Hyperthermia is the application of heat in a therapeutic setting. When cells are heated beyond their normal temperature they can become sensitized to therapeutic agents such as radiation and chemotherapy. If cells are heated to still higher temperatures the heat will cause irreparable damage resulting in cell death, a process referred to as thermal ablation.
The clinical field of hyperthermia emerged in the 1970s on a foundation built upon compelling radiobiologic evidence that hyperthermia was an ideal complementary treatment to radiation and certain chemotherapeutic agents. This well-deserved enthusiasm quickly became tempered by the realization that available technology for clinical hyperthermia treatment delivery was both cumbersome and limited in ability to provide effective treatment. The lack of meaningful quality assurance guidelines and treatment goals provided further roadblocks to wide-spread use.
Today as before, both challenges and opportunities remain in the application of hyperthermia for cancer patients. These areas include thermal biology, treatment planning, delivery, and monitoring, successful high-quality clinical trials, and integration of thermal therapy with emerging technologies and therapeutic strategies both established and evolving. The progress made in understanding of thermal biology, physics, and bioengineering, and advances in complementary clinical treatment modalities have all contributed to the next generation of clinical thermal therapy.
The advantages of combining hyperthermia with radiation and certain chemotherapeutic agents have been long understood and continue to be a compelling reason for integration of hyperthermia with other established cancer treatment modalities.1–7 Hyperthermia is an ideal complementary therapy to radiation. Cancer cells most resistant to radiation are precisely those most sensitive to heat. Cells that are resistant to radiation include those that are hypoxic, at low pH, nutritionally deprived, or in S phase of the cell cycle. All of these characteristics make cells particularly sensitive to heat. Hyperthermia also has been shown to increase perfusion resulting in improved tumor oxygenation for subsequent radiation treatments.8,9 Through heat shock protein (HSP)-mediated pathways there is also potential for induction of apoptosis and other cell death mechanisms.10–12 As HSPs are essential components of the cellular immune system, opportunities for enhancement of immune response exist and are an active area of investigation.
Heat shock proteins are a highly conserved ubiquitous class of proteins first identified in relationship to hyperthermia.13,14 They were initially identified in association with thermotolerance, a phenomenon whereby subsequent heating, typically within days of an initial heat treatment resulted in less cell kill. Since this initial discovery, HSPs have been found to have broad reaching roles in general cellular stress response and with immune system regulation.
Essentially, HSPs are down-stream effectors of multiple signal transduction pathways. Intracellularly HSPs protect cells from proteotoxic stress through “holding and folding” pathways that prevent denaturation and progression of lethal pathways.15–17 In the extracellular environment, HSPs have chaperokine effects with a central role in immune system response coupled with the ability to stimulate pro-inflammatory cytokine production.18 The chaperone function of HSPs relates to their role in chaperoning immunogenic peptides onto MHCs for presentation to T cells. The central importance of HSPs to this process is clear in that induction of immunity requires HSP-PC complexes with functional CD8+ cells and macrophages.19 Furthermore, several investigators have shown that HSP-PC complexes can be tumor specific and thereby induce tumor-specific immunity.20–22 This notable characteristic has been the focus of several HSP-based clinical vaccine trials.
Pertinent to targeting of HSP-mediated pathways is the availability of specific therapeutics to these pathways. The proteosome inhibitor, bortezimab targets the NFκ-B pathway which is in part regulated by HSP70 and HSP90. There are a range of new agents directed at the mammalian target of rapamycin/hypoxia inducible factor (mTOR/HIF) pathway including the HSP90 inhibitor geldanamycin which is being assessed in several clinical trials.23–26 Both of these pathways are part of the PI-3K/AKT pathway important for many common malignancies including prostate cancer. Geldanamycin may also target the androgen receptor. In addition, HSP70 inhibitors, including the bioflavinoid quercetin, have shown promise in enhancing the effect of hyperthermia.27,28
TREATMENT PLANNING, DELIVERY, AND MONITORING
The process of hyperthermia delivery has evolved in much the same way that radiation has over the past 30 years. Advances in treatment delivery with enhanced steering capabilities coupled with improvements in thermal monitoring have led to the need for and realization of meaningful treatment planning. Both superficial and deep heating have evolved significantly since the enthusiasm of the early 1980s led to implementation of crude treatment delivery programs that ultimately failed to provide the quality of heating necessary to effect changes in patient outcome. These shortcomings are now being convincingly addressed.
Superficial heating in the early 1980s involved a single channel or dual channel wave guide with no steering capabilities and in the case of dual channel applications a cold spot between applicators. By the early 1990s, 16 channel wave guides providing a larger and more uniform heating area became available. The early 21st century has seen further evolution of this technology. An example is a 32-element conformal wave guide that can be worn by the patient as a vest as opposed to having to position the patient against a rigid applicator (Fig. 1). 29
Deep heating has similarly evolved. An example is the advancement of radiofrequency treatment. In the early 1980s, several single-power applicators became commercially available with no steering capability and very limited field sizes. The use of a single-power source also limited application of heat much in the same way a single radiation field would for treatment of a deep-seated organ. A superficial hot spot became a limiting factor to effective heat treatment. In the early 1990s, a 360-degree applicator with 4 paired antennae arrays became commercially available. Currently an elliptical array of 12 paired antennae in 3 rings is now being used for deep regional heating. Advancements have also come with interstitial and transrectal ultrasound techniques. Novel approaches with magnetic resonance (MR)-heatable ferromagnetic seeds and injectable nanoparticles have also been developed.30–32
As treatment delivery has become more effective but also more complicated the importance of treatment planning has moved more toward the forefront. Again, much the same way that computed tomography, MR, and positron emission tomography led to evolution of simulation for radiation, treatment planning for hyperthermia has also benefited by improved imaging modalities. Commercial 3D computed tomography-based treatment planning is now available for deep-seated heating and phantoms available to provide initial validation of power application strategies. Hyperthermia not only involves the physics of treatment delivery but also must account for patient physiology. In particular, changes in vascular perfusion have been a challenge for modeling and delivering hyperthermia. Therefore, advances in treatment monitoring are important steps in ensuring high-quality hyperthermia delivery. Superficial treatment is more easily monitored but increasingly deep treatment is becoming easier to monitor in real time. For interstitial applications invasive thermal monitoring is relatively straightforward as hyperthermia antennae and thermal monitoring probes can be placed at the same time as brachytherapy catheters. The emergence of noninvasive MR-based thermometry is, however, the most exciting development in this arena. Although there are several techniques to use MR and other imaging modalities to measure temperature, most interest has focused on a technique correlating proton resonance frequency shift with temperature change.33,34 An example of correlation of proton resonance frequency shift and temperature in a phantom and color enhanced images from an actual patient treatment using a hybrid MR/RF heating system are shown in Figure 2.
Over 3 dozen clinical trials, approximately half of which are phase III studies, have been completed assessing the use of hyperthermia with radiation and/or chemotherapy. A summary of key superficial and deep hyperthermia trials is provided in Tables 1 and 2. As a result of the enthusiasm for the biologic rationale for combining hypethermia with radiation or chemotherapy which grew out of the 1970s, several phase III trials were developed in the 1980s. The Radiation Therapy Oncology Group (RTOG) conducted several trials both for superficial and deep heating across a mixed group of malignancies. RTOG 81-04 compared RT, typically 32 Gy at 4 Gy per fraction with or without hyperthermia for a range of malignancies including breast, head and neck, trunk, and extremity tumors. There was no difference in complete response between groups; however, a difference was noted for tumors less than 3 cm, which were more likely to be effectively heated with the technology available at the time.35 RTOG 84-19 was a phase III study of the use of radiation with or without interstitial hyperthermia for persistent or recurrent tumors after previous radiation or surgery. One hundred eighty-four patients, most with either head and neck or pelvic tumors, were accrued. There was no difference in any of the study endpoints; however, when the quality of hyperthermia was assessed only 1 patient met the minimum accepted criteria for adequate hyperthermia.36 Given the difficulties with hyperthermia delivery with the available technology and lack of widely applicable quality assurance guidelines enthusiasm for hyperthermia waned by the late 1980s.
Despite the challenges with hyperthermia delivery in the early 1990s, a number of investigators persevered and phase III trials have since been completed showing benefit, including survival benefit in several instances, with addition of hyperthermia to radiation or chemotherapy. A pooled analysis of 5 breast cancer studies by the Medical Research Council and European Society for Hyperthermic Oncology (ESHO) involving 306 patients showed a significant increase in complete response and local recurrence free progression, particularly for patients for recurrent disease, with the addition of hyperthermia.37 A more recent study at Duke University showed the importance of thermal dose to complete response, again with the greatest benefit shown for patients with recurrent previously irradiated chest disease with a 68% versus 23% complete response noted with versus without hyperthermia.38 In large part, as a result of these findings, hyperthermia has been included in the 2007 NCCN guidelines for treatment of chest wall recurrence of breast cancer.
The impact of hyperthermia on survival has been noted in several studies. In the Dutch Deep Hyperthermia Trial, a survival advantage with hyperthermia, similar to that seen in concurrently performed chemotherapy trials, was noted in addition to radiation for patients with locally advanced cervical cancer. At 3 years, overall survival was 51% versus 31% with versus without hyperthermia.39 As a result of the wide adaptation of cisplatin-based chemotherapy with radiation 2 new phase III studies including an international trial designed to look at the additional benefit of hyperthermia to chemoradiation is now underway. A study at the University of California at San Francisco randomizing patients with glioblastoma to interstitial radiation +/− hyperthermia showed a notable survival advantage for patients receiving hyperthermia. There was a doubling of overall survival at 2 years from 15% to 31% with the addition of hyperthermia.40 An Italian study of hyperthermia for head and neck tumors noted improved local control, which translated into a survival advantage for patients receiving hyperthermia.41 A phase III ESHO study for melanoma revealed improved local control with hyperthermia. The importance of improved local control was noted in the finding that patients experiencing overall complete response enjoyed improved overall survival.42 The benefit of hyperthermia is not limited to radiation. The first report of a completed EORTC/ESHO phase III study of the combination of hyperthermia and chemotherapy for sarcoma was provided at the 2007 ASCO meeting demonstrating a highly significant benefit of hyperthermia in improving progression free survival.
INTEGRATION OF HYPERTHERMIA WITH EMERGING TECHNOLOGIES
Beyond traditional use of hyperthermia with radiation or chemotherapy there are a number of novel applications emerging for this treatment modality. The use of HSP-based therapies, thermal enhancement of drug delivery, and thoughtful application of the principles of hyperthermia to thermal ablation are all promising avenues for integration of hyperthermia into a widening array of cancer therapies.
Apart from hyperthermia, the broad reaching roles of HSPs in regulation of signal transduction pathways and the immune system are being targeted including HSP-specific inhibitors such as geldanamycin and quercetin and development of HSP-based vaccines.25–28 In regard to drug delivery, thermally sensitive liposomes have been developed so that heat applied to the region of interest results in a highly concentrated release of chemotherapy in proximity to tumor.43 Thermal ablation, the use of heat to destroy tissue, is increasingly being used for oncologic applications. Although the primary goal is direct destruction of tissue, a hyperthermic but nonablated rim of tissue around the kill zone is created providing opportunity to apply the principals of hyperthermia to thermal ablation thereby enhancing the effective zone of ablation.44
There are presently a broad array of reasons why hyperthermia holds promise for improving outcomes for cancer patients: These include:
- New understandings of thermal biology with a focus on heat shock-regulated signal transduction and immune regulatory pathways.
- Development of conformal thermal therapy complete with user friendly treatment planning and thermal monitoring capabilities.
- Mounting evidence from phase III clinical trials for the favorable impact of hyperthermia on treatment outcome.
- Integration of hyperthermia with emerging and novel treatment strategies.
The present confluence of these factors are compelling reasons to consider how best to integrate hyperthermia into the care of the 21st century cancer patient.
1.Dewey WC, Hopwood LE, Sapareto LA, et al. Cellular response to combinations of hyperthermia and radiation. Radiology
2.Westra A, Dewey WC. Variation in sensitivity to heat shock during the cell cycle of Chinese hamster cells in vitro. Int J Radiat Biol
3.Kim J, Hahn EW. Clinical and biological studies of localized hyperthermia. Cancer Res
4.Gerweck LE, Nygaard TG, Burlett M. Response of cells to hyperthermia under acute and chronic hypoxic conditions. Cancer Res
5.Hahn GM, Shiu C. Adaptation to low pH modifies thermal and thermo-chemical responses of mammalian cells. Int J Hyperther
6.Henle KJ, Leeper DB. Combination of hyperthermia (40°, 45° C) with radiation. Radiology
7.Kano E. Hyperthermia and drugs. In: Overgaard J, ed. Hyperthermic Oncology
. London, Uk: Taylor & Francis; 1985:277–282.
8.Eddy HA. Alterations in tumor microvasculature during hyperthermia. Radiology
9.Song CW. Effect of local hyperthermia on blood flow and microenvironment: a review
. Cancer Res
. 1984;44(suppl 10):S4721–S4730.
10.Franceschi C. Cell proliferation, cell death and aging. Aging (Milano)
11.Fuller KJ, Issels RD, Slosman DO, et al. Cancer and the heat shock response. Eur J Cancer
12.Arya R, Mallik M, Lakhotia SC. Heat shock genes–integrating cell survival and death. J Biosci
13.McKenzie SL, Henikoff S, Meselson M. Localization of RNA from heat-induced polysomes at puff sites in Drosophila melanogaster
. Proc Natl Acad Sci USA
14.Lindquist S, Craig EA. The heat shock proteins. Annu Rev Genet
15.Beckman RP, Mizzen LA, Welch WJ. Interaction of HSP70 with newly synthesized proteins; implications for protein folding and assembly. Science
16.Gething MJ, Sambrook J. Protein folding in the cell. Nature
17.Netzer WF, Hartl FU. Protein folding in the cytosol: chaperone-in-dependent and independent mechanisms. Trends Biochem Sci
18.Asea A, Kraeft SK, Kurt-Jones EA, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med
19.Srivastava PK, Maki RG. Stress-induced proteins in immune response to cancer. Curr Top Microbiol Immunol
20.Udono H, Srivastava PK. Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70. J Immunol
21.Udono H, Levy DL Srivastava PK. Cellular requirements for tumor-specific immunity elicited by heat shock proteins: tumor rejection antigen gp96 primes CD8+ T cells in vivo. Proc Natl Acad Sci USA.
22.Udono H, Srivastava PK. Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med
23.Sydor JR, Normant E, Pien CS, et al. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci USA
24.van der Poel HG, Hanrahan C, Zhong H, et al. Rapamycin induces Smad activity in prostate cancer cell lines. Urol Res
25.Powers MW, Workman P. Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocr Relat Cancer
. 2006;13(suppl 1):S125–S135.
26.Xiao L, Lu X, Ruden DM. Effectiveness of hsp90 inhibitors as anti-cancer drugs. Mini Rev Med Chem
27.Asea A, Ara G, Teicher BA, et al. Effects of the flavonoid drug quercetin on the response of human prostate tumours to hyperthermia in vitro and in vivo. Int J Hyperthermia
28.Jones EL, Zhao MJ, Stevenson MA, et al. The 70 kilodalton heat shock protein is an inhibitor of apoptosis in prostate cancer. Int J Hyperthermia
29.Juang T, Neuman D, Schlorff J, et al. Construction of a conformal water bolus vest applicator for hyperthermia treatment of superficial skin cancer. Conf Proc IEEE Eng Med Biol Soc
30.Lilly MB, Brezovich IA, Atkinson WJ. Hyperthermia induction with thermally self-regulated ferromagnetic implants. Radiology
31.Meijer JG, van Wieringen N, Koedooder C, et al. The development of PdNi thermoseeds for interstitial hyperthermia. Med Phys
32.Wust P, Gneveckow U, Johannsen M, et al. Magnetic nanoparticles for interstitial thermotherapy–feasibility, tolerance and achieved temperatures. Int J Hyperthermia
33.Wust P, Cho CH, Hildebrandt B, et al. Thermal monitoring: invasive, minimal-invasive and non-invasive approaches. Int J Hyperthermia
34.Gellermann J, Hildebrandt B, Issels R, et al. Noninvasive magnetic resonance thermography of soft tissue sarcomas during regional hyperthermia: correlation with response and direct thermometry. Cancer
35.Perez CA, Pajak T, Emami B, et al. Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group. Am J Clin Oncol
36.Emami B, Scott C, Perez CA, et al. Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors. A prospectively controlled randomized study by the Radiation Therapy Group. Int J Radiat Oncol Biol Phys
37.Vernon CC, Hand JW, Field SB, et al. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys
38.Jones EL, Oleson JR, Prosnitz LR, et al. Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol
39.van der Zee J, González González D, van Rhoon GC, et al. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet
40.Sneed PK, Stauffer PR, McDermott MW, et al. Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost +/− hyperthermia for glioblastoma multiforme. Int J Radiat Oncol Biol Phys
41.Valdagni R, Amichetti M. Report of long-term follow-up in a randomized trial comparing radiation therapy and radiation therapy plus hyperthermia to metastatic lymph nodes in stage IV head and neck patients. Int J Radiat Oncol Biol Phys
42.Overgaard J, Gonzalez Gonzalez D, Hulshof MC, et al. Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology. Int J Hyperthermia
43.Needham D, Anyarambhatla G, Kong G, et al. A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model. Cancer Res
44.Horkan C, Dalal K, Coderre JA, et al. Reduced tumor growth with combined radiofrequency ablation and radiation therapy in a rat breast tumor model. Radiology