Biological rationale and clinical experience with hyperthermia

ELSEVIER

Biological Rationale and Clinical Experience with Hyperthermia Kayihan Engin, MD Department of Radiation Oncology, Philadelphia, Pennsylvania

Thomas Jefferson

University,

ABSTRACT: Hyperthermia (HT) as an adjunct to radiation therapy (RT) has been a focus of interest in cancer management. In recent years there have been numerous randomized and nonrandomized studies conducted to assess the efficacy of HT combined with either RT or chemotherapy especially in the treatment of superficially seated malignant tumors. The major impact of HT is currently on locoregional control of tumor. Heat may be directly cytotoxic to tumor cells or inhibit repair of both sublethal and potentially lethal damage after radiation. These effects are augmented by the physiological conditions in tumor that lead to states of acidosis and hypoxia. Blood flow is often impaired in tumor relative to normal tissues, and HT may lead to a further decrease in blood flow and augment heat sensitivity. Three major areas of clinical investigation have borne the greatest fruit for HT as adjunctive therapy to RT. These include recurrent and primary breast lesions, melanoma, and head and neck neoplasms. Thermal enhancement ratio was increased in all cases and is approximately 1.4 for neck nodes, 1.5 for breast, and 2 for malignant melanoma. In general, the most important prognostic factors for complete response (CR) are RT dose, tumor size and minimal thermal parameters [minimal thermal dose (fl&, mean minimal temperature (T,J or T,, i.e., temperature exceeded by 90% of thermal sensors]. The number of HT fractions administered per week appears to have no bearing on the overall response, which may be indicative of the effects of thermotolerance. The total number of HT fractions delivered also appears irrelevant provided adequate HT is delivered in one or two sessions. The major prognostic factors for the duration of local control were tumor histology, concurrent RT dose, tumor depth and Tmi,.Although numerous single institution studies showed increased CR rates and improved local control, the efficacy of HT as an adjunct to RT should be assessed with well-designed multi-institutional randomized clinical trials. Such clinical trials are underway. Controlled Clin Trials 1996:17:3X-342 KEY WORDS: Thermoradiotherapy,

hyperthermia,

radiation,

biology,

oncology,

cancer treatment

INTRODUCTION

In the last two decades there has been a great interest in the use of HT combined with RT (thermoradiotherapy; TRT) in cancer treatment. This is associated with a

This article was originally submitted and accepted for publication in Clinical Trials and Me&analysis formerly published by Elsevier Science B.V., Amsterdam. In 1995. Clinical Trials and Meta-analysiswas incorporated into Controlled Clinical Trials. Addressreprint requests to: Kayihan Engin, MD, Department of Radiation Oncology, Thomas jefferson University, Bodine Center for Cancer Treatment,111 South 11 th Street, Philadelphia, PA 19107-5097. Received September I, 1993. Controlled Clinical Trials 17316-342 (1996) 0 K. Engin 1996 655 Avenue of the Americas, New York, NY 10010

0197-2456/96 SSDI 0197-2456(95)00078-U

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greater understanding of several biological parameters such as radiosensitization, chemosensitization, direct cytotoxicity, thermotolerance, and stepdown heating, as well as of complex changes in the micromilieu involving especially the microvasculature and cytoskeleton. Although HT as a new and effective modality shows definite promise in the treatment of cancer, the major challenge is the translation of these benefits to clinical practice. This requires cooperative effort and relies on close interaction of biologists, physicists and oncologists specifically to determine the most important biological parameters affecting HT, to manufacture devices that can heat deeply and homogeneously, to determine temperature reliably, consistently and ideally noninvasively. It is obvious that the education of fellow clinicians of the utility of this modality is also very important. This paper presents an overview of the clinical applicationof local HT for superficial lesions. The practical application of regional and whole body HT remains confined to investigational protocols.

HISTORY The application of HT in the treatment of disease has a long tradition dating to antiquity, but took its modern form only in the last 20 years. Hippocrates is credited with the statement that “un illness not cured by heat is incurable.” The modern era of HT is thus relatively recent and occurred with the advent of new technology allowing the use of radiofrequency, microwave and ultrasound. In 1866 Busch first observed the effect of systemic HT on possible cancer eradication in human subjects [l]. He reported the disappearance of a sarcoma of the face after a bout of erysipelas. In 1893 Coley reported on 10 patients with advanced malignancies who developed prolonged febrile reactions to erysipelas [2]. Using filtered toxin or mixtures of bacterial toxins, he induced pyrogen therapy by injecting the toxins into the tumor itself. In 1909 Schmidt suggested that HT could be added to RT as a radiosensitizer [3]. In the last two decades, there has been a great interest in this modality. The radiobiological principles are firmly established and many clinical studies have shown that the modality is effective [4]. Problems of quality assurance are, however, still unresolved and a Radiation Therapy Oncology Group (RTOG 81-04) study highlighted the problems in the application of HT in a multi-institutional setting 151. These include (1) the difficulties associated with adequate thermometry, (2) the selection of patients with heatable lesions and (3) quality assurance affecting the administration of HT. The challenge nowadays is to prove HT as an effective modality through carefully designed and performed clinical trials.

BIOLOGICAL

RATIONALE

Hyperthermia

Cytotoxicity

The nature of HT-induced cell lethality is quite different from that of RT-induced killing. The G,-phase of the cell cycle is the most resistant to HT. Cells heated in G, die from membrane-related damage before entering mitosis. S-phase cells are quite sensitive to HT and die of chromosome-related damage after passing through mitosis 16-81. In other words, the cell cycle response to heat complements that of low energy transfer /LET) radiation. Exhibition of cell death in asynchronous populations is much sooner than after RT. HT also sensitizes cells and tissues to

318 RT. A time-temperature combination can be found that HT alone is without effect on cytotoxicity but will sensitize cells or tissues to RT and the maximum reaction occurs at the time characteristic of RT alone. Cellular RT-induced killing is mediated through damage to DNA and manifest by chromosome aberrations and loss of reproductive integrity. HT effects are brought about by alteration of proteins and/or lipids [9-101. Incorporating 5-bromodeoxyuridine (BrdUrd) into DNA does not sensitize to HT damage as it does to RT damage [7]. However, HT inhibits DNA synthesis by inhibition of replicon initiation and chain elongation, thus permitting erroneous rejoining of newly synthesized regions of DNA with resultant chromosome aberrations at mitosis [7,11,12]. Cells are sensitized to HT damage by membrane active agents such as local anesthetics (e.g., lidocaine, procaine, or ethanol) and by low pH and nutritional deprivation [8,10,13-161, whereas the response to HT is not affected by acute hypoxia 1171. The cell is protected against HT damage by the presence of deuterium oxide and by glycerol [18,19]. The agents that modify the HT response are those that affect the stability of proteins [9]. HT does not cause cell transformation to malignancy and is only weakly mutagenic [20]. Heated cells experience progression delay much longer than that after ionizing RT for equal levels of cell lethality 16,211. Cells accumulate and repair sublethal damage and potentially lethal damage [22-241. Heat inhibits metabolism and macromolecular synthesis, and alters cytoskeletal relationships 125-271. Heat-induced cytotoxicity can be quantitated by plotting cell survival as a function of time at a specific temperature much as for RT dose, and the parameters of a survival curve can be calculated such as Do, n, and d,, or a and B. In-vitro HT survival curves were first demonstrated by Westra and Dewey [6]. For temperatures of <42.5”C, there is a bend in the survival curves at 2-4 hours of exposure due to the development of thermotolerance. When the slope of the HT survival curve (l/ Do) is plotted as a function of the reciprocal of the absolute temperature, the result is called an “Arrhenius plot.” The “break’ in the Arrhenius plot at 42543°C is thought to be due to the development of thermotolerance during exposure to temperature <43”C, and the inhibition of thermotolerance development by exposure to temperatures >43”C [21,28]. When cells and tissues return to 37°C after exposure to temperatures >43”C, thermotolerance development occurs over a period of 8-10 hours and decays over the next 60-100 hours. A typical Arrhenius plot and the effects of modifiers are shown in Figure 1.

Thermal Dose Since the shape of the Arrhenius plot and the inactivation energy are similar for various cell lines and tissues, it provides a means of comparing the response of cells and tissues to various time-temperature combinations 1291. A comparative unit of response to different time-temperature combinations based on isoeffect relationships could be the basis for a thermal dose. A unit of thermal dose is critical to comparing results from different clinics. Saparetto and Dewey [301 have defined equivalent minutes at 43°C (tti; min E+& by the formula: Eq43”C = tR(43 - 7’) where t = time, T = temperature, and R = 0.5 for T >43”C and R = 0.25 for T (43°C.

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4 41

42

43

Temperature Figure 1

44

45

(0C)

A typical Arrhenius plot and the effects of modifiers.

Thermotolerance Thermotolerance is a nonheritable resistance to HT induced by exposure to HT and other cytotoxic agents such as arsenic, adriamycin, or ethanol [31,32]. Thermotolerance develops within 2-3 hours during exposure to temperatures <43”C, but not during exposure to temperatures ~43°C. When the cell is returned to 37°C after exposure to temperatures >43”C, thermotolerance develops over the next B-10 hours. The amount of thermotolerance that develops depends on the temperature and the amount of HT damage induced. Thermotolerance decays over the next 60-100 hours depending on the cell line or tissue and the amount of thermotolerance induced [33]. Thermotolerance leads to an increase of the Do of the survival curve by a factor of 4-10 which can result in a difference of cell survival from 10e5 in normotolerant cells to 10-l in maximally thermotolerant cells. Li and Hahn 1281 proposed a model of thermotolerance incorporating an induction phase, a development phase, and a decay phase. Each of these components may have its own temperature dependence as well as dependence on other factors such as pH and nutrients. Induction and decay are permissive at all temperatures, whereas development is permissive at temperatures ~43°C and restricted at temperatures 243°C.

The inhibition of thermotolerance development at temperatures >43”C is due to HT-induced inhibition of protein synthesis [26,34]. Heat shock proteins (HSPs) are the first proteins synthesized in response to HT and the synthesis of HSPs is intimately related to the development of thermotolerance 135-371. The HSPs found in most mammalian cells have molecular weights of 22, 26, 70, 87, and 110 kD. The decay of the three heavier HSPs correlates with the decay of thermotolerance and a good correlation exists between the residual levels of HSP 70, 87, and 110 and cell survival during the decay of thermotolerance 1381. Tissue or tumor levels of HSPs may provide a prognostic indicator of HT resistance and the synthesis of HSPs could provide a monitor of tissue thermotolerance development after HT.

320

K. Engin Thermotolerance develops in normal tissues after single or multiple HT fractions similarly to cells in culture 139,401. Since maximal thermotolerance occurs by 24 hours, daily fractionation would completely waste any cumulative effect of HT. All experimental normal tissues studied to date develop thermotolerance and tumors are no exception [32]. There is no reason to suspect that human normal tissues and well-perfused tumor cells are not perfectly capable of developing thermotolerante just as in murine tissues. Three clinical studies indicated that heating with two HT fractions per week combined with RT was no more effective than heating with one fraction per week [41-431. It is possible that thermotolerance could be used to influence the HT response of normal vs. tumor tissues. The magnitude of thermotolerance is reduced at low pH. Thermotolerance may decay faster in cycling than in noncycling cells, and it may be possible to protect transit normal tissues by inducing thermotolerance in them by heating with poorly penetrating microwaves 24 hours before heating the tumor [44,45].

Stepdown Heating Sensitization of cells to exposures to temperatures below 43°C after exposure to temperatures 243°C for a brief period is called “stepdown heating” (SDH), which results from the inhibition of thermotolerance development [28,4648]. Although temperatures of 3941°C have very little effect on cell lethality, 15 min exposure of at 45°C before exposure to 3941°C makes these temperatures quite cytotoxic.

PH Poor tumor blood flow, chronic hypoxia, and high lactic acid levels are commonly observed in tumors and lead to decreased extracellular pH(pHJ [49-521. Although there have been many reports on pH, in animal tumors, data on human tumor pH, have been relatively scarce [53-571. A wide range of measurements has been reported; 5.80-7.52 in rodents and 5.85-7.68 in human tumors [58]. Engin et al. showed that the tumor volume and the tumor histology were the most important factors determining the range of pH,. values in human tumors 1591.The mean tumor pH,. for the entire group of tumors was 7.06 -t 0.05 (range of 5.66-7.78). The mean tumor pH, was 6.93 2 0.08 in adenocarcinomas, 7.01 2 0.21 in soft-tissue sarcomas, 7.16 + 0.08 in squamous cell carcinomas, and 7.36 + 0.1 in malignant melanomas. Four histological groups were significantly different from each other. When histologies were grouped together, the mean pY was 6.94 2 0.08 in adenocarcinoma and soft tissue sarcoma lesions vs. 7.20 + 0.07 in squamous cell carcinoma and malignant melanoma lesions. The difference in pw between squamous cell carcinoma plus malignant melanoma and adenocarcinoma plus soft-tissue sarcoma was statistically significant. This finding corresponds with a previous report by Engin et al. indicating that the duration of local control after TRT was longer in adenocarcinomas and soft tissue sarcomas than in squamous cell cancers and malignant melanomas [60]. These observations further support the conclusion that tumor pH, is inversely correlated with CR rate after TRT [61]. Busse et al. 1621 showed that as murine transplantable tumors increased in size from 2.1 to 10.5 g, the mean pH fell from 6.7 to 6.5. When tumors were very necrotic the pH increased with increasing size rising from 7.2 to 7.4 as tumors increased from 1.7 to 25.7 g. Vaupel et al [63] also found alkaline values in very necrotic

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tumors and more acid values in large ulcerating tumors. Gullino et al [64] were not able to show any difference between small and large tumors. They also found that faster growing tumors were more acidic. Engin et al showed that there was a weak but significant correlation between tumor pH, and tumor volume [591. Tumor pH, increased as a function of logarithm of tumor volume. Variation in measurements between tumors was greater than the variation in measurements within tumor. One of the main causes for intratumoral variation is probably the proximity of the electrode tip to blood vessels. Greater distance from the blood supply results in lower pH due to restricted oxygen availability. Although the experimental literature suggests that an increase in the acidity of tumor tissue should enhance the therapeutic effect of HT, two clinical studies were unable to demonstrate that low pH indicated a favorable response to TRT in human tumors [57,65]. On the contrary, Engin et al. found a significant correlation of the pretreatment tumor pH, with tumor sensitivity to TRT [61]. Tumor cells at suboptimal PI-I may not be HT sensitive as suggested by Hahn and Shiu 1661. Chu et al [67] and Cook and Fox [68] have shown that cells adapt to an environment at low pH,, reestablish a near normal pH, and are no longer HT-sensitive. pH, is the important factor for HT sensitization [67,69,70]. However, when cells are adapted to low pH,., a further slight reduction in pH, by as little as 0.2 pH unit may have a similar effect as a 0.8 pH unit decrease in cells at physiologic pH [66]. Therefore, an acute reduction of tumor pH, as induced by hyperglycemia may provide a therapeutic advantage for TRT. Experimental results have shown that acute reduction of pH,. to below 7.0-7.2 sensitizes cells to HT damage [44,66,71] and inhibits the development of thermotolerance ]58,72]. Acute acidification also inhibits cell proliferation and decreases glycolysis and DNA synthesis [73]. However, little evidence exists that these factors affect the human tumor response to TRT. One of the possibilities for increasing the therapeutic ratio in the clinic is the manipulation of pH, by inducing hyperglycemia [74]. Blood Flow The neovasculature in tumors does not respond to increased temperatures as do blood vessels in normal tissues, and these differences in blood flow may lead to selective tumor heating. Song et al [75] have shown that rat muscle and skin have a greatly enhanced blood flow at temperatures above 42°C whereas transplantable tumors have a greatly reduced blood flow at these temperatures. On the other hand, Waterman et al [76] have shown that human tumors exposed to temperatures of 43.5-45”C have a slightly increased blood flow during heating for 60 min, but nonetheless, tumor blood flow does not respond to HT with the significant increase as seen in normal tissues. Interestingly, Kang et al 1771have shown in transplantable mouse tumors that vascular volume decreases to a minimum between 4 and 6 hours postheating at 43.5”C; and as might be expected, pH and pOz also fall. Recovery of vascular volume and blood flow occurs between 24 and 48 hours postheating. If such a decrease in blood flow did occur after heating in human tumors, it would certainly dictate the timing of a subsequent HT treatment. Radiosensitization In addition to HT-induced cytotoxicity, HT sensitizes cells to low LET ionizing radiation. Unlike the response to ionizing RT, HT cytotoxicity is influenced by

K. Engin

322

thermotolerance, low pH, and nutritional deprivation but is independent of acute hypoxia. Blood flow also influences the heating characteristics of a tumor relative to normal tissue. Thermal radiosensitization is also influenced by these parameters, and they may affect the response of human tumors to the combined modalities. The cell cycle-dependent sensitivities to HT and RT complement each other [6,78]. The predominant effect of temperatures a43”C on the radiation response is sensitization, i.e., a decrease in D,,; whereas the predominant effect of exposure to temperatures <42.5”C for an hour or less is removal of the shoulder of the radiation survival curve [48]. Modest HT also inhibits the repair of sublethal and potentially lethal radiation damage and inhibits the repair of radiation-induced DNA damage [79-811. The mechanism of HT radiosensitization is protein denaturation resulting in changes in DNA-protein structural relationships and preventing accessibility of repair and synthetic enzymes [ll]. Interaction between HT and RT is dependent on sequence and the time between exposures. The greatest interaction results when irradiation occurs in the middle of the heating interval 1821. In the clinical setting RT is generally followed by heating in order to prevent any possible effect of HT inducing hypoxic cells via decreased blood flow. Theoretically, there should be less radiosensitization by HT with low-dose RT fractions or high LET radiation, since most of the damage consists of single-hit, irreparable lesions [83,841. Gerner and Leith 1851 demonstrated that 43°C for 30 min does not sensitize CHO cells to high LET radiation. In fact, HT plus low LET radiation has been called “a poor man’s high LET.” Clinically, the greatest effect of thermoradiosensitization is expected the higher the HT dose, the larger the RT fraction, and the closer in time the two are together. Denekamp and Stewart [86] and Overgaard [87] examined the effect of sequence and interval between RT and HT on mouse tumors and skin. For the sequence of RT followed by HT, the repair of RT damage in skin was complete by 24 hours, and the thermal enhancement ratio (TER) fell to 1; whereas between 4 and 8 hours, the TER for tumor remained at 1.5. Therefore, the therapeutic gain factor, when using large RT doses and HT and comparing the response of tumor to that of skin at the same temperature, was enhanced by separating RT and HT by a 4-hour interval compared to simultaneous treatment.

Hypoxic Cell Sensitizers HT dramatically enhances the cytotoxicity of the electron affinic radiosensitizers in hypoxic cells 1881. Particularly noticeable is the enhancement by temperatures that by themselves are nontoxic. The combination of misonidazole and HT in vivo shows only a small beneficial effect. However, when HT and misonidazole are combined with RT, there is a marked therapeutic gain. Falk et al. have used metronidazole in combination with HT and chemotherapy 1891. Patients treated without metronidazole showed little or no tumor response, whereas the inclusion of an oral dose of 1.5 g metronidazole just prior to heating caused regression of some tumors. Metronidazole apparently caused up to a 2.5”C rise in the temperature of the heated tumors. The reason is not clear, but could be related to the known ability of nitro compounds to cause a breakdown of temperature regulation in vivo [90]. If these results are confirmed, they could have important implications for the future use of nitro compounds with HT [91].

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Chemosensitization HT sensitizes the cell to many cytotoxic agents and even converts some drugs that are innocuous to highly toxic [92-941. HT chemosensitization may occur by an increased reaction rate as for the alkylating agents, increased permeability as for the intercalating antibiotics such as adriamycin, or decreased repair as for bleomycin. Some compounds that are relatively nontoxic at 37°C have greatly enhanced cytotoxicity at 43°C. Two examples are the polyene antibiotic amphoteritin B and the sulfhydral radioprotectors such as mercaptoethylamine (MEA) or AET [S-(2-aminoethyl) isothiouronium bromide hydrochloride]. The metabolic inhibitors such as 5-fluorouracil (5-FU) seem not to be enhanced by HT. The most promising chemosensitization by HT would seem to be with alkylating agents and cis-platinum since they are enhanced at all elevated temperatures. Bleomycin, on the other hand, seems to have an enhancement threshold at or about 43°C. The intercalating antibiotics such as adriamycin and actinomycin-D do not appear to be good candidates for thermochemotherapy because of HT-induced drug resistance that may be related to thermotolerance. Simultaneous treatment by heating and by drugs was found to be much more effective in inducing tumor growth delay than when HT and chemotherapy were separated by 24 hr. Although there is precious little clinical experience with HT and chemotherapy, the in-vitro and in-vivo data suggest that thermochemotherapy could be a very useful treatment modality.

CLINICAL

RATIONALE

Locoregional failure remains a significant cause of cancer death as well as of considerable patient morbidity even when the the problem of disseminated metastases is more life threatening [95]. The major impact of HT is currently on locoregional control of tumor. Heat may be directly cytotoxic to tumor cells or inhibit repair of both sublethal and potentially lethal damage after RT 179,961. These effects are augmented by the physiological conditions in tumor that lead to states of acidosis and hypoxia. Blood flow is often impaired in tumor relative to normal tissue, and HT may lead to a further decrease in blood flow and augment HT sensitivity [97,98]. At lower, more realistic temperatures (~43”C), blood flow is not affected in human tumors by HT as it is in rapidly growing experimental tumors 1991. HT-induced radiosensitization is a general phenomenon but, in particular, cells in the radioresistant S-phase are sensitized to the greatest extent to RT by HT [6,100,101]. More recently, the interaction of HT and chemotherapy has gained increasing interest 11021. HT may increase the cytotoxic effects of certain chemotherapeutic agents, e.g., the alkylating agents, and help to overcome acquired drug resistance 11031. Furthermore, it can improve drug delivery to the tumor and possibly modify drug pharmacokinetics [104]. CLINICAL

EXPERIENCE

Randomized Studies Despite the fact that more than 11,000 patients had already been treated with HT by 1984 141, there have been few prospective randomized multi-institutional studies in HT, and to date a definitive study is still lacking. The RTOG reported on a randomized study [5] of superficial recurrent tumors that were treated with

K. Engin Randomized

Table 1

Reference

Trials of Hyperthermia Type of Tumors

Number of Patients

Perez et al 151

Misc.

300

Arcangeli et al [106]

Misc.

123

Valdagni et al [108]

Head and neck

Overgaard

Melanoma

et al [109]

Vernon et al [110]

Breast

Adjuvant

44

134 N300

to the Radiation

Therapy

Results RT alone; CR = 28% TRT; CR = 32% RT alone; CR = 42% TRT; CR = 73% RT alone; CR = 41% TRT; CR = 83% RT alone; 5-year nodal control = 24% TRT; 5-year nodal control = 69% RT alone; 2-year local control = 28% TRT; 2-year local control = 46% RT alone; CR = 40% TRT; CR = 60%

either RT alone or TRT (see Table 1). The positive feature of this study was that lesions that were ~3 cm in diameter and had received 22 sessions of 42.5”C HT showed an improvement in CR in the category of breast and extremity lesions. There was also a greater probability of maintaining a response over 12 months (82% vs. 12%) in those receiving HT, indicating a more durable CR. A prospective randomized study was initiated by Valdagni et al. who treated N3 neck disease arising from TI.z primary lesions or unknown primary sites [105]. Although the number of patients accrued is small, the trial was closed prematurely for ethical reasons. A CR was noted at 3 months in 82% of patients receiving TRT compared to 37% who were treated with RT alone. However, the difference in total response (complete and partial response) is not statistically significant (88% vs. 79%). This indicates that many of the patients achieving a partial response with RT were converted to complete responders by the HT. A clear distinction between clinical tumor regression and overall tumor control must also be made. HT appears to augment tumor control even though initial tumor response may not be significantly improved, which suggests that the clonogenicity of residual viable cells is affected by HT despite the absence of outright cell death. Engin et al. [42] showed that RT does and tumor volume, but not tumor temperature, were effective in achieving a CR (i.e., first one to two decades of cell kill), whereas the duration of local control (total cell kill) was more influenced by tumor temperature and tumor volume than by RT dose. Earlier work by Arcangeli et al. [106,107] involved a series of 77 patients with two or more superficial lesions, treated with various protocols in separate randomized studies. The best therapeutic effect was obtained by restricting the heat to the tumor site and using large fraction sizes and immediate heat, a schedule designed to produce maximal cytotoxicity. They also observed that tumor control was improved by the use of a larger number of HT fractions and increased thermal dose (tu, minE+&. Recently, Valdagni and Amichetti [lo81 reported on inoperable metastatic lymph nodes in patients with head and neck cancer, which were randomized to receive conventionally fractionated radical radiation therapy alone or combined with local hyperthermia. The addition of hyperthermia significantly improved early response rate and 5-year actuarial nodal control in the absence of severe toxicity.

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Effect of Hyperthermia Adjuvant Clinical Tumor Response

to the Radiation Therapy on

Reference

RT Alone”

TRT*

TER’

Kim et al [112] Overgaard et al [113] Arcangeli et al [107] Scott et al [114] Li et al [115] Hiraoka et al [116] Valdagni et al 11171 Perez et al [118] Valdagni et al [105] van der Zee et al [119] Steeves et al [120] Dunlop et al [121] Uozumi et al [122] Hornback et al 11231 Fuwa et al [124] Gonzalez et al [125] Lindholm et al [126] Goldobenko et al [127] Muratkhodzhaev et al [128] Datta et al [129]

39 39 38 39 29 25 36 41 36 5 31 50 63 35 63 33 25 86 25 46

72 62 74 87 54 71 73 69 73 27 65 60 88 72 83 50 46 100 63 66

1.8 1.6 2.0 2.2 1.9 2.8 2.0 1.7 2.0 5.4 2.1 1.2 1.3 2.1 1.3 1.5 1.8 1.2 2.5 1.4

* RT alone: radiation therapy alone (Lib).

bTRT: thermoradiotherapy (%). ’TER: thermal enhancement ratio.

Preliminary results of two major European multi-institutional studies appear to be very promising [109,110]. In ESHO protocol 3-85 [109], 134 metastatic or recurrent malignant melanoma lesions were randomized to receive radiotherapy alone (3 fractions in 8 days; 3 X 8 Gy or 3 X 9 Gy) or each fraction followed by hyperthermia. Two-year actuarial local tumor control was 28% in radiation alone group and 46% in thermoradiotherapy group (p = 0.008). Cox multivariate regression analysis showed that the most important prognostic parameters were hyperthermia (p = 0.02), tumor size (p = 0.05) and radiation dose (p = 0.05). Addition of hyperthermia did not significantly increase the acute or late radiation reactions. In a collaborative phase III superficial hyperthemia trial in primary and recurrent breast cancer lesions [llO], conducted by several institutions (MRC, ESHO, PMH), it was indicated that complete response rate could be increased from 40% (radiation alone) to 60% with the addition of hyperthermia. The difference was statistically significant.

Nonrandomized

Studies

In multiple nonrandomized single-institution studies, the benefit of HT has been clearly demonstrated and is remarkably consistent in showing an advantage in favor of HT for all histologies in all sites tested [ill]. A therapeutic gain is suggested in spite of the wide diversity of techniques used for heating, thermometry, and criteria for assessment of response. The thermal enhancement ratio ranged between 1.2 and 5.4 (see Table 2). Several studies of matched and paired lesion analysis in the same patient similarly confirmed the therapeutic benefit of HT 1120--1261. The

326 Table 3

Complete

Response

Rate as a Function of Tumor Histology

Author

No. of Lesions

Bicher et al [130] Corry et al [131] Kim et al [112] Hiraoka et al [116] Hofman et al [132] Luk et al [133] Matsuda et al [134] Bicher et al 11351 Gonzales et al 11251 Arcangeli et al [136] Howard et al [102] Perez et al [137] Valdagni et al [105] Engin et al [6O]~y <3 cm depth >3 cm depth

82 21 86 33 61 63 20 125 88 59 13 199 101 76 50

’ SCC:squamous

cell carcinoma.

‘MM:

melanoma.

malignant

(%)

SCC”

MMb

AC‘

37 100

47 64 82 67 67 57

73 57 90 43 30-61* 40 64 64 50-lo@

50 83 61 83 49 79 100 58 50-78’ 81 17

33 50 76 80 79 75 50 9

100 46 58 71 38

’AC: adenocarcinoma. ’ Inoperable

breast

cancer:

CR = 30%; chest wall recurrence:

’Inoperable

breast

cancer:

CR = 100%; chest wall recurrence:

‘Palliative

RT: CR = 50%; radical

r Soft tissue sarcoma;

<3 cm depth;

CR = 61%. CR = 50%.

RT: CR = 78%. CR = SO%, >3 cm depth;

CR = 0%.

difficulty of uniformly heating apparently favorable, superficial sites in areas where problems of contour and shape are minimal has been well described. Dunlop et al [121] reported that 58% of the patients treated with TRT reached a minimum dose of 20 minutes at 43”C, and 24% reached 60 rninEqUocand could achieve 20 minegUc at each occasion. However, 23% of tumors could not be heated effectively at any time. The tumors that were effectively heated had a CR rate of 86% vs. 35% for those inadequately heated. The CR rate of lesions receiving RT alone was also 35%. This study emphasizes the need to heat to minimum threshold temperatures and to improving intratumoral temperature distribution. Additional difficulties in heating capability arise from the site being treated. The head-and-neck region is more difficult to heat because of several factors, including changing contour and poor applicator apposition, the extent and depth of the tumor and the tolerance of the patient.

PROGNOSTIC

FACTORS

Three major areas of clinical investigation have borne the greatest fruit for HT as adjunctive therapy to RT. These include recurrent and primary breast lesions, melanoma, and head-and-neck neoplasms. The general experience of HT with regard to various prognostic factors is summarized in Tables 3-5. The TER was increased in all cases and is approximately 1.4 for neck nodes, 1.5 for breast, and 2 for malignant melanoma. Because of the apparent lack of histological specificity to thermosensitivity, sarcomas and other traditionally radioresistant tumors are

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Table 4

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Clinical Tumor Response as a Function of the Number of Total and Weekly Heat Treatments No. of Lesions

Author

Randomized

Arcangeli et al [107]

No

23

Hiraoka et al 11161

NO

40

Kim et al [112]

No

50

Valdagni et al [105]

No

Engin et al [42]

Yes

44

Arcangeli et al [136]

No

21

Kapp et al [43]

Yes

179

Emami et al [41]

Yes

240

Total No. of HT Sessions 5 10 2-7 8-12 6 10 <6 6 >6 4 8 5 8 2 6 4 8

No. of Weekly HT Sessions

CR

1 2 2 2 1 2 2 or 3 2 or 3 2 or 3 1 2 2 2 1 2 1 2

64 78 50 53 74 59 83 50 71 59 55 75 77 68 63 55 58

(%o)

also eminently suitable for this modality, provided they are accessible and of a size that is heatable. 11501 In general, the most important prognostic factors for CR are RT dose, tumor size and minimal thermal parameters [minimal thermal dose (t8min),mean minimal temperature (T,,,), or T,, i.e., temperature exceeded by 90% of thermal sensors], Table 4). The number of HT fractions administered per week appears to have no bearing on the overall response, which may be indicative of the effects of thermotolerance (Table 3). The total number of HT fractions delivered also appears irrelevant provided adequate heat is delivered in one or two sessions. The administration of multiple fractions of HT is advantageous only in leading to a greater probability of achieving at least one good HT session and of allowing full coverage of the tumor if a “patchwork’ approach is adopted [151]. The major prognostic factors for the duration of local control were tumor histology, concurrent TR dose, tumor depth, and T,, [42,43,60,143,149,152]. CRITERIA FOR SUITABILITY FOR SUPERFICIAL LOCALIZED HEATING The selection of the sites and types of lesions that are appropriate for this approach have been described by Kapp 11531. The most important indication for HT is the determination that a poor response is likely if RT alone was to be applied. This would apply to radioresistant histologies, recurrent disease, or excessive tumor bulk. The combination of HT and RT is an attempt to improve the therapeutic ratio and is akin to surgery and RT in being a form of localized combined modality treatment. The most important criterion is accessibility both in size and depth of lesion. Flat surfaces such as the chest wall and the limbs are ideally suited for external applicator HT. The depth of the lesion is critical and for practical purposes is limited to a maximum of 3-4 cm with 915 MHz microwave and 7-8 cm if 1 MHz ultrasound is used. The presence of bone and air-tissue interfaces in the treatment volume precludes the use of ultrasound. Cystic lesions may be heated to a greater

K. Engin

Table 5

Thermal

Parameters

Author

that Correlate

with Complete

Response

Thermal

Parameter

Rate

Dewhirst et al 11381 Dewhirst and Sim 11391 Hiraoka et al [116] Luk et al [133] Oleson et al 11401 Sim et al 11411 Van der Zee et al 11191

Minimum Eq43”C at first treatment Average minimum Eq43”C Average tumor center temperature Lowest daily average temperature Minimum tumor temperature Estimated treated volume (ETV) obtaining Mean temperature Mean of maximum temperature Average overall Eq42.5”C

Arcangeli et al [142] Kapp et al [43,143] Dewhirst et al [138]

% temperature <4O”C % temperature <42.5”C (first treatment) Minimum temperature Average temperature % temperature <4O”C % temperature >42.5”C Average all treatments minimum Eq43”C

Sapozink et al [144] Van der Zee et al [145]

No. of HT with any tumor Mean minimum T mean Mean minimum T max

Dunlop

Total muumum tusc No. of HT of Tmin > 20 minEqooc

et al 11211

temperature

Arcangeli et al [136] Storm et al [97] Seegenschmiedt et al 11461

Eq42.5”C Lowest tumor temperature/first treatment Eq43”C/first treatment Cumulative Eq43”C for all treatments Total/mean minimum Eq43”C

Emami et al 11471 Scott et al 11141 Oleson et al 11481 Engin et al [42,149]

>400 min Eq43”C Tave > 43°C outer shell Tedge plus slope (dT/dr) Mean minimum temperature Thermal dose/first session

>42.5”C

>42”C

depth because of increased penetrability of energy and transmission of heat. In general, patients should have a reasonable performance rating, sufficient to withstand a 60-minute session of heat therapy, and should have a life expectancy of 22 months for the response to be monitored.

CARCINOMA

OF BREAST

Locoregional failure in the breast still constitutes an important cause of morbidity and suffering, even when overshadowed by the problem of distant metastases. Even after radical or modified mastectomy the local recurrence rate is 1040% depending on size, tumor characteristics of the primary, underlying fixation, the presence of grave signs, and the number of regional lymph nodes involved [154]. There are few randomized studies of HT in chest wall disease. At least 40% of the 236 patients evaluated in the RTOG study (U-04) had carcinoma of the breast [5]. Although the overall result for all patients showed no significant difference between the two arms (30% and 32%, respectively), 62% of patients with lesions ~3 cm had a CR vs. 40% with RT alone. Besides size, RT dose was also critical.

Thermoradiotherapy

in Cancer Treatment

329

Van der Zee et al [155] treated 97 patients with recurrent carcinoma of the breast in combination with HT. Based on this experience, the authors suggested that a total dose of 32 Gy in 8 fractions administered with twice-weekly fractionation and accompanied by HT is safe and efficacious. Engin et al [151] reported excellent results by using patchwork HT fields in extensive chest wall recurrences due to advanced carcinoma of breast. Although most studies have concentrated on locoregionally recurrent lesions, advanced primary breast carcinoma is also an appropriate situation for evaluating the role of HT, especially when the presence of grave adverse prognostic features makes local control distinctly remote. Results with RT alone are poor, with 4565% of tumors recurring locally [156]. Vora et al [157] treated 11 patients with inoperable and inflammatory carcinoma of the breast with a combination of external and interstitial RT and interstitial HT. With a follow-up of 11-36 months, local control was obtained in 80% of patients. Similarly, Puthawala et al [158] reported 88%, local control with RT using combined external and interstitial RT to total doses of 80-90 Gy and accompanied by interstitial HT. The role of HT in an adjuvant setting where there is no gross evidence of residual disease is undefined. Because of the presence of large amounts of normal tissue and minimal tumoral elements, there would seem to be little indication for HT. However, this must be viewed in context, and factors of patients’ age and general condition must be considered as well as the risk of recurrence with conventional RT. Kapp et al [159] recently reported their experience with TRT for residual microscopic cancer. Various attempts to address the problem of tumor thickness and extent on heatability have included the use of multiple applicators, overlapping patchwork HT [151], combined interstitial and external applicator techniques to heat more deeply and uniformly 11601, and the use of multiple separately powered heating elements, which can be tailored to encompass wide surface areas [161]. MALIGNANT

MELANOMA

Local control is an important determinant of length of survival in this disease even though distant metastases is the major cause of death. Overgaard showed that local control was improved by locoregional HT [162]. He also found that the RT fraction size was an important prognostic factor. Emami et al [147] reported on 49 superficial recurrent, primary and metastatic malignant melanoma lesions [147]. They found that a thermal dose of 3500 minhgancwas associated with a 100% CR rate. Engin et al [149] observed a similar correlation between CR and the minimal thermal dose of first HT session. In a large study, Overgaard and Overgaard [163] reported an improvement in locoregional control in patients receiving HT. The EDSo (RT dose required for 50% control) was reduced by HT with a TER of 1.43 for simultaneous treatment and 1.24 for sequential treatment, i.e., RT followed 4 hours later by HT. Tumor control was also more durable with HT. The rate of persistent local control at 18 months was increased by the HT (86% vs. 56%). Although a high TER was obtained with simultaneous treatment, normal skin tissue reaction was also increased, thus yielding no improvement in therapeutic ratio. With sequential treatment, i.e., HT given at least 4 hours after RT, normal tissue sensitization did not occur, resulting in a therapeutic gain of 1.22. The favorable impact on larger tumors was reported earlier by Kim et al [164] which

K. Engin

330

was attributed to greater heatability of tumors to minimum tumor temperatures of 42°C. RT dose per fraction was demonstrated to be critically important in tumor control. Smaller tumors treated with high doses per fraction showed no beneficial effect of HT. With larger tumors, HT increased the rate of response and accelerated tumor regression with both large and small RT doses per fraction. HT appeared to aid in overcoming the adverse effects of large volume disease an the use of low RT fraction sizes. It was associated with a TER of 1.5.

HEAD AND NECK TUMORS Despite the aggressive use of combined modality therapy in the head-and-neck region, locoregional disease is the most important mode of failure. HT has been applied to the head-and-neck region mainly for metastatic deposits. In most cases, because of depth of tumor, the primary site cannot be adequately heated with currently available external equipment, and an interstitial implant is required for HT to be effective. This region presents considerable technical challenge because of rapidly changing contours and difficulties with coupling the external applicator to the tumor. Lesions are frequently extremely large and irregular in shape and cannot be well encompassed by available external applicators. Often the tumor is endophytic, extending deeply to the parapharyngeal space and base of the skull region, or situated deeply beneath muscle and other normal tissue.

Primary Treatment Arcangeli et al, [106,142] have reported on the use of multiple daily RT fractions and HT on N2-N3 multiple cervical lymph nodes. Matched lymph nodes were used in the same patient. A higher CR rate was obtained for the combined treatment compared to hyperfractionation alone or to a historical series of conventionally fractionated RT. A TER of 1.88 was obtained. When thermal dose was above 200 mmEqQ.PC, all responses were complete irrespective of volume. The combined use of hyperfractionation and HT in primary disease of the head and neck in a nonrandomized trial setting also makes this experience distinct. In a prospective randomized study with N3 disease arising from T,-TZ lesions or unknown primaries, Valdagni et al [105] reported that the results were highly significant in favor of TRT.

Recurrent Tumor It is clear that CR rates in the order of 50-85% may be obtained in advanced nodal disease in the head and neck with the combination of high-dose RT and HT. The effectiveness of standard RT may thus be improved without increased serious morbidity. This approach may help certain patients with advanced tumor to overcome the prognostic implications of inoperability by producing sufficient tumor shrinkage to allow resection to be performed. The major constraint is the ability to heat tumor adequately. The major limitation at this time is largely technical and related to the difficulty in delivering heat sufficiently deeply and to the whole tumor. In attempts to treat large nodal masses that are recurrent after full conventional therapy, a combination of interstitial and external applicator HT has been applied [160]. This approach allows catheters that are inserted into the base of the

Thermoradiotherapy

in Cancer Treatment

331

lesion to be used for interstitial heating and interstitial RT as well as for thermometry. Treatment of such masses presents considerable technical difficulties due to the greater medial extension than is appreciated clinically. For this reason, CT scanning is crucial in planning the placement of the temperature catheters [165]. Interstitial HT in combination with external beam and interstitial RT has also been applied to advanced and locally recurrent primary disease [166]. SKIN REACTIONS Several randomized and nonrandomized studies comparing RT alone with the combination of RT and HT have shown that skin reactions were not increased significantly by the addition of HT. Gonzalez Gonzalez et al 11251observed enhancement of acute skin reactions although the enhancement did not constitute a clinical problem. Lindholm et al 11261 reported that local pain and normal tissue reactions were. a problem with 2450 MHz microwaves but were reduced when 915 MHz microwaves were used. Gabriele et al [167] treated 57 patients with HT alone. They observed skin burns in two cases (3%). Other side effects were blisters with moist desquamation (10%) and local infection after invasive procedures of thermometry (13%). In their randomized study of the effects of TRT on spontaneous tumors in pets, Dewhirst and Sim [139] found that the incidence of direct thermal injury to skin was positively correlated with maximum intratumor equivalent minutes at 43°C. They also concluded that little or no enhancement of early or late radiation effects occurred with the addition of HT. In studies on human tumors, Luk et al [168] showed a positive correlation between the incidence of burns and blisters and the intratumoral temperature maxima, Howard et al [169] showed that the average maximum skin HT dose per treatment correlated with the incidence of severe skin reactions, and Seegenschmiedt et al [146] showed a correlation between total mean and maximum tumor Eq43 minutes and acute complications. Kapp et al [170] showed that the average of the maximum tumor temperature and the number of HT treatments per field were the most important predictive factors for complications in TRT. Engin et al [171] showed that the presence or absence of previous RT, previous RT dose, concurrent RT factors, i.e., concurrent RT dose, number of elapsed days, the minimal tumor temperature factors of T,,,, and f,lm,n,, and the number of HT treatments all correlated with occurrence of skin reactions. HYPERTHERMIA

TRIALS

Despite the strong scientific and rational basis for HT, its true efficacy when given as an adjuvant to primary RT still needs to be fully evaluated in objective randomized multi-institutional studies. In this same context, the early and late tolerance of normal tissues, also requires assessment. The identification of the technical, biological and clinical variables affecting tumor response and normal tissue tolerance remains a critical issue that will eventually lead to standardization of techniques including thermometry, method of heating, fractionation schedules, and quality assurance. Various international societies have been actively involved in conducting clinical trials to achieve these objectives. In investigating the role of HT in primary treatment, a strong priority is to minimize the risk of severe late effects. With this in mind, the general principle is to recommend conventional fractionation and to supplement this with HT either once or twice weekly. External

K. Engin HT combined

with RT can be applied to superficial

wall recurrences,

and melanoma

lesions of head and neck, chest

lesions with depth ~3 cm. For deeper lesions (i.e.,

3-6 cm), external and intersititial techniques can be combined. Interest has also developed in the use of endocavitary and whole-body HT [172]. Whole-body HT has most often been combined with chemotherapy 11731, frequently in the treatment of advanced small-cell carcinoma of the lung, but is associated with considerable widespread

morbidity

and is being investigated

is the use of hyperthermic

perfusion

in few institutions.

More

of the lower limbs for the treatment

of malignant melanoma. The combination of external applicator HT and chemotherapy, especially cisplatinum for the treatment of refractory superficial malignancies is also under investigation [174]. This is designed for patients who have already received full-dosage RT often in multiple concurrently studies

courses

(trimodality

of treatment. therapy)

[103]. This form of therapy

synergistic

interaction

be efficacious investigated

The use of all three modalities

is also being investigated holds

considerable

promise

of any two of the three modalities

in vitro [175]. Cisplatinum

in combination

because

to other agents. Maximum

cytotoxicity

with RT is being closely of normal

occurs when these modal-

ities are administered simultaneously, but optimal dose scheduling of therapy needs to be investigated in clinical studies.

QUALITY

of the

and has been found to

in several RT studies and seems to produce less sensitization

tissues compared

delivered

in single-institution

and sequencing

ASSURANCE

The need for quality assurance in HT is particularly great at this time because of the lack of standardization of equipment and techniques used for heating and monitoring quality different

temperatures.

of HT treatment institutions

data [176-1781.

There are few objective and quantitative

is fouled by variability

Of particular

importance

criteria with which to judge the

assessment

of patients

in patient treatment

is ensuring

the adequacy

derived

from

and temperature of heating pat-

terns for a given tumor volume while limiting normal tissue heating. Because there is no direct relationship phantom

between

the sulfarsphenamine

studies and temperatures

(SAR) pattern derived from

achieved in perfused tissue, considerable

experi-

ence is required to choose the appropriate applicator for a given tumor size and site. In general, the tumor volume and margin should be encompassed by the 50% iso-SAR and placement arranged to maximize power coupling and minimize reflected

and stray electromagnetic

use of an applicator always

be feasible

roughly

leakage.

Unfortunately,

this often requires

depending

on the location

of the tumor.

Moreover,

the SAR

pattern rapidly constricts with depth and a lesion of appreciable thickness not be adequately heated even with a generous applicator [179-1811. An area of particular

the

twice the surface area of the lesion, which may not

concern

is the standardization

of thermometer

may

placement

within the tumor. The need for ample multipoint thermometry or thermal mapping cannot be overemphasized. The RTOG Thermometry Task Force has formulated recommendations

and guidelines

for the insertion of catheters for monitoring

tumor

temperature for both microwave [180] and untrasound [182] modalities. Verification of thermometry catheter placement with computed tomography scans is necessary in tumors of >1.5 cm depth, both to confirm that the catheters in fact traverse tumor and to determine

the depth of placement

[165]. Documentation

of catheter

Thcrmoradiotherapy

in Cancer Treatment

locations

relative

employed

by using multisensor

under computer

to tumor

333

margins

is mandatory.

Thermal

thermal probes, preferably

mapping

performed

should

be

mechanically

guidance.

AREAS OF FUTURE DEVELOPMENT The major

limitation

at this time is the inadequacy

deliver

power homogeneously

greater

extent

monitoring

and depth.

systems

and without

necessity

to resort

multiarray

greater

tumor temperature

artefact.

A severe drawback and

the need

and analysis,

to locoregional homogeneity to therapeutic

at this time is the

all important

The combination

HT is being investigated pattern

multiple

adequately.

both as a

and raising

levels 11831. The interaction potential

the

of chemo-

in early phase l/II studies separately

with RT and has enormous

of

with good

to insert

taking into account

in the heating

to

of temperature

them also needs to be achieved.

and HT is also being explored

in combination

is the availability

in order to assess tumor temperature

design

HT in addition

of producing

minimum therapy

in protocol

equipment

of tumor volumes

reflect the tumor temperature

thermometry

sensors

factors and stratifying

of whole-body means

significant

to invasive

temperature

Improvement prognostic

No less important

that will accurately

resolution

of current

to tissue and allow inclusion

and

for clinical use.

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