[Late phase II study of S-1 in patients with advanced head and neck cancer].

A late phase II clinical study of S-1, a novel oral antitumor agent of fluorinated pyrimidines, in patients with advanced/recurrent head and neck cancer was conducted in 25 institutions across Japan as a multi-institutional cooperative study from August 1995 to March 1998. Out of 59 eligible patients, the objective responses were 4 complete responses (CR) and 13 partial responses (PR). The response rate was 28.8% (17/59, 95% CI: 17.8-42.1%). The response rate in previously treated patients was 28.3% (15/53), whereas that in treatment naive patients was 33.3% (2/6). The response rate in patients with prior chemotherapy was 26.7% (12/45). Major adverse reactions of grade 2 or more were anemia (25.4%, 15/59), leucopenia (22.0%, 13/59), neutropenia (25.4%, 15/59), thrombocytopenia (3.4%, 2/59), anorexia (6.8%, 4/59), nausea/vomiting (1.7%, 1/59), stomatitis (1.7%, 1/59), skin symptoms including eruptions or desquamation (5.1%, 3/59), and malaise (1.7%, 1/59). Grade 4 anemia was observed in one case; however, this returned to the normal level after the termination of drug administration and the blood transfusion. Therefore, this event was confirmed to be reversible. Based on these results, we conclude that S-1 is an active agent for the treatment of advanced/recurrent head and neck cancer.

[Late phase II clinical study of RP56976 (docetaxel) in patients with advanced/recurrent head and neck cancer].

A late phase II clinical study of RP56976 (docetaxel), a new anticancer agent for advanced/recurrent head and neck cancer, was conducted in 29 institutions all over Japan as a multi-institutional cooperative study. Docetaxel was administered by 1 to 2-hour intravenous infusion at a dose of 60 mg/m2 every 3 to 4 weeks. Of 63 patients eligible in this study, 59 were judged as complete cases. Complete response (CR) was observed in 1 patient, partial response (PR) in 13, no change (NC) in 25, and progressive disease (PD) in 20, for an overall response rate of 22.2% (14/63, 95% CI: 12.7-34.5%) in eligible cases, and 23.7% (14/59, 95% CI: 13.6-36.6%) in complete cases. Previously treated patients showed a 17.9% (10/56) response rate, whereas treatment--naive patients showed a 57.1% (4/7) response rate. Among 46 patients who received prior chemotherapy, one CR and 7 PR were observed with a 17.4% response rate. Major hematological toxicities were leucopenia in 95.1% (> or = grade 3, 59.7%) and neutropenia in 90.3% (> or = grade 3, 79.0%). Other severe toxicities (> or = grade 3) included anorexia in 9.7% (6 cases), diarrhea in 3.2% (2 cases), dyspnea in 3.2% (2 cases), and fatigue in 3.2% (2 cases). One patient had a grade 3 interstitial pneumonia; however, symptoms were resolved by the administration of corticosteroids. During this study, one patient died due to multiple organ failure (MOF) caused by disseminated intravascular coagulation (DIC), and this case was reported as a therapy-related death. Based on these results, docetaxel is an active agent for treatment of head and neck cancer.

Alternative use of medial and posterior upper-arm flaps.

There are such marked variations in the vascular anatomy of the nutrient vessels in medial and posterior upper arm flaps, that widespread usage of these flaps has been delayed. The authors have evaluated both medial and posterior upper arm flaps and have concentrated on the status of the skin perforators. Both types of flaps were considered for use as free transfers in 25 cases; island flaps were successfully elevated in 22 patients (11 medial and 11 posterior flaps). Because of the lack of suitable perforating vessels, this solution was abandoned in three patients. Perforators in both areas were found in 44 percent of the cases, in one or the other area in 44 percent, and not at all in 12 percent of the cases. Using the determination of perforators, the success rate of free-flap transfers from the medial and posterior upper arm increased from 64 and 68 percent, respectively, to 88 percent. When harvesting a flap from the medial or posterior upper arm, the risks attending questions of vascular stability in free-flap transfer, may be overcome by clinician experience.

[Early phase II study of S-1 in patients with advanced head and neck cancer. S-1 Cooperative Study Group (Head and Neck Working Group)].

In developing new anticancer agents, the most important thing is the balancing of antitumor activity and toxicity. To achieve high activity and low toxicity, S-1 was designed, in which tegafur, prodrug of 5-FU, was combined with two classes of modulators. CDHP, inhibitor of 5-FU degradation in liver and Oxo, inhibitor of 5-FU phosphoribosylation in digestive tract, respectively. This cooperative study with 15 nation-wide institutes was conducted to evaluate the antitumor activity and toxicity of S-1 in patients with advanced head and neck cancer from Jan. 1994 to March 1996 in Japan. Out of 26 patients, CR was achieved in 1 and PR in 11 with a response rate of 46.2%, while adverse events of grade 3 were as follows: hemoglobinemia (7.7%), leukocytopenia, neutropenia, stomatitis and anorexia (3.8%), each. Neither grade 4 adverse event nor treatment-related deaths were observed. Based on these findings, it was concluded that S-1 is a useful anticancer agent with the low grade toxicities for treatment of the patients with advanced head and neck cancer, and the effects of CDHP and Oxo found in preclinical studies might be also reflected in these results.

[Four cases of an extramedullary plasmacytoma of the head and neck].

From 1987 to 1988, four patients with solitary, extramedullary plasmacytomas of the head and neck were seen at the Gunma Cancer Center Hospital. With reference to such plasmacytomas, we have reviewed the medical literature regarding these tumors and mainly present the results of radiation therapy with respect to these patients. One patient, who had a local recurrence after surgical treatment, underwent radiation therapy (36Gy in four weeks) that resulted in good local control of the disease. Two patients developed multiple painful bone lesions during their long follow-up periods without manifesting any abnormal laboratory findings, suggesting multiple myeloma. It was found that radiation therapy (less than 30 Gy) was useful for the palliation of painful lesions.

[Three cases of thyroid cancer, including a component of squamous cell carcinoma].

A squamous cell carcinoma of the thyroid gland is rare and its prognosis is poor. Three cases of a rare thyroid cancer are reported, the first case being an adenosquamous cell carcinoma of a 75-year-old male and the second case being a pure squamous cell carcinoma of a 64-year-old male. These two cases were pathologically diagnosed on autopsy. The overall duration of these two cases was 6 months. The third case involved a 62-year-old male. His pathological diagnosis was a mixed squamous cell carcinoma and an undifferentiated carcinoma. Postoperatively 50 Gy of irradiation was performed. This patient is still alive and has shown no evidence of recurrence for 16 months.

[Autopsy findings in 255 cases of head and neck cancer].

Two hundred and fifty-five autopsies of patients with head and neck cancers were performed at Gunma Cancer Center between 1972 and 1986. This figure accounts for 27.8% of the total number of autopsies at the Center which was 917 cases during the period. The autopsies discussed are as follows: 1) Fifty-five cases (21.6%) were oral carcinomas, 43 cases (16.9%) maxillary carcinomas, 39 cases (15.3%) laryngeal carcinomas, 32 cases (12.5%) hypopharyngeal carcinomas and finally 22 cases (8.6%) of malignant lymphomas. 2) The incidence of visceral metastases in 200 cases of squamous cell carcinoma numbered 83, including 70 cases (84.3%) of lung metastases, the most frequently observed. 3) The causes of death in head and neck cancer were primarily of two types: Twenty five cases were due to major hemorrhage as a result of carotid rupture owing to tumor invasion and its intensive irradiation. The remaining 14 deaths resulted from interstitial pneumonitis occurring during bleomycin systemic chemotherapy. The brevity of survival from the onset of symptoms would seem to indicate that, by the time head and neck cancer manifest themselves clinically, they are already at a astage of development beyond the scope of treatment.

[An evaluation of the multidisciplinary treatment of carcinoma of the maxillary antrum in head and neck surgery].

Radiation therapy combined with surgery or regional chemotherapy was given to 114 cases of squamous cell carcinoma of the maxillary antrum from 1972 to 1983 at Gunma Cancer Center. The each treatment method was contributed to successful multidisciplinary treatment consists of partial maxillectomy, radiation therapy doses of 40 Gy and regional chemotherapy using 5 FU doses of over 2,000 mg. The 5 year cumulative survival rate was 34.7% in this study. The role of minor surgery of the antrum after radiation and chemotherapy was available for irradiated necrotizing tumor tissue, residual lesion or bone necrosis of the antrum. This additional surgery was very useful as a post radio-chemotherapeutic treatment in this study of multidisciplinary treatment.

[An evaluation of multi-disciplinary treatment combined with intra-arterial chemotherapy of head and neck cancer].

Seventy-five cases of head and neck cancer except of maxillary sinus, 27 cases of mesopharyngeal cancer, 6 cases of oral cancer, 9 cases of thyroid cancer and 9 cases of the other cancer, were treated with this multi-disciplinary treatment and the results were evaluated in this series. An intraarterial infusion drug, 5-FU, was used mainly through the superficial temporal artery. The five year survival rate was 46.1% in mesopharyngeal cancer, 34.4% in oral cancer and 33.3% in thyroid cancer. The results were relatively satisfactory despite the advanced stage of the cancer. Intraarterial chemotherapy has been a common treatment for maxillary cancer but the indication of this treatment should be developed in advanced head and neck cancer with radiotherapy or surgical treatment as a part of multi-disciplinary treatment.

[Radiotherapy in trimodal combination therapy of maxillary sinus squamous cell carcinoma].

From May 1979 to December 1982, 31 patients with reappraisable preoperative CT were treated with trimodal combination therapy for maxillary sinus squamous cell carcinoma. The three-year cumulative survival rate of all cases was 43% and the two-year cumulative local control rate was 44%. The 5-FU distribution in infusion chemotherapy was reappraised by the dye method and the radiation field was reappraised on the basis of preoperative CT. Only patients who received suitable infusion chemotherapy and radiotherapy showed a good local control rate. Suitably performed infusion chemotherapy and radiotherapy were essential in our trimodal combination therapy. Radiotherapy must be planned according to the individual patient on the basis of the preoperative CT and surgical findings.

An evaluation of neck dissection in carcinoma of the tongue.

Forty-six neck dissection cases were performed out of 117 cases of tongue cancer occurring from 1973-1981 at the Gunma Cancer Center. Among the 47 cases, 27 were initially treated surgically. In 14 cases radium therapy was used for the primary lesion and was followed by neck dissection. In another 13 cases hemiglossectomy and neck dissection were performed together. In addition, in 19 cases neck dissection was performed as secondary treatment for metastatic nodes or for recurrence of the primary lesion following radium therapy. In the cases of neck dissection performed as initial treatment along with hemiglossectomy, 84.6% had a two-year survival rate. Neck dissection performed as a secondary treatment resulted in a 46.7% survival rate over 3 years. It is evident from these figures that neck dissection performed as initial treatment results in better prognosis for the patients. In cases where metastatic nodes are present or suspected, neck dissection and hemiglossectomy should be undertaken.

[High dose methotrexate with CF rescue therapy in patients with head and neck cancer].

A clinical trial of high dose methotrexate (MTX)-CF rescue was conducted in 17 institutions. Forty-seven patients with head and neck cancer entered this trial, of which 29 were evaluable. In this series, the patients were divided into 2 groups (Arm I, Arm II), according to physician's selection. MTX was administered 700 mg/m2 (1000 mg/body) in Arm I and 1750 mg/m2 (2500 mg/body) in Arm II by i.v. drip over 6 hours. Twenty-four hours after initiation of MTX infusion, CF rescue was started. There was no complete response in 29 patients. Four patients showed partial response with an overall response rate of 13.8%. There were 4 partial responders out of 21 patients in Arm I, with a response rate of 19%, whereas there was no partial responders out of 8 patients in Arm II. These results showed no apparent dose response. MTX concentrations in plasma were determined at 6, 24, 48 and 72 hours after initiation of MTX infusion. The assay results revealed a safe range in Arm I, but exceeded in 3 cases of Arm II. GI disturbances were seen at the rate of 78%. Bone marrow suppression was remarkable and hepatic toxicity was observed as the rate of 41%. No renal toxicity was observed. The results of high dose MTX-CF rescue therapy were not better than those of moderate dose therapy, so that we concluded that MTX should be used as one agent at low or moderate dose in combination chemotherapy as far as Japanese patients with head and neck cancer are concerned.

[Evaluation of multi-disciplinary treatment combined with intra-arterial chemotherapy for carcinoma of the meso-pharynx].

Forty-seven cases of carcinoma of the mesopharynx , treated from 1973 to 1981 at Gunma Cancer Center, were evaluated. The following results were obtained, According to histopathologic diagnosis, 37 were well-differentiated squamous cell carcinoma and other cases were poorly differentiated squamous cell carcinoma. Classification of the site of the disease showed the most frequent site was lateral wall type (31 cases, 65.9 per cent) followed by anterior wall (9 cases), superior wall (5 cases), and posterior wall types (2 cases). According to TN classification, there were 1 case in T1, 14 cases in T2, 24 cases in T3, and 7 cases in T4, N distribution revealed 27 cases N0, 20 cases N1, N2 and N3. The most common treatment was intraarterial chemotherapy using 5-FU combined with external irradiation (15 cases, 31.9 per cent), external irradiation alone (14 cases, 29.7 per cent), external irradiation with Radium (8 cases, 17.0 per cent), and combined with cryosurgery 5 cases, 10.6 per cent). The five-year cumulative survival rate was 35.3 per cent. The lesion of mesopharyngeal carcinoma takes various forms, so the treatment policy cannot be a standard one. Thus multi-disciplinary treatment should be applied for this disease.

[Moderate dose methotrexate with citrovorum factor rescue therapy in the treatment of head and neck cancer].

A clinical trial of moderate dose methotrexate (MTX)-CF rescue was conducted in 12 institutions. Thirty-seven patients with head and neck carcinoma entered this trial, of which 32 were evaluable. MTX was administered 350 mg/m2 (500 mg/body) by i.v. drip over 6 hours. Three hours after completion of MTX infusion, CF rescue was started. There was no complete response in 32 patients. Nine patients showed partial response with the response rate of 28%. The response rates were 21% for the group of patients treated previously, and 75% for the group untreated previously. MTX concentration in plasma was determined at 6, 24, 48 and 72 hours after the initiation of MTX infusion, and the assay results revealed a safe range. GI disturbances were seen at the rates of 11 to 38%. Bone marrow suppression was mild and no renal toxicity was observed. We concluded that the moderate dose MTX-CF rescue therapy was useful for head and neck carcinoma. As a next step, we are planning to conduct a clinical trial of high-dose MTX.