Cancer Research and Treatment

Results of Hyperthermic Treatment Combiced with Radiotherapy/Chemotherapy in Locally Advanced Inoperable Gastric Cancer: Chang Woo Moon, Ha Yong Yeom, Tae Sik Jung, Young Ho Kim, Ja Young Koo; J Korean Cancer Assoc. 1998;30(4):639-651.

Abstract PDF: PURPOSE
This retrospective study is conducted to evaluate the local response rate, survival rate, median survival times and complication of hyperthermic treatment combined with radiotherapy/chemotherapy in locally advanced inoperable gastric cancer.
MATERIALS AND METHODS
One hundred and twenty-seven patients treated with hyperthermia from April, 1992 to December, 1994 were enrolled. Among 127 patients, 13(10.2%) were treated with thermo-radiotherapy(Group I), 4(3.1%) were treated with thermo-radio-chemotherapy(Group II) and 110(86.6%) were treated with thermo-chemotherapy (Group III). Hyperfractionated radiotherapy(135 cGy/fr., 2 times/day) using 6-MV X-ray Linac was delivered with total doses of 40.5~67.5 Gy(median: 45 Gy). Chemotherapy by FI(5-FU+ Interferon) or EAP(Etoposide+ Adriamycin+ Cisplatin) regimens was administered. Hyperthermia using 8-MHz RF(radiofrequency) capacitive heating eqiupment (CANCERMIA GHT-8) was applied with interval of 2 times/week, 40~60 minutes /session within 10~15 minutes following radiation, and was simultaneously done with chemotherapy. The estimation of local response was used computed tomography and endoscopy, and was divided into complete response(CR), partial response(PR), and no response(NR). The survival rate was calculated by Kaplan-Meier method.
RESULTS
Overall local response rate(CR+ PR) was 68.5% with 6.3% in CR and 62.2% in PR. The local response rates by treatment modality were 92.3% (CR: 15.4%, PR: 76.9%) in Group I, 100%(CR: 75.0%, PR: 25.0%) in Group II and 64.5%(CR: 2.7%, PR: 61.8%) in Group III. There was statistically significant difference(p=0.0001). The overall 1 and 2 years survival rates with median survival time(MST) were 20.5%, 7.1% with 9 months, respectively. The overall 1 and 2 years survival rates(with MST) by treatment modality were 7.7%, 0%(7 months) in Group I, 50.0%, 0%(9 months) in Group II and 20.9%, 8.2%(6 months) in Group III. There was no statistically significant difference. The incidence of side effect by heating was 3.1%(4 patients) and the most serious side effect was subcutaneous fat necrosis in anterior abdominal wall.
CONCLUSION
From this study we concluded that hyperthermic treatment combined with radiotherapy/chemotherapy may increase the local response rate in locally advanced inoperable gastric cancer.

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The Effect of Hydralazine on Hyperthermic Treatment of C3H Mouse Fibrosarcoma: Woo Yoon Park, Sung Whan Ha, Charn Il Park; J Korean Cancer Assoc. 1995;27(4):671-680.

Abstract PDF: Hypoxic cells comprise l0~20% of tumor cells and are more sensitive to hyperthermia. By decreasing tumor blood flow artificially and thus increasing the hypoxic fraction in the tumor, the cytotoxic effect of hyperthermia can be increased. Hydralazine is an antihypertensive drug and its main mechanism is relaxation of the vascular smooth muscle of arterioles rather than veins. Administration of hydralazine causes a decrease in vascular resistance and an increase in blood flow in normal tissue, but since the vasculature of tumor is not responsive to such a drug, blood flow in tumors is decreased because of steal phenomenon. Thus the hypoxic fraction in the tumor is increased, and the tumor becomes more sensitive to hyperthermia. Therefore, to evaluate the hydralazine effect on hyperthermia, the tumor growth delay was investigated and the change in the hynoxic fraction of the tumor was estimated using C3H mouse fibrosarcoma(FSaII) with hypoxic fractions af usual range. In 6 mm FSaII tumors grow- ing in the dorsum of the foot, administration af 5 or l0 mg/kg of hydralazine was followed by 43`C, hyperthermia for 60 minutes. Tumor growth times (TGT) to reach a tumor volume of 500 mm(2) were 7.11+-0.84 days and 7.44+- 1.13 days for controls and 10 mg/kg of hydralazine only. TGTs for hyperthermia alone and administration of 5 or 10 mg/kg of hydralazine followed by hyperthermia were 10.34+-2.17 days, 13.38+-1.82 days and 14.47+- 0.67 days, respectively. Elongation of tumor growth delay by administration of 5 or l0 mg/kg of hydralazine in addition to hyperthermia were statistically significant (0.025

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Clinical Result of Combined Radiotherapy and Hypertermia Indured by 915 MHz Microwave and Ultrasound in Locally Advanced Malignant Tumors: Kyoung Hwan Koh, Kyoung Hwan Koh, Chul Koo Cho, Seong Yul Yoo; J Korean Cancer Assoc. 1990;22(1):106-112.

Abstract PDF: Sixty six lesions of 66 patients with locally advanced malignant tumors were received thermoradiotherapy with ultrasound and/or 915 MHz microwave. Most of all patients were failed with previous conventional therapeutic trial. Hyperthermia had been done immediately after radiotherapy, twice a week, 43'C for one hour and radiotherapy had been done 5 fractions per week with a fraction size of 2 Gy up to total 30 to 60 Gy. Conclusions are as follows. 1) Total response rate (CR+ PR) to thermoradiotherapy with microwave and ultrasound was 85 %. 2) Tumor depth, minimum temperature of tumor center, number of heat fraction and irradiation dose were statistically significant factors affecting response. 3) Hyperthermia with microwave and ultrasound can be used efficiently to control locally advanced malignant tumars whether previously received near tolerance dose of radiotherapy or not.

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In Vitro Chemosensitivity Test for the Evaluation of Efficiency of Hyperthermia in Gastrointestinal Cancer Cell Lines: Jeong Hwan Yook, Byeong Yul Ahn, Geum Hee Koo, Hun Seo, Choon Sik Jeong, Sung Tae Oh, Byung Sik Kim, Kun Chun Park, Jin Cheon Kim; J Korean Cancer Assoc. 1999;31(5):931-938.

Abstract PDF: PURPOSE
This study was designed to establish the experimental background of intra- peritoneal hyperthermo-chemotherapy in gastrointestinal cancer.
MATERIALS AND METHODS
We established stomach cancer cell lines; KATO-III, MKN45, AMC1 and colon cancer cell lines; AMC5, AMC6, CloneA, CCL188, C106, KM-12C. We performed chemosensitivity test by using MTT assay and calculated ICso of each chemotherapeutic agent. We confirmed antitumor effect of hyperthermia at 40C and 43C and antitumor synergistic effect with each chemotherapeutic agent at 40C and 43C.
RESULTS
The ICso was calculated in 7 (78%) of 9 cell lines for 5-FU, 6 (67%) for MMC, 5 (56%) for ADM, 1 (11%) for CDDP and VP-16. Antitumor effect of hyperthermia at 40C was not found, but, that at 43C was found except KATO-III and AMC6. In stomach cancer cell lines, antitumor synergistic effect of hyperthermia with anticancer drugs at 43C was found in VP-16 for MKN45 and KATO-III and in all of 5 drugs for AMC1. In colon cancer cell lines, this effect at 43C was found in all of 5 drugs for CCL188, in S-FU, CDDP, ADM for AMC5, in 5-FU, MMC, ADM, VP-16 for CloneA, KM-12C, and in 5-FU, CDDP, MMC, ADM for C106.
CONCLUSION
Hyperthermia itself had antitumor effect at 43C. Hyperthermo-chemotherapy had antitumor synergistic effect, especially at 43C.

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Effect of Hyperthermia on Anticancer Drug - Resistant L1210 Sublines: Jeong Hee Kim, Sung Yong Kim, Jae Ryong Kim; J Korean Cancer Assoc. 1996;28(4):646-655.

Abstract PDF: The development of multidrug-resistant tumor cell populations is a major problem in the chemotheraphy of human cancer. These cells are often cross resistant to unrelated drugs. Current understanding of the mechanism of development of tumor drug resistance and its reversal, however, is limited. The present study was examined about sensitive Ll210 cell and resistant sublines (L1210AdR, L1210VcR and L1210Cis) for reversal of drug resistance by hyperthermia. Cell survival was determined by MTT assay after exposure to various heat(41, 42, 43¡ÆC) condition and to anticancer drug and heat combination. Survival rate of sensitive and resistant cells as various temperature exposure was revealed fifty percent on 42.8¡ÆC for L1210 cell and 41.4¡ÆC to 41.9¡ÆC for resistant sublines. The 50 percent survival for exposure times on 42¡ÆC was expressed as no change in L1210 cell and as 46 to 48 minutes on resistant cells, on 43¡ÆC, L1210 cell was 48 minutes, resistant cells were 10 to 14 minutes. Cytotoxicity of resistant sublines treated by combination of hyperthermia and adriamycin was not increased. mdr 1 gene of L1210AdR and L1210VcR were well expressed by hyperthermia but expression of hsp 70 gene were increased to compare increasing of exposure time at 41¡ÆC. Expressions of hsP 70 in L1210 and Ll210Cis cells were revealed the peak values at exposure for 45 min and 30 min. The cytotoxic effect of hyperthermia on resistant sublines were more effective than on sensitive L1210 cell. And then the suggestion of correlation between mdr 1 and hsp 70 gene brought about.

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