Results of a non-controlled trial of hyperthermia combined with radiation for superficial tumours

Fifty-four patients with 65 superficial malignant lesions were treated by local hyperthermia combined with radiation therapy at the National Cancer Center Hospital, Tokyo. Hyperthermia was delivered with an Aloka Model HMS-020 (2450 MHz) or with a horn-type applicator of BSD-1000 (80–90 MHz). Relatively small tumours, those less than 4 cm in thickness, were treated by using 2450 MHz while 80–90 MHz delivered through the horn-type applicator was used for tumours exceeding 5 cm in thickness. The radiation dose was 4 Gy twice a week or 2 Gy five times a week, the total dose being 40–60 Gy. A total of six to 10 hyperthermia treatments ranging from 40 to 60 min each, with the tumour heated to more than 42.5°C, were given twice a week within 1 h following radiation therapy. Complete response was achieved in 16 of the 30 patients (55 per cent) treated with the 2450 MHz microwave, and partial response in seven others (23 per cent). Tumours treated with the BSD-1000 achieved complete response in 10 out of 33 patients (30 per cent) and partial response in nine others (27 per cent). In five out of nine patients classified as partial responders, however, complete disappearance of tumour cells was noted by post-treatment histological examination. Complete plus partial response rates were thus essentially the same with the Aloka HMS-020 and the BSD-1000, though the rate of complete response was apparently higher with the Aloka unit, probably because it was used on smaller tumours.     

Randomized trial of one versus two adjuvant hyperthermia treatments per week in patients with superficial tumours

One test for thermotolerance development in a clinical situation is to evaluate the effects of altering the hyperthermia fractionation interval on tumour response to thermo-radiotherapy. Between 1983 and 1990 44 evaluable advanced superficial tumours of miscellaneous origin in 41 patients were randomized to receive either once-weekly or twice-weekly external microwave hyperthermia treatments combined with radiation therapy. The mean age of patients was 62 years, and 85% had failed previous therapy. All lesions were less than 8×8×4 cm (L×W×D) and were heated by external 915 MHz microwaves. The mean radiation dose was 44 ±3 Gy (mean ± SE) in the once-weekly group and 46±3 Gy in the twice-weekly group =0.64). The mean volume of the lesions heated once weekly was 17 ± 6 versus 23 × 5 cm³ for those heated twice weekly (p=0.45). Hyperthermia was administered once weekly for 4.6±0-2 sessions (range 3-7) or twice weekly for 8 1 ± 0 3 sessions (range 4-10). Thermometry was performed using 3–4 ± 0.2 catheters and 5 - 1 × 0 6 thermal sensors per tumour in the once-weekly group, and 2 7 ± 0–2 catheters and 5–8 ± 0–3 thermal sensors per tumour in the twice-weekly group. Of the 44 evaluable randomized lesions a complete response (CR) at 2 months post-treatment was observed in 59% (13/22) heated once weekly and 55% (12/22) in those heated twice weekly. The prognostic factors predictive of tumour complete response were found by logistic regression analysis to be radiation dose and tumour volume, while the prognostic factors predictive of duration of response (Cox proportional hazards analysis) were median minimum tumour temperature (T_min), minimum tumour temperature during the first heat treatment (T_minl) and tumour volume. The duration of local control in lesions with T_min < 39 5°C was 11 7 ± 1 a 9 months while for lesions with T_min39.5°C it was 23.0±4.2 months (p=0.01). The ED₅₀ was calculated by logistic regression to be 40 Gy (95% CI=22-54 Gy) for once-and twice-weekly heated lesions. There was not a significant difference in tumour response or duration of response between populations randomized to receive once- versus twice-weekly hyperthermia treatments. There was also no difference in skin reaction rates between once- and twice-weekly hyperthennia treatments, nor could a correlation be found between any thermal parameter and skin reactions. It is concluded that similar complete response rates, similar duration of response and similar skin reaction rates can be obtained with once- or twice-weekly hyperthermia regimens.     

Pilot study of local hyperthermia,radiation therapy,etanidazole, and cisplatin for advanced superficial tumours

Five patients (six hyperthermia sites) with advanced superficial tumours were treated with combined etanidazole, cisplatin, local hyperthermia, and radiation therapy as part of a Phase I pilot study. Treatment was given once weekly and consisted of etanidazole 3 gm/m² IV bolus, cisplatin 50 mg/m² IV bolus, hyperthermia for 60 min with a target temperature of 43°C, and radiation therapy 500 cGy/fraction (median total dose 3000 cGy) for a total of six weeks. Blood levels of etanidazole were taken during treatment at week 1 and week 4. Etanidazole drug exposure was calculated using the trapezoidal rule and expressed as the area under the curve (AUC) of plasma concentration X time. Five of six treatment sites had received prior irradiation. Prior chemotherapy had been given in three patients and tamoxifen therapy given in the other two patients. The median follow-up time is 34 months; 3/5 patients have died of disease. The most significant toxicity was grade I or II nausea and vomiting associated with 19/32 treatments (59%) and a second degree burn in 2/6 fields. None of the five patients experienced peripheral neuropathy, skin ulceration, or needed surgical repair. In addition, there was mild renal toxicity; pharmacokinetic analysis showed a 28–75% increase in the week 1 to week 4 AUC in three patients, all of whom had a decrease in creatinine clearance over the same time of 15–47%. This pilot study suggests this combined modality therapy can be delivered without major complications and that renal function, determined by creatinine clearance, affects clearance of etanidazole and alters the AUC. Therefore, monitoring renal function is important in patients receiving etanidazole in addition to other nephrotoxic agents such as cisplatin. The impact of etanidazole on the therapeutic index of hyperthermia, radiation therapy and cisplatin may be worthy of study, especially since a positive interaction between these modalities is found in laboratory models.     

Microwave-induced hyperthermia and radiotherapy in human superficial tumours: clinical results with a comparative study of combined treatment versus radiotherapy alone

Eighty-five evaluable superficial recurrent malignant tumours, mainly adenocarcinomas (78 per cent), in 38 patients were treated with either combined local hyperthermia (41-45 degrees C for four sessions) and low dose radiotherapy (30.0 Gy) or the same low dose radiotherapy alone. The treatment was given for two weeks. Hyperthermia was induced externally with 2450 MHz or 915 MHz microwaves. Totally 57 tumours were given combined treatment with a complete and partial response rate of 46 and 30 per cent, respectively (duration 1-38 months). In 18 patients with 2-10 superficial tumours each, 56 tumours were used in a comparative study, comparing the effect of combined hyperthermia and low dose radiotherapy versus the same low dose radiotherapy alone, the patients acting as their own controls. The total response rates were 89 and 50 per cent, respectively, in the two treatment modality groups. The difference in response rates is significant (p = 0.0039) in favour of the combined treatment, and this is also found when comparing complete remissions only (p = 0.0027). Local pain and normal tissue reactions presented problems during and after 2450 MHz microwave-induced hyperthermia treatment, performed without a coupling water bag system. Introduction of 915 MHz microwave-induced hyperthermia with a coupling deionized water bag system and refinement of microwave applicators, as well as the temperature control system considerably reduced these problems.     

热疗配合放射治疗不能手术的食管癌疗效分析

探讨不能手术的食管癌热疗配合放射治疗的效果。方法　回顾性分析 5 0例不能手术的食管癌热疗配合放射治疗的临床资料。 5 0例中男性 43例 ,女性 7例 ;鳞癌 46例 ,腺癌 1例 ,小细胞癌 3例。热疗采用 8MHz深部射频热疗机 ,在放射后 10～ 6 0min内进行加温 ,每次治疗 5 0min ,每周 1～ 2次。放射治疗采用 8MVX射线或6 0 Coγ射线 ,常规分割照射 ,总剂量 6 0～ 70Gy ,6～ 7周者 42例 ,72～ 76Gy ,7～ 8周者 4例 ,5 0Gy以下者 4例 ,治疗效果均以食管钡餐检查为评价手段。采用Kaplan Meier法进行生存率分析、Logrank法检验 ,分析不同的热疗参数对疗效的影响。 结果　热疗次数达 3次以上者 1、2年生存率均高于 3次以下者 ,分别为 42 .5 %、17.5 %及 10 .0 %、0 .0 % (P<0 .0 1) ;热疗有效功率 80 0W以上的 1、2年生存率比 80 0W以下高 ,分别为 46 .9%、18.8%及16 .7%、5 .6 % (P <0 .0 5 )。结论　热疗配合放射治疗食管癌亦应注意有效功率及热疗次数。     

A robot-controlled microwave antenna system for uniform hyperthermia treatment of superficial tumours with arbitrary shape

A system for microwave hyperthermia by scanning an antenna 'footprint' over a disease site is demonstrated. A computer-controlled robot arm scans a 2.45 GHz helical antenna and controls the absorbed power distribution. The 'ideal' power distribution required to achieve steady-state temperature uniformity over a given region has been calculated and a corresponding antenna trajectory programmed to approximate this pattern. Computer models, based on the solution of the bio-heat equation, have been implemented to allow various system parameters, such as antenna beam size, scan path and velocity profile, to be optimized. Experiments on a homogeneous muscle-equivalent phantom have shown that the scanning antenna system produces uniform temperature distributions over large areas of arbitrary shape. The addition of a thermal control system, based on temperature signal feedback, would enable 'real-time' modification of the power distribution and allow inhomogeneous and perfused tissue structures to be heated more uniformly.     

A robot-controlled microwave antenna system for uniform hyperthermia treatment of superficial tumours with arbitrary shape

A system for microwave hyperthermia by scanning an antenna ‘footprint’ over a disease site is demonstrated. A computer-controlled robot arm scans a 2.45 GHz helical antenna and controls the absorbed power distribution. The ‘ideal’ power distribution required to achieve steady-state temperature uniformity over a given region has been calculated and a corresponding antenna trajectory programmed to approximate this pattern. Computer models, based on the solution of the bio-heat equation, have been implemented to allow various system parameters, such as antenna beam size, scan path and velocity profile, to be optimized. Experiments on a homogeneous muscle-equivalent phantom have shown that the scanning antenna system produces uniform temperature distributions over large areas of arbitrary shape. The addition of a thermal control system, based on temperature signal feedback, would enable ‘real-time’ modification of the power distribution and allow inhomogeneous and perfused tissue structures to be heated more uniformly.     

腔内热疗合并体外放射治疗食管癌的疗效

目的：比较食管腔内微波加温合并体外放射治疗食管癌与单纯放射治疗的疗效。方法：对125例食管癌进行前瞻性分组研究。食管腔内加温合并体外照射（R＋H）组59例,单纯体外照射（RT）组66例,R＋H组外照射DT40Gy,腔内加温1－2次／周,45min／次,要求肿瘤表面温度＞43℃。RT组外照射DT60Gy,2Gy／次,5次／周。结果：近期疗效显著,R H 完全缓解率达46．0％,RT组为24．0％,差异有显著性意义（P＜0．05）。1、5、10年生存率R＋H组分别为81．2％,23．7％和15．2％,RT组分别为59．0％、16．7％和7．5％。将平均T90≥43℃的病例进行统计,R＋H组的5、10年生存率是26．9％和17．3％,分别高出对照组10．2％和9．8％。结论、食管腔内加温合并体外放射治疗可以提高食管癌的局部控制率,近期疗效和远期疗效均高于对照组,局部控制率的高低与加温的次数无明显关系,关键在于每次的加温质量（T90的高低）。     

放热疗联用的临床研究进展

1989年被美国FDA认证为第五大肿瘤治疗手段以来,热疗一直是肿瘤治疗方法中的一研究热点。已有临床前期及临床研究充分肯定了热疗的放疗增敏作用,本文基于临床证据就放热疗联用的研究进展做出综述,着重从治疗温度、热疗的次数及间隔时间、放热疗之间的间隔时间与时序等角度,分析讨论了热疗和放疗联用过程中的各类问题。该综述介绍了放热疗结合应用的进展与展望,为进一步进行放热疗联用的临床探索提供了参考。     

Response of 145 spontaneous canine head and neck tumours to radiation versus radiation plus microwave hyperthermia: Results of a randomized phase III clinical study

The results of a phase III, clinical trial of local microwave hyperthermia (target = 2 × 44°C for 30 min) and megavoltage radiation (4 × 9 Gy fractions) in the treatment of 145 naturally occurring canine head and neck cancers are reported. Patients were re-examined at regular intervals following treatment until death. The median follow up time was 90 weeks. Tumour response, patient survival and normal tissue toxicity were analysed by treatment allocation. There was no significant difference in best tumour response nor patient survival between the two treatment groups. There was no difference in acute normal tissue toxicity but there was a suggestion that patients receiving RT and HT may suffer a higher incidence of late skin reactions. Histological type and tumour volume were of prognostic significance with smaller tumours and carcinomas showing higher response rates. There were also positive associations between minimum tumour dose and best tumour response and percentage of tumour heated and best tumour response. The results of this study must be interpreted in the knowledge of limitations on the dose and fractionation schedule for radiation therapy, the small number of hyperthermia treatments applied and the variation in tumour type and size that is inevitable in a clinical study. It is concluded that the quality of hyperthermia in terms of intra-tumour temperatures and the uniformity of heating is of paramount importance in governing response to adjuvant hyperthermia.     

放热疗联用的临床研究进展

1989年被美国FDA认证为第五大肿瘤治疗手段以来,热疗一直是肿瘤治疗方法中的一研究热点。已有临床前期及临床研究充分肯定了热疗的放疗增敏作用,本文基于临床证据就放热疗联用的研究进展做出综述,着重从治疗温度、热疗的次数及间隔时间、放热疗之间的间隔时间与时序等角度,分析讨论了热疗和放疗联用过程中的各类问题。该综述介绍了放热疗结合应用的进展与展望,为进一步进行放热疗联用的临床探索提供了参考。     

Local superficial hyperthermia in combination with low-dose radiation therapy for palliation of locally recurrent breast carcinoma

From September 1984 through March 1987, 30 patients with locally recurrent breast carcinoma who had been heavily pretreated with conventional modes of therapy (radiation, chemotherapy, and hormonal therapy) were entered into a phase II study of hyperthermia and low-dose irradiation. The purpose of the study was to determine the feasibility, effectiveness, and morbidity of this treatment combination. Radiation therapy was administered twice weekly, 4 Gy per fraction, to a total dose of 32 Gy, with 6 or 9 MeV electrons depending on the thickness of the lesions. Hyperthermia generated by microwave frequencies of 200 to 700 MHz was administered immediately after radiation therapy, with a time and temperature aim of 60 minutes at 43 degrees C. Complete response (CR) was achieved in 17 patients (57%), and partial response (PR) in 11 patients (36%). Response was positively correlated with tumor size; lesions less than 5 cm in diameter achieved CR significantly more frequently than lesions greater than or equal to 5 cm (P less than .001). Eighty percent of the complete responders continued to experience sustained control of the treated site from 6 to 32 months but showed evidence of progressive systemic disease or locoregional progression to the adjacent untreated sites, reflecting the natural history of this disease and extensive dermal lymphatic permeation. True recurrence within the treated volume occurred in three patients. Nonhealing ulceration developed in nine patients and seven of those were associated with persistent tumor. This study confirms the palliative value of hyperthermia in combination with radiotherapy for previously irradiated recurrent chest wall tumors and sets the scene for its comparative clinical evaluation against radiation therapy alone as first line therapy for locally recurrent breast carcinoma.     

Treatment of superficial cancers by combination hyperthermia and radiation therapy.

Clinical studies are being carried out to evaluate whether radiation combined with hyperthermia evokes better tumor control than that achieved with radiation alone. Thus far, 54 patients with various superficial cancers have been treated with combination hyperthermia and radiation. The heating methods used have been temperature regulated water bath immersion and radiofrequency inductive heating. Hyperthermia alone has caused significant, though transitory, tumor regression in 10 out of 19 patients. Selective heating of tumor tissues has been achieved in 20 out of 24 lesions following radiofrequency inductive hyperthermia. The overall local tumor control rate after the combined therapy was 78 percent compared to 26 percent after radiation alone.     

重离子(12C6+)束治疗肿瘤初步临床报告

目的探讨碳离子（^12C^6＋）辐射对恶性肿瘤的治疗作用，初步确定治疗安全剂量，观察其急性副反应及近期疗效。方法12例表浅肿瘤患者（受试者）分为2个组，A组5．10～8．79GyE／次，1次／d，连续9d总剂量50．94～70．41GyE；B组5．04～8．58GyE／次，1次／d，连续7d总剂量35．88～60．06GyE。采用RTOG急性放射损伤分级标准判断急性损伤并通过局部肿物缩小程度评价近期疗效。结果治疗结束随访2个月后，A、B组受试者皮肤反应发生率分别为2／4、3／8，两组无明显血液毒性和严重皮肤反应。A、B组局部肿物缩小程度≥50％分别占3／4、5／8。结论 ^12C^6＋束治疗表浅肿瘤显示出良好的安全性和近期疗效。     

Parameters predictive for complications of treatment with combined hyperthermia and radiation therapy.

Pretreatment and treatment related factors were reviewed for 996 hyperthermia sessions involving 268 separate treatment fields in 131 patients managed with hyperthermia for biopsy confirmed local-regionally advanced or recurrent malignancies to ascertain parameters associated with the development of complications. A subset of 249 fields were identified in which multipoint or mapped temperature data were available for at least one treatment session per field. A total of 198 fields involved superficially located tumors (less than or equal to 3 cm from the surface), whereas 51 fields involved more deeply located tumors. Most of these patients had received extensive prior therapy: 77% had surgery, 75% chemotherapy, 65% radiation therapy and 28% hormonal therapy. They were treated with hyperthermia in conjunction with radiation therapy (244 fields) or hyperthermia alone (5 fields). The hyperthermia treatment objectives were to elevate intratumoral temperatures to a minimum of 43.0 degrees C for 45 minutes while maintaining maximum normal tissue temperatures to less than or equal to 43 degrees C and maximum intratumoral temperatures to less than or equal to 50 degrees C. The hyperthermia was given within 30 to 60 minutes following radiation therapy without the administration of additional analgesics. Hyperthermia treatment regimens using radiative electromagnetic, ultrasound, or radiofrequency interstitial techniques were individualized, with 3 to 4 days between hyperthermia treatments and an average of 3.6 treatments (range 1-14; standard deviation 2.2) utilized per field. A total of 38 complications in 33 treatment fields were noted; an incidence of 27/198 (13.6%) for fields with superficially located tumors, and 6/51 (11.8%) in fields with more deeply located tumors. Univariate analyses demonstrated statistically significant correlations between the maximum tumor temperature (p = 0.0005), average of the maximum tumor temperatures (p = 0.0006), the average of the % tumor temperatures greater than 43.5 degrees C (p = 0.0071), and the average number of hyperthermia treatments (p = 0.033), with the development of complications. The average of the maximum measured tumor temperature for fields without complications was 44.6 degrees C compared with 45.9 degrees C for fields with complications. The complication rate increased from 7.5% (9/120) in fields that received one or two hyperthermia treatments to 18.6% (24/129) in fields that received greater than two hyperthermia treatments. Multivariate logistic regression analyses revealed the best bivariate model predictive of the development of complications included average of the maximum tumor temperature and the number of treatments per field (p = 0.00012 for the bivariate model).(ABSTRACT TRUNCATED AT 400 WORDS)     

Edge-element based finite element analysis of microwave hyperthermia treatments for superficial tumours on the chest wall

Several three-dimensional hyperthermia treatment planning systems for deep regional hyperthermia have been successfully utilized for improving the performance of applicators such as the BSD Sigma 60. Treatment planning systems for superficial heating in contrast have been less utilized. This paper presents a study of the applicability of the finite element method that has been developed for modelling hyperthermia treatments of recurrent chest wall cancer using a patient geometry. The patient model was created by reconstructing the tissue geometry of a patient using a series of axial CT scans. Tetrahedral grids were generated from this geometry for use in finite element simulations of the SAR profile using edge-elements and in finite element simulations of the steady-state temperature profile using scalar elements. The predicted temperature profile was well correlated with thermometry readings taken after 30 min of heating during a hyperthermia treatment. The model predicted the presence of hot-spots in regions that were not monitored. Simulations also showed that the hot-spots can be manipulated by rotating the applicator by 90°. This study demonstrates the ability of the model to provide detailed and accurate heating profiles in a patient specific model for superficial microwave hyperthermia of the chest wall.     

Radiofrequency capacitive hyperthermia for superficial malignant-tumors

Eighteen patients with inoperable head, neck and upper chest wall cancers underwent radiofrequency hyperthermia in combination with chemotherapy and radiotherapy (HCR therapy). Of the eighteen patients, three showed complete response (CR); eight, partial response (PR); four, no change (NC); and three. progressive disease (PD). The overall efficacy (%CR+PR) was 61.1%. The efficacy tended to be higher in the patients treated with a maximal intratumoral temperature over or equal to 43-degrees-C (71%) than that in patients treated with under 43-degrees-C (25%). As the local control of the tumors was not related with their prognosis it is important that the patients should undergo not only regional hyperthermia but also systemic chemotherapy. Eight patients, who had suffered from heat burns, have all been cured by conservative therapy. These results suggested that HCR therapy might be useful in treating inoperable superficial malignant tumors, and be well tolerated under protection from skin bums.