Predictors of response and survival after concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck.

BACKGROUND: The objective of this study was to determine prognostic factors for response and survival on three consecutive institutional trials utilizing concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck (SCCHN). METHODS: Since 1985, patients with locally advanced SCCHN at the University of Maryland have been managed with concurrent chemotherapy and radiation therapy (RT). Three consecutive pilot studies have been performed evaluating the utility of weekly chemotherapy with standard fractionated RT. Chemotherapy consisted of carboplatin either alone (28 patients) or in combination with bleomycin (23 patients) or paclitaxel (60 patients). In all three studies, RT was given to 70.2 gray (Gy) at 1.8 Gy/fraction/day to the primary site. All patients had locally advanced SCCHN and were believed to be poor surgical candidates. Sixty-seven percent of patients had T4 disease, and 21% had T3 disease. Seventy-five percent of patients had N2-N3 disease. One hundred eleven patients were examinable for toxicity, response, and survival analysis. Factors including age, race, gender, primary site location, histologic grade, T classification, N classification, and treatment regimen were evaluated to identify predictors of these endpoints. RESULTS: The median follow-up for patients treated on study 1 (carboplatin and RT) and study 2 (carboplatin and bleomycin [C + B]/RT) was 98 months, and it was 30 months for study 3 (carboplatin and paclitaxel [C + P]/RT). The complete response rates were 54%, 52%, and 70% respectively (P = 0.01). Multivariate analysis identified length of treatment break (< 1 week vs. > 1 week) as the only predictor of complete response to therapy. The local control for the entire group was 50%. The local control for C + P/RT was 63%, versus 32% and 36% for C/RT and C + B/RT respectively (P = 0.004). The 2-, 3-, and 5-year disease free and overall survivals for the entire population were 41%, 41%, and 35% and 42%, 36%, and 33%, respectively. The 3-year overall survival rates by treatment regimen were 18% (C/RT), 35% (C + B/RT), and 47% (C + P/RT; P = 0.01). On univariate analysis, age younger than 50 years (P = 0.01), treatment with C + P/RT (P = 0.005), and treatment break of 5 days or fewer (P < 0.05) were also predictive of improved overall survival. On multivariate analysis, only complete response (P < 0.0001) and treatment with C + P/RT (P = 0.02) remained statistically significant. CONCLUSIONS: Chemoradiation provides patients with locally advanced SCCHN the opportunity for long term survival. Among the three chemoradiation regimens studied, C + P/RT was associated with the best complete response and survival rates. Complete response to therapy was the single most important predictor of overall survival. These three consecutive concurrent chemotherapy and radiation trials achieved a 5-year survival of greater than 30% for the entire population. These results support the use of this nonoperative approach for this group of patients with a historically poor prognosis.

The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck.

PURPOSE: Unresectable squamous cell carcinomas of the head and neck (SCCHN) continue to pose a significant therapeutic challenge. This report defines the toxicities, efficacy, and prognostic factors associated with the combination of carboplatin (CBDCA), paclitaxel, and once-daily radiation for patients with locally advanced disease. Additionally, the pharmacokinetics of paclitaxel were investigated. METHODS AND MATERIALS: From 1993-1998, 62 patients with Stage III-IV SCCHN were treated with 70.2 Gy of RT at 1.8 Gy/fraction/day to the primary site. Weekly chemotherapy was given during RT consisting of paclitaxel (45 mg/m(2)/wk) and CBDCA (100 mg/m(2)/wk). All patients presented with locally advanced disease; 77% had T4 disease and 21% had T3 disease. Fifty-eight percent had N2b-N3 disease. RESULTS: Sixty patients were evaluable for response and survival with a median follow-up of 30 months (range 7-70). Ninety-eight percent of patients completed prescribed therapy. One patient died after refusing medical management for pseudomembranous colitis and is scored as a Grade 5 toxicity. Two patients suffered Grade 4 leukopenia. Median number of break days was two. A clinical complete response (CR) at the primary site was obtained in 82%, with a total (primary site and neck) CR rate of 75%. The median survival for the entire cohort is 33 months. Response to therapy and status of the neck at presentation were the only prognostic factors found to influence survival. The median survival for patients who attained a CR is 49 months versus 9 months in those who did not attain a CR (p < 0.0001). The 2- and 3-year overall survival for complete responders are 79% and 61%. Plasma paclitaxel concentrations in the range shown to be radiosensitizing were achieved. CONCLUSIONS: Weekly carboplatin and paclitaxel given concurrently with definitive once-daily external beam radiation therapy is well tolerated with over 90% of patients completing prescribed therapy. An ultimate CR rate of greater than 70% was obtained, which translated directly into improved survival. With 48% 3-year overall survival for the entire group, this regimen is an excellent option for this group of patients with a historically poor prognosis.

Phase I trial of all-trans retinoic acid in patients with treated head and neck squamous carcinoma.

Although retinoids show promise for prevention of second primary upper aerodigestive tract tumors, the optimum retinoid, dose, and schedule are unknown. All-trans retinoic acid (ATRA) has greater affinity for retinoic acid receptors and may be more active than other retinoids but has a shorter plasma half life and may up-regulate its own metabolism. We defined the maximum long-term tolerable dose, dosing frequency, pharmacokinetics, and toxicity of ATRA in patients with treated squamous cell carcinoma of the head and neck (SCCHN). Twenty-one patients were randomized to 45, 90, or 150 mg/m2 ATRA either once daily, or as divided doses every 8 h, for 1 year. Pharmacokinetics were assessed periodically. Fourteen men and seven women with previous SCCHN of initial stage I-IV were treated. Grade > or =3 toxicities (reversible) included headache and hypertriglyceridemia in 5 and 6 patients each, mucositis in 2 patients, and hyperbilirubinemia, elevated alkaline phosphatase, colitis, lipasemia, xerostomia, eczema, and arthritis in 1 patient each. The 150-mg/m2 dose was not tolerable. Doses were reduced for grade > or =3 toxicity in seven of eight patients at 90 mg/m2 daily. Three of nine patients at 45 mg/m2/day required dose reduction, two at the once-daily dose. Day 1 ATRA area under the plasma concentration versus time curve (AUC) increased with dose, and after 1-2 months of continued dosing, the AUC declined in 7 of 13 patients (54%) studied. ATRA AUC did not correlate with toxicity severity or frequency. Fifteen mg/m2/day every 8 h is a tolerable dose for 1 year in patients with treated SCCHN. ATRA pharmacokinetics did not correlate with toxicity.

Temporal lobe injury in temporal bone fractures.

OBJECTIVE: To determine the incidence of intracranial injury, specifically in the temporal lobe, in patients with longitudinal fractures of the temporal bone. DESIGN: Prospective inception cohort. SETTING: University of Maryland Division of Otolaryngology-Head and Neck Surgery and the Maryland Shock Trauma Center, Baltimore. PATIENTS: Twenty-seven consecutive patients with unilateral or bilateral temporal bone fractures. MAIN OUTCOME MEASURES: Evaluation of temporal bone and intracranial trauma using computed tomography (CT) and magnetic resonance imaging (MRI). RESULTS: Of the 27 patients enrolled in the study, 12 had the complete battery of MRI, CT, and physical and audiological examinations. In all 12 patients, MRI demonstrated adjacent middle cranial fossa meningeal enhancement. Results of non-contrast-enhanced CT and MRI demonstrated ipsilateral temporal lobe contusions in 6 of the 13 fractures for an overall incidence of 46%. In addition, MRI demonstrated 4 cerebral contusions not seen in the results of non-contrast-enhanced CT. CONCLUSIONS: While high-resolution CT remains the criterion standard for evaluation of temporal bone fractures, MRI revealed a higher incidence of related temporal lobe injuries. Magnetic resonance imaging data may be valuable in preoperative evaluation of patients who require surgical intervention through a middle cranial fossa approach to document pre-existing injury and potential morbidity before retraction of the middle cranial fossa dura mater and temporal lobe.

Celebrating a decade of evaluation and treatment: the University of Maryland Tinnitus & Hyperacusis Center.

The University of Maryland Tinnitus & Hyperacusis Center in Baltimore was the first center in the United States dedicated to the evaluation and treatment of tinnitus and hyperacusis patients implementing an habituation-based protocol that has become known internationally as Tinnitus Retraining Therapy (TRT). A crucial feature of the model is the postulate that a number of systems in the brain are involved in the emergence of tinnitus. The cochlea and auditory periphery play only a secondary role. To facilitate the goal of habituation of the tinnitus signal, TRT implements both directive counseling to neutralize the negative emotional associations toward the tinnitus, and sound therapy to interfere with the signal. As an outgrowth of the work with tinnitus, the evaluation and treatment of hyperacusis has emerged as an increasingly important part of our program. This report describes the unique facility, staff, and services of the Center as we celebrate a decade of research and clinical management dedicated to the scientific understanding of tinnitus and hyperacusis.

Neurophysiological approach to tinnitus patients.

The principal postulate of the neurophysiological model of tinnitus is that all levels of the auditory pathways and several nonauditory systems play essential roles in each case of tinnitus, stressing the dominance of nonauditory systems in determining the level of tinnitus annoyance. Thus it has been proposed to treat tinnitus by inducing and facilitating habituation to the tinnitus signal. The goal is to reach the stage at which, although patients may perceive tinnitus as unchanged when they focus on it, they are otherwise not aware of tinnitus. Furthermore, even when perceived, tinnitus does not evoke annoyance. Habituation is achieved by directive counseling combined with low-level, broad-band noise generated by wearable generators, and environmental sounds, according to a specific protocol. For habituation to occur, it is imperative to avoid masking tinnitus by these sounds. Since 1991, > 500 tinnitus patients have been seen in our center. About 40% exhibited hyperacusis to varying degrees. A survey of > 100 patients revealed > 80% of significant improvement in groups of patients treated with the full protocol involving counseling and the use of noise generators. Notably, in patients who received counseling only, the success rate was < 20%. The improvement in hyperacusis was observed in approximately 90% of treated patients.

Anastomosis technique for high pharyngogastrostomy.

Pharyngogastric anastomosis, otherwise referred to as the "gastric pull-up" procedure, is the most reliable method of reconstruction after laryngopharyngectomy. We currently use a method of gastric to pharyngeal anastomosis that avoids excess tension, and thus decreases the incidence of fistulas and flap failures. With the stomach fully mobilized, the "pull-up" is brought high into the neck using a plastic bag to facilitate delivery via the posterior mediastinum. A curved, U-shaped incision is then made in the fundus of the tongue anteriorly, allowing the posterior nasopharynx to be reached without tension.

A reliable index for correct positioning of precision attachments into an existing overdenture.

Limited space over abutment teeth may make incorporation of a precision attachment system within an existing overdenture technique sensitive. A special diagnostic index can be made to depict the available space within the prosthesis over the abutment teeth. This index is critical to determine the feasibility of attachment incorporation, as well as the selection and correct positioning of an appropriate attachment system. A method to improve predictability for precision attachment incorporation into an existing overdenture is described.

Prognostic factors in squamous cell carcinoma of the larynx.

One hundred fifty-two patients with squamous cell carcinoma of the larynx were studied. The disease-free survival and overall survival rates were correlated to 12 variables. Seven of them seemed to affect survival. Poor prognosis was related to (1) advanced stage of disease at diagnosis, (2) cord fixation and massive local invasion, (3) ulceration of the primary tumor, (4) lymph node metastases at diagnosis, (5) glottic lesions had a poorer prognosis than supraglottic ones, (6) locoregional recurrences, and (7) male gender. However, most of these significant differences were in disease-free survival, and only primary tumor staging; lymph node status; and locoregional recurrences affected overall survival. On the other hand, the other five variables showed no effect on either disease-free or overall survival rates. These included age, race, cell differentiation, type of recurrence, and the initial definitive therapeutic modality.

Laryngeal configuration and constriction during two types of whispering.

Laryngeal functioning during the production of whispered speech is not well understood. The efficacy of whispering as a means of voice rest is a common clinical concern that is unresolved. This investigation examined vocal-fold configuration, glottal size, and airway constriction by supraglottal structures during whispering. Ten normally speaking adults produced consonant-vowel syllables with three different vowels while whispering in low-effort and high-effort manners. The larynx was visualized through fiberoptic endonasolaryngoscopy, and the views were recorded on videotape. Analysis and descriptions of the data revealed that low-effort and high-effort whispering were differentiated to a small extent by vocal-fold adjustments and to a somewhat larger degree by supraglottal constriction. However, for each dependent variable, individual subject differences tended to be considerably larger than any systematic effects due to whisper type or vowel.

Topical nasopharyngeal anaesthesia with vasoconstriction in preeclampsia-eclampsia.

We report the case of a 38-year-old eclamptic patient undergoing emergency Caesarean section who required awake nasotracheal intubation because of her massively swollen and lacerated tongue. Vasoconstriction, in addition to topical anaesthesia, was required due to thrombocytopaenia. The use of three per cent lidocaine with 0.125 per cent phenylephrine for anaesthesia and vasoconstriction is described with successful maternal and neonatal outcome.

Treatment of pneumothoraces utilizing small caliber chest tubes.

Pneumothorax is a common problem in both hospitalized and emergency room patients. Eight-four pneumothoraces in 79 patients were treated using a No. 9 French catheter. In 76 cases, the catheter was attached to a flutter valve, and in eight cases, suction was applied. The No. 9 French catheter provided definitive treatment in 73 (87 percent) of the pneumothoraces. Causes of catheter failure included kinking, malposition, inadvertent removal by patient, occlusion of the tube or valve by pleural fluid, and large air leak. No complication attributable to tube placement occurred. When the flutter valve was employed, the patient was able to ambulate allowing for potential outpatient therapy. The tube was found to be easy to use, safe, and efficacious in the treatment of pneumothoraces.

Preliminary experience with chemotherapy in advanced salivary gland neoplasms.

Eight patients with advanced incurable salivary gland carcinoma were treated with the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP). There were three clinical complete responses and two excellent partial responses. One of the three nonresponders had symptomatic improvement without any response in the measurable disease sites. Side effects were acceptable. All patients had moderate nausea and some degree of vomiting, which were adequately controlled by antiemetics. These results are preliminary but when considered with other reported trials using the same combination suggest an active treatment program for advanced neoplasms of the salivary glands.

Candida epiglottitis in immunocompromised patients.

Candida seldom has been reported to be a cause of epiglottitis. The clinical manifestations and management of three patients with Candida epiglottitis complicating their neoplastic disease are described. All patients were granulocytopenic. Candida epiglottitis occurred either as a localized infection, as a source of Candida bronchopneumonia, or as a manifestation of disseminated infection. Candida epiglottitis may be under-diagnosed and should be considered, especially in immunocompromised patients with symptoms of refractory pharyngitis. Treatment of Candida epiglottitis with intravenous amphotericin B is warranted in patients with sustained granulocytopenia. Prompt endotracheal intubation is indicated if the airway patency cannot be maintained.

Suppression of cellular immunity by head and neck irradiation. Precipitating factors and reparative mechanisms in an experimental model.

A model was developed in C3H mice to investigate the immunosuppressive effects of head and neck irradiation and to explore mechanisms for repair of the defects. Mice receiving 1200 rad (12 Gy) of head and neck irradiation showed significant depression of delayed-type hypersensitivity, peripheral blood lymphocyte counts, spleen cell counts, and spleen cell production of interleukin-2. Treatment with optimal dosages of thymosin alpha 1 (T alpha-1) produced significant increases in all of these values, in some instances to levels higher than in the nonirradiated controls. In identical experiments with mice irradiated to a portal limited to the pelvic region, T alpha-1 induced only partial remission of the abnormalities. The dose response of T alpha-1 with head and neck irradiation showed a relatively limited dose range for immune restoration, a finding that warrants similar determinations in clinical trials with immunomodulating agents. The results suggest a potential clinical usefulness of T alpha-1 and also interleukin-2 in restoring cellular immunity after irradiation for head and neck cancers. The model appears to be useful for investigating immunomodulating agents before they are clinically evaluated as adjuvants with head and neck irradiation regimens.

Aspergillus sinusitis in cancer patients.

Paranasal sinusitis occurred in 52 immunosuppressed cancer patients treated over 5 years at the University of Maryland Cancer Center. Twenty-one patients had aspergillus sinusitis; Aspergillus sp, including flavus and niger were directly recovered from sinus in 19 of the 21 infections. Two other patients with sinus involvement and positive nose cultures for Aspergillus flavus or fumigatus and microbiologically documented pulmonary aspergillosis were considered clinically, although not microbiologically, documented. Predisposing factors for aspergillus sinusitis during the 60 days prior to infection diagnosis were granulocyte count less than 500 microliter (mean duration, 42 days versus 14 days for sinusitis of other etiology; P less than 0.001), prolonged hospitalization (mean duration, 22 days versus 14 days for patients with nonfungal sinusitis; P less than 0.001), and prolonged antibiotic therapy (mean duration, 22 days versus 9 days; P less than 0.001). Treatment with amphotericin B was initially successful for 18 of 21 patients; however, 11 of 18 patients had infection recurrence that always developed at time of tumor exacerbation and reinstitution or intensification of chemotherapy. These findings suggest that aspergillus sinusitis in cancer patients is seen in association with prolonged neutropenia and antibiotic therapy, is amenable to therapy, but tends to recur with relapse of malignancy.

Proptosis from maxillary sinus inverted papilloma with malignant transformation.

We describe a 58-year-old woman who presented with proptosis, upward displacement, and decreased vision in her right eye. A computed tomography scan revealed a mass filling the right maxillary sinus, destroying bone and invading the inferolateral orbit. The tumor proved to be an inverted squamous papilloma with focal transformation to squamous cell carcinoma. Although a rare cause of proptosis, inverted papilloma with orbital invasion must be considered when a patient describes associated nasal or sinus disease.

Effects of radiation therapy on T-lymphocyte subpopulations in patients with head and neck cancer.

Cellular immunity was assessed in 85 patients with head and neck cancer with monoclonal antibodies to lymphocyte surface antigens that identify total T cells, helper cells, and suppressor cells. The control group consisted of 22 healthy volunteers. Nine patients who had surgical procedures for benign diseases were also studied. Compared with the controls, the patients with cancer who received radiation therapy had a significant decrease in total lymphocytes, T cells, helper cells, suppressor cells, and decreased helper/suppressor cell ratio. Significant decreases in lymphocyte subpopulations were not detected in patients tested before treatment or in patients treated with surgery alone. The immune deficits observed were prolonged in duration, with some present in the patients studied up to 11 years after radiation therapy. This long-lasting immune depression may have relevance to tumor recurrences and second primaries in patients with head and neck cancer treated by radiation therapy and to attempts at increasing cure rates with adjuvant agents that improve immune reactivity.