Int. 3. Radiation Oncology Bid. Phys., Vol. 21, pp. 1569-1574 Printed in the U.S.A. All rights reserved.

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0360-3016/91 $3.co + .cm 8 1991 Pergamon Press plc

??Hyperthermia Original Contribution

ONE VERSUS FOUR HEAT TREATMENTS IN COMBINATION WITH RADIOTHERAPY IN METASTATIC MAMMARY CARCINOMA GIORGIO ARCANGELI, M.D.,’ MARCELLO BENASSI,

CARLO CASALE, M.D.,2

D.SC.,~ GIORGIO LOVISOLO, D.Sc3

FERNANDOCOLISTRO,~ AND LUISA BEGNOZZI, D.Sc.’

‘G. Porki Oncology Center, S. Maria Goretti Hospital, Latina; ‘Regina Elena National Cancer Institute; 3ENEA Casaccia, Roma, Italy To optimize the total and the weekly number of heat treatments to he combined with a conventional radiotherapy course, a study was designed on a 75year-old woman with 40 cutaneous nodules of metastatic mammary carcinoma. All nodules were individually irradiated by means of orthovoltage radiation to doses of 36 to 44 Gy, given in 20 equal fractions in 4 weeks. The nodules were randomly assigned to receive radiotherapy alone or radiotherapy combined with one or four heat treatments. Eight lesions were left untreated as a control arm of the systemic therapy (endocrine manipulation). Hyperthermia at a minimum temperature of 43 “C was applied for 45 mln once per week for four times or only once, during a course of radiotherapy. Percent mean diameter of the treated lesions conthmously decreased, reaching a minimum of 25-30% of the initial value after 4 months from the beginning of treatment with no difference between the three arms. After this period, tumors treated with radiotherapy alone or radiotherapy plus one heat treatment started to regrow, whereas those treated with radiotherapy plus four heat treatments continued to decrease slowly. The actuarial analysis of freedom from local progression showed a trend of improvement of response duration with four hyperthermlc treatments with respect to radiotherapy alone or combined with one hyperthermic treatment. Hyperthermia, Number of heat treatments, Mammary carcinoma.

conventional radiotherapy course in a specific tumor site such as mammary carcinoma.

INTRODUCTION

Although the extensive clinical experience accumulated over the past decade in the treatment of tumors by a combination of radiotherapy and hyperthermia has shown a consistent superiority in the efficacy of the combined approach over radiotherapy alone (11, 14, 18), the optimal regimen for hyperthermia in terms of total number of treatments and the number of treatments per week to be combined with radiotherapy is not yet known. The retrospective evaluation and comparison of the data of different trials are difficult and can lead to erroneous interpretation of the results. The few clinical studies in the current literature that have been specifically directed to test the influence of the number of hyperthermia sessions on outcome (1, 2, 6, 8, 9, 13, 19) are summarized in Table 1. Two studies show a statistically significant difference in favor of more heat treatments, while others, although still ongoing and not fully published, do not show any statistical difference precluding any conclusion in favor of high or low number of hyperthermic treatments. This paper reports the results of a prospective randomized study attempting to address the problem of the optimum number of heat treatments to be combined with a

METHODS AND MATERIALS Tumor lesions The whole study was carried out on a 75year-old

woman, formerly operated mammary carcinoma, who nipulation (Tamoxifen and for a progressive systemic

by radical mastectomy for a was receiving endocrine mamedroxy progesteron acetate) disease (lung, bone, and skin

metastases) .

The patient had a total of 40 cutaneous metastatic lesions that were randomly assigned to receive radiotherapy alone (9 lesions), radiotherapy combined with one hyperthermic treatment (12 lesions), or radiotherapy combined with four hyperthermic treatments (11 lesions). Eight lesions were left untreated as a control arm of the systemic therapy (Table 2). The procedures were explained to the patient, who fully agreed with the study design. Radiotherapy

All lesions, except the control group, were individually irradiated by means of orthovoltage radiation using a 200 KVp energy with a 1.1 mm Cu HVL.

Reprint requests to: Giorgio Arcangeli, M.D., G. Porfii Oncology Center, S. Maria Goretti Hospifal, 04100 Latina, Italy.

Accepted for publication 24 May 1991.

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Table 1. Clinical studies directed to test the influence of the number of heat treatments on outcome Authors (type of lesions)

No. patients or lesions

Alexander et al. (1) (Miscellaneous)

48

Arcangeli er al. (2) (Miscellaneous)

17 14 9

Kapp er al. (6) (Miscellaneous)

126

“C/Min

No. HT per week

42.5~160 42.5-44/60

2

4 8

43.5145 43.5145

0 1 2

0 5 10

43-45145 4345145

1 2

2 6

5 10

1

Leopold et al. (8) (Soft Tissue Sa.)

8 9

42160 42160

1 2

Lindholm et al. (9) (Miscellaneous)

? ?

? ? 4Ol60 40160

2

42.5130 42.5130

2 2

Oleson et al. (13) (Miscellaneous)

108

Valdagni et al. (19) (neck nodes)

7 10

Total No. HT

Statistical difference

% CR 42 21

Comments to studies

NA

Randomized; still ongoing

-

35(a) 64(b) 78(c)

b vs a NS c vs a p 0.10). Also, the difference be-

Fig. 2. Actuarial analysis of freedom from local progression in lesions treated with radiotherapy alone (RT), radiotherapy plus one heat treatment (RT + IHT), and radiotherapy plus four heat treatments (RT+4HT); the difference between the (RT+ 1HT) and (RT + 4HT) curves was not statistically significant (p>O. 10); the difference between the (RT +4HT) and the (RT+ 1HT) together with the (RT) groups was not statistically significant @>O.lO).

tween the RT plus four HT and the RT plus one HT group together with the RT alone group was not statistically significant @ > 0.10). However, the trend of the curves indicates a higher efficacy with four heat treatments.

DISCUSSION As already pointed out in the introduction, it is not possible to draw conclusions from the few studies that have specifically tested the influence of the number of heat sessions on outcome of disease. Preliminary results of four ongoing randomized studies failed to demonstrate an improvement of complete response rate with greater numbers of hyperthermic treatments (Table 1). Alexander et al. showed no improvement using two heat sessions per week compared to one; however, this study has been carried out on a variety of lesions and, unfortunately, has not yet been published in detail (1). Kapp et al. also failed to demonstrate a superiority of six over two hyperthermic treatments in 126 miscellaneous tumors of different histologies; however, since no comparison with a control group of radiotherapy alone has been reported in their study, any conclusion about the efficacy of the addition per se of hyperthermia to radiotherapy cannot be drawn from their data (6). Valdagni et al., in a study on neck node metastases, compared two versus six heat treatments in combination with a radical course of conventional radiotherapy and showed no benefit with the higher number of heat treatments; however, the number of lesions in each group was too low (10 vs 7) to be able to show any statistically significant difference below 60% (19). Oleson et al. (13) and Lindholm et al. (9) also explored the effect

One vs. four heat treatments

of combining radiotherapy with one versus two hyperthermia sessions per week in a variety of lesions. They failed to show a statistically significant difference between the two regimens in a preliminary report; these studies, however, need more patient accrual and follow-up. Thermotolerance, that is, a temporary resistance to a later heat treatment after an initial exposure, has been suggested as a possible explanation of the lack of correlation between complete response and the number of heat treatments (11). The development and decay of thermotolerante, however, are not clear when hyperthermia is combined with radiation and, what is more, its importance in humans has not been clarified to date. In contrast to these studies, two papers reported a significant correlation of response with the number of heat treatments. In a study comparing the results of a conventional course of radiotherapy alone and radiotherapy combined with 5 or 10 heat treatments, given once or twice weekly in a variety of matched paired lesions, our group showed a statistically significant improvement of complete response rate of radiotherapy plus two weekly heat treatments with respect to radiotherapy alone, whereas no statistically significant difference could be demonstrated between radiotherapy alone and radiotherapy plus one heat treatment per week (2). Leopold et al. compared the results of preoperative radiotherapy combined with one versus two weekly heat sessions in resectable soft tissue sarcomas and found a statistically significant enhancement of histopathological response in tumors randomized to two hyperthetmic treatments per week (8). Three additional experimental studies analyzed the influence of the number of heat treatments in combination with a fractionated radiotherapy. Zywietz and Jung (20), in experiments on the RlH rhabdomyosarcoma of the rat, found an improvement of local control for 10 over 5 heat treatments given once weekly (73% vs 42%, respectively). Cividalli et al. found a lower TCDSO when radiotherapy was combined to four than to one heat treatment in a murine mammary carcinoma (3). However, Meyer et al. showed similar tumor responses for hyperthermia plus radiation when 1, 2, 3, 4, or five heat treatments were utilized (12). There are several reasons why the results from the previous clinical studies are conflicting. First, most of those trials have been carried out on a variety of miscellaneous metastatic lesions of different histologies and sites. This means a large sample inhomogeneity that can be responsible for a large bias between the control and the test group, leading to an erroneous interpretation of the data. Second, all trials reported the percentage of complete response. However, there are two main difficulties related to this problem, that is, the definition of a small palpaple induration after treatment as a residual disease or scar (especially when one or more catheters were inserted) and the time at which the response was assessed, since the response at the completion of therapy or shortly thereafter may not represent the maximum response. Both these facts can lead to

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an underestimation of response and, consequently, to an erroneous evaluation of the results. Furthermore, if tumor heating has been less than optimal, the evaluation of complete response could underestimate the thermal enhancement; in this situation, total response (complete plus partial) should represent a more correct endpoint for estimating the value of hyperthermia as adjuvant to radiotherapy. Third, none of the previous studies examined the duration of response by means of an actuarial analysis of local control. This was likely due to a difficulty in selecting patients with a long life expectancy or patients who are not subject to subsequent systemic therapy. However, the actuarial analysis of local control, although influenced by the uncertainty of the complete response assessment, is the only way to demonstrate an actual improvement in response. Our data of tumor regrowth delay, in fact, show that the tumor size was continuously decreasing for up to 4 months with no difference between the curves; only after this period could differential responses be appreciated (Fig. 1). Likewise, a differential response duration between the treatment arms could be noticed only after 6-month follow-up (Fig. 2). This means that any response analysis performed at the completion of therapy or even several months thereafter would have shown no difference between the treatment arms, leading to erroneous conclusions. On the other hand, in small tumors where the acidic and nutritionally deprived hypoxic cell fraction is supposed to be low, hyperthermia may have no influence on tumor shrinkage and immediate response, whereas it could be of great value for late response. The present study has been carried out on a patient with multiple nodules of the same histology, with only minor and statistically irrelevant differences in size. This clinical situation provided a very homogeneous material for the study purpose. Furthermore, to overcome the difficulty of assessment of complete response and of response duration, we evaluated both the tumor regrowth delay and the actuarial freedom from local progression in all lesions that had obtained at least a 50% reduction in the mean diameter during the follow-up period (for instance, all lesions, except those of the control group, showed more than 50% reduction). Our results show a correlation of tumor regrowth delay with the higher number of heat treatments given in combination with a conventional fractionation course of radiotherapy. In contrast, the combination with one hyperthermic treatment produced a delay similar to that obtained with radiotherapy alone. This correlation is also shown for response duration. The actuarial analysis of freedom from local progression shows a prolongation of response duration with four heat treatments when compared with one heat treatment or with radiotherapy alone accounting for responses of 79% versus 35% and 40%, respectively, at 18 month of follow-up. Unfortunately, due to a small number of lesions, the difference between the treatment curves is not statistically significant. However, also in consideration that the treat-

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ment options were applied to the same tumor in the same patient, the trend of the curves strictly suggests an improvement in response duration with four heat treatments in contrast to one heat treatment or radiotherapy alone. In conclusion, although an optimum regimen for hyperthermia in terms of total number of treatments and number

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of treatments per week to be combined with radiotherapy has not yet been established, our data indicate that more than one heat treatment may result in better control rates and response duration. Additional clinical studies on specific tumor sites with adequate follow-up are warranted to clarify these problems further.

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