Combined treatment with radiation and hyperthermia in metastatic malignant melanoma

In 24 patients with metastatic malignant melanoma, combined treatment with radiation and hyperthermia was administered to 38 localizations, radiation alone to 8 comparative localizations and hyperthermia alone to 3 localizations. Hyperthermia was administered during one hour by using a 433 MHz microwave generator. The heat treatment was given within 30 min following irradiation. Although an intratumoral temperature of 43 degrees C was aimed, considerable variations occurred during one session and from session-to-session. Radiation schedules consisted in either one large fraction (6-8 Gy) once a week in 14-21 days or two fractions (4-5 Gy) twice a week in 21 days. In the group of patients receiving irradiation once a week, three heat treatments were administered. In the twice-a-week radiation schedule, six heat sessions were given. The overall complete response (CR) rate in patients receiving combined treatment was 50%. In the group of patients treated with hyperthermia and irradiation schedules of 8 Gy per fraction, the CR rate was 83%. Irradiation alone achieved 38% CR rate but some of these CR relapsed during follow-up whereas the comparative area treated with radiation and heat remained under control at this time. The lesions treated with heat alone did not show any response to treatment. Enhancement of the acute skin reactions was generally observed. However, because the total doses were relatively low, this enhancement did not constitute a clinical problem. CR appears to occur more frequently in small tumor sizes. The highest and lowest temperature ever registered during any session of hyperthermia did not seem to correlate with the tumor response.     

Hyperthermia as an adjuvant to radiotherapy in the treatment of malignant melanoma

One hundred and fifteen cutaneous or lymph node metastases from malignant melanoma were treated with three fractions of irradiation alone in 8 days (62 tumours) or followed by heat either immediately (simultaneous treatment, 26 tumours) or after an interval of 3-4 h (sequential therapy, 27 tumours). In addition, three tumours were treated unsuccessfully with heat alone. The total doses of radiation varied between 15 and 30 Gy, allowing a dose-response analysis. For irradiation alone the isoeffective dose to obtain 50 per cent complete response (TCD50) was 26.3 Gy. Addition of heat reduced the TCD50 significantly (p less than 0.05) with a thermal enhancement ratio (TER) of 1.43 for simultaneous treatment and 1.24 for sequential therapy. Also the persistent local control at 18 months was improved by hyperthermia (56 per cent versus 86 per cent, p less than 0.05). However, simultaneous treatment also enhanced the acute skin response to the same extent as the tumour (TER 1.42 for severe erythema). This schedule thus gave no therapeutic gain. In contrast, no normal tissue enhancement was found after sequential treatment (TER 1.02). Such a treatment schedule resulted in a significantly improved therapeutic ratio of 1.22. This effect was especially prominent in larger tumours (if sufficiently heated) and an analysis corrected for volume showed a TER of 1.51. A special analysis was performed in patients with multiple lesions. 15 pairs of tumours were given the same radiation dose, with or without hyperthermia. Out of these, 11 showed a better response, three showed the same response, and only in one pair was the best response in the tumour obtained by radiation alone.     

Combined radiation and hyperthermia: comparison of two treatment schedules based on data from a registry established by the Radiation Therapy Oncology Group (RTOG)

A registry established by the Radiation Therapy Oncology Group provides data for assessing the impact of clinical heating in a set of non-randomized patients treated with hyperthermia in participating member institutions from 1/77 to 6/81. This analysis focuses on tumor response when localized hyperthermia is produced by microwave and applied pursuant to two distinctly different treatment schedules. Hyperthermia treatments were biweekly and combined with daily radiation treatments in one patient group, and combined with biweekly radiation treatment in another. Sample X consists of 65 patients who received a course of therapy using combined hyperthermia and radiation in consecutive treatment sessions each separated by at least 48 hours, but no more than 96 hours. Sample Y consists of 34 patients who received further radiation after the start of a course of combined therapy--either between or at the end of a series of combined treatment sessions. The average length of heat treatment was 72 minutes for Sample X and 32 minutes for Sample Y patients. None of the patients received concurrent chemotherapy; all received between 3 and 13 hyperthermia treatments; all had superficial, measurable tumors. On the average, Sample X patients received 704 total minutes of heat compared to Sample Y patients who received 233 total minutes of heat. Total tumor radiation doses ranged from 17.0 Gy to 44.0 Gy among Sample X patients with 92.3% receiving radiation at either 3 Gy or 4 Gy per fraction. In Sample Y the range for total tumor dose was 16.0 Gy to 70.2 Gy with 73.4% of the patients receiving radiation at 2.5 Gy or less per fraction. Generally, the two treatment schedules achieved similar levels of tumor response. Among treated tumors in Sample X and Sample Y, complete regression rates were 52.4 and 61.8%, respectively, and partial regression rates were 16.9 and 14.7%. Adenocarcinoma and squamous cell carcinoma in both samples responded well to these combined treatments. Only in Sample X was there a statistically significant trend of decreasing complete regression rate when the treated tumor sizes increased. Best responses to treatment generally occurred between 28 and 84 days after completion of the combined therapy course. There were no differences between the two samples with respect to median days to best response or response duration. Blister, ulcer or wet desquamation were reported in 47.7% of Sample X as the maximum skin reaction. In contrast, only 20.6% of Sample Y had these complications.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

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.     

Significance of additive heat effect in the therapeutic gain factor in combined hyperthermia and radiotherapy: murine tumor response and foot reaction

The thermal enhancement ratio (TER) and therapeutic gain factor (TGF) were evaluated for combined hyperthermia and radiation treatments of a murine fibrosarcoma, FSa-II. The TER is the ratio of the radiation dose that induces a given reaction without hyperthermia to that with hyperthermia. The TGF is defined as the ratio of TER for tumor response to TER for normal tissue response. Tumors in the subcutaneous tissue of the right foot were irradiated with graded radiation doses when they reached an average diameter of 6 mm (110 mm3). Hyperthermia was given by immersing animal feet in a constant temperature water bath 10 min before or after irradiation. The tumor growth time to reach 500 mm3 was obtained for each tumor and the median tumor growth time was calculated for each treatment group. For the normal tissue study, the non-tumor bearing murine foot was treated, as was the tumor, and the foot reaction was scored after treatment, according to our numerical score system for radiation damage, until the 35th post-treatment day and averaged. Using the fraction of animals showing a given average foot reaction score in a treatment group, the RD50, or the radiation dose to induce the given foot reaction or greater, was calculated. A single heating at 45.5 degrees C for 10 min and a step-down heating (first heat at 45.5 degrees C for 10 min immediately followed by the second heat at 41.5 degrees C for 60 min) prolonged the tumor growth time, indicating that hyperthermia per se resulted in some cell killing. The prolongation was greater following step-down heating than following single heating. These heat treatments alone induced no noticeable heat damage on the foot, but decreased the threshold dose observed on the radiation dose response curves for the foot reaction. Accordingly, TER and TGF were evaluated with or without normalizing this thermal effect. TER's for both tumor and foot responses without normalization were greater than the TER's after normalization and decreased with increasing radiation dose (between 1.9 and 7.1 or greater for tumor and between 1.3 and 4.3 or greater for foot reaction), whereas the normalized TER's were relatively constant (between 1.6 and 1.7 for tumor and between 0.7 and 1.5 for foot reaction). TGF's without normalization were greater than those obtained after normalization. The former was large at small doses and decreased with increasing radiation dose (between 1.5 and 4.0 or greater), whereas the latter was within 0.8 and 1.3 and relatively independent of radiation dose.(ABSTRACT TRUNCATED AT 400 WORDS)     

Chestwall recurrences of breast cancer: results of combined treatment with radiation and hyperthermia

In 35 patients with chestwall recurrences of breast carcinoma, 45 lesions were treated with combined radiation and hyperthermia. The majority of the lesions received 6 fractions of 4 Gy, twice a week during 3 weeks. Hyperthermia was administered within 30 min after irradiation, aiming a tumor temperature of 43 degrees C during one hour. The percentage of complete response (CR) was 57%. In small lesions, the percentage of CR was 80%. The mean duration of the response was 7 months. Response rate increased with increasing temperature. Particularly, mean temperature and isoeffect thermal dose correlated very well with response rate. In nine cases, comparative lesions were treated with either radiation alone or radiation combined with hyperthermia. The response rates were 3/9 and 7/9, respectively. Acute skin reactions were enhanced by the combined treatment. However, late skin reactions were not increased. Although the prognosis of patients with chestwall recurrences is determined by the presence of distant metastases, local control remains an important objective. Combined treatment with radiation and hyperthermia offers the possibility of obtaining a high local control rate particularly in relatively small lesions.     

Thermoradiotherapy of malignant melanoma

From 1978 through February 1986, 49 measurable lesions in 18 patients with recurrent primary or metastatic malignant melanomas were treated with a combination of radiation therapy and hyperthermia. The primary sites were head and neck (eight), chest wall (two), pelvis (one), upper extremities (three), and lower extremities (35). Because of the length of the study, the dose and fractionation of radiation therapy varied (dose per fraction from less than 400 cGy to 800 cGy and a total dose of 2000 cGy to 6000 cGy). This variation was mostly dependent on the prior course of radiation therapy of these lesions. The hyperthermia technique used in these patients was superficial local microwave hyperthermia; a minority of patients were treated with ultrasound. Complete response was achieved in 29 lesions (59–2 per cent) and partial response in six lesions (12 per cent). In a separate analysis of 67 lesions with superficial malignant melanoma who were treated by radiation therapy alone, a 24 per cent complete response and a 34 per cent partial response were achieved. Detailed analyses are presented in regard to dose per fraction, total radiation dose, and the size of lesions.     

Thermoradiotherapy of malignant melanoma

From 1978 through February 1986, 49 measurable lesions in 18 patients with recurrent primary or metastatic malignant melanomas were treated with a combination of radiation therapy and hyperthermia. The primary sites were head and neck (eight), chest wall (two), pelvis (one), upper extremities (three), and lower extremities (35). Because of the length of the study, the dose and fractionation of radiation therapy varied (dose per fraction from less than 400 cGy to 800 cGy and a total dose of 2000 cGy to 6000 cGy). This variation was mostly dependent on the prior course of radiation therapy of these lesions. The hyperthermia technique used in these patients was superficial local microwave hyperthermia; a minority of patients were treated with ultrasound. Complete response was achieved in 29 lesions (59.2 per cent) and partial response in six lesions (12 per cent). In a separate analysis of 67 lesions with superficial malignant melanoma who were treated by radiation therapy alone, a 24 per cent complete response and a 34 per cent partial response were achieved. Detailed analyses are presented in regard to dose per fraction, total radiation dose, and the size of lesions.     

Tumour response to heat and radiation: prognostic variables in the treatment of neck node metastases from head and neck cancer

A total of 38 patients with 81 multiple neck node metastases from squamous cell carcinoma of head and neck were treated with radiotherapy alone or with radiotherapy plus hyperthermia. Irradiation was delivered following a three fractions per day schedule of 2 + 1.5 + 1.5 Gy/day, with 4 h intervals between fractions, up to a total dose of 60 Gy. Heat was applied by means of a 500 MHz apparatus. Temperature data were converted to equivalent minutes at 42.5 degrees (Eq 42.5). Initial complete response rates and local control distribution were compared for subgroups of tumour volume and thermal dose. The data indicated that the volume effect was less pronounced in the combined modality than in the radiation alone arm, suggesting that the addition of heat was more damaging to the large than to the small lesions. A striking thermal dose-response relationship was shown, although complete response rates increased only after a certain thermal dose was accumulated, clearly indicating the presence of a threshold dose.     

Clinical experiences with local microwave hyperthermia

At the Claire Zellerbach Saroni Tumor Institute, Mount Zion Hospital and Medical Center, 38 patients who failed definitive radiotherapy and chemotherapy were treated with 915 megahertz and 2450 megahertz microwave hyperthermia to observe normal tissue tolerance and therapeutic responses. Superficial and measurable lesions were selected. Thirty-seven courses were given with radiation and eleven courses were given alone. When hyperthermia was combined with radiation, complete clinical regression occurred in 41 % ($\text{15}\text{37}$) of patients and partial regression in 37% ($\text{14}\text{37}$); however with hyperthermia alone, complete regression occurred in 18% ($\text{2}\text{11}$) of patients and partial regression in 18 % ($\text{2}\text{11}$). Thus, moderate local tumor hyperthermia (42.5°C) following low dose irradiation (1800–2700 rad) has resulted in significant responses in recurrent tumors in previously irradiated areas. The maximum temperature achieved during a course of treatment appeared to correlate with tumor responses. Also a relationship existed between radiation dose and tumor response. There was no relationship between radiation dose and thermal side effects. Thermal dosimetry remained an outstanding problem for clinical hyperthermia, in part because of inadequacy of heat delivery and measurement systems, and in part because of patient variations in terms of tolerance to beat and tumor physiological changes with fractions of hyperthermia. Side effects of thermal blistering and burns were correlated with maximum temperatures attained during heat treatments. They were tolerable by patients, and can be decreased by appropriate skin cooling in some patients. Further protocol studies are needed to determine the optimal temperature/radiation dosage, treatment schedules and sequences, and treatment techniques.     

Simultaneous superficial hyperthermia and external radiotherapy: report of thermal dosimetry and tolerance to treatment.

BACKGROUND: In vitro and animal studies indicate that a moderate temperature of 41 degrees C maintained for approximately 1 h will provide radiosensitization if radiation (RT) and hyperthermia (HT) are delivered simultaneously, but not with sequential treatment. A minimum tumour temperature of 41 degrees C is a more feasible goal than the goal of >42 degrees C needed for sequential treatment. METHODS AND MATERIALS: Forty-four patients with 47 recurrent superficial cancers received simultaneous external beam radiotherapy and superficial hyperthermia on successive IRB approved phase I/II studies. All lesions had failed previous therapy, 35 were previously irradiated (mean dose 52.7 Gy). Hyperthermia was delivered with 915 MHz microwave or 1-3.5 MHz ultrasound using commercially available applicators. The average dimensions of 19 lesions treated with microwave were 4.7 x 3.6 x 1.7 cm and the average dimensions of 28 lesions treated with ultrasound were 8.0 x 6.1 x 2.9 cm. The most common sites were chest wall (15 cases) and head and neck (21 cases). Temperatures were monitored at an average of six intratumoral locations using multisensor probes. The median number of hyperthermia treatments was three and the median radiation dose 30 Gy. Radiation dose per fraction was 4 Gy with hyperthermia and 2 Gy or 4 Gy (depending on protocol) on non-hyperthermia days. RESULTS: Six different measures of minimum monitored temperature and duration were found to be highly correlated with each other. There was nearly a one-to-one correspondence between minimum tumour time at or above 41 degrees C (Min t41) and minimum tumour Sapareto Dewey equivalent time at 42 degrees C (Min teq42). After four sessions 63% of cases had a per session average Sapareto Dewey equivalent time at 41 degrees C which exceeded 60 min in all monitored tumour locations. The complete and partial response rate in evaluable lesions were respectively 21/41 (51%) and 7/41 (17%) and were best correlated with site (chest wall showing best response). Toxicity consisted of 10/47 (21%) slow healing soft tissue ulcers which healed in all cases but required a median of 7 months. The most important predictors for chronic ulceration were cumulative radiation dose >80 Gy and complete response to treatment. CONCLUSIONS: Minimum tumour temperatures maintained for durations compatible in vitro with thermal radiosensitization (if RT and HT are delivered simultaneously) are clinically feasible and tolerable for broad but superficial lesions amenable to externally applied ultrasound or microwave hyperthermia. The current in-house protocol is evaluating the impact of more than four hyperthermia sessions on the overall thermal dose distribution and toxicity.     

Increased tumour response of a murine fibrosarcoma to low temperature hyperthermia and low dose rate brachytherapy

The present animal tumour study was carried out to determine the effectiveness of low temperature hyperthermia combined with low dose rate radiation based on the cell culture studies of our laboratory and others that demonstrated a significant radiosensitization obtained by low temperature hyperthermia and low dose rate radiation. Well-oxygenated murine fibrosarcoma Meth-A tumours growing in Balb/c mice were treated with heat (41d`C tumour temperature) by immersion of the tumour-bearing leg in a waterbath concurrently with low dose rate radiation. Radiation was delivered using <sup>192</sup>Ir interstitial implantation at absolute dose rates of 0.416–0.542 Gy/h. The effect of heat alone on tumour growth and normal tissue was minimal. Tumour growth delay following 30 Gy radiation was 4.9 days. Significant delay in tumour growth was observed with the addition of low temperature hyperthermia delivered concurrently. Enhancement in radiation response was seen with increasing duration of heat treatment; tumour growth delays were 9.5 days following 4h heat (41d`C) treatment and 16 days following 6 h treatment. Three sessions of fractionated hyperthermia 4 h/day during the course of low dose-rate radiation significantly delayed tumour growth to 18.6 days. The results indicate that fractionated heat treatment in conjunction with low dose rate radiation has potential for improving tumour response without adversely affecting normal tissue reaction. This in vivo study represents an extension of the cell culture data and provides further radiobiological basis for the combined use of low temperature hyperthermia and low dose rate radiation.     

Simultaneous superficial hyperthermia and external radiotherapy: report of thermal dosimetry and tolerance to treatment

Background : In vitro and animal studies indicate that a moderate temperature of 41°C maintained for ～ 1h will provide radiosensitization if radiation (RT) and hyperthermia (HT) are delivered simultaneously, but not with sequential treatment. A minimum tumour temperature of 41°C is a more feasible goal than the goal of >42°C needed for sequential treatment. Methods and materials: Forty-four patients with 47 recurrent superficial cancers received simultaneous external beam radiotherapy and superficial hyperthermia on successive IRB approved phase I/II studies. All lesions had failed previous therapy, 35 were previously irradiated (mean dose 52.7Gy). Hyperthermia was delivered with 915MHz microwave or 1-3.5MHz ultrasound using commercially available applicators. The average dimensions of 19 lesions treated with microwave were 4.7 3.6 1.7cm and the average dimensions of 28 lesions treated with ultrasound were 8.0 6.1 2.9cm. The most common sites were chest wall (15 cases) and head and neck (21 cases). Temperatures were monitored at an average of six intratumoral locations using multisensor probes. The median number of hyperthermia treatments was three and the median radiation dose 30Gy. Radiation dose per fraction was 4Gy with hyperthermia and 2Gy or 4Gy (depending on protocol) on non-hyperthermia days. Results: Six different measures of minimum monitored temperature and duration were found to be highly correlated with each other. There was nearly a one-to-one correspondence between minimum tumour time at or above 41°C (Min t41) and minimum tumour Sapareto Dewey equivalent time at 42°C (Min teq42). After four sessions 63% of cases had a per session average Sapareto Dewey equivalent time at 41°C which exceeded 60min in all monitored tumour locations. The complete and partial response rate in evaluable lesions were respectively 21/41 (51% ) and 7/41 (17% ) and were best correlated with site (chest wall showing best response). Toxicity consisted of 10/47 (21% ) slow healing soft tissue ulcers which healed in all cases but required a median of 7 months. The most important predictors for chronic ulceration were cumulative radiation dose >80Gy and complete response to treatment. Conclusions: Minimum tumour temperatures maintained for durations compatible in vitro with thermal radiosensitization (if RT and HT are delivered simultaneously) are clinically feasible and tolerable for broad but superficial lesions amenable to externally applied ultrasound or microwave hyperthermia. The current in-house protocol is evaluating the impact of more than four hyperthermia sessions on the overall thermal dose distribution and toxicity.     

‘Patchwork’ fields in thermoradiotherapy for extensive chest wall recurrences of breast carcinoma

Summary Chest wall lesions of advanced breast carcinoma in 23 patients were treated with thermoradiotherapy with clinical intent between January 1987 and March 1992. Treatment consisted of external 915 MHz microwave hyperthermia with commercially available applicators and radiation therapy to doses between 32–58 Gy. Twenty-three large, diffuse lesions were treated with multiple field patchwork hyperthermia. All lesions were diffuse with or without multiple nodules 3 cm depth. All lesions had failed previous therapy. The mean number of hyperthermia fields per patient was 3.2 ± 0.4 (range of 2–7). The complete response rate was 91% in this group of extensive, diffuse lesions treated by the patchwork technique. Mean total radiation dose administered concurrently with multiple field patchwork hyperthermia was 42 ± 1 Gy. The recurrence rate was 5%. The mean survival in patients who had a complete response was 9.0 ± 1.3 months. The reduced survival among patchwork treated patients was due to the extensive tumor burden existing outside of the treated fields in these patients. The skin reactions were minor, causing minimal discomfort. There was no evidence of increased thermal damage to skin, or of tumor recurrence at junctions of hyperthermia field overlap. It is concluded that extensive, diffuse lesions of chest wall recurrence of advanced carcinoma of the breast can be treated effectively with multiple field patchwork thermotherapy.Presented in part at the 15. San Antonio Breast Cancer Symposium (December 1992).     

Predictive factors for skin reactions in patients treated with thermoradiotherapy

In this study we performed univariate analyses to analyse the predictive factors for skin reactions, i.e. erythema, thermal blisters and ulceration, that occur during thermoradiotherapy. One hundred and twenty-six fields in 126 patients were treated with thermoradiotherapy using 915 MHz external microwave hyperthermia. Mean age of patients was 62 years. All but 11 lesions received previous therapy. Prior treatment included surgery (75%), chemotherapy (60%) and/or radiation therapy (51%). The mean previous radiation dose was 54 ± 2 Gy. The concurrent tumour radiation dose was 45 ± 1 Gy, in 16 fractions, over 35 elapsed days (dose per fraction of 1·6–4·8 Gy). The mean number of heat sessions administered was 5·5 ± 0·2 (range 1–14). In 83% of cases hyperthermia was administered biweekly. Forty-two patients were treated without any skin reaction (33%), erythema occurred in 59 fields (47%), transient thermal blisters occurred in 25 fields (20%) and ulceration occurred in 23 fields (18%). In 25 cases, two or more skin reactions (20%) were observed concurrently. Concurrent radiation dose correlated with skin reactions (p = 0·02). The incidence of skin reactions was inversely correlated with previous radiation therapy (p = 0·04) and previous radiation therapy dose (p = 0·04) possibly due to fibrosis. None of the tumour or skin thermal parameters correlated with the reaction rate.     

Tumor control and therapeutic gain with different schedules of combined radiotherapy and local external hyperthermia in human cancer

Tumor control and therapeutic gain have been evaluated in a series of studies on patients with multiple lesions employing different protocols of combined radiotherapy (RT) and local external hyperthermia (HT). Tumor response has been evaluated during a follow-up ranging 6 to 18 months. Therapeutic enhancement factor (TEF) was defined as the ratio of thermal enhancement (TE) of tumors to TE of skin, where TE was clinically evaluated as the ratio of percent response (i.e., complete tumor clearance and moist desquamation, respectively) after combined modality to percent response after RT alone. Local tumor control was constantly better in lesions treated with any combined modalities in comparison with RT alone. The use of high RT dose per fraction appeared to increase tumor control only in the combined modalities groups, the immediate (so called "simultaneous") schedule (HT at 42.5 degrees C/45 min, applied immediately after each RT fraction, twice a week) being more effective than the delayed (so called "sequential") treatment (HT at 42.5 degrees C/45 min, delivered 4 h after each RT fraction, twice a week). The combination of high RT dose per fraction with high temperature HT (45 degrees C for 30 min) achieved the best tumor control. No increased radiation skin reaction was observed when a conventional fraction size of RT was used (3 daily fractions of 1.5-2 Gy, 4 h interval between fractions) in association with HT (42.5 degrees C/45 min, every other day, immediately after the second daily RT fraction). A remarkable enhancement of skin reaction was observed, however, when using high RT doses per fraction in association with 42.5 degrees C HT, especially with the immediate treatment schedule. No enhancement of skin reaction was obtained after high RT doses per fractions and 45 degrees C HT because an active skin cooling by means of circulating cold water was used in these cases. Consequently, a good TEF (1.58) was obtained when conventional RT doses per fraction were used in association with 42.5 degrees C HT. TEF values of 1.40 and 1.15 were observed when high RT doses per fraction were employed in association with the delayed and immediate 42.5 degrees C HT, respectively. HT at 45 degrees C can be safely employed only when tumors can be heated selectively or at least preferentially in comparison with normal tissue; in the lesions treated with such a schedule a TEF of 2.10 was obtained.     

Hyperthermia in combination with radiotherapy: a review of five years experience in the treatment of superficial tumors

Facilities for regional tumor hyperthermia has been in use at RPMI since 1976, and have been routinely used to treat patients according to protocol since 1977. Hyperthermia delivery has been exclusively by microwave using 434 MHz, 915 MHz and 2450 MHz. Greatest success at reaching tumor temperatures of 43-44 degrees C with minimal skin heating was obtained using 915 MHz. The majority of the patients were treated with this frequency. Approximately 125 patients have been treated and 70 have achieved completion of therapy and follow-up. Follow-up has been at least one month and several patients have been followed for one to two years. Initially, for entry into the hyperthermia protocol, patients were required to have three or more lesions. One lesion on each patient was treated with 800 rad fractions repeated three times on a 72 hour schedule. The second lesion was treated with 700 rad fractions and the third with 500 rad plus hyperthermia on the same schedule. Twelve patients with multiple melanoma lesions completed this study. One of 12 patients showed no response to the combination of hyperthermia plus radiotherapy, while four showed no response to radiotherapy alone. Of eight patients who survived three months, all lesions treated by hyperthermia plus radiotherapy responded completely, while only five lesions treated by radiotherapy alone so responded. In a second study, 58 patients with superficial tumors were treated by a protocol where hyperthermia was added to optimal conventional radiotherapy. Of the total, 43 patients had complete tumor response at follow-up varying from one month to 18 months. A subgroup of 24 of these patients had two lesions, one of which was treated with hyperthermia in addition to radiotherapy while the other served as control, receiving radiotherapy only. Nineteen lesions demonstrated complete response to hyperthermia plus radiotherapy, while only 14 of the controls had complete response. None of the lesions treated with hyperthermia responded less well than those treated by radiotherapy alone. Morbidity, as measured by skin reaction, was rarely increased in the heated field.     

Irradiation alone or combined with hyperthermia in the treatment of recurrent carcinoma of the breast in the chest wall: a nonrandomized comparison

Tumour response and control (freedom from local relapse) were compared in two non-randomized groups of patients with recurrences from carcinoma of the breast (95 per cent in the chest wall and 5 per cent in the axillary or supraclavicular lymph nodes) receiving treatment at the Mallinckrodt Institute of Radiology. One group, comprising 48 patients treated between March 1978 and December 1984, received varying doses of irradiation (2000-4000 cGy in fractions of 400 cGy every 72 h) followed by local microwave hyperthermia (41-43 degrees C, 30-60 min). Irradiation was usually delivered with electrons ranging from 9 to 16 MeV. Hyperthermia was administered with 915 MHz external microwaves. The second group of 116 patients, with lesions similar to those treated with hyperthermia and irradiation, were treated with irradiation alone between January 1964 and December 1984. Doses of irradiation ranged from 2000 to 6000 cGy, usually delivered in daily fractions of 200-300 cGy TD. Irradiation was administered with Cobalt-60, 4 MeV photons or electrons (9-13 MeV) and occasionally with superficial X-rays. Patients with lesions 1-3 cm in diameter treated with irradiation and hyperthermia exhibited a complete tumour response rate of 80 per cent (12/15) while patients receiving irradiation alone had a complete response rate of 33 per cent (P = 0.04, Fisher exact test, two tail). The complete response rate for tumours larger than 3 cm treated with irradiation and heat was 65 per cent (13/20) compared to 42 per cent (18/43) for lesions receiving irradiation alone (P = 0.1, Fisher exact test, two tail).(ABSTRACT TRUNCATED AT 250 WORDS)