Nuclear factor-kappa B pathway and response in a phase II trial of bortezomib and docetaxel in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Our previous study has shown that nuclear factor-kappa B (NF-kappaB)-signaling pathway was associated with a higher rate of recurrence in head and neck squamous cell carcinoma (HNSCC). The combination of bortezomib, an NF-kappaB inhibitor by inhibition of proteasomes, plus docetaxel was assessed for efficacy and toxicity. MATERIALS AND METHODS: Patients with recurrent and/or metastatic HNSCC were enrolled on a phase II bortezomib/docetaxel trial (bortezomib 1.6 mg/m(2) and docetaxel 40 mg/m(2) on days 1 and 8 of a 21-day cycle). Response was assessed using RECIST. Tissue specimens were evaluated for the presence of human papillomavirus (HPV) and expression of NF-kappaB-associated genes. RESULTS: Twenty-one of 25 enrolled patients were assessable for response; one partial response (PR, 5%), 10 stable disease (SD, 48%) and 10 progressive disease (PD, 48%). Patients with PR/SD had significantly longer survival compared with patients with PD and the regimen was well tolerated. Only one of 20 tumors was positive for HPV. Patients with PD had higher expression of NF-kappaB and epidermal growth factor receptor-associated genes in their tumors by gene expression analysis. CONCLUSION: Further understanding of treatment resistance and interactions between bortezomib and docetaxel may provide novel approaches in managing HNSCC.

Microsatellite mutations in buccal cells are associated with aging and head and neck carcinoma.

Carcinogen exposure from tobacco smoking is the major cause of upper aerodigestive tract cancer, yet heavy smokers only have about a 10% life-time risk of developing one of these cancers. Current technologies allow only limited prediction of cancer risk and there are no approved screening methods applicable to the general population. We developed a method to assess somatic mutational load using small-pool PCR (SP-PCR) and analysed mutations in DNA isolated from cells obtained by mouth rinse. Mutation levels in the hypermutable tetranucleotide marker D7S1482 were analysed in specimens from 25 head and neck squamous carcinoma (HNSCC) cases and 31 controls and tested for associations with age, smoking history and cancer status. We found a significant association between mutation frequency and age (P=0.021, Generalized Linear Model (GLM), N=56), but no influence of smoking history. Cases had higher mutation frequencies than controls when corrected for the effects of age, a difference that was statistically significant in the subgroup of 10 HNSCC patients who were treated with surgery only (P=0.017, GLM, N=41). We also present evidence that cancer status is linked to levels of nonunique, and presumably clonally derived, mutations in D7S1482. Insertion mutations were observed in 833 (79%) of 1058 alleles, of which 457 (43%) could be explained by insertion of a single repeat unit; deletion mutations were found in 225 (21%) of tested alleles. In conclusion, we demonstrate that the sensitive detection of single molecule mutations in clinical specimens is feasible by SP-PCR. Our study confirms an earlier report that microsatellite mutations increase with age and is the first to provide evidence that these mutations may be associated with cancer status in individual subjects.

Phase I study of paclitaxel given by seven-week continuous infusion concurrent with radiation therapy for locally advanced squamous cell carcinoma of the head and neck.

PURPOSE: Paclitaxel is one of the most active agents for squamous cell carcinoma of the head and neck (SCCHN) and an in vitro radiosensitizer. The dose-response relationship for paclitaxel may depend more on exposure duration than on peak concentration. This National Cancer Institute-sponsored phase I trial was designed to determine the feasibility of combining continuous-infusion (CI) paclitaxel with concurrent radiation therapy (RT). PATIENTS AND METHODS: Patients with previously untreated stage IVA/B SCCHN were eligible. Primary end points were determination of the maximum-tolerated dose, dose-limiting toxicity, and pharmacokinetics for paclitaxel given by CI (24 hours a day, 7 days a week for 7 weeks) during RT (70 Gy/7 weeks). RESULTS: Twenty-seven patients were enrolled and assessable for toxicity. Nineteen of the patients who completed > or = 70 Gy were assessable for response. Grade 3 skin and mucosal acute reactions occurred at 10.5 mg/m(2)/d, but uninterrupted treatment was possible in five of six patients. At 17 mg/m(2)/d, skin toxicity required a 2-week treatment break for all three patients. The mean paclitaxel serum concentration at dose levels > or = 6.5 mg/m(2)/d exceeded that reported to achieve in vitro radiosensitization. Initial locoregional control was achieved in 14 (58%) of 24 of patients treated to 70 Gy, and control persisted in nine (38%). CONCLUSION: CI paclitaxel with concurrent RT is a feasible and tolerable regimen for patients with advanced SCCHN and good performance status. Preliminary response and survival data are encouraging and suggest that further study is indicated. The recommended phase II dose of paclitaxel by CI is 10.5 mg/m(2)/d with RT for SCCHN.

Hypothyroidism after treatment for nonthyroid head and neck cancer.

OBJECTIVES: To determine the incidence of posttreatment hypothyroidism in patients treated with surgery with or without radiotherapy for advanced-stage nonthyroid head and neck cancer and to make recommendations for its detection. DESIGN: A prospective study to assess the incidence and time frame of occurrence of hypothyroidism in patients by primary tumor site and treatment modality. Thyroid function tests were performed preoperatively, at the first postoperative visit, and then approximately every 6 months. Patients were followed up for up to 3 years. SETTING: Arthur G. James Cancer Hospital and Research Institute, Columbus, Ohio. PATIENTS: A total of 251 patients with nonthyroid head and neck cancer were originally enrolled; 198 patients with evaluable data were studied to determine the incidence of posttreatment hypothyroidism. Approximately 80% of the patients had advanced stage (III or IV) or recurrent cancer. RESULTS: The overall incidence of posttreatment hypothyroidism was 15% in 198 patients followed up for a mean of approximately 12 months. Hypothyroidism developed in 12% of patients treated with nonlaryngeal surgery and radiotherapy. The group undergoing total laryngectomy (with thyroid lobectomy) and radiotherapy had a 61% incidence of hypothyroidism. The average time to detection of hypothyroidism was 8.2 months. CONCLUSIONS: Approximately 15% of patients treated for advanced head and neck cancer with surgery and radiotherapy will develop hypothyroidism. Those treated with total laryngectomy and radiotherapy are at greatest risk.

Systematic management of chyle fistula: the Southwestern experience and review of the literature.

Postoperative cervical chyle fistula after neck dissection is a complication with potentially serious morbidity. Once it is recognized, treatment decisions to optimize patient care can be difficult. Different management strategies have been advocated on the basis of institutional and personal experience. In this study we comprehensively review the published protocols and retrospectively review our experience in the management of 15 patients with chyle fistula. All patients in this study were given a trial of nonoperative management with nutritional modification, pressure dressings, and closed drainage. Medical management ultimately failed in 3 patients (20%). Two patients had prolonged courses of medical management with associated complications. An analysis of our data supports early operative intervention if the peak 24-hour drainage is greater than 1000 mL without a prompt response to medical management. Persistent low-output drainage after 10 days is associated with a prolonged management course and treatment-related complications. Optimal treatment of these patients is unclear.

Seven-week continuous-infusion paclitaxel concurrent with radiation therapy for locally advanced non-small cell lung and head and neck cancers.

The goal of these National Cancer Institute-sponsored phase I trials is to determine the feasibility, toxicity, and pharmacokinetics of continuous-infusion (24 hr/d, 7 d/wk, 7 weeks total) intravenous paclitaxel combined with standard, curative-intent thoracic radiation therapy (XRT) for previously untreated, locally advanced non-small cell lung cancer and squamous cell cancer of the head and neck (HNSCC). Eligible patients have locally advanced (T4NXM0 or TXN2-3M0) non-small cell lung cancer ineligible for potentially curative surgical resection or locally advanced HNSCC with an expected 5-year survival rate of less than 25%, as well as a good performance status, adequate hematologic, hepatic, and renal function, and no distant metastases. Non-small cell lung cancer patients receive a total tumor dose of 64.8 Gy megavoltage XRT in 7 weeks at 1.8 Gy once daily, 5 d/wk. Patients with HNSCC receive 70 Gy megavoltage XRT in 7 weeks at 2 Gy once daily, 5 d/wk. Paclitaxel is delivered by continuous intravenous infusion starting 48 hours before XRT and continuing for its duration. The dose of paclitaxel is escalated in cohorts of three patients in a standard phase I design. To date, 49 patients have been entered on both studies and 43 are evaluable for toxicity. Paclitaxel dose is currently at the 17 mg/m2/d dose level, with no dose-limiting toxicity thus far. Clinical outcomes suggest significant activity for this combination. This therapy is feasible and has been well-tolerated through current dose levels. Dose escalation is ongoing.

Delayed regional metastasis from midfacial squamous carcinomas.

BACKGROUND: Metastases from mucosal and cutaneous carcinomas can present in a delayed fashion, and this late presentation may confer a different prognosis after conventional treatment. METHODS: We present a series of patients in which there was a significant time delay between the treatment of a squamous carcinoma of the skin or mucosa of the midface and the detection of regional metastases in 12 of the 13 cases. Primary tumors were located on the lower lip and commissure (n = 3), nasal tip (n = 2), nasal ala (n = 1), columella (n = 1), nasofacial crease (n = 2), maxillary alveolus (n = 3), and mandibular alveolus (n = 1). Metastatic spread manifested by palpable perifacial or submandibular lymph nodes was not evident until greater than 11 months after the treatment of the primary site in 12 of 13 patients (range, 3-45 months). Nine of the patients were clinically staged as N1, whereas there was one each in the N2a, N2b, N2c, and N3 categories. Eleven of the 13 patients were initially seen with palpable disease involving the perifacial nodes within or around the submandibular gland. All patients were treated with neck dissection except one, who refused surgical treatment and underwent a second course of radiotherapy to the cervical region. The nine patients initially seen with clinical stage N1 disease underwent neck dissection with preservation of the sternocleidomastoid, internal jugular vein, and accessory nerve. RESULTS: Of 10 patients with perifacial node metastases who underwent neck dissection, 8 required sacrifice of the marginal mandibular nerve and overlying platysma to gain adequate margin. Extracapsular spread was present in 11 patients, (8 of 9 who were clinically N1). Postoperative radiotherapy was recommended to all patients with extracapsular spread, although only 7 of the 11 received radiotherapy. There were no regional recurrences after a minimum follow-up of 1 year (range, 12-65 months; mean, 31.4 months). Histologic grade appeared to have no influence on prognosis. CONCLUSIONS: This cohort demonstrates the ability of midfacial squamous cell carcinoma to manifest regional metastatic disease over a delayed time. This delayed presentation appears to confer a more favorable response to treatment. For midfacial cancers, the perifacial nodes are at greatest risk for metastatic spread. For tumors in this region, primary treatment of the neck is probably not warranted, but careful extended follow-up for the potential of delayed cervical metastasis is prudent.

Seven-week continuous-infusion paclitaxel with concurrent radiotherapy for locally advanced head and neck squamous cell cancer: a phase I study.

The goal of this National Cancer Institute-sponsored phase I trial is to determine the feasibility, toxicity, and pharmacokinetics of continuous-infusion (24 hr/d, 7 d/wk, 7-week total) intravenous paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with standard curative radiotherapy (RT) for previously untreated, locally advanced head and neck squamous cell cancers. Eligible patients have squamous cell cancers of the head and neck with expected 5-year survival rates of < or =25%; a good performance status; adequate hematologic, hepatic, and renal functions; and no distant metastases. All patients receive 70 Gy megavoltage RT in 7 weeks (2 Gy/d x 5 d/wk). Paclitaxel is delivered by protracted venous infusion starting 48 hours before RT and continuing for its duration. Biopsies for cell-cycle distribution analyses and paclitaxel tissue levels are obtained, if possible, before beginning paclitaxel and after 48 hours just before RT begins. The dose of paclitaxel is escalated in cohorts of three patients. Eighteen patients are evaluable for toxicity. Treatment has been completed through the 6.5 mg/m2/d dose level and is ongoing at 10.5 mg/m2/d. There has been no dose-limiting toxicity thus far. With the exception of anemia, toxicity is commensurate with what would be expected from RT alone. A slowly progressive normocytic anemia with no renal dysfunction was found to be associated with an acquired hypoerythropoietin state. Tumor biopsies have suggested the possibility of paclitaxel-induced mitotic arrest. This therapy is feasible and has been well tolerated through current dose levels with no dose-limiting toxicity. There is a suggestion of biologic activity evidenced by the anemia and the possibility of alteration in cell-cycle distributions. Dose escalation is ongoing.

Analysis of histamine as a hair-cell transmitter in the lateral line of Xenopus laevis.

The actions of histamine and histamine antagonists on afferent nerve activity were investigated in the lateral line of Xenopus laevis. Histamine (0.002-2.0 mM) had no effect on spontaneous activity or excitatory responses to water motion. In contrast, pyrilamine, an H1 receptor antagonist, suppressed spontaneous activity beginning at 0.01-0.05 mM. Below 0.3 mM the suppression was often preceded by a small excitatory response and responses to high (24-30 dB re threshold), but not low (0-18 dB) levels of water motion were selectively suppressed. Higher concentrations (0.3-2.0 mM) abolished spontaneous activity and suppressed responses at all levels of water motion. Cimetidine, an H2 receptor antagonist, had similar actions but was one-tenth as potent as pyrilamine. Tetrodotoxin (0.001-0.1 microM), which blocks voltage-sensitive Na+ channels, mimicked the suppressive effects of the histamine antagonists. Histamine (2.0 mM) failed to block the actions of pyrilamine (0.1 mM) indicating its effects are mediated through a mechanism other than histamine receptors. In addition, pyrilamine (0.05-0.1 mM) non-selectively suppressed excitation to exogenously applied L-glutamate (1.0-2.0 mM), L-aspartate (1.0-2.0 mM), kainate (0.005-0.01 mM), and quisqualate (0.002-0.005 mM) and altered responses to N-methyl-D-aspartate (0.5-1.0 mM). The results are inconsistent with histamine being a transmitter in the Xenopus lateral line and reveal that the actions of histamine antagonists are nonspecific, possibly due, in part, to blockade of voltage-sensitive Na+ channels.