TOPICAL ADMINISTRATION OF EMULSIONIZED BLEOMYCIN FOR METASTATIC LYMPH NODES OF PATIENTS WITH ESOPHAGEAL CANCER

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1 THE KURUME MEDICAL JOURNAL Vol.24, No.2, p , 1977 TOPICAL ADMINISTRATION OF EMULSIONIZED BLEOMYCIN FOR METASTATIC LYMPH NODES OF PATIENTS WITH ESOPHAGEAL CANCER AS AN ADJUVANT THERAPY FOR OPERATION TETSUZO INOGUCHI, MOTOICHI IWAMOTO AND YUZO AOYAMA First Department of Surgery, Kurume University School of Medice, Kurume, 830, Japan (Received for publication April 8, 1977) As an adjuvant procedure of operation, topical admistration Bleomyc to metastatic was carried out order to support surgical dissection. Tracers were admistered before operation uptake regional was measured. Uptake of the tracer was sufficient degenerative changes of cells were also recognized histologically. This procedure is useful as a preventive procedure of metastasis recurrence caused by remaed metastatic at operation. INTRODUCTION Sce the first successful thoracic esophagectomy had been reported 1913 by Torek, various combed therapies for esophageal have been performed order to improve curability late result. Preoperative irradiation had been advocated by Cliff ton others (1960). Then Nakayama colleagues (1904) had demonstrated the value of stagg procedures for reestablishg contuity a large series of cases. While the reduced mortality as a result of stagg the adjuvant use of irradiation between stages had been reported, postoperative longterm survival rate is not always satisfactory. The treatment for metastasis of esophageal, especially, adequate treatment of atic metastasis should be improved to obta better results. We carried out selective contnuous admistration of anti- agent to paraesophageal space as an adjuvant procedure order to support surgical dissection. MATERIALS AND METHODS The effectiveness of the preoperative topical admistration of Bleomyc (BLM) for metastasic was evaluated on 43 patients with esophageal, most of which had metastasis of regional Investigation was carried out from three aspects, namely, uptake of tracer, concentration of BLM histological fdgs. The site of BLM fusion was decided accordg to the localization of esophageal. In cases of the carcoma of the upper thoracic esophagus, the 105

2 INOGUCHI, 106 IWAMOTO level of the 4th tercostal paravertebral space was selected the level of the 7th was detemed cases of lower thoracic esophagus. A small cision was made paravertebral region a fe tube was serted to paraesophageal space through bluntly dissected extrapleural space. Through this tube, emulsionized BLM was contuously admistered by an fusion pump to the retromediastal space of patients with esophageal for two weeks. The admistered BLM attaed from 100 to 200 mg total dose preoperatively. The emulsionized BLM is made by ultrasonic generator from the mixture of sesame oil, span 80, the solution of BLM as water oil (W/O) type. Then many droplets of emulsion can be observed by Sudan III stag. The carcostatic potency of BLM is not decreased by this process. Comparative measurement on the potency BLM the solution of BLM by bioassay is shown 1. No significant difference was noted the si.e of bacterial growth hibition. AND AOYAMA tracer on the third day before operation were examed. Moreover, the fluence on metastatic cells were observed histologically. In order to ensure the filtration of admistered anti- agent to metastatic, fundamental studies had been carried out on twenty three dogs prior to this clical trial. RESULTS The observation on the flow the retromediastum the determation of adequate location of admistration was studied by contrast-medium another tracers experimentally dogs. A photograph of filtratg contrast-medium to the upper retromediastum is shown left side of 2. 2 mediastum Flow to side Fig 1 BLM tency (by Comparison BLM solution bloassay). between on emu carcostatic sionized po- On extirpated at operation, the concentration of BLM by bioassay the uptake of radioactive Au colloid which had been admistered as The flow of (by contrast-medium). proximal side (L) the retro- to distal (R) In these experimental series, the flow of lipiodol streamed up even to cervical region through this upper mediastal fection. Likewise, it could be arrived to the retroperitoneum cases of the jection to lower retromediastal space. The radioactivity which were removed on the third day after the admistration of radioactive colloidal Au is shown 3. The sufficient uptake of tracer

3 ADJUVANT 3 admistered 198 Radioactivity Au THERAPY OF ESOPHAGEAL CANCER 107 of colloid. 4 Schematic presentation on distribution of tracer (198 AU) to regional to the upper or lower retromediastal was counted both admistration site. In series of this experiment, sufficient radioactivity contralateral mediastal was presented simultanously. This fact many important value when this method is applied clical cases. 4. is a schematic presentation of summarized results clical cases of esophageal whom tracer was admistered to the retromediastum. The size of black circles dicates the magnitude of radioactivity Higher radioactivity been presented which have high metastatic rate. Secondly, removed after admistration BLM were observed by Sudan III - stag histologically. In most cases, Sudan positive granules could be found atic sus ( 5). On metastatic cells extirpated after contuus local admistration BLM, degenerative changes of various degree such as swellg or pycnosis of nucleus, tic sus 5 Sudan (Sudan positive granula III stag). a- vacuolization, filtration of neutrophil leukocyte, fibrosis, necrosis have been observed histological specimens generally. In these cases, the BLM concentration of 3 to 50 micrograms per gram of atic tissues been proved by bioassay metastatic, i. e., bilateral cervical, upper mediastal, gastric pericardial These results are consist with remarkable histological changes such as destruction of cells metastatic

4 108 INOGUCHI, IWAMOTO AND AOYAMA DISCUSSION The radical operation for esophageal been performed together with adjuvant therapy such as irradiation or the systemic admistration of anti- agents order to improve postoperative longterm survival rate (Akakura, 1970; Sato, 1975; Watanabe, 1974). But we have not yet obtaed satisfactory results cases with multitudous metastatic However careful we may be, even enbolc operation, a part of the upper mediastum cervical region is left behd easily. And those remaed were one of the important factors which affect postoperative survival rate. Moreover, the presence of metastatic the contralateral mediastum which can not be removed enough by surgical technic is another important problem. Therefore we have considered that pricipal purpose of this adjuvant therapy must be directed to those The distribution of anti- agent to regional was observed by tracer such as radioactive colloidal 138 Au or contrast-medium which were fused to the posterior mediastum. Accordg to the results of fundamental studies, we could recognize the sufficient arrival of tracer to cervical, upper mediastal perigastric, which are also most usual site of atic metastasis of patients with esophageal statistical studies. This fact implies that the tracer was itially up-taken to abundant flow through extravascular fluid pathway from coarse periesophageal conncetive tissue further reached to distant Mori (1960 had also described that the retromediastum maly flows to proximal or distal side along the esophagus. By this attempt, we could contuously admistrate an anti- agent to regional selectively. Then we could measure high concentration of BLM metastatic by bioassay its potency was higher than cases of systemic admistration. We could simultaneoutly proved destructive changes of various degree of cells those metastatic histologically. This procedure was applied clically to 43 cases data are the process of beg accumulated from those cases. Therefore, we would like to empize that the satisfactory effects on metastatic can be expected short period likewise the metastatic the contralateral mediastum which can not be dissected enough by surgical technic can satisfactorily be managed by this procedure. It is assumed that preoperative topical admistration BLM to metastatic is hopeful as an ad juvant therapy for the operation of esophageal one of favorable procedures order to improve postoperative longterm survival rate. REFERENCES AKAKURA, I. (1970). Surgery of carcoma of the esophagus with preoperative radiation. Chest, 57, CLIEETON, E. E. GOODNER, J. T. (1960). Preoperative irradiation for of esophagus. Cancer, 13, M0RI, K. (1968). Lymphatic vessels of the trachea the esophagus. J. Jap. Broncho-esophagological Society, 19, NARAYAMA, K., YANAGISAWA, F. WAGNER, B. (1960. Erfahrungen mit der praeoperativen Strahienbehlung des Oesophaguskrebses. Langenbecks. Arch. Kl. Chir., 305, SATO, H. IsoNo, K. (1974). Longterm results for treatment of Esophagus carcoma. Surgical Therapy, 30,

5 ADJUVANT THERAPY OF ESOPHAGEAL CANCER 109 TOREK, F. (1913). The first successful case of resection of the thoracic portion of the esophagus for carcoma. S. G. O., 16, WATANASR, H. (1974). Combed therapy of the esophageal carcoma. Jap. J. Cancer Cl., 20,

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