Thermal dose-response of magnetic-induction thermoradiotherapy.

Sixty-three patients with advanced cancer underwent greater than or equal to 5,000 cGy combined with Concentric Coil magnetic-induction localized hyperthermia. Tumor regression (CR + PR) was compared to thermal dose received, incorporating the premise that hyperthermia response is a function of time as well as temperature. A computer program was developed (after Sapareto and Dewey [2]) which stored minimum tumor temperatures recorded spatially and temporally during treatment and correlated response with T43 (equivalent minutes at 43 degrees C during the first treatment) and CT43 (cumulative T43, computed by multiplying T43 by the actual number of identical subsequent treatments received during the course of therapy). Those who responded--N = 46 (73%)--had significantly higher median thermal doses than those who did not respond. Comparison of T43 and CT43 thermal dose values between responders and nonresponders was significantly different at p values of 0.05 and 0.04, respectively. The data indicate that magnetic-induction hyperthermia and high-dose XRT was an effective treatment combination in advanced disease and that tumor response improved as thermal dose increased.

Tumor stabilization after hyperthermia: an important criterion of response to thermal therapy.

Several investigators have indicated that changes in tumor size may not occur after hyperthermia therapy even with substantial tumor cell kill, because of early edema and subsequent fibrosis of background stroma, suggesting that "tumor stabilization" might be an important benefit of thermal therapy. Recently, 9 institutions completed a national cooperative study of localized hyperthermia for patients with advanced, recurrent, or metastatic solid cancer that evaluated the potential significance of this response variable in a standardized clinical trial. Of 960 evaluable patients who completed at least one course of hyperthermia, thermoradiotherapy, or thermochemotherapy, 85 (9%) had complete responses for 1-34 months, 173 (18%) had partial responses for 1-39 months, 95 (10%) had minimal responses for 1-15 months, and 313 (33%) had disease stabilization for 1-32 months. Of 313 patients who had no change (i.e., +/- 25%) in the size of their tumors after hyperthermia, the response lasted only 1-3 months in 170 (54%) patients, a finding of questionable clinical significance. However, disease stabilization was observed for more than 3 months in 143 (46%), for more than 6 months in 67 (21%), more than 9 months in 33 (10%), and more than 12 months in 16 (5%). Disease stabilization was also associated with improved activity for 1-22 months in 79 (25%) of these patients, and improved pain for 1-22 months in 100 (32%). Disease stabilization appeared to be independent of tumor histology, location, or depth within the body, size, or minimum treatment temperature, but was somewhat more frequent after hyperthermia combination therapy. There is sufficient accumulative data to suggest that tumor stabilization after hyperthermia should not be dismissed as a placebo effect. This response variable well may be a unique and potentially important criterion of response to localized hyperthermia therapy.

Enhanced therapeutic efficacy of cisplatin by combination with diethyldithiocarbamate and hyperthermia in a mouse model.

A spontaneously metastasizing solid tumor model derived by transplanting the TA3Ha murine mammary carcinoma into the s.c. tail tissue of mice was used to develop a treatment strategy for enhancing the therapeutic efficacy of cisplatin (CDDP). This strategy was based on the findings that diethyldithiocarbamate (DDTC) reduces the toxicity of CDDP, and that localized hyperthermia (HT) augments the antitumor efficacy of CDDP. DDTC (500 mg/kg) reduced the CDDP-induced nephrotoxicity and gastrointestinal toxicity as well as increased the CDDP LD10 from 8 to 20 mg/kg in strain A mice. When CDDP and DDTC were used in multiple treatment schedules at 5-day intervals, DDTC protected the hosts but not the tumors against the toxicity of CDDP. HT administered locally to the tumor 1 h after the injection of CDDP (8 mg/kg) in 1 ml Hanks' balanced salt solution increased the antitumor effect but not the host toxicity. While administration of 8 mg/kg CDDP alone or with HT three times at 5-day intervals caused 100% host mortality, this dose of CDDP could be used with no mortality by combining it with DDTC. A combination of 8 mg/kg CDDP with DDTC (750 mg/kg) and HT (43 degree C for 60 min), administered three times at 5-day intervals, retarded the local tumor growth significantly compared to the untreated, CDDP plus DDTC plus HT control groups of mice. The frequency of lung metastasis in these groups on day 30 of tumor inoculation were 0, 90, 90, and 80%, respectively. The mean survival days of the mice treated with CDDP plus DDTC plus HT was 61 +/- 6 compared to 34 +/- 5 in the controls. The results presented here demonstrate that by combining CDDP with DDTC, high doses of CDDP can be safely administered. When localized HT is combined with high dose CDDP and DDTC, the tumor growth retardation and the host survival prolongation are significantly better than those obtained with the highest tolerable dose of CDDP alone or CDDP plus HT.

Early onset of tetany following thyroidectomy: report of two cases.

The most common complication of total thyroidectomy is hypocalcemia. Following thyroidectomy, especially total thyroidectomy, the serum calcium usually falls gradually and patients do not usually require supplementary medication before 24 hours. Two cases of total thyroidectomy are presented in which the preoperative serum calcium levels were normal and hypocalcemic tetany developed in the recovery room immediately after the operation. The hypocalcemia was a temporary phenomenon, and neither patient requires supplementary calcium at the present time. There is no good explanation for this precipitous drop in the serum calcium levels in these two patients.

Magnetic-induction hyperthermia. Results of a 5-year multi-institutional national cooperative trial in advanced cancer patients.

Nine US institutions performed 14,807 Phase I-II treatments of magnetic-induction (Magnetrode [Henry Medical Electronics, Inc., Los Angeles, CA]) hyperthermia in 1170 adults. All had advanced tumors: 20% had untreated inoperable cancer or disease progression despite surgery (10%), radiation therapy (XRT) (3%), chemotherapy (27%), or combinations (40%); 67% had pain; and 79% had reduced activity. Eighteen percent were advanced primaries, 26% were recurrent, and 56% metastatic tumors in the head and neck (7%), body wall (7%), extremity (4%), abdominal cavity (17%), pelvis (17%), lung (15%), or liver (30%); 36% were less than 5 cm and 64% greater than or equal to 5 cm. Treatments were to safe tolerance for 30 to 60 minutes for five or more treatments. Results in 960 evaluable patients were complete response 9% (1-34 months; median, 7 months), partial response 18% (1-39 months; median, 4 months), minimal response 10% (1-15 months; median, 3 months), and no change 33% (1-32 months; median, 3 months), with decreased pain in 30% and improved activity in 21%, independent of histologic type or site. Regression was dependent on treatment type and minimum temperature: heat only, 23%; heat + XRT, 60%; heat + less-than-standard XRT because of prior XRT failure, 39%, heat + intravenous (IV) chemotherapy, 28%; heat + same previously failed IV chemotherapy, 20%; heat + intraarterial (IA) chemotherapy, 28%; heat + same previously failed IA chemotherapy, 15%; heat + standard XRT + chemotherapy, 58%; heat + less-than-standard XRT + chemotherapy, 47%; less than 40 degrees C, 31%; 40 to 40.9 degrees C, 45%; 41 to 41.9 degrees C, 54%; 42 to 42.9 degrees C, 47%; 43 to 43.9 degrees C, 40%; 44 to 44.9 degrees C, 33%; 45 to 45.9 degrees C, 55%; 46 to 46.9 degrees C, 63%; greater than 47 degrees C, 100%. There were 49 (0.33%) skin burns and 2 systemic injuries (stomach ulcer at 1 month; lung fibrosis at 9 months). This trial indicates that localized hyperthermia has a significant role in palliation of human advanced solid cancer.

Treatment of breast carcinoma recurrent after adjuvant chemoimmunotherapy.

Between July 1975 and June 1979, 194 patients with State II or III breast carcinoma were randomized to receive either L-phenylalanine mustard (L-PAM), cyclophosphamide and 5-fluorouracil and prednisolone (CFP), or CFP and BCG. Sixty-one patients have recurred despite the adjuvant chemoimmunotherapy trial. Fifty-three are evaluable for survival and 36 for response to chemo-hormonal therapy. Those treated with a chemo-hormonal regimen for their first recurrence exhibited a 53% objective response rate to cytotoxic therapy or a 35% response to hormonal therapy. Prior exposure to L-PAM, cyclophosphamide, or 5-fluorouracil did not preclude response to "salvage" therapy regimens containing those agents. Neither menopausal status, estrogen receptor content, size of the primary tumor, adjuvant treatment, nor extent of the recurrence had any effect on subsequent survival. Overall, the entire group exhibited median survival of 37 months from initial diagnosis and 13 months from recurrence. Unlike recurrent Hodgkin's disease, there was no demonstrable relationship between the length of the disease-free interval and the likelihood of subsequent response to cytotoxic or hormonal treatment. Comparison is made to the results of "salvage" therapy administered after three other large adjuvant treatment series.

Follow-up adjuvant chemotherapy and chemoimmunotherapy for stage II and III carcinoma of the breast.

Patients with stage II or III carcinoma of the breast were assigned to one of three adjuvant chemotherapy and chemoimmunotherapy treatment groups following radical or modified radical mastectomy. This study compares the efficacy of single drug treatment (melphalan) versus multiple drug regimens (CFP and CFP + BCG). In the initial phase of the project participants in the melphalan group showed a higher recurrence rate than those in the CFP and CFP + BCG groups. The recurrence rate of the melphalan group was 4.4 times higher than the recurrence rate of the combined polychemotherapy arms. However, after the initial phase, the recurrence rates for the polychemotherapy arms steadily increased and approached the dropping rate of the melphalan group. Currently (247 weeks after the beginning of the study and nine months after the last patient accrual), 194 patients have been treated (median follow-up time of 101 weeks), and no significant differences can be detected between the three treatment arms using any of the following criteria: disease-free interval, proportion of recurrence and recurrence rate. The only factors which are significant with respect to recurrence are the two prognostic factors: tumor size and degree of nodal involvement. The two chemotherapy groups, CFP and CFP + BCG, show no significant difference with respect to recurrence rate along the entire span of the study.