hyperthermia and radiation in advanced malignant melanoma

Inl J Radmrmn Onmlo~y Bml Phyr Vol. 25. pp. 87-94 0360.3016/93 $6 00 + .OO

Pnnted I” the U.S.A. All rights reserved. Copyright G) 1992 Pergamon Press Ltd.

??Hyperthermia Original Contribution

HYPERTHERMIA AND RADIATION IN ADVANCED MALIGNANT MELANOMA

KAYIHAN ENGIN, M.D., LESLIE TUPCHONG, M.D., D. PHIL., FRANK M. WATERMAN, PH.D., DAVID J. MOYLAN, M.D., RUDOLPH E. NERLINGER, B.S. AND DENNIS B. LEEPER, PH.D.

Department of Radiation Oncology and Nuclear Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA

Advanced melanoma (48 lesions in 40 patients) was treated with external microwave hyperthermia combined with radiation therapy between 1980-1988. Thirty-three lesions in 28 patients were evaluable for tumor response (mean age 64 years, 19 male, 9 female). Evaluable lesions received 13 to 66 Gy (mean 37 f 2 Gy) over 5 to 16 fractions (mean of 10) in 14 to 56 elapsed days (mean of 25). Tumor volume (?r/6*length*width*depth) was 62 -+ 16 cm3 (l-377 cm3). Hyperthermia was administered in 6.6 f 0.4 sessions (range l-14), there were 3.2 + 0.4 thermal sensors per tumor (range l-11) and 27 fields were treated twice-weekly (82%). Of the 33 evaluable lesions, 12 exhibited a complete response (36%), and 17 had a partial response (52%). Among the 12 complete responders four recurrences (33%) were observed at 8.6 f 1.4 months (median of 8.2 months). In superficial tumors with depth 5 3 cm and with lateral dimensions within 2 cm of the boundaries of the microwave applicator, the complete response rate was 50% (11/22); whereas for patients with deeper tumors with depth > 3 cm, the complete response rate was 9% (l/11), p = 0.02. The minimal tumor thermal dose during the first hyperthermia treatment session correlated with response (t,3minl = 20 * 7 vs. 6 f 3 minEq43”C for complete responders and noncomplete responders, respectively, p = 0.06); and 7 of 10 lesions that had tA3minl > 8 minEq43”C achieved a complete response whereas only 5 of 22 lesions (23%) that had &,minl < 8 minEq43”C did so (p = 0.01). However, neither the minimum tumor temperature during the first treatment, the median minimum tumor temperature over all treatment sessions nor the sum of minimum thermal dose over all treatment sessions correlated with tumor response. Twenty-three patients with 28 lesions died during follow-up (82%). The survival for complete responding patients with superficial lesions was 21.3 * 1.5 months compared to 4.5 ? 0.5 months for patients with superficial lesions that did not experience a complete response (p = 0.0001). For patients with noncomplete responding lesions deeper than 3 cm survival was 4.4 f 0.6 months. Twenty lesions were treated without any skin reaction (42%, 20/48). Of the rest, 23 had erythema (48%, 23/48), seven had blistering (14%, 7/48) and one had ulceration of the skin. It is concluded that hyperthermia can increase the complete response rate of superficial lesions of malignant melanoma to approximately 50% from approximately 9% in deeper seated tumors > 3 cm depth that probably are not completely heatable with a superficial device.

Malignant melanoma, Hyperthermia, Radiation, Thermal dose.

INTRODUCTION In a review comparing the results of thermoradiotherapy for malignant melanoma with radiation therapy alone,

Several studies indicate that achieving local tumor control is very important in predicting the survival in malignant melanoma. Overgaard (22) found 49% actuarial 5-year survival in patients who achieved local tumor control whereas survival was only 3% among patients in whom local control failed. He concluded that the individual fraction size and tumor volume were the two most important factors influencing the outcome of radiotherapy (2 1,22,24). However, Sause et al. (28) found no difference in response between conventional and high dose per fraction arms of an RTOG study of malignant melanoma.

Overgaard (20, 23) showed that the tendency for recurrence in complete responders was lower after radiation plus hyperthermia than after radiation alone. The biolog- ical explanation proposed for this higher tendency was that the most radioresistant cells are in a dormant state and after some time will give rise to a recurrence if not sterilized. When hyperthermia is combined with radiation, such cells are more likely to be destroyed and a lower probability of a tumor containing viable cells can be achieved. Based on this rationale, several studies inves- tigating the potential role of hyperthermia in the locore-

Presented in part at 9th International Congress of Radiation Research, Toronto, Canada, July 7- 12, 199 1.

Reprint requests to: Dennis B. Leeper, Ph.D. Acknowledgements-The authors gratefully acknowledge the statistical assistance of Mr. Charles Scott and Dr. Tom Pajak of

87

the Statistics Center, American College of Radiology, Philadel- phia, and Dr. Jacqueline R. Cater, Thomas Jefferson University. The able secretarial assistance of Mr. David Jiang is also greatly appreciated.

Accepted for publication 24 July 1992.

88 1. J. Radiation Oncology 0 Biology 0 Physics Volume 25, Number 1, 1993

gional treatment of malignant melanoma have been pub- (Y/P ratio of 2.5 was used for malignant melanoma (20). lished, and the results have been encouraging (2, 4, 10, The mean equivalent total radiation dose (ETD) was 51 13, 31). -t 3 Gy, ranging between 14-8 1 Gy.

This paper presents the results of a 9-year experience with thermoradiotherapy for advanced malignant melanoma comparing tumor response and survival of patients with superficial versus deep lesions.

MATERIAL AND METHODS

Patient population Forty-eight malignant melanoma lesions in 40 patients

were treated with hyperthermia combined with radiation therapy between January 1980 and December 1988. Thirty-three lesions in 28 patients were evaluable for tumor response (mean age 64 years, range 28-87, see Table 1, 19 male, nine female). Forty-eight fields in 40 patients were evaluable for the analysis of skin reactions.

Hyperthermiu. Hyperthermia was applied with 2450 MHz microwave applicators until 1982 (13 fields) and after that with 915 MHz microwave applicators (20 fields).* Hyperthermia was administered within 1.5-30 min after radiation therapy. Only patients treated with external microwave applicators and external beam radiation therapy techniques were considered for evaluation. The aim was to achieve the highest tumor temperature permitted by patient tolerance for the duration of a 60 min treatment. The hyperthermia technique varied depending on the clinical situation, size and location of tumor. Applicators used in hyperthermia sessions were 15 X 15 cm flat, 10 X 10 cm flat, 7.5 X 7.5 cm flat, 7.5 X 15 cm flat (H/N) and 7.5 X 15 cm curved (H/N). Mineral oil bolus at room temperature was used.

Of the 33 lesions, 26 (86%) were Stage IV according to American Joint Committee staging system, and the others were Stage III. The anatomical localization of the lesions was head and neck (20) chest wall (4) lower extremity (6), abdominopelvic region (1) shoulder and supracla- vicular fossa (2).

All but two cases had some kind of previous treatment including surgery (82%) radiotherapy (36%) chemotherapy (54%) prior to thermoradiotherapy. The mean radiation dose administered for the previous radiation therapy sessions was 45 & 2.5 Gy, in 14 fractions over 3 1 elapsed days.

There were 3.2 -t 0.4 thermal sensors per tumor (range l- 1 I). When more than one temperature catheter was used, the guidelines for catheter placement were similar to those established by the RTOG (25). However, it was very difficult to fully apply the guidelines to deep lesions (depth > 3 cm). Thus, in deep lesions it was unlikely temperature catheters extended to the base of the tumor.

One to three thermal sensors were placed on the surface of each treatment field. The mean number of hyperthermia sessions administered was 6.6 -t 0.4 (range 1-14). In 27 cases (82%) of cases, hyperthermia was administered twice-weekly.

The mean length of the lesions was 5.5 + 0.7 cm (range 2-16 cm), width was 4.5 + 0.5 cm (range 1.5-1 1 cm) and depth was 2.5 + 0.3 cm (range 0.2-8 cm). Two lesions were diffuse. The mean volume (r/6*length*width*depth) was 62 f 16 cm3 (range l-276 cm3). Tumor dimensions were estimated by palpation, and in about one-third of the cases they were confirmed by computed tomography (CT) scan. Lesions were said to be superficial if tumor depth was 3 cm or less from the surface, and if the lateral tumor dimensions were at least 2 cm less than the boundaries of a microwave applicator.

Treatment Radiotherapy. All patients were treated externally with

high-voltage irradiation, with electrons or photons, from 6 MeV or 25 MeV linear accelerators. Type, technique and energy of the radiation beam varied depending on the clinical situation. The mean radiation dose was 37 ? 2 Gy, ranging between 13-66 Gy. Radiation therapy was given in a mean number of 10 fractions (range 5-l 6) in 25 elapsed days (range 14-56). The mean radiation dose per fraction was 3.6 + 0.1 Gy (median of 4 Gy, range 2- 5.5 Gy). The equivalent total radiation dose (ETD) was calculated by using the linear-quadratic model (9). An

Individual hyperthermia treatments were characterized by the average steady-state temperature of the minimum and maximum tumor thermal sensor and the median temperature of all tumor thermal sensors. Steady-state temperature was usually attained during the period of lo- 60 min after turning on microwave power. The median of the minimum steady state temperatures over all heat treatments was characterized as Tmin, and the steady state temperature of the lowest thermal sensor of the first hyperthermia session as Tmin 1. Likewise, the median ofthe maximum tumor thermal sensors at steady state temperature over all heat treatments was Tmax. The highest single tumor temperature recorded over all heat sessions was MaxTmax. MaxTskin was the highest single surface temperature recorded over all heat sessions. The thermal dose (td3) combining the effects of time X temperature in minEq,,“C based on the model of Sapareto & Dewey (27) was calculated.

Method of analysis. Tumor response was evaluated by tumor size eight weeks after the last treatment. Twelve patients with thirteen lesions died in the 8 weeks between the end of treatment and the assessment of response and were excluded from the analysis. These patients were re- ferred from outside institutions to our center specifically

* Clini-Therm, Dallas, TX.

Hyperthermia and radiation in advanced malignant melanoma 0 K. ENGIN et al. 89

Table 1. Age distribution of patients with malignant melanoma treated with thermoradiotherapy (n = 33)

Age O-30 31-40 41-50 51-60 61-70 > 70 Number of

uatients 2 0 4 8 6 13

for thermoradiotherapy. All twelve patients had advanced systemic disease with lung or brain metastasis, and all but three of the lesions were bulky and deeper than 3 cm. Two patients who were evaluable for tumor response developed “out of field” secondary lesions that were treated but were excluded from tumor response analysis since the patients died within 8 weeks after treatment of the secondary lesion. In all, thirty-three lesions in 28 patients were evaluable for the assessment of tumor response, and 48 fields in 40 patients were evaluable for the analysis of skin reactions. The assessment of tumor response was carried out under WHO/UICC criteria and the definitions were as follows:

1. 2.

3.

4.

5.

Complete response (CR): disappearance of the tumor; Partial response (PR): tumor volume was reduced 50% or more: No response (NR): tumor volume was not reduced to 50 percent; Partial responders and nonresponders (PR + NR) were defined as noncomplete responders (NCR) in the text; Three superficial lesions which were assessed as a partial response initially at eight weeks after completion of treatment continued to regress during the course of follow-up (continuing regression).

fhe duration of response was measured in months from the date of the completion of treatment to the date of either the detection of local recurrence or last follow-up. Survival and duration of local control (i.e., time to recurrence) were calculated.

Unless otherwise noted, confidence intervals represent the standard error of the mean. The significance of the difference between means was determined by t-test. Where appropriate curves were fitted by linear regression. Tumor response endpoints for radiation dose and minimal tumor thermal dose during the first heat treatment were determined by applying a logistic regression model. Survival was analyzed the Kaplan and Meier method (11) and the significance of differences determined by the Log-Rank test. Quanta1 responses were analyzed by Chi Square.

RESULTS

Overall response The complete response rate (CR) for all lesions was

36% (12/33). In 17 lesions a partial response (PR) was observed (52%) and in four cases ( 12%) there was no response (NR). The overall response rate (CR + PR) was 88%.

Tumor depth and response Lesions were stratified by depth to compare the response

of superficial and deeper tumors (25). Twenty-two superficial lesions (i.e., depth I 3 cm and lateral dimensions within 2 cm of the boundaries of the microwave applicator) were analyzed separately for the analysis of the effects of thermoradiotherapy (Table 2). Of the 22 superficial lesions, a complete response was observed in eleven (50%). Seven lesions (32%) exhibited a partial response, and four (18%) did not respond. In deeper lesions with depth > 3 cm, the complete response rate was only 9% (l/l 1) al- though the rest of the group of lesions deeper than 3 cm exhibited a partial response to thermoradiotherapy (9 1%). The difference in the CR rates between these two groups based on depth of the lesion was significant (p = 0.02).

Radiation dose and response The complete response rate was plotted as a function

of radiation dose for superficial and deeper lesions (Fig. 1). In order to estimate the response rate, lesions were grouped in 10 Gy intervals and the mean and standard error ofthe dose in that group plotted. The EDso (radiation dose at 50% CR) was estimated by logistic regression to be 44 + 16 Gy (ETD = 50 Gy). The EDso for deep lesions could not be estimated because only one lesion exhibited a CR; but it must exceed 66 Gy since radiation doses up to 66 Gy (ETD = 81 Gy) were administered and only I/ 11 CR was observed. There was not a significant difference in the radiation dose delivered to superficial compared to deeper lesions, that is, lesions I 3 cm depth received 37 + 2 Gy (ETD = 52 & 3 Gy) and lesions > 3 cm depth received 38 + 5 Gy (ETD = 50 t 7 Gy). A CR of 65% ( 1 l/ 17) was observed in superficial lesions when the concurrent radiation dose (ETD) was 2 45 Gy, and when the concurrent radiation dose (ETD) was < 45 Gy, the CR was 0% (O/5), p = 0.02.

Neither previous radiation therapy nor chemotherapy influenced tumor response to thermoradiotherapy. Three of eight lesions (38%) that had failed previous radiation therapy showed a complete response after thermoradiotherapy with a mean concurrent radiation dose of 34 k 5 Gy (ETD = 46 -t 8 Gy), whereas the complete response rate was 57% (8/ 14) among superficial lesions that did not have prior radiation therapy (mean concurrent dose of 39 f 2 Gy, ETD = 54 + 3 Gy). The difference was not

Table 2. Response of malignant melanoma to thermoradiotherapy

Tumor depth* CR PR NR Total

5 3 cm I1 (50%) 7 (32%) 4 (18%) 22 (100%) > 3 cm 1 (9%) 10 (91%) 0 (0%) 11 (100%) Total 12 (36%) 17 (52%) 4 (12%) 33 (100%)

* Maximum depth of tumor from surface determined by palpation and/or CT scanning.

90 1. J. Radiation Oncology 0 Biology 0 Physics Volume 25, Number I. 1993

I z

60

ii a

40 c r

t z 20

0

(2) 0 I ,, I_ ,

40 50 60 70

DOSE, GY

Fig. 1. Radiation dose-response curve for malignant melanoma treated with thermoradiotherapy. Lesions were grouped by radiation dose in 10 Gy intervals with mean f SE shown. Number in parentheses is number of lesions. Superficial lesions 5 3 cm depth shown by open symbols; deeper lesions > 3 cm depth shown by closed symbols. Curve for lesions I 3 cm depth drawn by eye; EDSo = 44 -t 16 Gy by logistic regression.

statistically significant (p = 0.24). Previous chemotherapy did not correlate with tumor response (p = 0.28).

Thermal parameters and response The effect of various treatment parameters relative to

tumor response in superficial lesions of malignant melanoma are shown in Table 3. A relationship was found between tumor response and td3minl. There was a significant difference between the response of lesions that achieved a t43min 1 greater than 8 minEq43”C and those that did not. The frequency distribution of Liminl in superficial CR versus NCR lesions is shown in Figure 2. The t43min1/50 for lesions with a CR was 15.5 minEq43”C (r = 0.99) compared to 2.4 minEq43”C for lesions with a NCR (r = 0.99), where t4imin1/50 was defined as the t43min 1 which was exceeded in 50% of the lesions in a particular group. The mean of t43min1 for superficial lesions exhibiting a CR was 20 k 7 minEq43”C

whereas for NCR lesions it was 6 k 3 minEq43”C (p = 0.06). Seven of 10 lesions (70%) that had t4,minl 2 8 minEq43”C achieved a CR, whereas only 5 of 22 lesions (23%) that had t43min1 < 8 minEq43”C achieved a CR (p = 0.01). The EDso for t4,min1 in superficial lesions calculated by logistic regression was 23 f 12 minEq43”C.

No other thermal parameters were found that correlated with tumor response to thermoradiotherapy (Table 3). For instance the mean of Tminl for superficial lesions exhibiting a CR was 40.9 k 0.6”C and for NCR lesions it was 40.4 + 0.4”C (p = 0.48); Tmin was 40.6 f 0.5” vs. 40.7 + 0.5” for CR vs. NCR lesions, respectively; and neither Bt43min nor Tmax correlated with tumor response.

Superficial lesions exhibiting a CR received a mean radiation dose of 4 1 k 2 Gy whereas superficial lesions exhibiting a NCR received a mean radiation dose of 33 f 4 Gy, p = 0.09. Because ofthe limited number of evaluable lesions and the limited number of doses employed, a significant difference in radiation dose between complete responders and noncomplete responders, if it existed, could not be identified.

Rccurrcncc und survival The recurrence rate in complete responders was 33%

(4/12), and the time to recurrence varied between 5.8 and 12.1 months with a mean of 8.6 k 1.4 months (median of 8.2 months). Eight lesions were recurrence-free at last follow-up at a mean of 19.7 +- 1.6 months (median of 19.4 months).

Of twenty-eight patients with 33 evaluable lesions, twenty-three with 28 lesions died during follow-up (82%). Five patients were alive at the last follow-up visit. The mean survival for all patients was 16.6 4 2.2 months (median of 16 months, range 2.4-49.3 months). In Figure 3, the survival time of complete responding superficial lesions including three “continuing regression” lesions was compared to that of noncomplete responding superficial and noncomplete responding deep (> 3 cm) lesions. Four deep lesions with a NCR and two superficial lesions were excluded from the analysis since they had additional ther-

Table 3. Treatment parameters and tumor response in superficial malignant melanoma lesions (5 3 cm depth) treated with thermoradiotherapy*

Mean tumor No. of dimensions No. of Radiation T min It T mint tlli mm lb iZtb3 min** lesions Response (cm) sensors dose (Gy) (“C) (“C) (minEq43”) (minEq43”)

II CR 2.8 x 2.7 X 1.5 2.4 41”2* 40.9 f 0.6 40.6 f 0.5 20.5 k 7.2 57.6 k 29.1 II NCR 3.8 x 3.5 X 1.9 2.9 33 f 4 40.4 2 0.4 40.7 k 0.5 5.9 k 2.8 95.2 -t 34.8

p values N.S. 0.09 N.S. N.S. 0.06 N.S.

* Mean + S.E. + Average temperature of minimum tumor thermal sensor during first heat session. * Median temperature of minimum tumor thermal sensor over all heat sessions. 8 Thermal dose of minimum tumor thermal sensor during first heat session. ** Sum of thermal dose of minimum thermal sensor over all heat sessions.


apy after thermoradiotherapy (i.e., amputation, reirradiation, chemotherapy, interferon). A complete responding superficial lesion with a survival of 43.4 months was also excluded from the analysis because of retreatment of a secondary lesion. The mean survival for complete responding patients with superficial lesions was 2 1.3 f 1.5 months (range 8.9-26.6 months, median 20.9), while for patients with superficial lesions who did not experience a complete response the mean survival was 4.5 f 0.5 months (range 2.4-8.1 months, median 3.5). For patients with noncomplete responding lesions deeper than 3 cm the mean survival was 4.4 f 0.6 months (range 2.9-6.6 months, median 4.0). The survival difference between patients with superficial responding lesions and the two groups of noncomplete responding lesions was significant, p = 0.0001 (Log-Rank test).

Skin reactions Of forty-eight fields receiving thermoradiotherapy,

twenty were treated without any skin reaction (42%). Skin reactions developed in 28 fields, with erythema seen in 23 cases (48%), thermal blistering in seven cases (14%). Ulceration occurred in eight cases. In all but one of these cases the ulceration may have been due to tumor breakdown as there was direct invasion of the skin by tumor prior to the initiation of treatment. Eight lesions (8/48) had more than one skin reaction during the course of their treatment, and three skin reactions were observed together in two cases (2/48).

There was no correlation between the occurrence of skin reactions with Tmax, MaxTmax or MaxTskin. MaxTskin was 42.2 + 0.3”C for no skin reactions, 42.5 + 0.5”C for erythema and 42.1 -t 0.6”C for thermal blistering (Table 4).

I I

1’ I I I I 0 20 40 60 60

T43(index), minEq43”C

Fig. 2. Distribution of minimum tumor thermal dose during the first heat session (td3minl) in superficial lesions, I 3 cm depth. Lesions with complete response (CR, 11 lesions)-open symbols; lesions with incomplete response (NCR, 10 lesions)- closed symbols. Linear aspect of curves fitted by least squares; the ta3minl/50 for CR lesions was 15.5 minEq43”C (r = 0.99) and for NCR lesions 2.4 minEq43”C (r = 0.99).

loo-

60

z 60

;ir .E 2

z 40

20

0

Months

Fig. 3. Survival times of patients with complete responding superficial lesions (including three “continuing regression” lesions), of patients with noncomplete responding superficial lesions and of patients with noncomplete responding deeper lesions (> 3 cm depth), p = 0.0001, Log-Rank test. Four deep lesions and two superficial lesions with a NCR were excluded from the analysis since they had additional therapy after thermoradiotherapy (i.e., amputation, reirradiation, chemotherapy, interferon). A complete responding superficial lesion with a survival of 43.4 months was also excluded from the analysis because of retreatment of a secondary lesion.

DISCUSSION

Since local tumor control is a critical factor in determining final outcome and the survival of patients with malignant melanoma, improvement in local control has been sought by using different cancer treatment modali- ties. After surgical treatment, 2-year survival rates vary between 29-4370, and the median survival time varies between 3-28 months (7, 8, 19, 32). These studies indi-

Table 4. Relationship of skin reactions and treatment parameters in 48 fields treated with thermoradiotherapy*

Skin reaction+

No. of fields

T maxi (“C)

Max T max5

(“C)

Max T skin**

(“C)

None Erythema Thermal

blistering

20 42.6 f 0.4 43.8 f 0.5 42.2 + 0.3 23 42.5 f 0.4 43.9 -+ 0.6 42.5 It_ 0.5

7 42.0 + 0.3 43.6 f 0.5 42.1 f 0.6

* Mean + S.E. + Ulceration associated with tumor breakdown was noted in

eight fields when skin was infiltrated with tumor. * Median of the highest tumor thermal sensor per treatment

over all heat sessions. B Highest tumor thermal sensor over all heat sessions. ** Highest thermal sensor on skin surface per treatment over

all heat sessions.

92 1. J. Radiation Oncology 0 Biology 0 Physics Volume 25. Number 1. 1993

cated that the completeness of the surgical resection was the most important factor influencing local tumor control and survival. Chemotherapy, single or multi-agent, has been extensively used in the management of metastatic melanoma. Overall response (CR + PR) rates varied between O-22% for single agent regimens and 27-52% for multi-agent regimens. The CR rates observed varied between O-5% for single agent and 0- 18% for multi-agent regimens ( 15, 16).

Radiation therapy has been investigated extensively in malignant melanoma. Overgaard stated that radiation fraction size and tumor volume were the most important prognostic factors determining final outcome in patients treated with radiation therapy alone (2 1, 22, 24). Large doses per fraction produced a significantly better response (59% CR for doses > 4 Gy vs. 33% CR for doses per fraction < 4 Gy) (22). In another study performed by the same author (24), it was shown that tumor response was significantly improved with radiation fraction sizes > 8 Gy when compared with lesions treated with fractions less than 4 Gy. In contrast to these results, Sause et al. (RTOG 83-05) found that there was no difference in complete response rates between dose fractionation schemes of 4 X 8 Gy and 20 X 2.5 Gy (CR = 24% vs. 23%, respectively) (28).

25% iso-SAR line encompassed the tumor and each thermal sensor exceeded t43 of 30 min for at least one treatment session. Analogous to these findings, we found that after thermoradiotherapy a CR rate of x90% for tumor deposits in the head and neck with depth I 2.5 cm depth decreased sharply when tumor depth exceeded 2.5 cm (6). In subsequent analyses, Myerson et (11. (18) applied parameterized temperature computations to a model as- suming uniform conduction and blood flow to calculate equilibrium solutions which identically obey boundary conditions at the surface of a phantom and at infinite depth. They found in the idealized situation that MaxTskin, SAR, Tmax and a parameter defined as the diffusion length (X) may be able to predict the 42°C iso- temperature boundary. However, in the real case where tumor blood flow is extremely heterogeneous the appli- cation of this model may be tenuous.

In addition to attempts to improve results by altering radiation fractionation schedules, hyperthermia has been combined with radiation therapy (1, 4, 10, 13, 20, 26, 3 I). Complete response rates varying between 59% and 90%, and thermal enhancement ratios between 1.43 and 4.88, have been reported. In the present study of 48 lesions of all depths, treated with hyperthermia and various radiation schedules over a 9-year period, we obtained a complete response rate of 36% and a partial response rate of 52% (overall response rate 88%). In superficial lesions, that is, less than or equal to 3 cm depth and with lateral dimensions less than 2 cm of the boundaries of the microwave applicator (18), the CR rate was 50% and PR rate 32%. The CR rate was 9% for deeper lesions greater than 3 cm depth (p = 0.02).

The most important factors influencing the complete response rate in the present study were tumor depth, radiation dose administered concurrently with hyperthermia and t4,min 1. Neither previous radiation dose nor previous chemotherapy had any effect on the CR rate. The EDSO for lesions I 3 cm depth was estimated by logistic regression to be 44 + 16 Gy (ETD = 50 Gy) and was significantly smaller than the EDSo for larger lesions. Superficial lesions treated with radiation doses (ETD) greater than 45 Gy showed a 65% CR rate while the CR rate was 0% in superficial lesions which received radiation doses (ETD) less than 45 Gy (p = 0.02). In deep lesions the average radiation dose was 38 ? 5 Gy (ETD = 50 f 7 Gy) and the CR was only 9%.

Perez et al. (25) reviewed the RTOG hyperthermia experience (Protocol 8 l-04) and reported a 54% CR rate for all lesions < 3 cm by greatest dimension and a 260/o CR rate for lesions whose greatest dimension exceeded 3 cm. This compared to a 28% CR rate for all lesions receiving radiation only, independent of size. The radiation dose in all cases was approximately 30 Gy. The results suggest that for lesions < 3 cm hyperthermia significantly en- hances local control, whereas in larger and deeper lesions that are not completely heatable, local control primarily represents the effect of radiation only.

The minimal tumor thermal dose during the first heat session correlated with response in the present study. The response of lesions that achieved a t,,minl r 8 minEq43”C was significantly greater than in those lesions that did not; and the t43minl/50 of lesions exhibiting a CR was 15.5 minEq43”C wherea’s it was 2.4 minEq43”C for those that did not exhibit a CR. No other tumor thermal parameters correlated with response. This suggests that much of the effect of hyperthermia contributing to local control may be exerted in the first hyperthermia session ( 14). Dewhirst et al. (3) observed that the lowest thermal dose of the first heat session correlated with tumor response after thermoradiotherapy to spontaneous canine malignancies. However, they also observed that the minimal thermal dose summed over all hyperthermia sessions correlated with tumor response (2, 3). Furthermore, Kapp et al., ( 12) have shown that chest wall recurrences respond equally well to thermoradiotherapy whether the hyperthermia is administered in 2 fractions over 2 weeks or in 6 fractions over 3 weeks.

Tumors deeper than 3 cm from the surface are probably It is apparent that patients with complete responding not encompassed by the 25% iso-SAR envelope with lesions after thermoradiotherapy have an increased sur- commercially available 9 15 MHz external microwave ap- vival time. The survival for patients with complete re- plicators (29). Furthermore, Myerson et al. (18) showed sponding superficial lesions was 2 1.3 + I .5 months while that the best tumor response rates (determined when local for patients with superficial lesions that did not show a control exceeded 8- 12 months) were obtained when the complete response survival was 4.5 + 0.5 months, and


for patients with noncomplete responding lesions deeper burden unless the aim is acute palliation (that is reduction than 3 cm survival was 4.4 ? 0.6 months, p = 0.0001. of pain or hemorrhage).

Three superficial lesions were assessed as a partial response initially at eight weeks after completion of treatment but continued to regress during the course of follow- up. This observation was consistent with other reports. Kapp et al. categorized these patients separately as “continuing regression, that is, < 50% of initial volume” (13) and Valdagni et al. stressed that it might take 3 to 6 months to achieve a CR (30).

The frequency of skin reactions was not dissimilar to that after high dose radiation therapy; 42% of the patients were treated without any skin reaction. A correlation could not be detected between skin reaction rates and thermal parameters.

Patients with bulky lesions of malignant melanoma greater than 3 cm depth and with extensive systemic tumor burden may not benefit from thermoradiotherapy. Four- teen of twenty four patients with extensive disease died within two months of completion of thermoradiotherapy; and while ten patients with extensive disease were evaluable at two months post-treatment, the survival time was 4.4 k 0.6 months. Thermoradiotherapy would seem to be of marginal benefit in the care of patients with bulky lesions of malignant melanoma and with extensive tumor

Recently published results with thermoradiotherapy for soft tissue sarcoma indicated that hyperthermia in this disease increased the CR rate to 50% (4/8) in superficial lesions from a CR of zero percent (O/7) in deeper lesions (p = 0.10, see reference 5). The radiation dose was approximately 40 Gy for both superficial and deeper lesions. The mean survival for complete responders was 28.5 f 5 months and was 7.1 2 1.8 months in noncomplete responders. No recurrences were observed in complete responding tumors. Similarly to the melanoma study, 38% of the soft tissue sarcoma fields exhibited no skin reactions, erythema was observed in 47%, blistering in 12% and ulceration associated with tumor breakdown in 6%.

REFERENCES

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2. Dewhirst, M. W.; Sim, D. A.; Forsyth, K.; Grochowski, K. J.; Wilson, S.; Bicknell, E. Local control and distant metastases in primary canine malignant melanomas treated with hyperthermia and/or radiotherapy. Int. J. Hyperther. 3:219-234;1985.

3. Dewhirst, M. W.; Sim, D. A.; Sapareto, S.; Connor, W. G. The importance of minimum tumor temperature in determining early and long term responses of spontaneous pet animal tumors to heat and radiation. Cancer Res. 44:43- 50;1984.

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