13-cis-retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin.

BACKGROUND: Retinoids (vitamin A derivatives) and interferon-alpha (IFN-alpha) are potent regulators of malignant cell differentiation and proliferation, and both have immunomodulatory and antiangiogenesis activity. A large body of preclinical and clinical data supports the use of combination therapy with 13-cis-retinoic acid (13-cRA) and IFN-alpha in patients with squamous cell carcinoma of the skin. This carcinoma is an extremely common and frequently severely disfiguring cancer, for which about 10% of patients remain uncured following standard local therapy. PURPOSE: Our purpose was to test whether a 20% or greater complete response rate could be achieved using a combination of these two agents in patients with advanced squamous cell carcinoma of the skin in whom local therapy had failed or was unfeasible or who had regional and/or distant metastases. METHODS: Thirty-two patients with heavily pretreated, advanced inoperable cutaneous squamous cell carcinoma of the skin were given a combination of oral 13-cRA (1 mg/kg per day) and subcutaneous recombinant human IFN alpha-2a (3 million units per day) for at least 2 months, unless disease progressed earlier, in a phase II trial. RESULTS: Nineteen (68%) of the 28 assessable patients responded, seven (25%) of whom had complete responses. Response rates were 93% (13 of 14) in patients with advanced local disease (six complete responses), 67% (four of six) in patients with regional disease (no complete responses), and 25% (two of eight) in patients with distant metastases (one complete response). The relationship between decreased response rate and increased extent of disease was highly statistically significant (P less than .005, chi-square test). The median response duration was greater than 5 months. No life-threatening toxic effects occurred in assessable patients treated with this combination, although dose reductions were required in 18 patients. The major limiting side effect in this elderly patient population (median age, 67 years) was cumulative fatigue. CONCLUSION: These results indicate that combined systemic therapy with 13-cRA and IFN alpha-2a is highly effective in patients with advanced squamous cell carcinoma of the skin.

p53 mutations in nonmelanoma skin cancer of the head and neck: molecular evidence for field cancerization.

Multiple and distinct p53 mutations were detected by DNA sequence analysis in tumor and adjacent nonmalignant skin samples from eight patients with nonmelanoma skin cancer of the head and neck, providing unambiguous evidence for field cancerization. The mutations consisted of C-->T transitions at dipyrimidine sequences (30% of all single base substitutions), T-->C transitions (47%), and G-->T transversions (12%), suggesting that other carcinogens may act along with UV radiation in the development of nonmelanoma skin cancer. Patient interviews revealed that, in addition to substantial exposure to solar UV radiation, most had a history of smoking and were exposed to carcinogens from industrial or agricultural sources. These data show that extensive molecular epidemiological investigations are necessary to elucidate risk factors associated with the disease in localities where patients often report substantial exposure to environmental carcinogens.

Effectiveness of combined induction chemotherapy and radiotherapy in advanced nasopharyngeal carcinoma.

PURPOSE: This prospective trial was conducted with the goal of achieving an improvement in both overall and progression-free survival in previously untreated patients with stage IV nasopharyngeal carcinoma who received an induction chemotherapy regimen of fluorouracil (5-FU) and cisplatin followed by radiotherapy. PATIENTS AND METHODS: From January 1985 to January 1990, 47 patients with T1-4N2-3M0 squamous cell carcinoma of the nasopharynx were treated at The University of Texas M.D. Anderson Cancer Center with two to three cycles of 5-FU (1,000 mg/m2 continuous infusion per day x 5 days) plus cisplatin (100 mg/m2 continuous infusion on day 1 only) followed by radiotherapy using the conventional time/dose schedule. RESULTS: The response rate to chemotherapy was 93.2% (20.5% complete response [CR]; 72.7% partial response [PR]), and the overall CR rate after radiotherapy was 86%. With a median follow-up period of 53 months, the 2-, 4-, and 6-year survival rates were 80%, 71.6%, and 67.4%; the overall treatment failure rate was 27%. Treatment was well tolerated and without significant acute or chronic toxic effects. CONCLUSION: The results of this prospective study demonstrate that 5-FU plus cisplatin followed by radiotherapy can induce a durable remission in a high proportion of patients with poor-prognosis stage IV nasopharyngeal carcinoma.

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.

ICAM-5 (telencephalin) gene expression in head and neck squamous carcinoma tumorigenesis and perineural invasion!

ICAM-5 (telencephalin) is an intercellular adhesion molecule reported to be expressed only in the somatodendritic membrane of telencephalic neurons. We recently identified high ICAM-5 expression in a cDNA array study of head and neck neoplasms with a propensity for perineural invasion. To determine the association of this gene in tumorigenesis and perineural invasion, we analyzed the expression and functional status of ICAM-5 mRNA transcripts in 30 different human cancer cell lines and 25 head and neck squamous carcinoma specimens by reverse-transcriptase polymerase chain reaction (cell lines and specimens) and in vitro functional assays (cell lines). ICAM-5 transcripts were detected in 28 (93%) of 30 cell lines derived from primary head and neck, colon, thyroid, cervical, pancreatic, skin, and adenoid cystic carcinomas. In cell lines, small interfering RNA blocked ICAM-5 expression and inhibited cell proliferation. Treatment with the phosphatidylinositol 3'-kinase (PBK) inhibitor LY294002 resulted in ICAM-5 down-regulation. In tissue specimens, none of the 25 histologically normal oral mucosal specimens had detectable ICAM-5 level, whereas 16 (64%) of the 25 matched primary squamous carcinomas showed expression. Carcinoma specimens high ICAM-5 expression had a high incidence of perineural invasion. Our study indicates that ICAM-5 may play a role in tumorigenesis and perineural invasion, most likely through the P13K/Akt-signaling pathway.

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.

The influence of positive margins and nerve invasion in adenoid cystic carcinoma of the head and neck treated with surgery and radiation.

PURPOSE: Surgery is the primary treatment for adenoid cystic carcinomas arising from major and minor salivary glands of the head and neck. However, local recurrence is frequent because of the infiltrative growth pattern and perineural spread associated with these tumors. At UTMDACC, we have had a longstanding policy of using postoperative radiotherapy to reduce the risk of local recurrence and to avoid the need for radical surgery; this 30-year retrospective study analyzes the results of this combined modality approach. METHODS AND MATERIALS: Between 1962 and 1991, 198 patients ages 13-82 years, with adenoid cystic carcinomas of the head and neck, received postoperative radiotherapy for known or suspected microscopic residual disease following surgery. Distribution of primary sites was: parotid: 30 patients; submandibular/sublingual: 41 patients; lacrimal: 5 patients; and minor salivary glands: 122 patients. Eighty-three patients (42%) had microscopic positive margins and an additional 55 (28%) had close (< or = 5 mm) or uncertain margins. One hundred thirty-six patients (69%) had perineural spread with invasion of a major (named) nerve in 55 patients (28%). Using radiation techniques appropriate to the primary site, a median dose of 60 Gy (range 50-69 Gy) was delivered to the tumor bed. Follow-up ranged from 5-341 months (median, 93 months). All surviving patients had a minimum of 2 years follow-up. RESULTS: Twenty-three patients (12%) had local recurrences with 5-, 10-, and 15-year actuarial local control rates of 95%, 86%, and 79%, respectively. Fifteen of the 83 patients (18%) with positive margins developed local recurrences, compared to 5 of 55 patients (9%) with close or uncertain margins, and 3 of 60 patients (5%) with negative margins (p = 0.02). Patients with and without a major (named) nerve involved had crude failure rates of 18% (10 out of 55) and 9% (13 out of 143), respectively (p = 0.02). There was a trend toward better local control with increasing dose. This was significant in patients with positive margins, in whom crude control rates were 40 and 88% for doses of < 56 Gy and > or = 56 Gy, respectively (p = 0.006). Actuarial 5-, 10-, and 15-year freedom from relapse rates were 68%, 52%, and 45%, respectively. Base of skull and neck failures were uncommon with or without elective treatment, developing in 2 and 3% of patients, respectively. Distant metastases were the most common type of disease recurrence, developing in 74 patients (37%) of whom 62 (31%) were disease-free at the primary site. CONCLUSIONS: Excellent local control rates were obtained in this population using surgery and postoperative radiotherapy and we recommend this combined approach for most patients with adenoid cystic carcinomas of the head and neck. Perineural invasion was an adverse prognostic factor only when a major (named) nerve was involved. Microscopic positive margins was also an adverse prognostic factor, but even when present, local control was achieved in over 80% of our patients. We recommend a dose of 60 Gy to the tumor bed, supplemented to 66 Gy for patients with positive margins. Despite effective local therapy, one-third of patients fail systemically, and good treatment to address this problem is lacking.

A phase I trial of 96-hour paclitaxel infusion plus accelerated radiotherapy of unrespectable head and neck cancer.

PURPOSE: To determine the maximum tolerated dose (MTD) of paclitaxel given as a 96-hour continuous infusion during Weeks 1 and 5 of an accelerated radiotherapy schedule for the definitive treatment of advanced (nonmetastatic) unresectable squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Thirteen patients with Stage IV SCCHN were enrolled. Radiotherapy consisted of 70-72 Gy over 6 weeks, with a fractionation scheme of 2 Gy q.d. for 4 weeks followed by 1.6 Gy b.i.d. for 2 weeks, with no planned interruptions. Paclitaxel was administered over a 96-hour continuous infusion during Weeks 1 and 5 of radiotherapy at the following dose levels: Dose Level 1: 40 mg/m(2)/96-hours (3 patients); Dose Level 2: 80 mg/m(2)/96-hrs (5 patients); Dose Level 3: 120 mg/m(2)/96-hours (2 patients); and Dose Level 2A: 100 mg/m(2)/96-hours (3 patients). RESULTS: The MTD of Paclitaxel was 100 mg/m(2)/96-hours. All but one patient (who experienced progressive disease after receiving 61 Gy and both cycles of paclitaxel) completed therapy as planned. Dose-limiting toxicity occurred in both patients enrolled at Dose Level 3, with one patient experiencing Grade 4 diffuse moist desquamation and the other patient experiencing Grade 4 mucositis and febrile neutropenia. Thus, Dose Level 2A was opened and no dose limiting toxicity was noted. Grade 3 non-dose limiting mucositis and dermatitis occurred at all paclitaxel dose levels. There were no treatment-related deaths. All Grade 3 and 4 toxicities were reversible. Complete responses were seen in 8 of 13 patients, 4 patients achieved partial responses, and 1 patient had no response/progressive disease. CONCLUSIONS: Infusional paclitaxel over 96 hours during Weeks 1 and 5 of this accelerated radiotherapy schedule is feasible. The MTD of paclitaxel in this protocol was 100 mg/m(2)/96-hours. Dose-limiting toxicities were primarily enhanced epithelial reactions, but febrile neutropenia also occurred. All patients develop non-dose limiting Grade 3 skin and mucosal reactions, reflecting the high treatment intensity. This regimen merits further investigation.

Concomitant boost radiotherapy for squamous carcinoma of the tonsillar fossa.

PURPOSE: To assess the efficacy of a concomitant boost fractionation schedule of radiotherapy for treating patients with squamous carcinoma of the tonsillar fossa. PATIENTS AND METHODS: Between December 1983 and November 1992, 83 patients with squamous carcinoma of the tonsil were treated with concomitant boost fractionation. The distribution of American Joint Committee on Cancer T stages was TX-4, T1-5, T2-29, T3-41, T4-4; N stages were NX-1, N0-26, N1-13, N2-31, N3-12. Patients were treated with standard large fields to 54 Gy in 6 weeks. The boost treatment consisted of a second daily 1.5 Gy fraction for 10-12 fractions, usually delivered during the final phase of treatment. The tumor dose was 69-72 Gy, given over 6 weeks. Twenty-one patients, who all had N2 or N3 regional disease, underwent neck dissections, either before (13 patients) or 6 weeks after radiotherapy (8 patients); the other patients were treated with radiotherapy alone. RESULTS: The 5-year actuarial disease-specific survival and overall survival rates were 71 and 60%, respectively. Patients with T2 and T3 primary tumors had 5-year actuarial local control rates of 96 and 78%, respectively. Patients with T3 disease who received the final-phase boost had a 5-year actuarial local control rate of 82%. Actuarial 5-year regional disease control rates were N0, 92%; N1, 76%; N2, 89%; and N3, 89%. The 21 patients who had neck dissections all had their disease regionally controlled. Patients presenting with nodal disease or after a node excision who were treated with radiation alone had a 5-year actuarial regional disease control rate of 79%. All but five patients had confluent Grade 4 mucositis during treatment. Severe late complications attributable to radiation included mandibular necrosis [1], in-field osteosarcoma [1], and chronic dysphagia for solid foods [5]. CONCLUSIONS: High rates of local and regional disease control were achieved with the concomitant boost fractionation schedule, with few cases of severe late morbidity. Patients with N2 and N3 neck disease were effectively treated with radiation and the selective use of neck dissections. The concomitant boost schedule is our preferred fractionation approach for treating patients with intermediate stage tonsil cancer who are not participating in our current research protocols.

Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx.

Concomitant boost schedules are characterized by delivering the boost (10-12 fractions) as second daily treatments during rather than following the basic wide field irradiations. This results in shortening the overall time to administer 69-72 Gy from 7 1/2-8 weeks to 6 weeks, which we hoped would improve the tumor control rate by reducing the opportunity for tumor clonogens to regenerate during treatment. From August 1985 to August 1988, 79 patients with T2-4 carcinomas of the oropharynx (72 patients) or nasopharynx (7 patients) were treated according to 1 of the 3 variants of the concomitant boost technique. The median age of patients was 60 years (range: 19-84 years) and the male-to-female ratio was 2.6. The overall 2-year actuarial primary and nodal control rates by radiotherapy alone were 74% and 76%, respectively. The ultimate 2-year control rates after surgical salvage were 82% and 84%, respectively. If the boost given during the last 2-2 1/2 weeks of basic treatment, a slightly better primary control rate (p = 0.11) resulted than if the boost was delivered during the first 2-2 1/2 weeks or twice a week throughout the basic treatment. The 2-year actuarial primary control rate of the 13 patients receiving induction chemotherapy prior to radiotherapy was significantly lower than that of patients treated with radiation only (81% vs 34%, p = 0.01), but this could be partly attributed to a more advanced stage in the chemotherapy group. The acute mucosal reactions were, as expected, more severe than those observed with conventional fractionation. Fifty patients developed confluent mucositis covering more than half of the boost area. Such reactions lasted for more than 6 weeks in seven patients. Late complications, however, so far observed, have been few. Three patients experienced chronic mucosal tenderness, 1 chronic mucosal ulceration, 2 transient bone exposure, and 1 carotid rupture following salvage surgery. The results so far appear to be better than the outcome of conventional radiotherapy. Its real value will be determined in a prospective randomized study.

Postoperative radiotherapy for cutaneous melanoma of the head and neck region.

PURPOSE: To assess the efficacy and toxicity of elective-adjunctive radiotherapy given in five 6-Gy fractions to patients with cutaneous melanoma of the head and neck at high risk for local-regional relapse. METHODS AND MATERIALS: From 1983 to August 1992, 174 patients (132 men and 42 women) were enrolled. The ages ranged from 16 to 89 years (median: 54 years). One group (n = 79) received elective irradiation after wide local excision of lesions > or = 1.5 mm thick, or Clark's level IV-V, a second group (n = 32) received adjunctive irradiation after excision of primary lesions plus limited neck dissection, and a third group (n = 63) received irradiation after neck dissection for nodal relapse. Each group had a projected local-regional recurrence rate of approximately 50%. The radiotherapy consisted of five fractions of 6 Gy each, specified at Dmax, delivered twice a week, to a total dose of 30 Gy in 2.5 weeks. Electron beams of appropriate energies were used whenever possible. Junction lines between adjoining fields were moved twice to minimize dose heterogeneity. Patients were seen at regular intervals to assess disease status and therapy-related complications. Patients who relapsed were treated as indicated by the clinical status. RESULTS: With a median follow-up of 35 months, 111 of 174 patients were alive. The disease recurred above the clavicles only in six patients, at distant sites in 58 patients, and both local-regionally and at distant sites in nine patients. The actuarial 5-year local-regional control (LRC) and survival rates for the whole group were 88% and 47%, respectively. The thickness of the primary lesion, presence of more than three positive nodes, and extracapsular extension did not influence the LRC rate after radiotherapy (range: 85-92%). However, lesion thickness strongly affected the 5-year survival rate of group 1 patients (i.e., 100% for < or = 1.5 mm thick, but Clark's level IV, 72% for > 1.5-4 mm, and 30% for > 4 mm). In groups 2 and 3, the 5-year survival rate of patients with > three involved nodes was lower than that of patients with one to three positive nodes (23% vs. 39%). The acute tolerance to adjunctive radiotherapy was excellent. Late radiation complications were observed in only three patients. These were moderate neck fibrosis, mild ipsilateral hearing impairment, and transient exposure of external auditory canal cartilage. CONCLUSION: The safety of this hypofractionated radiotherapy regimen in the management of cutaneous melanoma was established in this study. The overall 5-year actuarial LRC rate of 88% was much higher than that of our historical group and that reported in the literature (50%). The survival rate of patients with lesion of 1.5-4 mm thickness was also higher than that observed in other series. Based on these results a prospective randomized study to further define the role of adjunctive postoperative radiotherapy is planned.

Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial.

PURPOSE: This study was designed to determine in a prospective randomized trial the optimal dose of conventionally fractionated postoperative radiotherapy for advanced head and neck cancer in relation to clinical and pathologic risk factors. METHODS AND MATERIALS: Between January 1983 and March 1991, 302 patients were enrolled on the study. This analysis is based on the first 240 patients entered through September 1989, of whom 221 (92%) had AJC Stage III or IV cancers of the oral cavity, oropharynx, hypopharynx, or larynx. The patients were stratified by postulated risk factors and randomized to one of three dose levels ranging between 52.2 Gy and 68.4 Gy, all given in daily doses of 1.8 Gy. Patients receiving > 57.6 Gy had a field reduction at this dose level such that boosts were only given to sites of increased risk. RESULTS: The overall crude and actuarial 2-year local-regional recurrence rates were 25.4% and 26%, respectively. Patients who received a dose of < or = 54 Gy had a significantly higher primary failure rate than those receiving > or = 57.6 Gy (p = 0.02). No significant dose response could be demonstrated above 57.6 Gy except for patients with extracapsular nodal disease in the neck in whom the recurrence rate was significantly higher at 57.6 Gy than at > or = 63 Gy. Analysis of prognostic factors predictive of local-regional recurrence showed that the only variable of independent significance was extracapsular nodal disease. However, clusters of two or more of the following risk factors were associated with a progressively increased risk of recurrence: oral cavity primary, mucosal margins close or positive, nerve invasion, > or = 2 positive lymph nodes, largest node > 3 cm, treatment delay greater than 6 weeks, and Zubrod performance status > or = 2. Moderate to severe complications of combined treatment occurred in 7.1% of patients; these were more frequent in patients who received > or = 63 Gy. CONCLUSION: With daily fractions of 1.7 Gy, a minimum tumor dose of 57.6 Gy to the whole operative bed should be delivered with a boost of 63 Gy being given to sites of increased risk, especially regions of the neck where extracapsular nodal disease is present. Treatment should be started as soon as possible after surgery. Dose escalation above 63 Gy at 1.8 Gy per day does not appear to improve the therapeutic ratio.

Allergic fungal sinusitis: a clinicopathologic study of 16 cases.

Allergic fungal sinusitis (AFS) has been clinicopathologically defined as a noninvasive form of fungal infection. Etiologically, most reported cases have been attributed to pigmented dematiaceous fungi. The authors report 16 cases of AFS from our institution, along with a review of cases from the literature. The patients' age ranged from 8 to 71 years, with a mean age of 25 years. All patients were immunocompetent, although six had a strong history of atopy. Multiple sinuses were affected in all cases; nine patients had bilateral involvement, and seven patients manifested unilateral involvement. Histopathologically, all cases were characterized by the presence of "allergic mucin," with scattered fungal organisms without invasion of mucosa or bone. Fontana-Masson stain identified fungi in all but one case and assisted in distinguishing the pigmented dematiaceous organisms from other septated fungal forms. Accordingly, Fontana-Masson stain can be useful in confirming the diagnosis of AFS in the lack of tissue culture results. Fungal cultures performed on six cases grew Exserohilum (three cases), Bipolaris (one case), Drechslera (Bipolaris) (one case), and Curvularia (one case). All patients were treated with surgical debridement and sinus aeration. Follow-up of at least 6 months was obtained in six cases, of which four showed recurrent disease between 8 months and 4 years after the initial surgical procedure. A literature review showed that the most common etiologic agents were members of the dematiaceous family (81%), with the most common genus being Bipolaris (42%), followed by Curvularia (21.3%). It is believed that type I and III hypersensitivity reactions underlie the pathogenesis of this disease.

Clinical restoration of voice function after loss of the vagus nerve.

One hundred eleven patients with unilateral vocal cord paralysis underwent Teflon injection for the rehabilitation of laryngeal function. The most common etiology was vocal cord paralysis after surgical treatment of thoracic abdominal aortic aneurysms, which accounted for 36.9% of patients. Of the 111 patients, 85% had improved voice function after Teflon injection. Two patients developed airway obstruction secondary to edema and required temporary tracheostomy. Twenty-four patients with paralysis after aneurysm surgery were injected acutely with no morbidity and immediate restoration of voice function. We now advocate Teflon injection in patients with vocal cord paralysis after thoracic aneurysm surgery in the immediate convalescent period to restore voice function and lessen pulmonary complications.

Growth and progression of head and neck cancer: a report of the Upper Aerodigestive Cancer Task Force Workshop.

Factors governing the initiation, growth, and progression of squamous cell carcinoma were the focus of a recent Upper Aerodigestive Cancer Task Force workshop sponsored by the National Cancer Institute. The goal of the daylong workshop was to identify critical research concepts in head and neck cancer biology. Discussed were the multistep processes potentially involved in tumor evolution, including the role of carcinogens, viral promotors, host and tumor karyotypes, microenvironment growth factors and growth factor receptors, as well as host/tumor components inherent to the metastatic process. Concepts developed from research in other neoplastic processes but potentially relevant to head and neck cancer were emphasized. The process of identifying critical research directions is the first step by the National Cancer Institute in program development designed to advance the treatment of head and neck cancer.

Thyroid carcinoma.

During the past years advances have been made in the understanding of the molecular mechanisms involved in the initiation and progression of thyroid carcinoma. Mutations in tumor suppressor genes such as p53 and oncogenes such as N-ras may be important for progression of well-differentiated thyroid carcinomas. Activation of the ret protooncogene located on chromosomal region 10q11.2 has been identified as a key factor in the initiation of papillary and medullary carcinoma. Integration of these discoveries into a prognostic classification scheme may allow us to better predict the biologic behavior of tumors in individual patients. Despite the recent advances in our understanding of the molecular events occurring during thyroid carcinogenesis, major questions persist regarding aspects of patient management. New diagnostic modalities may enable us to noninvasively discriminate between benign and malignant thyroid nodules, and to detect recurrent disease earlier. Although the optimal surgical procedure for well-encapsulated tumors is still debated, recent clinical studies have shown that for those patients with tumors > 1.5 cm, the routine use of RAI and hormone suppression can improve local control and survival rates. Findings in two recent reviews suggest that patients with widely invasive thyroid masses benefit from the surgical removal of all gross tumor. Further investigation is required to define the role of adjuvant radiotherapy and the most appropriate management of unresectable disease. Incorporation of prognostic markers into clinical staging systems should allow surgeons to better tailor their treatment plans for each patient. Translation of recent basic science advances into the clinical arena may also aid in the development of novel treatment strategies for patients with aggressive tumors.

Anterior transcranial (craniofacial) resection of tumors of the paranasal sinuses: surgical technique and results.

Transfacial approaches, traditionally used for malignant tumors of the paranasal sinuses, provide limited exposure when several sinuses are involved and are unsuitable for tumors that erode through the floor of the anterior cranial fossa. A transcranial approach may aid in the removal of such lesions. To better understand the risks and benefits of this surgical approach, we reviewed all patients (n = 76) who underwent a transcranial approach as part of the excision of paranasal sinus lesions between 1984 and 1993 at our institution. The spectrum of disease included adenocarcinoma (13 patients), squamous cell carcinoma and olfactory neuroblastoma (11 patients each), adenoid cystic carcinoma and poorly differentiated forms of carcinoma (6 patients each), melanoma (5 patients), and miscellaneous others (24 patients). Most patients had ethmoid sinus involvement; tumors were also commonly found in the cribriform plate, sphenoid sinus, and nasal fossa. In each patient, a bifrontal craniotomy was performed with extradural dissection to the floor of the anterior fossa and osteotomies for resection of involved elements. In 47 patients (62%), disease in the orbit, the anterior nasal cavity, or the soft tissues of the face required transfacial as well as transcranial resections. Bony defect in the anterior fossa floor was repaired with a pedicled pericranial flap. Patients with major complications included six patients with epipericranial and/or epidural hematomas requiring evacuation, three with transient cerebrospinal fluid leaks, two who developed bifrontal cerebral infarcts, and one who died soon after surgery. No meningitis was seen. To date, 26 patients (34%) have died; of those living (mean follow-up, 34 mo), 42 (84%) remain in full remission. The transcranial approach can achieve removal of erosive, invasive tumors from this area with predictable morbidity and may be considered whenever sinus tumors breach the anterior cranial base or extend beyond the reach of conventional transfacial approaches.

Transcranial resection of tumors of the paranasal sinuses and nasal cavity.

Combined cranial and facial procedures for resection of malignancies of the paranasal sinuses and nasal cavity have been used with variable success and complication rates in the last 25 years. A series of nine patients undergoing 10 exclusively transcranial procedures for these tumors is presented, and an effective technique for reconstruction without free tissue transfer is described. The patients in this series suffered no major complications, and all have remained free of disease during the short follow-up period. The technique described in this report offers the advantage of wide exposure, symmetrical approach to the superstructures of the face and orbits, the potential for resection of a large portion of the anterior cranial floor, and substantial reconstruction which is a major factor in avoiding complications.

Intraoral soft tissue reconstruction after cancer ablation: a comparison of the pectoralis major flap and the free radial forearm flap.

We compared, by retrospective chart review, the free radial forearm flap and the pectoralis major flap in repairing intraoral soft tissue defects resulting from tumor ablation. Statistical significance of differences was determined using Fisher's exact test and chi-square analysis. Fifty-one free flap and 126 musculocutaneous flap transfers were analyzed. The former were used more often for defects in the anterior part of the oral cavity, whereas the latter were used more frequently in the posterior part. Significantly more patients with pectoralis major flap transfers had late-stage (T3 and T4) disease than did those in the free radial forearm flap group (p = 0.004). Also, the complication rate was significantly higher in the pectoralis major flap group (p = 0.01); this was due to differences in the rates of dehiscence, fistula formation, and flap loss. We thus conclude that, despite the need for microsurgery, the free radial forearm flap is at least as reliable as the pectoralis major flap and that the choice of flap should be based on defect considerations rather than on the perceived reliability of the reconstructive method.

Soft tissue sarcomas of the head and neck in adolescents and adults.

Between 1960 and 1982, 188 patients were treated for soft tissue sarcomas of the head and neck. These patients had a heterogeneous group of neoplasms whose biologic behavior was determined by histologic classification, differentiation, and size. Histologic classification of these tumors was important and had prognostic significance. Differentiation affected local control and the propensity for distant metastases. Tumor size also contributed to outcome: patients with tumors of more than 5 cm had a worse survival than those with smaller sarcomas. Wide surgical excision with an adequate margin of normal tissue offered the best means of local control. The addition of postoperative radiotherapy was utilized for patients with positive margins or high grade aggressive sarcomas. Finally, despite multimodality therapy, achieving local control and prevention of distant disease in high grade sarcomas remains a major therapeutic challenge.