Hidemasa Matsufuji

Heat, drugs, and radiation given in combination is palliative for unresectable esophageal cancer

From April 1966 to April 1986, 101 men and women with unresectable squamous cell carcinoma of the esophagus were treated in our clinic. Since 1983, 21 were treated with a combination of hyperthermia, chemotherapy, and radiotherapy (group I). Before 1983, for another 80 patients, radiation plus chemotherapy had been prescribed (group II). Nine of 21 patients in group I had an unresectable carcinoma due to an advanced tumor, 9 had an associated severe clinical status, and 3 refused surgery. Out of 80 in group II, 50 had a far advanced tumor, 21 had a poor clinical condition, and 9 refused operation. With regard to staging, for 21 in group I, 6 were classified as Stage I, 5 as Stage II, 7 as Stage III, and 3 as Stage IV. As to the 80 in group II, those in Stage I, II, III, and IV accounted for 8, 22, 39, and 11, respectively. The median doses of each modality, for patients in group I, were 6 times of hyperthermia at 42-45 degrees C for 30 minutes, 40 Gy of X ray and 30 mg of bleomycin. For patients in group II, a median dose of 56 Gy of X ray was given. Response rates determined by esophagograms and endoscopies for the patients in groups I and II were 76.2% (16/21; 4 CRs, 12 PRs) and 39.2% (31/79; 2 Crs, 29 PRs), respectively (p less than 0.001). The effective rates determined by improvement in quality of life (relief of pain and dysphagia) for groups I and II were 61.9% and 37.2%, respectively. A longer survival was obtained for patients in group I (median survival: 9 months vs 6 months). Especially for the patients classified as Stage I, a significantly longer survival was obtained with a combination of hyperthermia, chemotherapy, and radiotherapy (p less than 0.01).

Preoperative hyperthermia combined with radiotherapy and chemotherapy for patients with incompletely resected carcinoma of the esophagus.

Two hundred eighty‐nine patients with squamous cell carcinoma of the esophagus underwent subtotal esophagectomy from December 1965 to June 1986. Resection of esophageal carcinoma was absolutely noncurative in 64 patients (20%) due to invasion to the surrounding structures. These 64 patients were subdivided as follows into three groups based on the type of preoperative treatment: Group I included 16 patients without preoperative treatment; Group II included 38 patients with preoperative radiotherapy combined with chemotherapy (average doses: radiation 37.3 Gy, 1‐(2‐tetrahydrofuryl)‐5‐fluorouracil [tegafur] 8.4 g); Group III included 10 patients who underwent preoperative hyperthermia (42°C to 45°C) combined with chemotherapy and radiotherapy (average doses: radiation 33 Gy, bleomycin 33.9 mg, or cis‐diamine dichloroplatinum 75 mg, hyperthermia 6.2 times). There were no significant differences in terms of postoperative therapy among the three groups. The median survival times for patients in Groups I, II, and III were 6, 7.5 and 11 months, respectively. The 2‐year survival rates for patients in Groups I, II, and III were 0, 15.6%, and 34.3%, respectively. The prognosis in Group III was superior to that for Group I (P < 0.05) and Group II. These results suggest that preoperative hyperthermia combined with radiotherapy and chemotherapy could prolong survival even in patients who have had noncurative resection.

Cytophotometric DNA analysis of esophageal dysplasia and carcinoma induced in rats by N-methyl-N-amylnitrosamine

A series of esophageal lesions, mild, moderate and severe dysplasia, carcinoma in situ (CIS), early and advanced squamous cell carcinoma were induced in rats with N-methyl-N-amylnitrosamine (MAN). To evaluate the biological nature of each lesion, the ploidy level was estimated by microspectrophotometrical measurement of cell nuclear DNA content. DNA distribution patterns were classified into types I, II, III and IV, according to the degree of dispersion and the peak modal value on the DNA histogram. The incidences of type III of high ploidy in early cancer, CIS and severe dysplasia were 3/11 (27.3%), 5/13 (33.3%) and 4/16 (25%), respectively. On the other hand, in moderate and mild dysplasia, 15/16 (93.8%) and 20/21 (95.2%) were low ploidy (types I and II), respectively. The mean DNA content of advanced and early cancer, CIS and severe dysplasia were 3.88c, 3.34c, 3.24c and 3.13c, respectively, while those of moderate and mild dysplasia were near diploid, showing 2.67c and 2.51c, respectively. These findings indicate that the biological nature of severe dysplasia may be considered as serious a lesion as cancer, in terms of DNA analysis. Cytophotometric DNA analysis aids the evaluation of various degrees of dysplasia and carcinoma of the esophagus.

Combined effects of hyperthermia, bleomycin, and X rays on Ehrlich ascites tumor

The combined effects of water-bath hyperthermia at 42.5 degrees C for 30 min, 1/10 LD50 Bleomycin iv, and 200 rad x irradiation were studied in DDD strain male mice with Ehrlich ascites tumor. The objective was to acquire data on the optimum regimen for a combined administration of these three modalities. The treatments were given 10 days after the inoculation of 2 X 10(6) of the cells into the right hind limb. Concomitant application of the three modalities led to an 80% regression. A single modality produced no significant effect and a 30-50% regression occurred when only two modalities were combined. To assess the influence of timing and sequence, hyperthermia was applied at 1, 2, 4, and 6 hr before, after, or simultaneously with the combination of Bleomycin and 200 rad X ray. A significant effect was obtained in the case of concomitant application of the three and hyperthermia was effective when applied within 2 hr before or after administration of Bleomycin plus irradiation. This enhancement disappeared at 4-hr intervals.

Mucoepidermoid carcinoma of the esophagus--a case report.

We treated a 66-year old woman with mucoepidermoid carcinoma of the esophagus. The histologic features of this tumor seemed to originate from esophageal glands and their ducts. This deduction was based on the subepithelial growth pattern and the presence of in-situ carcinoma showing a glandular or squamous pattern at the location of the esophageal gland duct. Although the biological nature of this tumor was not elucidated, the prognosis is similar to that seen with the ordinary type of esophageal squamous carcinoma.

Radiation-induced esophageal carcinoma responded well to hyperthermic chemotherapy--a case report.

A 66-year-old man with multiple malignant lesions of the esophagus, as apparently induced by irradiation of 60 Gy of60Co for a mediastinal tumor at the age of 36 y.o., was a poor operative risk because of severe lung disease. This man was treated with a combination of hyperthermia, oral administration of oil Bleomycin-polyacrylate paste and intravenous infusion of cis-Platinum. During 20 administrations of hyperthermia conducted at 42–45°C for 30 min, 600 mg of oil Bleomycin and 200 mg of cis-Platinum, no complications occurred and the heat treatments were completed with no side effects. Repeatedly performed esophagogram and endoscopy showed a complete disappearance of three of the four lesions and a marked regression in the other one. There has been no regrowth or distant spread of the carcinoma up to the present 10 months of follow up. This combination of hyperthermia and chemotherapy may prove to be the optimal strategy for treatment of unresectable esophageal cancer, particularly when radiotherapy is contraindicated.

Promotion by 12–0-Tetradecanoyl, Phorbol-13-Acetate of Esophageal Carcinogenesis Induced in Rats by N-Methyl-N-Amylnitrosamine

The induction of tumors can generally be divided into two stages, initiation and promotion. Experiments have suggested two-stage carcinogenesis in the induction of liver, urinary bladder, and skin tumor [1–3]. Little is known regarding the induction of esophageal cancer. The promoting effects of phorbol diesters on esophageal carcinogenesis have been given little attention, hence the epidemiologic evidence reported by Hecker [4] has not been supported. We found that 12–0-tetradecanoyl, phorbol-13-acetate (TPA), a potent tumor-promoting phorbol diester, promoted the induction of esophageal tumors in rats initiated with N-methyl-N-amylnitrosamine (MAN). The possibility of two-stage carcinogenesis in esophageal cancer is discussed.

Preoperative Hyperthermochemoradiotherapy for Carcinoma of the Esophagus

Hyperthermia to treat clinical malignant lesions has gained increasing interest. Hyperthermia combined with chemo- and radiotherapy appears to have a synergistic effect on malignant lesions. The major problem limiting wide application of diathermy is the difficulty in heating deeply located tumors.