热疗临床应用进展

热疗联合手术、放疗和化疗等综合治疗能明显降低恶性肿瘤局部复发率,提高患者生存率,改善生活质量,且不增加术后并发症.对于恶性肿瘤,尤其是进展期肿瘤,可以根据预测指标来决定综合治疗方案.现综述热疗与化疗、放疗以及术前热疗联合放疗、化疗等综合治疗的临床应用进展.     

Status of hyperthermia in the treatment of advanced liver cancer

The vast majority of patients with malignant liver tumors have inoperable disease. These patients must rely on chemotherapy, radiotherapy, and various locoregional treatments. Although these treatments have demonstrated encouraging response rates, symptom palliation and occasional down staging of tumors, their impact on survival is minor. As a result there has been renewed interest in hyperthermia as a treatment option. This study reviews the current modalities of hyperthermia in terms of clinical results, side effects, limitations, and therapeutic standing.     

A practical system for clinical radiofrequency hyperthermia

This paper describes an apparatus for inducing local hyperthermis by passing high-frequency electrical currents through tissues between electrodes placed against the skin of the patient. The electrodes use a temperature-controlled saline solution contained by a thin rubber membrane to make contact. The resistivity of the saline solution is matched to that of body tissues. This yields a smooth transition from electrode to tissue, thereby greatly reducing the possibility of producing the skin burns which frequently appear along the edges of metallic electrodes. Use of the thin rubber membrane allows easy molding of a given set of electrodes to complex body contours for many different patients. The equipment has proven capable in clinical tests of heating bulky tumors in the head and neck and extremities without significant skin toxicity. Excessive beating of the subcutaneous fat, however, restricts the application of this heating method to tumors located in areas of the body with sparse adipose tissue.     

An assessment of local hyperthermia in clinical practice

A total of 116 small superficial tumours have been treated by radiation alone, hyperthermia alone, or radiation and hyperthermia combined in a Phase I/II study. Most tumours were metastases or local recurrences of adenocarcinoma of breast but other histologies were involved including melanoma. Hyperthermia was delivered predominantly by microwaves, but radiofrequency and ultrasound methods were also used. Rigorous thermal dosimetry, based on measurements from invasive multipoint thermocouple arrays, has shown that 58 per cent of hyperthermal treatments reached a minimum dose within tumour equivalent to 20 min at 43 degrees C (minEq43); 24 per cent reached at least 60 minEq43. Minima of 20 minEq43 were achieved successfully on every intended occasion in a quarter of the 75 tumours heated, and on one/two occasions in 39; unfortunately, this minimum threshold was not reached at any point monitored at any hyperthermia session in 17(23 per cent) tumours. Tumours that received radiation and effective hyperthermia were more likely to disappear completely (CR rate 86 per cent) than those that were irradiated but inadequately heated (CR rate 35 per cent) (P less than 0.001) or were treated by the same doses of radiation alone (CR rate 35 per cent) (P less than 0.05). This improvement with hyperthermia became more apparent with suboptimal radiation doses. A small but measurable growth delay was imposed by heat alone with a poor complete response rate (11 per cent). The real-time use of a thermal dose unit in clinical practice facilitates hyperthermal treatment comparisons and provides an important parameter for checking the technical performance of a heat delivery system. The results of this study emphasizes the need for improvements in intratumour temperature distribution, in order to establish minimum threshold temperatures to enhance tumour response rates.     

肿瘤热疗的机制及其临床应用

高温热疗对肿瘤细胞具有选择性破坏作用,可影响其物质及能量代谢、核酸及蛋白质合成、细胞凋亡、细胞周期等;同时,热疗还可降低肿瘤局部血供、抑制肿瘤生长、上调机体免疫功能以及提高放化疗敏感性,从而发挥抗肿瘤作用.目前,全身热疗、局部热疗等多种热疗方法已被广泛应用于消化系统、神经系统、生殖系统等部位的临床肿瘤治疗.     

Site and disease selection for hyperthermia clinical trials

Significant progress has been made in the past 20 years in understanding the biological basis of hyperthermia-induced cytotoxicity, thermoenhancement of radiation therapy and chemotherapy, and in the development of clinically applicable microwave, radiofrequency, ultrasound and thermometry equipment. Numerous uncontrolled trials have suggested strongly that hyperthermia in conjunction with radiation therapy or chemotherapy may contribute to improved local control rates for recurrent or metastatic cancer without excessive morbidity. Carefully designed and well-controlled site and disease-specific prospective randomized trials with standardized hyperthermia and radiation therapy techniques, adequate thermometry, precise end points for tumour control and normal tissue toxicity are now essential to establish the role of hyperthermia in cancer management. Criteria for tumour site selection will be explored for trials employing radiation therapy and local-regional hyperthermia. Examples of sites selected will be presented which represent areas that can, with current technology, usually be adequately heated, and in which significant patient benefit may result from improved local-regional control.     

Site and disease selection for hyperthermia clinical trials

Significant progress has been made in the past 20 years in understanding the biological basis of hyperthermia-induced cytotoxicity, thermoenhancement of radiation therapy and chemotherapy, and in the development of clinically applicable microwave, radiofrequency, ultrasound and thermometry equipment. Numerous uncontrolled trials have suggested strongly that hyperthermia in conjunction with radiation therapy or chemotherapy may contribute to improved local control rates for recurrent or metastatic cancer without excessive morbidity. Carefully designed and well-controlled site and disease-specific prospective randomized trials with standardized hyperthermia and radiation therapy techniques, adequate thermometry, precise end points for tumour control and normal tissue toxicity are now essential to establish the role of hyperthermia in cancer management. Criteria for tumour site selection will be explored for trials employing radiation therapy and local-regional hyperthermia. Examples of sites selected will be presented which represent areas that can, with current technology, usually be adequately heated, and in which significant patient benefit may result from improved local-regional control.     

Scanned focussed ultrasound hyperthermia: initial clinical results

Between November 1986 and July, 1987, a preliminary study to determine the feasibility of scanned focussed ultrasound for clinical hyperthermia at various sites was conducted. Fourteen patient (17 tumors) have been treated using a microprocessor-controlled apparatus developed at the University of Arizona by modifying a commercially available diagnostic ultrasound unit. We have treated nine pelvic tumors, four extremity tumors, two brain tumors, and two extracranial head and neck tumors for a total of 42 treatments. Multipoint thermometry was achieved for all patients, with 2-25 (mean = 10) points monitored during each treatments within the scanned tumor volume. Average maximum temperature within the scanned tumor volume was 44.2, 44.7, 44.8, and 42.0 degrees C for pelvic, extremity brain, and extracranial head and neck tumors, respectively; similarly, 55%, 45%, 71%, and 0 of monitored points exceeded 42.5 degrees C. Pain limited applied power in 15 of 42 treatments, and bone pain with a periodicity similar to the scanning periodicity was seen in 11 treatments. A non-randomized comparison of temperatures achieved using scanned focussed ultrasound to those achieved using the microwave annular array and the CDRH Helix suggests that scanned focussed ultrasound may have promise and potential advantages in heating selected pelvic tumors.     

In search of the optimal heat interval in clinical hyperthermia

The influence of thermotolerance on clinical hyperthermia was reviewed and analysed on CR ratio by weekly heat fractionation numbers. In combined radiotherapy (40 Gy greater than or equal to), 434 cases, CR ratio was 74%, 60%, 40% and 37% for each 1, 2, 3 and 5 heat fractions weekly. In group of hyperthermia alone, consisting of 162 cases CR ratio was 25%, 14% and 0% for 2, 3 and 5 weekly heat fractions respectively. That of radiotherapy alone (40 Gy, greater than or equal to), 168 cases, was 40%. In view of CR ratio, as heat fractions decreases weekly, thermotolerance plays increasingly negative role on treatment effect on both hyperthermia alone and combined radiotherapy group.     

Development of scanned focussed ultrasound hyperthermia: clinical response evaluation

Selective heating of irregularly shaped tumors at depth can now be accomplished through focussing and controlled scanning of energy deposition patterns by ultrasound. A scanned focussed ultrasound (SFUS) hyperthermia system developed at the University of Arizona has been used to deliver 220 treatments to 87 tumors in 71 patients with extracranial malignancies between October 1986 and May 1990. Patients received an average of three SFUS hyperthermia treatments, spaced weekly, during ongoing fractionated radiotherapy. The most common anatomic sites treated were the pelvis (22 patients), chest wall or breast (14), neck (8), and axilla (7), while the most common histologies were adenocarcinoma (36), squamous cell carcinoma (11), and melanoma (10). Concurrent radiotherapy was delivered (range 1000-7640 cGy, mean 4320 cGy) to 67 SFUS hyperthermia patients; 4 received concomitant chemotherapy. Tumor volumes ranged from 1-2100 cubic centimeters (mean 325 cc), and 75% were located at depths greater than 3 cm from skin. A 62% overall response rate was observed, with 22% of treated tumors demonstrating a complete response (defined as complete disappearance of treated tumor), and 40% exhibiting a partial response (defined as greater than or equal to 50% reduction in tumor volume). Dramatic local pain reduction was achieved in 42% of the tumors treated. The acute tolerance of SFUS hyperthermia was quite good, and chronic toxicities (persistent skin blisters/burns) were identified in two patients. The versatility of the SFUS system is discussed, as well as its future potential for improving control of advanced loco-regional malignancies treated with curative intent.     

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。     

Strategies for optimized application of annular-phased-array systems in clinical hyperthermia

A theoretical framework is presented for optimized heating of deep-seated tumours by phase and amplitude steering. The optimization problem for a specific tumour and perfusion case results in a functional dependency between power-level and maximum obtainable therapeutic efficiency. Different optimization criteria and strategies are outlined, which cause an increase of power or thermal dose in the tumour. Three tumour models (central pelvic tumour, eccentric abdominal tumour with or without necrosis) are analysed in detail. The simulation studies predict that appreciable parts of these tumours (50–100%) can be heated efficiently (42.5–43°C) within the range of available and clinically tolerated power levels (1–5 kW/m), if tumour perfusion is less than 20–25 ml/100 g min. Some improvements are obtained by increasing the number of independent channels (from four to eight) and by the application of time-dependent (complementary) power-deposition patterns.     

Strategies for optimized application of annular-phased-array systems in clinical hyperthermia

A theoretical framework is presented for optimized heating of deep-seated tumours by phase and amplitude steering. The optimization problem for a specific tumour and perfusion case results in a functional dependency between power-level and maximum obtainable therapeutic efficiency. Different optimization criteria and strategies are outlined, which cause an increase of power or thermal dose in the tumour. Three tumour models (central pelvic tumour, eccentric abdominal tumour with or without necrosis) are analysed in detail. The simulation studies predict that appreciable parts of these tumours (50-100%) can be heated efficiently (42.5-43 degrees C) within the range of available and clinically tolerated power levels (1-5 kW/m), if tumour perfusion is less than 20-25 ml/100 g min. Some improvements are obtained by increasing the number of independent channels (from four to eight) and by the application of time-dependent (complementary) power-deposition patterns.     

The importance of thermotolerance for the clinical treatment with hyperthermia

Thermotolerance (i.e. a temporary heat resistance following a prior heat treatment) is a general phenomenon occurring in both normal tissues and tumours. Besides affecting a fractionated heat treatment, thermotolerance may also influence the effect of fractionated combined heat and radiation. The importance of thermotolerance for fractionated clinical hyperthermia is discussed on the basis of a series of in vitro experiments in L1A2 cells and in vivo studies of a C₃H mouse mammary carcinoma.If maximal tumour interaction is wanted, thermotolerance should be avoided, but it would be preferable in normal tissues in order to reduce the amount of damage. Unfortunately, there is a considerable variation in the kinetics and magnitude of thermotolerance between different tissues, and it is currently not possible to predict how thermotolerance will develop in a given tumour or normal tissue. However, both the magnitude and the kinetics appear to depend on the heat damage induced by the priming heat treatment. Thus, in a given tissue, thermotolerance will develop later, but will reach a higher maximum by a larger priming heat treatment. It follows that if a homogeneous temperature cannot be applied to a given tissue, different parts will develop thermotolerance at different kinetic patterns. Therefore, at the time of subsequent heat treament, the tissue may express different heat sensitivities in different areas. With the current knowledge, the best way to overcome the problems of thermotolerance when heat is given alone or sequentially with radiotherapy will be by application of a single or few, but large heat fractions given with an interval that allows thermotolerance to develop and decay before the next hyperthermic treatment is given. With a simultaneous heat and radiation treatment which optimally requires heating in association with all radiation fractions, the fractionation interval should also be long, which is complicated by the fact that such long fractionation intervals may not result in an optimal radiation treatment.     

The clinical effect of hyperthermia combined with induced hypertension chemotherapy

In cancer therapy, the authors have attempted to decrease the side effects. Since 1975 they have used immuno-thermo-chemotherapy(so-called ITC therapy). At this time the ITC therapy is used in combination with induced-hypertension-chemotherapy (IHC therapy). This new approach has been applied to patients with terminal or advanced malignancy, which have been unsuccessfully treated by conventional ITC therapy. This report compares the clinical effects of conventional ITC therapy those of new modality in the same patient. The clinical results are 6 cases of I-A and one case of I-B according to Karnofsky's criteria. This New modality is more effective than the conventional ITC therapy in all 7 patients.     

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。