From:

HYPERTHERMIA Edited by Haim I. Bicher and Duane F. Bruley (Plenum Publishing Corporation, 1982)

RESULTS OF A PHASE I/II CLINICAL TRIAL OF FRACTIONATED HYPERTHERMIA IN CC~BINATI(lq WITH LOW DOSE IONIZING RADIATION HaimI. Bicher, M. D., Ph, D., Fred W. Hetzel, Ph.D., and Taljit S. Sandhu, Ph.D. Department of Therapeutic Radiology, Henry Ford Hospital, Detroit, Michigan 48202

Abstract .This paper addresses, in part, the current status of hyperthermia as a new clincal modality and reports the results .of a large, prospective clinical trial employing microwave hy~_rthezmia in ccmbination with low doses of ionizing radiation. In the prot~zol employed, each treated area received 8 hyperthe~mia treatments of 1.5 hour combined: with 1600 rad over a total period of 5 w~ks. Patients were heated with microwaves of 915 or 300 employing exte!nal-applicators or internal intracavitary.antennas. The results-of this fractionation scheme are encouraging s~ in 121 fields that w~re treated completely according to protocol and were available for follow-up for at least 2 months, complete responses w~re observed in 65% of all cases, partial response in 30% and no response in cnly 5%. It is also important to note that toxicity was minimal throughout the study. Introduction The use of hyperthermia as a clinical mcdality b~s taken great strides in the, past few years as more investigators-realized the importance of ccmplete t~perature and trea~,ent documentation. Recent studies (1-7) involving a c~nbi~ation of ~hyperthermia and x-irradiation have made a serious effort to measure and document the hyperthermia treatments more accurately. In most cases a comparison with radiation alone controls is made. Kim et al. (5) have treated 50 patients with a variety of cutaneous t~nors.
87

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HAIM :I.BICHER E[ AL.

Improved results are reported for both the radiosensitive (i.e. mycosis fungoides) and radioresistant (i.e. melanoma) tumors with the combined hyperthermia and radiation treatment as cc~pared to either of these modalities used alone. These authors report complete disappearance of n~itiple recurrent melancma nodules without unusual normal skin reactions. However, cembination therapy did produce enhanced skin reactions in patients whose treated areas included either a skin graft or heavily scarred skin frcm extensive surgery. Hornback et al. (3) treated 72 patients with advanced cancer using the combined therapy. Of the patients treated with hyperthermia prior to radiation therapy, 53% experienced ccmplete remission of symptcms while in the group of patients treated with heat following radiotherapy, 92% showed cc~plete remission. Again ~e was no set protocol and the radiation doses varied frcm 500 to 600 rad per. day with-total doses frcm 3000 to 6500 rads. Heat treatments w~re given using 433.92 MHz microwaves. Although the authors mention having attempted to measure t~or t~ature during these treatments, there is no mention of tL~nor temperatures achieved in the patients. Manning et al. (6) reported a very limited study combining localized heat and radiation. The response rate for heat-radiation combination was~B0-90% ~ccmpared with 50% response rate for heat alone and radiation alone groups. The authors suggest a beneficial therapeutic ratio and minimal side effects frcm the ecmbined treatAnother limited study. (7) treated t~o groups of patients with radiotherapy alone, hyperthe/mlia alone, and ~ccmbined treatment. One group.of patients received 200-600 rad fractions, 2-5 times per-w~ek to a total of 1800-2400 rad~ in 5-14 fractions. The other group of patients received the combined thermoradiotherapy treatments only, radiation fractions of 200-600 rad, 2-5 times a w~ek to a total of 2000-4800 rad in 6-20 fractions. Hyperthermic treatments for.both groups was 42,44C, 2-3 times per w~ek to a maximum of ten sessions in .four weeks. Hyperthermia treatments were given using either 2450 or 915 MHz microwaves. The first group of 8 patients, six patients experienoed ccmplete regression of lesions treated with radiation plus hyperthermia within one month ~of therapy. None of the tn~nors treated with hyperthermia alone regressed,ccmpletely. In the secor~ group of patients 73% showed tumor regression. Melanema regressed completely in 2/4 cases. No adverse side effects w~re observed on normal tissue .fr~n the~ccmbined treatment. Another interesting study was reported by Arcangeli et al. (i) ~ In-fifteen .patients with multiple neck node metastases frem head and neck treated witheither radiation alone or in combination wie~h hyperthermia. A total of 33 neck nodes w~re treated, 12 with

RESULTS OF A PHASE 1/11 CLINICAL TRIAL

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radiation alone ar~ the rest with the combination.

The radiation schedule resulted in 46% cc~plete response which was enhanced to 85% ccmplete response when ccmbined with hyperthermia, the r~naining 15% showed partial response. It should be noted that in the treatment schedule, when radiation was cc~bined with hyperthermia, heat was applied i~nediately after the secor~ daily fraction. The authors did not observe any abnormal reactions in areas that were treated with ocmbined therapy.

In a preliminary publication (2) we reported an effective fractionation regime using 45C regional hyperthermia combined with low dose (1600 rads) x-irradiation, yielding an overall total response rate of 65%. These results are now expanded to include an enlarged, series as well as introducing an intracavitary device for the treatment of deep seated t~nors. The above mentioned clinical studies are both interesting and encouraging. In addition, recent physiological evidence sho~s a differential "breaking point" in blood flow in t~nors as ccmpared to normal tissues which results in dramatic shifts in intratumor pH (8). These observations may, in part, explain the results of the clinical trial we are reporting here.

The exact protocol followed has been reported in detail elsewhere (2) (also RTOG protocol #78-06A). Briefly, treatment consisted of 4 fractions of hyperthermia alone follow~d after a ~ne week rest by 4 additional fractions of hyperthermia this time immediately following radiation. All treatments were separated by 72 hours following a Monday-Thursday or Tuesday-Friday pattern. Each hyperthermia treatment was for 1 hours at the prescribed temperature (45oc alone; 42oc with radiation) and each radiation dose was 400 rad. Therefore, treatment consisted of a total of 8 hyperthermia treatments and 1600 rad over a total period of 5 w~eks. Ccmplete therm~netry was performed during every patient treatment employing microthermocouples (100p). The microthermDcouples w~re implanted in the tumor (whenever possible) and in surrounding or overlying normal tissues. Throughout treatment, temperature readings were taken at 5 minute intervals under "po~eroff" conditions to eliminate any possible interference artifacts. Heating was accc~plished using either 915 or 300 MHz microwaves delivered with partially dielectric loaded external beam applicators or intracavitary antennas. In all cases air cooling was applied either to the skin (external applicators) or to t~]e jacket of the antenna to minimlze normal tissue heating (an~ hence damage). With

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HAIM I. BICHER EI- AL.

_he w~iety of heating equi~nent available w~ have been able to heat uniformly externally up to 7 ~n in depth as w~ll as internally heating the head and neck, mediastinum and pelvis (I).
Results

At this time 178 patients have been treated at our clinic with a multimodality regime involving hyperthermia administered in multifraction fashion (8 hyperthermia treatments per field). Since many of these patients had multiple tumors, at least 250 tumors have been treated (over 2,000 treatment sessions). Not all of them fitted all criteria for inclusion in the specific protocol, but ~ng evaluable results the follwing can be cited: 121 fields (tumors) were treated according to our 8 fraction protocol with 1600 rads in 4 fractions. The final results show almost no t~xicity, and a rate of 65% of total responses and 30% partial response. Further analysis of this series is shown in Tables I-VII. Table I shows a ~ of all the patients treated which ocmpleted the entire protocol and were follow~d up at least two months. Table II provides a breakdown of the summarized data by histology. Fr~n this table it is clear that every histological type treated does respond to this therapy. Table III reports the results of our toxicity study employing the intracavitary microwave antenna system. Following 212 (All equipment was supplied by Medtra Inc., 1350 W. Bethune, Detroit, Michigan, 48202. ) treatment sessions of 1 hours each, the only observed t~xicity was one central pneumonitis. Since response is only evaluated after 2 months at this time only 14 patients are evaluable (Table IV). Even in these patients with deep seated t%m~Drs (mediastin~n, pelvis) only 14% failed to respond. Tables V-VII evaluate response to the c~nbined modality in different anatcmical locations. In head and neck recurrences, breast and chest wall, and skin tumors only a small percentage (9%, 10% -and 3% respectively) failed to respond to combined hyperthermia and radiation while total responses varied frem 46% to 76% yielding our reported average of 65.5% (Table I). Discussion As seen in the detailed response breakdown shown in Table II, the hyperthermia-radiation fractionation regime chosen se~ms to be at least partially successful in a wide variety of tumors. Detailed examination of the data shows essentially no treatment toxicity with the antenna applicators (Table III) since 212 sessions (318 hours) of treatment resulted in only one case of minimal t~xicity. During these treatments (Table IV) tumor response was

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TABLE I
121 Fields Treated: fotal Response Partlal ~esponse No Response

SU~qARY OF RESULTS (82 patients) 79 (65.5%) 36 (29.?~) 6 (5.0%) Local: Harginal: Skin burns: 5 3 2 (completely healed)

Recurrence:

Tongue & Pharynx 2 (completely healed) burns: Grand seizure: 1 (neck treatment) (epileptlc patient)

TABLE II

RESULTS BY HISTOLOGY
RESPONSE 9 Total 7 Pnrtisl 3 No Response

NO. OF FIELDS 19

FOLLOU-tn 2 - I~

Hali~nen~ l.y~phome Squamous Cell C~rcinome

8 25

R Total 9 Total 15 ~art~s~ 1 No Response

2 - 9 2 - 8

Adenocarcinoma

60

~8 Total I0 Partl~l 2 No Respnnse

Other (Transitional Cell. basal Cell, Gllo~e, Sarcoma)

5 Total

2 - ll
-1-

s UHHARY

121

79 Total 36 PArt|el 6 No Response

To[ai Response: Partial Response:

NO tumor et 2 months f~ll0u-up and thereafter Tumor decreased in size to hale or less at 2 months follow-tip

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93

TABLE III

RESULTS-INTRACAVITARY ANTENNA-TOXICITY

i0 14

Complete Complete

(Less

Than) 2 Month Follow Up 2 Month Follow Up

I0 AT Eacl~ 8 AT Each TOTAL

i00 I12 212 Sessions

(At Least)

Toxicity -

1 Central .Pneumonltis

Hyperthermla Treatment of 1 hours

TABLE IV 14~ PATIENTS

RESbLTS-INTRACAVITARY ANTENNA~RESPONSE

COMPLETE

AI_IVE

AT

MONTHS

Hyperthermia Treatments 1600

TR PR NR

Rads 6 6 2

2. Weeks -

4 Fractions

1 Local Recurrence

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HAIM I. BICHER ET AL.

TABLE V

RESULTS-HEAD AND NECK PATIENTS

NECK RECURRENCES No ~_e~pons~.

Total Patients

Total Response

Partial Re_sponse

Recurrence

22

I0

I0

TABLE Vl

BREAST AND CHEST WALL

Total No. of Fields

Total Respon~se

Partial ~e

No Response

No. o Incompletes

29

.TABLE VII

SKIN TUMORS

Total No. of Fields 33

Total

Partial

No

Response
25

~ponse

Response

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95

seen in all but 2 cases. Site specific analysis (Tables V-VII) also shows the relative effectiveness of this therapy regardless of anatomical location. The fractionation regime employed in this study (regional hyperthermia plus low dose radiation) should be ccrapared with those employed in other reported clinical trials. In their study, Kim et al, (5) report 78% overall tutor control rate after cxmabined therapy as cc~pared with 26% after radiation alone. These investigators utilized t~D heating methods. Scme patients with t~nors on extremities were heated by ~sion in waterbath. The rest of the patients were treated using RF (27.12 MHz) inductive heating. It should be pointed out that there is a great deal of variation in both the radiation dose and the hyperthermia treatment duration as ~ell as in the number of fractions. The radiation dose e~ployed varied fr~n 800 rad in t~o fractions for melancma to 2400 rad in 8 fractions for Kaposis sarcoma. Similarly hyperth~rmia (43.5C) treatments varied frown 2 fractions of 30 minutes for melanoma to 5 fractions of 60 minutes for mycosis fungoides. The hyperthermia treatments followed inraediately the radiation treatments in all cases. This data does not suggest any particular treatment schedule for a particular tu~or. The study does, however, demonstrate the improved effectiveness of ccrabined thermoradiotheapy as ccr~pared to hyperthermia or radiation alone. In the study by Manning et al. (6), of the 40 patients treated with hyperthermia, four were treated in ccmbination with radiation. Each had a minimum of 3 nodules. One nodule received a heat treatment of 43C for 40 minutes using radiofrequency currents. Another nodule received radiation alone frcm t~o radium needles to a dose of 4000 fads in 100 hours. A third lesion had the same dose plus simultaneous heat to 43oc for 40 minutes using radish needles as heating electrodes. A 30-40% increase in response was observed for the ccmbination therapy. Arcangeli and co-workers (i) ~mployed a rather unique technique in their protocol. Hyperthermia was induced by 500 MHz microwaves using a non contact applicator. These investigators used a very interesting fractional sch~ne. Described as a multiple daily fractional (MDF) scheme, it consisted of 200 + 150 + 150 rad/day, 4-5 hours interval between fractions, 5 days per ~=ek, up to a total of 4000/7000 rad. All the lesions were irradiated with the same total dose, whether or not they received hyperthermia. Again a 40% increase in response was seen for the cc~abined modality therapy. Johnson et a~. (4) conducted a pilot study to evaluate normal skin and melanc~a tumor thermal er~ancc~m~t ratios of 41.5 to 42C hypertherntia with radiation. The response of nominal skin to the

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HAIM 1. BICHER ET AL.

treatment was measured by evaluating the degree of erythema according to a numerical scoring syst~n. Tumor response was assessed by measuring ttm~Dr diameter. Although the study was not conclusive about the thermal enhancement ratio, it did bring to light scme of the problems associated with obtaining useful clinical data. The study involved patients with multiple metastatic mel~ lesions. At least three lesions were chosen on each patient. The patients w~re divided into three groups and given one, 3 or 4 fractions, with a ~ of 72 hours interval between each fraction. Radiation dose per fractic~ for different lesions on a patient varied frcm 500 to 900 rad. In scme cases single fractions of i000, 1200 or 1300 rad ~are used. On all patients one lesion was heated inm~diately following radiation therapy arK~ the other two or mere lesions treated with radiation alone were used for comparison. Hyperthermia trea~tments were administered using 915 MHz direct contact microwave applicators (4). Duration of hyperthermia treatments varied between 1 and 2 hours at 41.5 - 42.0oc. Skin enhancement ratio (SER) and thermal enhancement ratio (TER) could be evaluated only for a limited number of patients because of lack of follow up data. SER values varied for i. 2 to I. 7 while TER values in most cases were i. 3. This study demonstrated, however, that superficial tt~ors up to 4 ~n in diameter and 2 ~ in depth could be treated with an accuracy of + 0.5C either during, or after radiation with 915 MHz microwaves. The study reported here as well as the results of other investigators tend to indicate the relative effectiveness and lack of overall adverse effects frcm ccmbined hyperthermia and radiation. Further prospective, site specific trials are now planned or in progress to further evaluate both the safety and effectiveness of fractionated hyperthermia and radiation. In addition, the patients already treated will continue to be follow~d at 2 month intervals.

i. Arcangeli, G., Barni, E., Dividalli, A., et al. Effectiveness of microwave hyperthermia ccmbined with ionizing radiation: clinical results on neck node metastases. Int. J. Badiat. On~ol. Biol. Ph_vs. 1980; 6: 143-148. 2. Bicher, H. I., Sandhu, T. S., Hetzel, F. W. Hyperthermia and radiation in combination: a clinical fractionation regime. Int. J. Radiat. Oncol. Biol. Phys. 1980; 6: 867-870. 3. Hornback, N. B., Shupe, R. E., Hcmayon, S., et al. Preliminary clinical results of ccmbined 433 MHz microwave therapy and radiation therapy on patients with advanced cancer. Cancer 1977; 40: 2354-2863. 4. Johnson, R. J. R., Sandhu, T. S., Hetzel, F. W., et al. A pilot study to investigate the therapeutic ratio of 41.542.0 C hyperthermia radiation. Int. J. Radiat. Oncol.

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Biol. Phys. 1979; 5: 947-953. 5. Kim, J. H., Hahn, E. W., Benjanin, F. J. Treatment of superficial cancers by ccmbination hyperthermia and radiation therapy, clin. Bul. 1979; 9: 13-16. 6. Manning, M. R., Cetas, T., Boone, M. L. M., Miller, R. C. Clinical hyperthermia: results of the phase I clinical trial c~nbining localized hyperthermia with or without radiation. (Abstr.) Int. J. Radiat. Oncol. Biol. Phys. 1979; 5: $2: 173. 7. U. R., Noell, K. T., Woodward, K. T. et al. Microwave-ir~ local hyperthermia ".Ln ccmbination with radiotherapy of human malignant t~nors. Cancer 1980; 45: 638-646. 8. Bicher, H. I., Hetzel, F. W., Sandhu, T. S., et al. Effects of hyperthermia on normal and t~a~or microenvirorm~nt. Radiology 1980; 137: 523-530.