Chemoradiotherapy for advanced inoperable head and neck cancer: A phase II study.

The beneficial effects of chemotherapy in patients with advanced head and neck cancer remain controversial in terms of survival, but have shown some promise in improving locoregional control and quality of life. In an effort to improve locoregional control and survival, a prospective phase II study was initiated using paclitaxel and carboplatin with concurrent conventional fractionated external-beam radiotherapy. Paclitaxel and carboplatin have both shown excellent radiosensitization through two discrete mechanisms, cell blockage in G2/M phase and inhibition of DNA repair, respectively. Patients were stratified as either operable or inoperable. This report pertains to the inoperable patient group, who received eight cycles of weekly paclitaxel (60 mg/m2), carboplatin (area under the concentration-time curve of 1) with conventional radiotherapy (72 Gy). Chemoradiotherapy was followed by neck dissection for those patients who presented with clinically palpable lymph nodes. Thirty-three patients were enrolled in this group (23 men and 10 women with a median age of 56 years). Eleven patients (33%) had stage III disease; 22 (67%), stage IV disease. The median follow-up period was 14 months. Clinical complete response occurred in 20 patients (60%) and partial response occurred in 10 (30%), for an overall response rate of 90%. Following completion of therapy, 18 patients have undergone biopsy at the primary tumor site and 17 were negative. Eight of the 16 patients with clinically palpable neck nodes at presentation underwent neck dissection; five (63%) had negative nodes. Mucositis was the most common toxicity. Grade 3 or 4 mucositis occurred in 30 of the 33 (90%) patients. Other grade 3 or 4 toxicities included skin (22%), candidiasis (19%), neutropenia (9%), and dehydration (6%). One patient with laryngeal carcinoma who had pathologic complete response developed cartilage necrosis and is undergoing hyperbaric oxygen therapy. Survival data are early but encouraging. Concurrent paclitaxel, carboplatin, and external-beam radiotherapy yielded excellent clinical and pathologic responses. Mucositis remains the most common and significant morbidity. The study will continue for necessary accrual.

Cisplatin as a radiation sensitizer in the treatment of advanced head and neck cancers. Results of a phase II study.

BACKGROUND: Surgery and radiotherapy mainstays in the management of advanced head and neck cancer, although historically, only 20-30% of patients survive. Therefore, in an attempt to improve locoregional control and survival, a multimodal protocol using cisplatin as a radiosensitizer was implemented. METHODS: Between 1984 and 1990, 68 patients with advanced head and neck cancer (Stages III and IV) were treated with a regimen consisting of an induction phase of 4500 cGy and two cycles of cisplatin followed by an eradicative phase of either radical surgery (Group A, 27 patients) or radical radiotherapy (Group B, 41 patients). The maintenance phase chemotherapy consisted of adjuvant 5-fluorouracil (5-FU) and cisplatin after completion of locoregional treatment. Of the 68 patients, 19 had Stage III disease, and 49 had Stage IV; 21 had no regional lymph node metastases (N0), and 47 had regional lymph node metastases (N+). RESULTS: The induction phase yielded a 26% (18 patients) complete response (CR) rate and a 57% (39 patients) partial response (PR) rate (response > 50%), yielding an overall response rate of 83%. Eleven patients (16%) had stable disease (ST) (i.e., < 50% response). The 2-year survival rates by initial treatment response for patients who had a CR, a PR, and stable disease were 53%, 56%, and 36%, respectively; for Groups A and B, 63% and 45%, respectively; for Stages III and IV, 68% and 43%, respectively; and for N0 and N+, 69% and 43%, respectively. In Group A, 14 of 27 patients (52%) had no viable tumor in the surgical specimen (i.e. had pathologic complete tumor clearance [CTC]); this subgroup had a 5-year survival rate of 58%. Ten patients (37%) who had gross total resection of tumor with negative margins but had tumor present in the specimen had a 5-year survival of 22%. In Group B, the 5-year survival rate was 43% for 27 patients who achieved CR after completion of radical radiotherapy (total tumor dose, 6480-7020 cGy). The 5-year survival rate of the 14 patients who had a PR and stable disease after radical radiotherapy and 3 patients whose resection was incomplete was 0%. The overall 2- and 5-year survival rates for all patients were 53% and 32%, respectively. Of 21 patients in whom treatment failed, most (90%) had a locoregional recurrence: 13 local recurrences (62%), 5 regional (24%), and 1 locoregional (5%). Two patients (10%) experienced failure at distant sites (the lung). Major treatment-related morbidity developed in two patients. CONCLUSIONS: Although induction chemotherapy-radiotherapy produces a high clinical response rate, this does not translate into improved survival compared with historical controls. A subgroup that showed complete tumor clearance (CTC or pathologic complete response) at surgery had an apparent improved survival and merits further study. Patient selection did not appear to be a factor for the CTC group, because the majority of patients in this group had partial responses to induction therapy, nodal disease and advanced tumor stage, and tumor presence in unfavorable sites.

Leukotriene-associated toxic oxygen metabolites induce airway hyperreactivity.

The effect of toxic oxygen metabolite scavengers was examined in a guinea pig trachealis model of leukotriene (LTD4)-induced synergism upon histamine contractures. Under both physiologic (2.5 mM) and low (OmM) extracellular calcium conditions, LTD4 (10(-7) to 10(-9) M) potentiated histamine isometric tension responses. This LTD4-induced histamine hyperresponse was inhibited by pretreatment with superoxide dismutase. Inhibition of LTD4 receptor binding by FPL 55712 (10(-5) M) also aborted this interaction. Actual trachealis superoxide anion (O2-) generation by LTD4 was observed with a maximal release of 15 nM O2-/CPK unit X 10(-2) over 60 min. Phorbol myristate acetate (PMA) also generated O2- in this preparation. Trachealis muscle hyperreactivity to histamine induced by 10(-8) M LTD4 assayed in OmM (Ca++)E was not induced by PMA. It is concluded that exogenous LTD4 activates toxic oxygen metabolites which interact to induce an acquired hyperreactivity to agonist histamine in trachealis smooth muscle.

Superoxide anion generation during airway anaphylaxis.

Extracellular release of superoxide anion (O-2) during in vitro anaphylaxis in guinea pig trachealis was found to exhibit both a time- and a concentration-dependent generation of O-2. Trachealis O-2 release was unaffected by treatment with diphenhydramine HCl (10(-5) M, 10(-6) M). While indomethacin (10(-5) M) augmented anaphylaxis tension it did not enhance O-2 release. However, the semiselective SRS-A antagonist FPL 55712 (10(-5) M) resulted in essentially complete inhibition of O-2 generation. These data indicate that O-2 generation occurring during acute airway anaphylaxis is associated with the activation of SRS-A products.

Control of malignant melanoma of the nasal mucous membrane.

Malignant melanoma of the nasal mucous membrane continues to be a rare disorder which is difficult to treat. Five year survival rate appears to be less than 30% and most patients who die of the disease have distant metastasis. At this time, the otolaryngologist and head and neck surgeons must strive to control local and regional disease with surgical means. Unfortunately, these means are usually inadequate because survival is critically dependent on the biology of the melanoma and its interaction with the patient's immune system.