND: Extracapsular spread (ECS) of metastatic squamous cell carcinoma of the head and neck to regional lymph nodes is the most reliable predictor of poor treatment outcomes. Recently, the authors have shown that ECS is significantly associated with higher rates of locoregional recurrence, distant metastasis, and decreased survival in patients with squamous cell carcinoma of the oral tongue (SCCOT). The purpose of this review was to determine if the degree of ECS impacts distant metastasis rates and survival. METHODS: Two hundred sixty-six patients treated for SCCOT with surgery +/- adjuvant radiotherapy from 1980-1995 were reviewed. The setting was a tertiary referral center. The extent of ECS on histopathologic review of involved lymph nodes was measured from the capsular margin to the farthest perinodal extension in mm. Extent of ECS and the number of pathologic lymph nodes with or without ECS were analyzed for disease-free interval, survival rates, and distant metastases. RESULTS: No differences in the survival of patients with ECS of 2 mm was found (P = 0.92). Patients with both ECS and multiple positive lymph nodes had decreased overall survival (P = 0.0003), disease-specific survival (P = 0.0005), and a shorter disease-free interval (P = 0.019) when compared with those with a single positive lymph node with ECS. Those with multiple ECS+ lymph nodes had the worst prognosis (P = 0.001). CONCLUSIONS: Based on these findings, the authors recommended that all patients with SCCOT with ECS or multiple positive lymph nodes with or without ECS on pathologic review be considered for clinical trials that intensify regional and systemic adjuvant therapy.