Harold J. Pelzer

Weekly Carboplatin and Paclitaxel Followed by Concomitant Paclitaxel, Fluorouracil, and Hydroxyurea Chemoradiotherapy: Curative and Organ-Preserving Therapy for Advanced Head and Neck Cancer

PURPOSE The paclitaxel, fluorouracil, and hydroxyurea regimen of paclitaxel, infusional fluorouracil, hydroxyurea, and twice-daily radiation therapy (TFHX) administered every other week has resulted in 3-year survival rates of 60% of stage IV patients. Locoregional and distant failure rates were 13% and 23%, respectively. To reduce distant failure rates, we added a brief course of induction chemotherapy to TFHX. PATIENTS AND METHODS Sixty-nine patients received six weekly doses of carboplatin (AUC2) and paclitaxel (135 mg/m2) followed by five cycles of TFHX. RESULTS Ninety-six percent had stage IV disease. Response to induction chemotherapy was partial response 52% and complete response (CR) 35%. Symptomatically, there was a significant reduction in mouth and throat pain. The most common grade 3 or 4 toxicity was neutropenia (36%). Best response following completion of TFHX was CR in 83%. Toxicities of TFHX consisted of grade 3 or 4 mucositis (74% and 2%) and dermatitis (47% and 14%). At a median follow-up of 28 months, locoregional or systemic disease progression were each noted in five patients. The overall 3-year progression-free survival was 80% (95% confidence interval [CI], 71% to 90%), and the 2- and 3-year overall survival rates were 77% (95% CI, 66% to 87%) and 70% (95% CI, 59% to 82%), respectively. At 12 months, five patients were completely feeding-tube dependent. CONCLUSION Administration of carboplatin and paclitaxel before TFHX chemoradiotherapy results in high response activity and may decrease distant failure rates. Overall survival, progression, and organ preservation/functional outcome data support definitive evaluation of this approach.

Concomitant Chemoradiotherapy as Primary Therapy for Locoregionally Advanced Head and Neck Cancer

PURPOSE To achieve locoregional control of head and neck cancer, survival, and organ preservation using intensive concomitant chemoradiotherapy. PATIENTS AND METHODS This study was a phase II trial of chemoradiotherapy with cisplatin 100 mg/m(2) every 28 days, infusional fluorouracil 800 mg/m(2)/d for 5 days, hydroxyurea 1 g orally every 12 hours for 11 doses, and radiotherapy twice daily at 1.5 Gy/fraction on days 1 through 5 (total dose, 15 Gy). Five days of treatment were followed by 9 days of rest, during which time patients received granulocyte colony-stimulating factor. Five cycles (three with cisplatin) were administered over 10 weeks (total radiotherapy dose, </= 75 Gy). Adjuvant chemoprevention with retinoic acid and interferon alfa-2A was offered. RESULTS Seventy-six patients were treated (stage IV, 93%; N2, 54%; N3, 21%). At a median follow-up of 38 months, the 3-year progression-free survival is 72%, locoregional control 92%, systemic control 83%, and overall survival 55%. Toxicities included mucositis (grade 3, 45%; grade 4, 12%), neutropenia (grade 4, 39%), and thrombocytopenia (grade 4, 53%). Surgery at the primary site was performed in 13 patients, and 39 had neck dissection. A majority of patients declined adjuvant chemoprevention. Pharmacokinetic parameters were not prognostic of tumor control. Quality of life declined during treatment but returned from good to excellent by 12 months after treatment. CONCLUSION Intensive concomitant chemoradiotherapy leads to high locoregional control and survival rates with organ preservation and a reversal of the historical pattern of failure (distant > locoregional). Surgery after concomitant chemoradiotherapy is feasible. Compliance with adjuvant chemoprevention is poor. Identification of less toxic regimens and improved distant disease control emerge as important future research goals.

Swallowing dysfunction--preventative and rehabilitation strategies in patients with head-and-neck cancers treated with surgery, radiotherapy, and chemotherapy: a critical review.

BHARAT B. MITTAL, M.D.,* BARBARA R. PAULOSKI, PH.D., DANIEL J. HARAF, M.D., HAROLD J. PELZER, M.D., ATHANASSIOS ARGIRIS, M.D., EVERETT E. VOKES, M.D., ALFRED RADEMAKER, PH.D., AND JERILYN A. LOGEMANN, PH.D. Departments of *Radiology, Section of Radiation Oncology, Communication Sciences and Disorders, Head and Neck Surgery, Medical Oncology, and Biostatistics Core Facility, Northwestern University Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; Departments of Radiation and Cellular Oncology, and Medicine, Division of Hematology-Oncology, University of Chicago Pritzker School of Medicine, Chicago, IL

Concomitant Infusional Paclitaxel and Fluorouracil, Oral Hydroxyurea, and Hyperfractionated Radiation for Locally Advanced Squamous Head and Neck Cancer

PURPOSE To improve local disease control and survival with organ preservation, we conducted a phase II multi-institutional trial with a concomitant taxane-based chemotherapy and hyperfractionated radiation regimen. PATIENTS AND METHODS Sixty-four patients with locally advanced squamous cancers (stage IV, 98%; N2/3, 81%) were treated on an intensive regimen consisting of 5-day (120-hour) infusions of paclitaxel (20 mg/m(2)/d) and fluorouracil (600 mg/m(2)/d), oral hydroxyurea 500 mg every 12 hours for 11 doses, and radiation 1.5 Gy bid (T-FH2X). Chemoradiation was administered concomitantly on days 1 to 5 of each 14-day cycle. A full treatment course consisted of five cycles during a 10-week period to a total radiation dose of 72 to 75 Gy. RESULTS The median follow-up for the group is 34 months. At 3 years, progression-free survival is 63%, locoregional control is 86%, and systemic control is 79%; overall survival is 60%. Seventeen patients died of recurrent cancer, two died of second primary cancers, and four died of other causes. Side effects observed include anemia (22% required transfusion), leucopenia (34%, grade 3 to 4), and mucositis (84%, grade 3 to 4). Organ preservation principles were maintained. At 1 year posttreatment, 61% of patients had severe xerostomia and 47% had compromised swallowing. There was little disturbance of speech quality in 97% of patients at the same follow-up point. CONCLUSION T-FH2X is a highly active and tolerable concomitant chemotherapy and hyperfractionated radiation regimen that induces sustained local tumor control and holds promise for improved survival with organ preservation in high-risk patients. Identification of less toxic therapy and improved distant disease control are needed. T-FH2X should be tested in a randomized trial and compared with a less intensive concomitant regimen that uses once-daily radiation fractionation.

Neck dissection in the combined-modality therapy of patients with locoregionally advanced head and neck cancer

The purpose of this study was to evaluate the role of neck lymph node (ND) in the combined dissection modality therapy for locoregionally advanced head and neck.

Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: improved disease control and survival.

PURPOSE To determine tumor response rate, patterns of failure, toxicity, and survival in advanced squamous head and neck cancer after a combined treatment program that consists of induction chemotherapy, organ-sparing surgery, and concurrent chemoradiation. Long-term outcome data are presented. PATIENTS AND METHODS Between July 1991 and March 1993, 93 patients received three cycles of induction chemotherapy that consisted of cisplatin, fluorouracil (5-FU), l-leucovorin, and alpha-interferon2b (PFLl-alpha) followed by optional limited surgery and six to eight cycles of 5-FU, hydroxyurea, and concurrent radiation (FHX) to a total radiation dose of 65 to 75 Gy. RESULTS Ninety-three patients were entered onto this study and 97% had stage IV disease, with 66 patients who were N2 or N3. Sixty-one patients (66%) achieved a clinical complete remission (CR) after induction therapy. Thirty-four patients underwent surgery. Seventy-nine patients proceeded to FHX. With a median follow-up time of 43 months for surviving patients, 20 patients have had disease progression (13 local, two distant, five both), and there have been 35 deaths (18 from disease, six treatment-related, two from a second primary, and nine for other medical reasons). At 5 years, progression-free survival is 68%, and overall survival is 62%. Surgery was organ-preserving, as only a single laryngectomy and no glossectomies were performed in primary management. Acute toxicity related to PFLl-alpha consisted of severe or life-threatening mucositis in 57% and leucopenia in 65% of patients. During FHX, 81% of patients had grade 3 or 4 mucositis. CONCLUSION PFLl-alpha is a highly active regimen that induced clinical CR in two thirds of patients. When followed by limited surgery and FHX, resultant local and distant disease control, organ preservation, and overall 5-year survival are very promising in high-risk stage IV patients. Based on these local control and survival data, further evaluation of this treatment sequence, induction chemotherapy followed by concurrent chemoradiation, is warranted. Identification of similarly active but less toxic regimens is a high priority.

SURGICAL VARIABLES AFFECTING SWALLOWING IN PATIENTS TREATED FOR ORAL/OROPHARYNGEAL CANCER

Postoperative swallowing function may be influenced by a number of treatment variables; this study examines the relationship of various treatment factors to measures of swallow function.

Overexpression of p53 in squamous cell carcinoma of the tongue in young patients with no known risk factors is not associated with mutations in exons 5–9

This study investigated the status of the p53 tumor suppressor gene in patients less than 40 years of age who had squamous cell carcinoma of the tongue develop with no known risk factors.

Nitric Oxide Synthase Type 3 is Increased in Squamous Hyperplasia, Dysplasia, and Squamous Cell Carcinoma of the Head and Neck

The implication of nitric oxide (NO) in the multistep process of carcinogenesis prompted us to examine the expression of endothelial constitutive nitric oxide synthase (NOS3) in head and neck squamous cell carcinoma (HNSCCa). Eleven paraffin-embedded samples of normal oral mucosa, 3 reactive oral lesions, 13 samples of squamous dysplasia, and 120 specimens of HNSCCa were immunostained with an anti-NOS3 monoclonal antibody and graded on a 0 to 4+ scale of intensity. Normal squamous mucosa demonstrated very little NOS3 expression. Areas of normal mucosa, reactive mucosa, and dysplastic lesions associated with inflammation tended to demonstrate regional expression of NOS3. Reactive mucosal lesions, squamous dysplasia, and HNSCCa demonstrated a significant (p < .0001) increase in global expression of NOS3. Therefore, NOS3 is expressed very little in histologically normal squamous mucosa, while squamous hyperplasia, dysplasia, and HNSCCa express significantly more NOS3. Regional variation in NOS3 expression appears to be associated with perilesional inflammation.

Management of chronic aspiration by subtotal and submucosal cricoid resection

Modern techniques of conservation surgery of the laryngopharynx often result in narrowing, immobility, and decreased sensation of the hypopharynx. These procedures also compromise the most vital function of the larynx — protection of the airway. Permanen tracheostomy is always necessary for protection of the airway. Teflon injection, cartilage implant to the larynx, and extended pharyngeal myotomy can provide only temporary relief. Swallowing studies under fluoroscopy as well as laryngopharyngoscopy verify a narrowed pharyngeal inlet with the pharynx trapped between the cricoid and the cervical spine. Extrapharyngeal, subtotal, submucosa resection or the posterior cricoid ring results in a flaccid posterior laryngeal wall and enlarged hypopharyngeal inlet. At the same time the laryngeal inlet is narrowed, reducing aspiration and still preserving the voice.