Int. J. Radiation Oncology Biol. Phys., Vol. i2, pp. 1667-1671 Printed in the U.S.A. All rights reserved.

0360-3016/86 $3.00 + .00 Copyright 1986 Pergamon Journals Ltd.

Original Contribution
MICROWAVE HYPERTHERMIA AS AN ADJUNCT TO RADIATION THERAPY: SUMMARY EXPERIENCE OF 256 MULTIFRACTION TREATMENT CASES HAIM I. BICHER, M.D.,* RALPH S. WOLFSTEIN, M.D.,* B. S. LEW~NSKY, M.D.,~ H. S. FRE, M.D. AND A. G. FINGERHUT, M.D.]"
Valley Cancer Institute, 14427 Chase St., Suite 203, Panorama City, CA 91402
Results in 256 cases of malignant disease treated by multifraction combination hyperthermia-radiation therapy under the supervision of one physician are presented. The overall response rate was 94% including a 62% complete response. Complications specifically ascribed to hyperthermia were minor, and most side effects of combined treatment were radiation dose related. Tumor response was somewhat better for chest wall recurrence (72% CR) and for adenocarcinoma in general (64% CR), but no significant dependence on tumor site or type was found. Most patients were treated with low dose external radiation with hyperthermia given by air cooled microwave applicators or intracavitary antennae operating at 915 or 300 MHz, and some by interstitial microwave antennae plus 192 Ir. Results appeared to be independent of the microwave source employed. Response did depend on radiation dose: complete response rate with 4000 rad was 65%, and with 2000 rad was 42%. Hyperthermia, Radiotherapy, Cancer treatment.

hyperthermia treatment of tumors in several body sites. They were designed and tested for physical characteristics, Hyperthermia is past the stage of experimental laboratory heat distribution in phantoms, and treatment fields in technique and in some aspects is well into Phase II clinical patients. All patients accepted for treatment signed contrials. Mechanisms of action, that is, direct cell kill with sent forms after learning the potential risks and benefits or without radiation,7 microcirculation changes,3 and pH of the clinical investigation. Homogeneity of temperatures shift,3 are being established. Even with evolving equipment and minimum leakage levels were determined and found and changing protocols, its value as an adjunct in cancer satisfactory. Routinely, treatment temperatures of 42treatment is acceptable in the rapidly increasing number 45C were obtained at tumor depths while the surface of clinical studies1249-2123-25 published since 1977. Results was kept below 40C using air cooling of skin (with expresented here show that the same percentage of tumor ternal treatment) or of antenna jacket (with intracavitary response and favorable therapeutic indices have been treatment). Using 300 MHz increased the effective penmaintained at our Hyperthermia Clinics as compared with etration from 3 to 5 cm. previously published clinical experiences. A system for interstitial radiotherapy with hyperthermia In previous publications47 we reported an effective has also been devised using microwave induced heat defractionation regimen using 42-45 C local hyperthermia livered through a series of interstitial micro-antennae incombined with low dose (1600 rads) irradiation, yielding troduced into the plastic carriers that area normal coman overall complete response rate of 65% in 121 treatment ponent of the Syed-Neblitt device and other implant apfields evaluable at 2 months post treatment. These results plicators.5 According to the volume of implantation include an enlarged series using intracavitary and interrequired, the system can operate at 915 or 300 MHz, the stitial air cooled microwave antennae, as well as external lower frequency being used when greatbr penetration of applicators. microwaves is desired either because of a larger implant volume or bigger inter-antenna spacing. A special feature METHODS AND MATERIALS of this system is air cooling of the antenna jackets which Air cooled microwave applicators and intracavitary avoids hot spot formation around them, and is progresantennae operating at 915 and 300 MHz* were used in sively important as the inter-antenna spacing increases.

INTRODUCTION

* Dept. of Hyperthermic Oncology, Daniel Freeman Memorial Hospital, Inglewood, CA 90301. ]" Western Tumor Medical Group, Inc., Van Nuys, CA 91411. Reprint requests to: Haim I. Bicher, M.D.
1667

Accepted for publication 24 March 1986. * Supplied by HBCI Medical Group, 14427 Chase St., Panorama City, CA.

1668

I.J. Radiation Oncology Biology O Physics

September 1986, Volume 12, Number 9

Complete thermometry was performed during every patient treatment (more then 2200 treatments to the 256 tumors included in this report) employing (100 micron) microthermocouples implanted in the tumor (whenever possible) and in surrounding or overlying normal tissues. Throughout treatment, temperature readings were taken at 3-4 minute intervals under "power off? conditions to eliminate any possible interference artifacts. Temperatures were recorded using a modified microprocessor computer with a special interface which also controls the microwave "on-off? cycle. A minimum off 4 probes were used in each treatment placed in the tumor, normal tissue at risk, surface at risk (usually skin), and a waterbath (for control of system drift.) Thus, tumors up to 2-3 cm had one probe inserted centrally. Larger tumors had at least two probes, inserted to maximum depth centrally and about 1 cm from the periphery. Tumor fields covering 8 cm or more, as commonly found in chest wall recurrence, routinely had probes placed in more than one peripheral area. For interstitial treatments, 2 to 4 thermcouples were inserted in plastic carriers not used for microantennae insertion, with additional 1-2 thermocouples implanted directly in tumor. In our current series, the previous protocolv was modified to include a higher dose of radiation with conventional fractionation given throughout the treatment course. The radiation dose was either 2000 rads in 10 fractions or 4000 rads in 20 fractions over 5 weeks. Patients were adjudicated to either category depending on the previous radiation dose (Table 1). Hyperthermia treatments were given twice weekly on a Monday/Thursday or Tuesday/Friday schedule for a total of 10 treatments in this protocol. Each hyperthermia session was delivered immediately following a 200 rad radiation fraction, with tumor temperature maintained at 42-45 C for 1 hour. Most of the patients entered into these protocols had previously failed radiation therapy and/or had no proven treatment alternative left. Included also, are a few recent patients with disease in previously untreated areas who have been treated under protocols permitting full dose radiation.

Table 2. Summary of results--Current series Evaluable patients 100 Response Total response (100%) Partial response (>50%) No response (<50% or recurrence at 2 months) Complications Thermal burns Ulcerations Proctitis, esophagitis Pleuritis 135 fields 79 (58.5%) 48 (35.5%) 8 (6.0%) 16 (completely healed) 6 (completely healed) 4 (completely healed) 2 (1 required hospitalization)

The protocol for implants provides for two 192 Ir loadings separated by 1 week, each giving 1500-2500 rads over a period of 2-3 days, the dose depending on previous radiation dose. Interstitial hyperthermia treatments are given before and after each implant and up to four times in the intervening week along with an external radiation fraction. RESULTS Current clinical results include 135 fields in 100 patients. Of these, 58.5% showed a total response and 35.5% partial response at 2 months post treatment evaluation (Table 2): Results were better with higher radiotherapy dose (Table 3). Patients in the 20/10 protocol showed 65% complete response with only 3% not responding (in these analyses, no response means less than 50% tumor regression 2 months following treatment), while patients in the 10/10 protocol showed 42% complete response with 16% not responding. The difference in results for Cr vs. PR + NR was statistically significant (p = 0.037) by Fisher Exact Test.22 Preliminary results using interstitial hyperthermia have been gratifying, (6/9 CR). One patient with a large fibrosarcoma in the thigh and another with a large metastatic melanoma in the axilla showed complete response to interstitial treatment after partial response using external treatment under the 20/10 protocol.
Table 3. External hyperthermia results by radiation dose

Table 1. Protocol Previous radiation therapy Less than 5,000 rads or 5,000 rads More than 1 year ago More than 5,000 rads or 5,000 rads Less than 1 year ago Treatment 20/10 10/10

Dose 5-7400 rad + 12-17 A 4000 tad + 10 A

Fields 16 69 26

Response 11 CR (69%) 4 PR (25%) 1 NR (6%) 45 CR (65%)* 22 PR (32%) 2 NR (3%) 11 CR (42%)* 11 PR (42%) 4"NR (16%)

Description of treatment: 20/10:20 XRT fractions of 200 rads over 5 weeks for 4,000 rads total; 10 A fractions at 43C for 1 hour twice weekly. 10/10:10 XRT fractions of 200 fads over 5 weeks for 2,000 rads total; 10 A fractions at 43C for 1 hour twice weekly.

2000 tad + 10 A

* p = 0.037.

Hyperthermia/radiotherapy summary experience H. I. BICHER et al.

1669

Use of intracavitary antenna has been less successful. Several patients have been unable to tolerate insertion of the antenna for a full course, and proctitis or esophagitis was severe in four of the 20 patients completing treatment. Seven (35%) showed total response, while 3 (15%) showed no response. Overall results in the current series of patients treated at Western Tumor Medical Group and Daniel Freeman Memorial Hospital analyzed by cell type, are shown in Table 4. Little variation in response has been noted. Best results have been obtained in adenocarcinoma of breast including chest wall, lymph node and breast recurrence, and advanced primary disease. This is also the largest single group of patients in the series including 53 separate fields. All fields showed at least partial response, with complete response in 72% (Table 5). Since skin reaction was no greater than expected for the same dose of radiation alone, except for occasional thermal burns, we began giving hyperthermia along with full dose radiation for previously unirradiated recurrent breast carcinoma. Tumor regrowth was arrested for about 3 months in partial responses. Total responses persisted on average 5 to 6 months, in many cases up to the life of the patient. Toxicity is summarized in Table 2. Proctitis secondary to the use of a rectal intracavitary antenna in combined therapy was, in general, more than anticipated from radiation therapy alone and persisted somewhat longer, occasionally up to 6 weeks following completion of treatment. Otherwise, except for focal burns occurring in less than 10% of patients at some point during the treatment course, side effects were those anticipated from a similar dose of radiation therapy alone. The few cases of ulceration and fistulae that developed appeared most likely because of rapid tumor regression. Although listed as complications, pleural effusion can be expected in patients with extensive lymphangitic disease of the chest wall without treatment. Overall, more than half the treated patients showed no side effects whatsoever.

Table 5. Results: Breast and chest wall--Current series Response Treatment 5-6000 rad 25-30/12-15 4000 rad 20/10 2000 rad i0/10 Total Fields 10 31 12 53 Complete 8 (80%) 23 (74%) 7 (57%) 38 (72%) Partial 2 (20%) 8 (26%) 5 (43%) 15 (28%)

DISCUSSION Note that all of the patients included in this report were treated under the supervision of one physician using the same equipment in all patients. In the current series each hyperthermia session followed a radiation fraction. Heat was delivered for 1 hr at the therapeutic range of 42C minimum and 45C maximum tumor temperature. Analysis of results as to the effect of variations from this ideal treatment in the clinical setting, have not been undertaken. We have observed, however, that areas of incomplete tumor response or early recurrence appear to be at the periphery or in an area otherwise inaccessible to microwave heating. Therefore we conclude that the importance of maintaining all areas of tumor at the therapeutic range is paramount, and this has been elegantly demonstrated by Dewhirst et al.8 Other conclusions concerning the optimal number of hyperthermia sessions or duration of each session; the radiation fraction required for optimum hyperthermia effect; or whether hyperthermia should be given before rather than after a radiation fraction, remains for the future. Results of this study and others, including our own, show remarkable similarity both as to safety and effectiveness of combined hyperthermia-radiation therapy, irrespective of the parameters of hyperthermic treatments. In previous publications,47 we described a low radiation-hyperthermia combination (also recorded as RTOG protocol 78-06A). Briefly, treatment consisted of four fractions ofhyperthermia alone followed after 1 week rest by four additional fractions of hyperthermia this time immediately following 400 rad radiation fractions. All treatments were separated by 72-96 hours following a Monday/Thursday or Tuesday/Friday pattern. Each hyperthermia treatment was for 11/2 hr at the prescribed temperature (45C alone or 42C with radiation). One hundred twenty-one fields (tumors) were treated according to this protocol and evaluable for at least 2 months post treatment. The final results showed no major toxicity and a rate of 65% complete responses and 30% partial responses (Table 6). In our overall experience, treating 256 fields in 182 patients, tumor response was complete in 158 (61.7%), and partial in 84 (32.4%). YAm et al. 12 reported an overall tumor control rate of

Table 4. Results by histology--Current series Histology Malignant melanoma Squamous cell Ca Adenocarcinoma No. of fields 6 41 Response 2 CR (33%) 4 PR (67%) 20 CR (48.8%) 15 PR (36.6%) 6 NR (14.6%) 50 CR (64.1%) 26 PR (33.3%) 2 NR (2.6%) 8 CR (80%) 2 PR (20%) 80CR (59.3%) 47PR (34.8%) 8 NR (5.9%)

78 10 135

Other (sarcoma, basal cell, lymphoma, thymoma) Total

1670

I.J. Radiation Oncology Biology Physics

September 1986, Volume 12, Number 9

for superficial lesions, most with radiation only internal control, both with similar excellent results: 121 fields treated (82 patients) Arcangeli et al. ~ used three different treatment regimens Complete response 79 (65.3%) with slightly better response but more side effects in the Partial response 36 (29.7%) two groups given high radiation fractions twice weekly. No response 6 (5.0%) In an internal control group, 26 patients with multiple Recurrence Local 5 Marginal neck node metastases were given three fractions per day 3 totalling 500 rads to a total dose of 6000 rads. Of tumors Complications 2 (completely healed) Skin burns Tongue and given hyperthermia (twice weekly for 45 minutes at pharynx 43.5C using 500 MHz microwaves, after the second raburns 2 (completely healed) diation fraction, for a total of 7 sessions), 73% completely Grand mal 1 (neck treatmentregressed. Complete response rate of lesions that received epileptic history) seizure MDF radiation alone was 42%. Both speed and duration of tumor control were increased by heat, with three of seven patients surviving at 18 months showing recur78% in 50 patients with a variety of cutaneous lesions given a wide range of radiation dose and fraction size and rence--all in areas treated by radiation alone. Toxicity was no greater in areas receiving combined treatment. hyperthermia (43.5 C using water bath immersion of RF In 31 paired lesions given 6000 rads in 6 weeks, Scott (27.12 MHz) induction) ranging from two 30 minute to et aL2~ reported 39% total response to radiation alone at five 60 minute treatments (following radiation), with good results independent of both radiation sensitivity (Mela6 months, but lesions also receiving hyperthermia (twice weekly for 45 minutes at 42-43C by 915 MHz micronoma, Mycosis Fungoides) and treatment parameters. Hornback et al.91 also employed a wide range of rawaves, immediately following radiation) showed 87% total response at 6 months. All lesions receiving combined diation and hyperthermia (433.92 MHz microwave) dose treatment remained controlled in 19 patients alive at 1 in the treatment of 72 patients with advanced cancer, reyear compared to 53% of lesions treated by radiotherapy porting better control with hyperthermia given after rather alone. Six patients evaluable at 2 years showed one rethan before a radiotherapy fraction (complete remission currence, in an area given radiotherapy alone. They also of symptoms respectively 92% and 53%). Reports on Interstitial Thermoradiotherapy have shown concluded that adding local hyperthermia to definitive excellent tumor response without increased morbidity. radiotherapy resulted in more rapid and more complete Manning et al., 13,14 Vora et al.25 and Oleson et al. 16 gavetumor response and better long term control. Whereas Arcangeli concluded that optimal treatment should result a single 30 minute hyperthermia treatment prior to ra17 by adding 5-7 sessions of hyperthermia to a full convendiation, whereas Puthawala and Syed gave two hypertional radiotherapy course, Scott gave 12 sessions. thermia treatments for 1 hour immediately preceding and following 192 Iridium treatment. Oleson et al. reported Based on our preliminary experience and with these reports12~ confirming safety and efficacy, we are encour81% complete and partial response rate in 52 patients given 3000 rad interstitial radiation following hypertheraged to continue full dose standard fraction size radiomia, the most favorable technique in their overall expetherapy combined with hyperthermia for accessible adrience using various hyperthermia treatment methods revanced primary and previously unirradiated recurrent or metastatic malignant disease. sulting in 56% response rate in 162 patients.16 We have found that both the degree of tumor regression Hyperthermia has attained well-deserved acceptance in the treatment of recurrent and metastatic superficial maand the length of response depend on radiation dose. (Ta7 ble 3) We have also concluded that hyperthermia is safe, lignant disease as a result of the many reported clinical and adds nothing to the effect of radiation therapy alone studies, including our own. We may also cautiously anticipate significant improvement in long term control of on normal tissue. Therefore, we have began to give full advanced head and neck superficial primary disease. dose radiation therapy plus hype~hermia for previously However, for hyperthermia to become firmly established untreated recurrence and for primary tumors with a poor as a fourth modality in the pantheon of cancer treatment, prognosis for local control by radiation therapy alone or the ability to safely heat deep tumors, including those other modalities. Early results in the few cases given 5000 such as adenocarcinoma of pancreas that respond so disto 7400 rad plus hyperthermia have been promising (Table mally to current therapy, is required. Several groups are 3), but these require long term follow-up to assess response studying hyperthermia treatment of deep seated tumors duration. using various techniques, so far with limited sucTwo groups have reported long term follow-up data in cess.6,15,18,19,23 patients given full course radiotherapy plus hyperthermia
Table 6. Summary of results--Previous series

REFERENCES
1. Arcangeli, G., Cividalli, A., Nervi, C., Creton, G.: Tumor control and therapeutic gain with different schedules of combined radiotherapy and local external hyperthermia in human cancer, lnt. J. Radiat. Oncol. Bio!. Phys. 9:11251134, 1983. 2. Arcangeli, G., Barni, E., Cividalli, A., Mauro, F., Morelli,

Hyperthermia/radiotherapy summary experience H. I. BICHER et aL

1671

D., Nervi, C., Spano, M., Tabocchini, A.: Effectiveness of microwave hyperthermia combined with ionizing radiation: Clinical results on neck node metastases. Int. J. Radiat. Oncol. Biol. Phys. 6: 143-148, 1980. 3. Bicher, H., Hetzel, F.: Effects of hyperthermia on normal and tumor microenvironment. Radiology 137: 523-530, 1980. 4. Bicher, H., Hetzel, F., Sandhu, T.: Results of a phase I/II clinical trial of fractionated hyperthermia in combination with low dose ionizing radiation. Hyperthermia, H. Bicher, and D. Bruley (Eds.). New York, Plenum Press. 1982, pp. 87-89. 5. Bicher, H., Moore, D., Wolfstein, R.: A method for interstitial thermoradiotherapy. Proc. of 4 Int Syrup. Hyperthermic Oncol. (Aarhus, Denmark) 1: 595-598, 1984. 6. Bicher, H., Moore, D., Wolfstein, R.: Air-cooled 300 MHz applicators used in a parallel opposed phased system (POPAS). Int. J. Radiat. Oncol. Biol. Phys. 11: S1:217, 1985 (abst.). 7. Bicher, H., Sandhu, T., Hetzel, F.: Hyperthermia and radiation in combination: A clinical fractionation regime. Int. J. Radiat. Oncol. Biol. Phys. 6: 867-870, 1980. 8. Dewhirst, M., Sim D., Sapareto, S.: Importance of minimum tumor temperature in determining early and long term responses of spontaneous canine and feline tumors to heat and radiation. Cancer Res. 44: 43-50, 1984. 9. Hornback, N., Shupe, R., Homayon, S., Joe B., Sayoc, E., Marshall, C.: Preliminary clinical results of combined 433 MHz microwave therapy and radiation therapy on patients with advanced cancer. Cancer 40: 2854-2863, 1977. 10. Hornback, N., Shupe, R., Shidnia, H., Joe, B., Sayoc, E., George, R., Marshall, C.: Radiation and microwave therapy in the treatment of advanced cancer. Radiology 130: 459464, 1979. 11. Johnson, R., Sandhu, T., Hetzel, F., Kowal, H., Bicher, H., Song, S.: A pilot study to investigate the therapeutic ratio of hyperthermia 41.5-42.0C and radiation. Int. J. Radiat. Oncol. Biol. Phys. 5: 947-954, 1979. 12. Kim, J., Hahn, G., Benjamin, F.: Treatment of superficial cancers by combination hyperthermia and radiation therapy. Clin. Bull. 9: 13-16, 1979. 13. Manning, M., Cetas, T., Miller, R., Oleson, J., Conner, W., Gerner, E.: Clinical hyperthermia: Results of a phase I clinical trial employing hyperthermia alone or in combination with external beam or interstitial radiotherapy. Cancer 49: 205-216, 1982.

14. Manning, M., Cetas, T., Gerner, E.: Interstitial thermoradiotherapy. NatT. Cancer Inst. Monog. 61: 357-360, 1982. 15. Oleson, J., Manning, M., Heusinkveld, R.: Hyperthermia by magnetic induction. II. Clinical experience with concentric electrodes. Int. J. Radiat. Oncol. Biol. Phys. 9: 549556, 1983. 16. Oleson, J., Manning, M., Sim, D., Heusinkveld, R., Aristizabal, S., Cetas, T., Hevezi, J., Connor, W.: A review of the University of Arizona human clinical hyperthermia experience. Front. Radiat. Ther. Onc. 18: 136-143, 1984. 17. Puthawala, A., Syed, A., Sheikh, K.: Thermoendocurietherapy in the treatment of persistent and/or recurrent tumors (Abst.) International Clinical Hyperthermia Society, American Clinical Hyperthermia Meeting, Palm Springs, CA, December 1984. 18. Sapozink, M., Gibbs, F., Gates, K., Stewart, J.: Regional hyperthermia in the treatment of clinically advanced deep seated malignancy: Results of a study employing an annula array applicator. Int. J. Radiat. Oncol. Biol. Phys. 10: 775786, 1984. 19. Sapozink, M., Gibbs, F., Thomson, J., Eltringham, J., Stewart, J.: A comparison of deep regional hyperthermia from an annular array and a concentric coil in the same patients. Int. J. Radiat. Oncol. Biol. Phys. 11: 179-190, 1985. 20. Scott, R., Johnson, R., Kowal, H., Krishnamsetty, R., Story, K., Clay, L.: Hyperthermia in combination with radiotherapy; a review of five years experience in the treatment of superficial tumors. Int. J. Radiat. Oncol. Biol. Phys. 9:13271333, 1983. 21. Scott, R., Johnson, R., Story, K., Clay, L.: Local hyperthermia in combination with definitive radiotherapy: increased tumor clearance, reduced recurrence rate in extended follow-up. Int. J. Radiat. Oncol. Biol. Phys. 10:21192123, 1984. 22. Siegel, S.: Non Parametric Statistics. NY, McGraw Hill, 1956. 23. Storm, K., Silberman, A., Ramming, K, Kaiser, L., Harrison, W., Elliot, R., Haskell, C., Sarna, G., Morton, D.: Clinical thermochemotherapy: A controlled trial in advanced cancer patients. Cancer 53: 863-868, 1984. 24. U, R., Noell, K., Woodward, K., Worde, B., Fishburn, R., Miller, L.: Microwave induced local hyperthermia in combination with radiotherapy of human malignant tumors. Cancer 45: 638-646, 1980. 25. Vora, N., Forell, B., Joseph, C., Lipsett, J., Archambeau, J.: Interstitial implant with interstitial hyperthermia. Cancer 50: 2518-2523, 1982.