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

PURPOSE: 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. METHODS: We identified patients with N2-N3 head and neck cancers who were enrolled in three consecutive multicenter phase II studies of concurrent chemoradiotherapy utilizing 5-fluorouracil and hydroxyurea on an alternate-week schedule with radiotherapy twice daily plus either cisplatin (C-FHX) or paclitaxel (T-FHX). Patients with unknown primary tumors, nasopharyngeal or paranasal sinus primaries, nonsquamous histology, progression or death during therapy, or incomplete therapy were excluded. RESULTS: A total of 131 patients were analyzed. Seventy-nine percent had N2 stage. ND was performed in 92 patients (70%), either prior to enrollment (n = 31) or after chemoradiotherapy (n = 61). With a median follow-up of 4.6 years, the 5-year locoregional and neck progression-free survival (PFS) rates were higher in patients with ND versus patients without ND: 88% versus 74% (p =.02) and 99% versus 82% (p =.0007). respectively; there was also a trend toward improved overall survival (OS) with ND, but PFS and distant PFS were comparable. In the subset of patients with N3 disease, ND was associated not only with better locoregional control but also with improved distant PFS. However, in patients with clinical complete response (n = 92), no significant differences in PFS (68% vs 75% at 5 years, p =.53) or any other survival parameters with or without ND were observed. CONCLUSIONS: ND improves neck control and is required for patients with clinically residual disease or N3 neck cancer but has no significant impact on the outcome of patients with N2 stage disease who are rendered clinically disease-free with intensive concurrent chemoradiotherapy.

Competing causes of death and second primary tumors in patients with locoregionally advanced head and neck cancer treated with chemoradiotherapy.

PURPOSE: The purpose of this retrospective analysis was to evaluate the emergence of second primary malignancies and the contribution of different causes of death to the outcome of patients with locoregionally advanced head and cancer receiving primary chemoradiotherapy. EXPERIMENTAL DESIGN: We studied 324 patients with stage IV squamous cell head and neck cancer who were enrolled on five consecutive multicenter Phase II studies of concurrent chemoradiotherapy. All of the regimens included concurrent 5-fluorouracil and hydroxyurea on an alternate week schedule with radiotherapy, either alone (FHX) or with cisplatin (C-FHX) or paclitaxel (T-FHX). The cumulative incidence of second primary tumors or death from any cause was estimated using methods of competing risk analysis. RESULTS: Median follow-up of surviving patients was 5.2 years (2-10.6 years). The 5-year overall survival and progression-free survival of the cohort were 46% and 65%, respectively. Causes of death and median time of occurrence were as follows: disease (n = 88; 1.5 years), treatment-associated acute or late complications (n = 30; 4 months), second primary tumors (n = 18; 3.5 years), comorbidities (n = 41; 1.9 years), and unknown (n = 20; 5.1 years). Predominant causes of death from comorbidities were cardiac and respiratory illnesses. Twenty-six patients (8%) developed a second primary tumor at a median time of 2.8 years (4 months to 10 years). The cumulative incidence of second primary tumors was 5%, 7%, and 13% at 3, 5, and 10 years, respectively. The most frequent site of second primaries was the lung (n = 13), followed by the esophagus (n = 3) and head and neck (n = 2) CONCLUSIONS: Patients with locoregionally advanced head and neck cancer treated with concurrent chemoradiotherapy are potentially curable but face significant risks of mortality from causes other than disease progression. Ameliorating toxicity, and implementing secondary screening and chemoprevention strategies are major goals in the management of head and neck cancer.

Severe dermatologic reactions at multiple sites after paclitaxel administration.

OBJECTIVE: To report a case of a severe dermatologic reaction at the infusion site, as well as at multiple distant sites, after paclitaxel administration. CASE SUMMARY: A 53-year-old white male with cancer of the base of the tongue was treated with paclitaxel 100 mg/m2 infused over 3 hours and carboplatin dosed at an AUC of 6 mg/mL x min infused over 30 minutes via a peripheral vein on the left arm. After 4 doses of paclitaxel, the patient developed erythematous patches on both forearms and both thighs. The lesions on the left arm worsened into a necrotic ulcer, exposing underlying tissues. All of the lesions healed after paclitaxel was withheld from subsequent cycles. Based on the Naranjo probability scale, it is probable that paclitaxel was the causative agent for these lesions. DISCUSSION: Most of the previously reported paclitaxel-induced dermatologic reactions occurred following extravasation. There are few reports of generalized dermatologic rashes. These rashes are thought to be due to delayed hypersensitivity either to paclitaxel or the solubilizing agents. Our patient had dermatologic toxicity at the infusion site, as well as at multiple other sites, that developed about 6 weeks after the first paclitaxel infusion. CONCLUSIONS: Generalized dermatologic toxicity after paclitaxel administration is uncommon and seems to be immunologically mediated. This toxicity could be secondary to paclitaxel or the additives. The use of paclitaxel is increasing in various malignancies. Newer formulations are under development. Until these formulations are available, clinicians should report any dermatologic reactions in order to identify the cause of toxicity and develop safer administration technique.

Induction chemotherapy followed by concomitant TFHX chemoradiotherapy with reduced dose radiation in advanced head and neck cancer.

PURPOSE: Induction chemotherapy with carboplatin and paclitaxel followed by concomitant TFHX (paclitaxel, infusional 5-fluorouracil, hydroxyurea, and twice-daily radiation therapy administered every other week) has resulted in 70% 3-year survival in stage IV patients. Locoregional and distant control rates were 94 and 93%, respectively. In an attempt to decrease toxicity without compromising local control, a second cohort of patients was treated with a lower dose of radiation to sites of potential microscopic disease. EXPERIMENTAL DESIGN: Sixty-four patients were entered on study. Patients received six weekly doses of carboplatin (area under the curve 2) and paclitaxel (135 mg/m2) followed by five cycles of TFHX. The radiation dose to gross disease was 75 Gy as in the previous trial. The radiation dose to high-risk microscopic disease was reduced from 60 to 54 Gy, and the dose to low-risk microscopic disease was reduced from 45 to 39 Gy. RESULTS: Ninety-seven percent of patients had stage IV disease. The response rate to induction chemotherapy was 82% with a complete response rate of 42%. At the completion of therapy the clinical complete response rate rose to 100% with a median follow-up of 29 months. The actuarial 2 and 3-year survival was 77 and 70%, respectively. Five patients developed progressive disease for an overall 3-year progression-free survival of 90%. Two patients failed in locoregional sites alone, resulting in a 3-year locoregional control of 97%. The 3-year systemic control was 95%. Four patients were completely feeding tube dependent at the time of analysis. Only 1 of these patients had normal swallowing function before treatment. CONCLUSIONS: In this second trial, induction chemotherapy with carboplatin and paclitaxel followed by TFHX chemoradiotherapy results in high survival and progression-free survival. The reduction in radiation dose did not compromise survival or disease control compared with our prior study using higher radiation doses. Data continues to support definitive evaluation of this approach.

Multicenter randomized Phase II study of paclitaxel (1-hour infusion), fluorouracil, hydroxyurea, and concomitant twice daily radiation with or without erythropoietin for advanced head and neck cancer.

PURPOSE: To expand on our experience with the combination of paclitaxel, fluorouracil, hydroxyurea, and twice daily irradiation (T-FHX) and to assess the impact of weekly administration of erythropoietin (r-HuEpo) on transfusion requirements, we conducted a Phase II multi-institutional trial with a simplified 1-h paclitaxel infusion schedule and randomized patients to receive weekly doses of r-HuEpo. PATIENTS AND METHODS: A total of 90 patients with locally advanced head and neck cancers (stage IV, 96%; N(2)/N(3), 66%) were treated on a regimen of 1-h infusion of paclitaxel (100 mg/m(2)/day, day 1), 120-h infusion of 5-fluorouracil (600 mg/m(2)/day, days 0-5); hydroxyurea 500 mg p.o. every 12 h for 11 doses; and radiation 150cGy bid, days 1-5 of each 14-day cycle repeated for five cycles over 10 weeks (7200-7500 cGy). Before initiating therapy, patients were randomized to receive r-HuEpo 40,000 IU s.c. once weekly. RESULTS: At median follow-up of 40 months, 3-year progression-free survival is 62%, locoregional control is 84%, and systemic control is 79%. Overall survival is 59%. Anemia, leucopenia, dermatitis, and mucositis were the most frequent grade 3 or 4 toxicities. Patients randomized to erythropoietin experienced less grade 2/3 anemia (52 versus 77%; P = 0.02), but transfusion requirements were not significantly different. CONCLUSIONS: T-FHX is an active and tolerable regimen inducing local tumor control and promising survival with organ preservation in high-risk patients. One h infusion of paclitaxel simplified the regimen without compromising efficacy. Addition of erythropoietin does not reduce the need for transfusion with this nonplatinum-containing regimen. T-FHX should be advanced to a randomized trial and compared with a cisplatin-based concomitant regimen.

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.