Foreword

The Office of Health Assessment (OHTA) evaluates the risks, benefits, and clinical effectiveness of new or unestablished medical technologies that are being considered for coverage under Medicare. These assessments are performed at the request of the Health Care Financing Administration (HCFA). They are the basis for recommendations to HCFA regarding coverage policy decisions under Medicare.

Questions about Medicare coverage for certain health care technologies are directed to HCFA by such interested parties as insurers, manufacturers, Medicare contractors, and practitioners. Those questions of a medical, scientific, or technical nature are formally to OHTA for assessment.

OHTA's assessment process includes a comprehensive review of the medical literature and emphasizes broad and open participation from within and outside the Federal Government. A range of expert advice is obtained by widely publicizing the plans for conducting the assessment through publication of an announcement in the Federal Register and solicitation of input from Federl agencies, medical specialty societies, insurers, and manufacturers. The involvement of these experts helps assure inclusion of the experienced and varying viewpoints needed to round out the data derived from individual scientific studies in the medical literature.

After OHTA receives information from experts and the scientific literature, the results are analyzed and synthesized into an assessment report. Each report represents a detailed analysis of the risks, clinical effectiveness, and uses of new or unestablished medical technologies considered for Medicare coverage. These Health Technology Assessment Reports form the basis for the Public Health Service recommendations to HCFA and are disseminated widely. Individual reports are available to the public once HCFA has made a coverage decision regarding the subject technology.

OHTA is one component of the Agency for Health Care Policy and Research (AHCPR), Public Health Service, Department of Health and Human Services.

• Thomas V. Holohan, M.D.
• Director
• Office of Health Technology Assessment
• J.Jarrett Clinton, M.D.
• Administrator
• Questions regarding this assessment should be directed to:
• Office of Health Technology Assessment
• AHCPR
• Executive Office Center
• 2101 East Jeferson Street, Suite 400
• Rockville, MD 20857; (301) 227-8337

Introduction

Hyperthermia has been used to augment other of forms of cancer treatment for about 100 years. In 1893 W. B. Coley used infections with bacteria and/or injections of bacterial extracts to treat patients with cancer; it is unknown whether the beneficial results he obtained were due to the fever induced or to the patients' production of factors such as tumor necrosis factor (TNF) (1) Increased interest in the used of hyperthermia for the treatment of cancer developed in the 1960s, and various devices to produce either systemic hyperthermia or hyperthermia in selected parts of the body were developed.(2,3) In the past 30 years hyperthermia has been used alone and together with radiotherapy and/or chemotherapy. In addition, local isolated limb perfusion of heated chemotherapeutic agents has also been performed.(4,5) The literature contains several thousand papers on these subjects.

The purpose of the present assessment is to evaluate the clinical effectiveness of hyperthermia alone and hyperthermia combined with chemotherapy. A previous review in 1984 by the Office of Health Technology Assessment of the National Center for Health Services Research (now the Agency for Health Care Policy and Research) dealt primarily with the subject of hyperthermia alone or combined with radiotherapy. That review concluded that hyperthermia combined with radiotherapy may provide useful local palliative effects.(6)

The scientific basis for the use of hyperthermia as an adjunct for the treatment of cancer rests on four main observations. First, there is evidence that some tumor cells may be more sensitive to the effects of increased temperature compared with their normal cellular counterparts. Second, the combination of chemotherapeutic agents and hyperthermia produces additive and synergetic killing effects on tumor cells. These effects appear more dramatic at low pH. Third, hyperthermia produces changes in the blood flow and oxygen levels in tumors that may have beneficial clinical effects, especially in combination with other agents. Fourth, the immune responses of the patient toward his or her tumors may be augmented by hyperthermia. These would include effects on macrophages, natural killer (NK) cells, and T-cell cytotoxic effector functions.

In addition, hyperthermia may have beneficial therapeutic effects on cancer because of actions on systems of which we have no precise knowledge. All these rationales will be discussed in more detail below.

Background

Cancer therapy has been performed since the dawn of recorded history. The earliest treatments involved crude modalities such as burning, caustic agents, and primitive surgery, as well as nonspecific, toxic oral agents such as arsentic. Modern cancer therapy started in the first part of the 20th century with external beam x-ray therapy, radium implantation, and sophisticated surgery. Modern chemotherapy began in the mid-1940s with the use of nitrogen mustard, which was soon followed by the development of many other chemotherapeutic agents. In spite of the many advances made in cancer therapy in the past 100 years, the treatment of cancer still remains unsatisfactory because of the nonspecific and toxic actions of all the standard therapeutic modalities. In an attempt to improve these current standard forms of therapy, various other treatments have also been First, biological agents are used that can act in the patient to stimulate a beneficial immune response directed against the tumor cell.(7) Nonspecific agents such as Calmette-Guegraverin bacillus were used initially. More recently, genetically cloned cytokines and lymphokines, which can be produced in large amounts, have been used. These agents can also combined with infusion of immune-component effector cells to enhance further the immune response directed to killing the tumor cell.(8)

Another form of therapy used in addition to more standard forms of therapy is hyperthermia. Hyperthermia can be administered either systemically or locally, either to superficial (less than 5 cm) or to deeper lesions. Several different types of devices for hyperthermia have now been approved for use by the Center for Devices and Radiological Health, Food and Drug Administration (FDA). The National Cancer Institute (NCI), National Institute of Health (NIH), has provided contractual support for comparative testing of several different types of devices used for hyperthermic therapy. Centers in the United States, Europe, and Japan are currently investigating the clinical usefulness of hyperthermia combined with either radiation, chemotherapy, or both.

In the past 30 years thousands of patients have been entered into clinical hyperthermia trials using heat alone or in various combinations with radiotherapy and chemotherapy. A whole spectrum of devices, treatment schedules, and drugs in a variety of combinations have been used.

The combined use of hyperthermia and chemotherapy for the treatment of cancer is usually considered to be a "last resort" treatment for patients who have either failed to respond or who are not suitable candidates for conventional therapy.

Several reviews on hyperthermia have appeared in the literature.(2,3,9-12) These reviews discuss both clinical results as well as extensive background material on hyperthermia, effects on cells in vitro, and results of small-animal studies. This assessment presents:

1. Scientific rationale for the use of hyperthermia
2. Description of devices used to produce either systemic or local hyperthermia
3. Reports of toxicity associated with hyperthermia treatment
4. Review of available information on:

   • Effects of isolated heated perfusion of melanomas of an extremity
   • Results of systemic hyperthermia and chemotherapy
   • Results of local/regional hyperthermia and chemotherapy
   • Results of a combination of hyperthermia, chemotherapy, and radiotherapy (triple therapy) and the results of hyperthermia alone
   • Overall assessment of the efficacy of hyperthermia and chemotherapy for the treatment of cancer

Scientific Rationale for the Use of Hyperthermia

If tumor cells were more sensitive to the detrimental effects of heat than normal cells, this would obviously be a rationale for the use of hyperthermia to treat cancer.(13) Indeed, a number of such reports have appeared in the literature. These in vitro studies are rather straightforward because pure populations of either normal or cancer cells can be prepared.(10,14) Doing similar studies in vivo is far more difficult because of the complex admixture of the normal neoplastic cells during heat treatment and the inability to do careful measurement of surviving cell populations. A phenomenon that may have some practical importance is thermotolerance. Thermotolerance is defined as a heat-induced cellular resistance to subsequently elevated temperature.(2) Thus in therapy where the heat treatments are fractionated, careful timing between fractions may be necessary to obtain the desired effects.

The mechanisms of cellular damage after hyperthermia are multiple, complex, and poorly understood. The reasons for the differential sensitivity of tumor cells compared with normal cells are even more obscure. Changes in a number of intracellular biochemical pathways; effects on DNA and RNA, phospholipids, membrane fluidity, and DNA binding proteins; production of heat-shock proteins; and cytoskeletal changes have all been studied, (13). but rigorous studies in this complex area are lacking.

Another rationale for treatment of patients with hyperthermia is a large amount of evidence that a variety of anticancer drugs demonstrate either additive or synergistic killing effects on tumor cells in the presence of elevated temperatures. Some of these effects may be further enhanced by decreases in pH and levels of oxygenation; however, these effects vary from drug to drug, and the exact mechanisms by which these effects are produced are not known. In some cases, heat can have tumor-promoting effects. Some of these in vitro results are summarized in Table 1.(13).

Table

Table 1. Cytotoxic interaction between anticancer drugs and hyperthermia.

The scheduling of hyperthermia and drug administration also is important. In vitro, simultaneous addition of the two modalities appears most effective, whereas in vivo animal experiments show superior results when the drug is given just before hyperthermia. In clinical practice optimal scheduling may be harder to determined and may depend on the method of drug delivery, bolus vs continuous perfusion, and time of peak concentration of the drug in the tissue; again, these parameters may vary from drug to drug.(12,13)

Changes in blood vessels and blood flow have been invoke as yet another explanation for the beneficial effects of hyperthermia on cancer.(15,16) Most of the information in this area is derived from mouse and dog studies. It is not clear whether responses of human blood vessels, either normal or in tumors, are the same.(2) The following observations, made in animals, are purported to explain the beneficial effects of hyperthermia: tumors may have inefficient heat transfer mechanisms because of changes in the microvasculature (therefore, the tumor becomes hotter than the surrounding normal tissues); tumor vasculature may be more easily destroyed by heat, and therefore, the tumor becomes anoxic; vasodilation after hyperthermia id more efficient in normal tissues, and therefore, they remain cooler.

Enhancement of the immune response by hyperthermia is another explanation for the possible therapeutic benefit of this modality. A number of different studies have investigated the role of hyperthermia in the immune response and the results are relevant to the question of how hyperthermia might be beneficial for cancer therapy. Both positive and negative effects of hyperthermia on various aspects of the immune response have been observed.

Some examples of positive results include the following data. Macrophages can exert cytotoxic effects on U937, a lymphoma line. Incubation of the macrophages at 40 degreesC instead of 37 degreesC greatly enchances their cytotoxicity; moreover, lymphokine-stimulated macrophages also demonstrate the same phenomena.(17). When human lymphocytes are cultured at 40 degreesC, their proliferative responses to mitogens are increased. In addition, their ability to kill allogenic cells is also enhanced.(18)

The antigenicity of B 16 melanoma cell membranes is increased by microwave hyperthermia compared with unheated membrances. This may be a useful strategy for preparing melanoma vaccines.(19)

The effect of hyperthermia was investigated in different T-cell subsets. Hyperthermia enhanced the mitogen-induced proliferation of Lyt-1(+) cells but decreased the proliferation of Lyt-23(+) cells. In contrast, B-cell responses to lipopolysaccharide were uniformly inhibited. Thus, the effects of hyperthermia on various subcomponents of the immune response are complex.(20)

The effects of hyperthermia on interleukin-1 (IL-1) production were studied in mice. Mice subjected to hyperthermia showed a transient fall in IL-1 and then a rebound at 16-20 hours. IL-1 levels remained elevated for 5-6 days.(21)

However, other studies have revealed mixed or negative effects of hyperthermia; a few examples are provided below.

Individuals with elevated temperatures were examined for mitogen-induced lymphocyte proliferation, the function of leukocyte-inhibiting factors, and the production of plaque-forming B cells (stimulated by pokeweed mitogen). All these responses were decreased in a dose-response fashion in febrile patients.(22)

Tumor necrosis factor is a potent cytokine capable of killing certain types of tumor cells. When fibrosarcoma cells were heated they became less susceptible to killing by TNF. Also, heat transiently decreased the ability of T cells to secrete TNF, and thus heating of cells can downregulate their cytotoxic functions.(23)

The effects of hyperthermia were investigated in human peripheral blood by heating cells to various temperatures and then testing their function. Natural killer activity and mitogen-induced blastogenesis both were markedly decreased by hyperthermia. This result was in part explained by decreases in NK cell subsets in the heated population of cells. The authors concluded that these facts must be considered when hyperthermia is used for cancer therapy.(24,25)

The effects of hyperthermia on mouse T-lymphocyte cytotoxic function were examined. At temperatures of 43 degreesC for 20 minutes this function was markedly decreased; however, when the cells were later incubated at 37 degreesC the function of these cells recovered.

Another study looked at the effects of hyperthermia on tumor metastases. A rat limb bearing a Yoshida sarcoma was heated to 42 degreesC, and central body temperature was also increased. Under these circumstances there was an increase in metastases and a decrease in lifespan of these animals compared with controls.(26)

In sum, it would appear that hyperthermia can both augment and depress certain aspects of the immune response as well as the biology of the tumor.

Very few studies of these changes have been performed in patients receiving hyperthermia. Therapy using immune modulation together with hyperthermia in patients has not been reported, and no studies were found that described immmunologic studies at the tumor site itself in patients undergoing hyperthermia. Therefore, although enhancement of immune functions has been mentioned often as a rationale for the use of hyperthemia to treat patients with cancer there is little substantial evidence to support this view.

Techniques and Devices Used to Produce Hyperthermia

Toxicity of Hyperthermia Treatments

Review of Available Information

The combined use of hyperthermia and chemotherapy will be discussed in four sections: 1) hyperthermia combined with regional perfusion of a limb with a chemotherapeutic agent, 2) systemic hyperthermia combined with chemotherapy, 3) local/regional hyperthermia combined with chemotherapy, and 4) triple therapy, that is, the use of radiotherapy, chemotherapy, and hyperthermia. Finally, the use of hyperthermia alone will also be briefly discussed.

Hyperthermia Combined With Regional Perfusion of a Chemotherapeutic Agent

The advantages of regional perfusion are that a high local concentration of the chemotheraputic agent can be achieved in the tumor-bearing limb with minimal systemic toxicity.(40) Hyperthermia was first added to this regimen in 1967.(14)

Briefly, the technique use is as follows: General anesthesia is administered, the major artery and vein supplying the extremity are exposed, the patient is heparinized, and plastic catheters are inserted into the vessels. The catheters are then connected to an extracorporeal perfusion circuit; the chemotherapeutic agent is added to perfusate. A heat exchanger is included in the arterial line to regulate the perfusion temperature. Thermistor probes are placed subcutaneously to monitor the temperature of the extremity, which is maintained at about 41 degreesC. The blood is also oxygenated. An external tourniquet is placed at the roof of the extremity to minimize systemic distribution of chemotherapy. The treatment usually lasts about 60-90 minute.(5) Heated perfusion is usually performed at some time after surgery. The scheduling of surgery and heated perfusion vary with the stage of disease and with the particular clinical situations of each patient.

The great majority of the tumors treated have been melanomas. However, in a few cases sarcomas and other less common tumors have also been treated. The chemotherapeutic agent most commonly used is L-phenylalanine mustard (L-PAM), also called mephalan. It should be noted that the parenteral formulation of this drug is not approved by the FDA. However, other agents such as dacarbazine, cisplatin, actinomycin, and interferon alfa have also been used. In some cases these agents have been combined.

The results of this therapy are difficult to evaluate and even to describe for the following reasons: Melanoma of the limb is a complex malignancy that may present in various disease stages (Table 2 shows a commonly used stagingsystem). The prognosis and responses to therapy are different for different stages of disease. Most studies using regional perfusion have not been randomized prospective trials but rather retrospective analyses and comparisons. Some of the trials included only a few patients. The drugs used and the hyperthermia conditions and techniques used varied from trial to trial. The criteria of response were often not described in detail and were not constant from trial to trial, and the duration of different trials also varied. Finally, even when all these variables are taken into account, the results of the studies are inconsistent. A review of this subject appeared in 1985; results from the 15 trials were reported.(41) The summary of this review is as follows:

Table

Table 2. M.D. Anderson melanoma staging.

The role of perfusion, normothermic and hyperthermic, in the curative treatment of melanoma remains controversial. Survival appears to be somewhat improved over that of surgery alone in all stages, especially with hyperthermic perfusion, but all comparisons have been retrospective and uncontrolled. In addition to the usual problems with historical controls, melanoma presents its own special problems because of its unpredictable natural history in any given individual and the multiplicity of factors known prognostic factors. It is unfortunate that hundreds of patients have been treated in uncontrolled studies. Randomized trials continue to be necessary to define this role and even then careful attention will have to paid to the distribution of known prognostic factors in each group to insure a comparable cohort of patients.

The response of melanoma to perfusion is clearly significant, however, and the response rate seems to be improved with hyperthermic perfusion. Hyperthermic perfusion appears to be a useful palliative treatment for locally advanced melanoma of the extremity, especially for which the alternative surgical therapy would be amputation.

Results of several more recent papers will be discussed. The data in these papers are summarized in Table 3.

Table

Table 3. Use of heated perfusion to treat melanomas of the extremities[a].

As can be seen from this table, since the 1985 review(41). a number of other papers have been published, but only the one prospective controlled trial by Ghussen et al, (39). appeared in the literature. However, this single prospective controlled trial clearly demonstrated a significant advantage (increase in disease-free survival and overall survival) of surgery followed by heated perfusion with melphalan for the treatment of melanoma of the limb compared with surgery alone.

With the exception of Ghussen et al, (39). the investigators cited in Table 3(5,42-50). claimed, on the basis of uncontrolled clinical studies, that their results with this technique were superior to results --both their own and those described in the literature --with conventional treatment(surgery and/or chemotherapy). However, these claims are anecdotal and retrospective impressions and not based on rigorous prospective randomized trials.(42) In some of these trials, the earlier patients were treated with perfusion at normothermic temperatures and the later patients in the same trials were treated with hyperthermic perfusion. In several such clinical studies, these later patients had a superior result.

Hyperthermic perfusion of the limb is an expensive and complicated therapy requiring a team approach, as several hours of operating time by a vascular surgeon and a perfusionist are necessary. In addition, equipment to oxygenate and heat the blood is required. Moreover, this type of therapy appears to be most effectively performed in institutions with considerable experience in this field. As noted above, a moderate degree of toxicity is associated with this form of therapy.

The use of heated intra-arterial perfusion with melphalan (FDA-unapproved formulation) as the chemotherapeutic drug for the treatment of melanoma of the limb appears to be a useful, albeit complex and expensive, therapy. It should be performed only under an investigational new drug (IND) protocol in institutions with considerable experience in this modality of therapy.

Systemic Hyperthermia and Chemotherapy

Several reviews of this subject have been published in the past few years.(2,3,9-12) The problems in interpretation and evaluation of the literature on this topic are the same as that mentioned above; that is, there is great heterogeneity of the patients and their types of cancer, variations in techniques and drugs used, and lack of standard criteria for assessment of response. In addition, most patients treated with systemic hyperthermia and chemotherapy previously had had multiple forms of therapy, and their performance status was usually quite low.

The results of some of these trials are summarized in Table 4. Objective responses were seen in 30-40 of patients. These responses were usually of short duration, though an occasional patient had a response lasting for several months. Unfortunately, there is no way to determine whether the patients might also have benefited to the same degree from treatment with chemotherapy alone. Further, while it may well be that a small fraction of the patients treated did benefit from the combination of systemic hyperthermia and chemotherapy, one could not tell in advance which particular patient might benefit.

Table

Table 4. Use of systematic hyperthermia combined with chemotherapy to treat patients with advanced cancer.

In summary, systemic hyperthermia together with chemotherapy has been used over the past 15 years to treat several hundred patients. These patients were almost always in advanced stages of cancer, and no randomized controlled studies have been performed. The technology is cumbersome and difficult to use and has a significant degree of toxicity. At the present time, this form of therapy must be considered to be of indeterminate effectiveness. Devices so employed are considered to be investigational by the FDA and are subject to the Investigational Device Exemption (IDE) regulations.

Local/Regional Hyperthermia Combined With Chemotherapy

Compared with the types of trials discussed above, the use of local/regional hyperthermia combined with chemotherapy presents the evaluator with an even more complex and heterogeneous group of factors to be considered.

Regarding the scheduling of chemotherapy and hyperthermic treatments, ideally, one would like to have peak blood levels of the chemotherapeutic agent in the tumor at the time of hyperthermia. Either bolus or continuous infusion of drug may be optimal to accomplish this and may vary from drug to drug. Vascular damage produced by prior radiation of the tumor could affect the success of the therapy because it may prevent the administered drug from reaching the tumor. The depth of the tumor being treated is important, since more superficial lesions of less than 5 cm are easier to treat than deeper tumors because more reliable and uniform heat can be applied to them. Tumor volume is also an important factor, in that larger tumors may be more difficult to heat in a uniform A number of different devices are used to create the local hyperthermia, and there is also the serious problem that no standard measurement of the amount of heat delivered (Thermal Dose) to a particular tumor has been used in a uniform manner by the many clinical groups performing these therapies. In many studies a Thermal Dose is not even mentioned. Moreover, uniform and reproducible heating of tumors, especially large ones, is difficult to achieve in practice. The vast majority of patients treated with this modality of therapy had had extensive prior therapy with more standard forms of treatment and had a poor performance status. The results of representative studies are shown in Table 5.(59-70).

Table

Table 5. The use of local/regional hyperthermia and chemotherapy to treat far advanced cancer.

Most of these trials were not randomized controlled trials and are therefore difficult to interpret. However, there were three trials that could be considered as prospective controlled trials. The first involved only 15 patients with head and neck tumors; 7 of these patients received chemotherapy and hyperthermia.(59). In these patients only 11 lymph nodes were evaluated for regression after therapy for a period of 4 months.

In another study, Kohno et al(62). evaluated 65 patients with gynecologic malignancies. Patients receiving chemotherapy and hyperthermia had a higher frequency of regressing lesions than patients receiving chemotherapy alone. However, the duration of responses in both groups of patients was short; most patients in both groups were dead within 2 years.

In the third controlled study of patients with surgical removal of gastric cancer, (65). one group of postoperative patients also received heated perfusion with mitomycin into the peritoneal cavity. The other group of patients had surgery only. At 30 months there was no difference in survival between the two groups.

In summary, most of the trials did not allow firm conclusions regarding effectiveness because they were not randomized controlled trials. The few controlled trials cited showed marginally beneficial responses of short duration.

The clinical effectiveness of local/regional hyperthermia combined with chemotherapy should be considered as unestablished at the present time.

Discussion and Overall Assessment

Despite an enormous effort and many studies by basic scientists, clinicians, and physicists devoted to the study of hyperthermia alone or combined with chemotherapy for cancer therapy, the usefulness of this modality of therapy remains unclear. The reasons for this are several: the complexity and heterogeneity of the patients being studied, the heterogeneity of the devices used to produce hyperthemia, the lack of standardized methods to measure a Thermal Dose, and the almost complete lack of well-done, large, rigorous, prospective, randomized, controlled trials. The problem is as follows: The reason for the lack of such large prospective randomized trials is that they are extremely expensive and complicated and the proponents of hyperthermia have not yet produced sufficient preliminary evidence in its favor to convince peer review bodies to support such trials. In the absence of definitive trials, substantial evidence is lacking that hyperthemia alone or combined with chemotherapy has an established role in the spectum of available therapies for malignant disease. The only exception is the use of hyperthermic regional limb perfusion with melphalan to treat melanomas; however, it should be noted that although melphalan has been the most widely used agent for this purpose, the intravenous formulation of this agent has not been approved by the FDA.

What is the outlook fo future controlled trials in this area? The Cancer Therapy Evaluation Program of the Division of Cancer Treatment, NCI, funds cooperative trial groups in a consortium of universities in the United States. One such group that is involved in hyperthermia research is the Radiation Therapy Oncology Group. This group is not now funding any trials of chemotherapy and hyperthermia but they stated that they may do so in the next few years. They do not plan to fund any trials of hyperthermia alone (personal communication, B.N. Emani, M.D., August 15, 1990, Washington University School of Medicine).

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AHCPR Pub. No. 92-0014