Hyperthermia Therapy for Cancer

Questions from the Clinic:

What is hyperthermia? Are there different kinds of hyperthermia therapies? In which cancers are hyperthermia therapies most effective? Is it safe?

I. Introduction

Hyperthermia or the heating of body tissue to temperatures of 40 to 42°C (104 to 107.6 °F) is among the oldest forms of cancer treatment known to humanity. According to surviving records, the Egyptians, Greeks, and Romans used vapors from heated liquids to treat breast cancer; similar heat-based treatment methods also appear to have been known in ancient India.(1) In modern medicine, Swedish gynecologist Frans Westermark pioneered the use of hyperthermic therapy in cancer patients and published a case report in 1898. In his report, Westermark noted that he was able to achieve an “excellent response” in locally advanced cervical carcinomas by running hot water through an intracavitary spiral tube.(2,3) The next year, Gottschalk confirmed Westermark’s findings in patients with cervical cancer and offered suggestions on how to improve outcomes further.(4) Despite these compelling data, scientific interest in hyperthermia as a cancer treatment waned into the 20th century. The discovery and widespread application of penicillin in the 1930s substantially reduced the number of patients experiencing high fever secondary to bacterial infections – a patient population in which clinicians sometimes observed spontaneous tumor regression.(1)

After several decades of relative obscurity, hyperthermia therapy in cancer is experiencing a resurgence in popularity.(5) Scientific insights clarifying the biological mechanisms underlying hyperthermia and better delivery technologies have both made heat therapy an increasingly viable complement to standard cancer treatment protocols.

Although chemotherapy, radiotherapy, and other modern treatments are effective in treating many cancers, these options often induce highly undesirable side effects like cachexia, fatigue, and pain.(6) Considering these limitations, better tolerated, low-cost treatment strategies are increasingly in demand by healthcare professionals and patients alike.

II. Mechanism of Action

Figure 1: A demonstration of regional hyperthermia. Improvements in medical technology have helped make this adjunctive cancer technique more popular and feasible in recent years. Image courtesy of Orange County and Radiation Oncology Cancer Center.

Although hyperthermia alone generally cannot fully eradicate cancer cells, it can enhance the efficacy of cytotoxic drugs and radiation.(4) At the molecular level, higher temperatures increase the fluidity of tumor cell membranes, which makes it easier for drugs to permeate this outer barrier.(7) Concurrently, by increasing blood flow, hyperthermia abolishes the protective, hypoxic tumor microenvironment and leaves cancer cells vulnerable to radiotherapy.(8) Directing heat at a targeted tumor site additionally stimulates a robust, antitumor response from the immune system. In response to heat, the body synthesizes heat shock proteins (HSPs), which participate in signaling pathways that culminate in enhanced T-cell, B-cell, and dendritic cell activation.(9,10) Finally, higher temperatures also facilitate the trafficking of immune cells across the tumor vascular barrier.(11) Because of their modified vasculature, tumor cells are highly thermosensitive and will undergo apoptosis (cell death) at lower temperatures (42°C) than will adjacent, healthy cells (45°C).(12) Consequently, hyperthermia can kill cancer cells at the proper temperature range while leaving normal cells unscathed.

Most clinical applications of hyperthermia are regionalized to a section of the body, such as the involved tumor bed or compartment of invasion, while the whole body maintains a stable base temperature. For optimal results, clinical hyperthermia requires close monitoring of core temperatures while the targeted sections of the body undergo heating. Some of the human body’s core proteins undergo denaturation at temperatures of 45°C or higher, although the precise threshold depends on the area of the body. Unsupervised attempts to heal the body with baths, infrared saunas, or steam baths may offer some independent health benefits, but these protocols will not match the level of benefits possible with clinical hyperthermic treatments for cancer. In baths, saunas, or steam baths, the body will attempt to maintain homeostasis by dispersing heat through peripheral vasodilation and sweating. As such, attempts at “home hyperthermia” efforts are highly discouraged and can prove dangerous in patients with poor functional status or an inability to tolerate high temperatures.

III. Clinical Trial Data

Available scientific evidence suggests that hyperthermia is effective in addressing soft tissue malignancies, particularly sarcomas. In an open-label, phase 3 randomized trial, researchers compared the efficacy and tolerability of regional hyperthermia coupled with chemotherapy against chemotherapy alone in adult patients with soft tissue sarcoma. At a median follow-up of approximately 11 years, study investigators found that hyperthermia with chemotherapy led to a 27% improvement in survival compared with chemotherapy alone.(13) This improvement, in progression-free survival, mirrors the benefits observed in older studies gauging the value of hyperthermia in bladder cancer, metastasizing breast cancer, and melanoma.(14,15) Notably, because of its mechanism of action, hyperthermia may also have considerable value in malignancies characterized by hypoxia, like pancreatic cancer. Authors of a meta-analysis noted a trend towards significance favoring the use of hyperthermia to treat these patients with regional and whole-body hyperthermia. That said, the quality of evidence from the studies was low, leading the analysts to conclude that more randomized controlled trials are needed to confirm its efficacy.(16) To date, one Cochrane review exists on concomitant hyperthermia and radiation therapy in the context of rectal cancer. Across the six randomized trials included in the review, researchers concluded that hyperthermia had an additional positive effect when paired with radiotherapy in patients with advanced rectal cancer.(17)

Currently, there are 133 studies registered with Clinicaltrials.gov that are actively assessing hyperthermia in patients with various forms of cancer.(18) Many are specifically testing a procedure known as hyperthermic intraperitoneal chemotherapy, often abbreviated as HIPEC. Sometimes called “hot chemotherapy,” HIPEC entails filling the abdominal cavity with heated chemotherapy drugs for approximately 90 minutes (Figure 2) after the removal of tumors and lesions.(19) Compared with standard chemotherapy, HIPEC has many advantages for patients and physicians alike. Logistically, HIPEC is a single procedure instead of one that is performed multiple times over several weeks. Additionally, it allows for a more targeted, intensive dose of chemotherapy. Because the drugs are physically confined, there are also fewer toxic effects on the rest of the body.(20) Clinical trials are currently testing its effectiveness in unresectable colorectal cancer and gastric cancers; HIPEC is already an option for advanced cancers, like appendiceal cancer and peritoneal mesothelioma, that has spread throughout the abdomen.(20)

Figure 2: A simplified diagram illustrating how hyperthermic intraperitoneal chemotherapy is administered in patients. The advantages of HIPEC have attracted the attention of researchers, who are evaluating its benefit in a variety of advanced cancers. Image courtesy of Oncohemakey.com

IV. Cost and Availability

The precise cost of hyperthermia treatment is difficult to determine, as patients seeking care have different kinds of cancer at various stages and may be eligible for a variety of chemotherapy drugs. According to the Hyperthermia Cancer Institute, based out of Santa Monica, CA, medical insurers like United Healthcare and Anthem Blue Cross will consider hyperthermia treatment on a case-by-case basis.(21) Functional oncology cancer treatment centers, like Angeles Health International, provide both regional and systemic hyperthermia to patients with cancer and quote patients between $25,000 and $35,000 for their treatment protocol.(22) More “mainstream” medical providers, like Chicago’s Loyola Medical Center, offer hyperthermia for breast, cervical, prostate, and rectal cancer, as well as for soft-tissue sarcoma. Prospective patients interested in learning more about hyperthermia and its associated costs are encouraged to schedule a telehealth appointment online or to call them at a dedicated phone line.(23)

V. Conclusions & Future Directions

New scientific evidence is increasingly validating the use of hyperthermia – one of humanity’s oldest naturally-based therapies for cancer. Although high temperatures alone cannot eradicate malignancies, heat appears invaluable in making cancer cells much more susceptible to chemotherapies and radiotherapies that constitute the backbone of modern cancer medicine. Hyperthermia’s ability to negate the protective effects of hypoxia on cancer cells makes it particularly invaluable in cancers that have historically resisted treatment, like bladder and prostate cancers. While many investigations have already yielded promising results in many cancers, hyperthermia requires further examination in high-quality clinical trials with larger sample sizes, well-defined staging, and clearly defined protocols. As mentioned above, such trials are in progress and currently enrolling patients. Despite the limitations in some of the available scientific literature though, the data together indicate that hyperthermia is a valuable, complementary therapy warranting clinicians’ consideration in many types of cancer. The remarkable success of hyperthermia, particularly HIPEC, makes it a justifiably “hot topic” in the ever-changing world of cancer therapy.

Stay strong and curious,

- Chuck

Charles J. Meakin MD, MHA, MS

Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.

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1 Datta NR, Ordonez SG, Gaipl US, et al. Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future. Cancer Treat Rev. 2015;41(9):742-753.

2 Januszewski A. Hyperthermia in cancer: is it coming of age? Lancet Oncol. 2014;15(6):565-566.

3 Westermark F. Uber die behandlug des ulcerierenden Cervixcarcimons mittels knostanter Warme. Zentralblatt fur Gynakologie. 1898;22:1335-1337.

4 Gottschalk S. Zur behandlung des ulcerierenden inoperablen Cervixcarcinoms. Zentralblatt fur Gynakologie. 1899;3:79-80.

5 Yi GY, Kim MJ, Kim HI, et al. Hyperthermia treatment as a promising anti-cancer strategy: therapeutic targets, perspective mechanisms and synergistic combinations in experimental approaches. Antioxidants (Basel). 2022;11(4):625.

6 Side effects of cancer treatment. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/side-effects/. Accessed April 30, 2022.

7 Reinhold HS, Endrich B. Tumor microcirculation as a target for hyperthermia. Int J Hyperthermia. 1986;2:111-137.

8 Cheng Y, Weng S, Yu L, et al. The role of hyperthermia in the multidisciplinary treatment of malignant tumors. Integr Cancer Ther. 2019;18:1-11.

9 Multhoff G, Pockley AG, Streffer C, et al. Dual role of heat shock proteins (HSPs) in anti-tumor immunity. Curr Mol Med. 2012;12:1174-1182.

10 Gandhapudi SK, Murapa P, Threlkeld ZD, et al. Heat shock transcription factor 1 is activated as a consequence of lymphocyte activation and regulates a major proteostasis network in T cells critical for cell division during stress. J Immunol. 2013;191:4068-4079.

11 Vardam TD, Zhou L, Appenheimer MM, et al. Regulation of a lymphocyte-endothelial-IL-6 trans-signaling axis by fever-range thermal stress: hot spot of immune surveillance. Cytokine. 2007;39:84-96.

12 University College London. Heat treatment may make chemotherapy more effective. ScienceDaily. https://www.sciencedaily.com/releases/2021/01/210105130114.htm/. Published January 5, 2021. Accessed April 30, 2022.

13 Issels RD, Lindner LH, Verweij J, et al. Effect of neoadjuvant chemotherapy plus regional hyperthermia on long-term outcomes among patients with localized high-risk soft tissue sarcoma. JAMA Oncol. 2018;4(4):483-492.

14 Owusu RA, Abern MR, Inman BA. Hyperthermia as adjunct to intravesical chemotherapy for bladder cancer. BioMed Res Int. 2013;2013:262313.

15 Mantso T, Vasileiadis S, Anestopoulos I, et al. Hyperthermia induces therapeutic effectiveness and potentiates adjuvant therapy with non-targeted and targeted drugs in an in vitro model of human malignant melanoma. Sci Rep. 2018;8:10724.

16 Van der Horst A, Versteijne E, Besselink MGH, et al. The clinical benefit of hyperthermia in pancreatic cancer: a systematic review. Int J Hyperthermia. 2018;34(7):969-979.

17 De Haas-Kock D, Buijsen J, Pijls-Johannesma M, et al. Concomitant hyperthermia and radiation therapy for treating locally advanced rectal cancer. Cochrane Database Syst Rev. 2009;3:CD006269.

18 ClinicalTrials.gov Results: Hyperthermia | Cancer. https://clinicaltrials.gov/ct2/results?term=hyperthermia&cond=cancer&Search=Apply&recrs=d&age_v=&gndr=&type=&rslt=. Accessed April 30, 2022.

19 Fox Chase Cancer Center. Hyperthermic intraperitoneal chemotherapy (HIPEC). Fox Chase Cancer Center. https://www.foxchase.org/clinical-care/departments-programs/clinical-departments/surgical-oncology/surgical-techniques/hipec/. Accessed April 30, 2022.

20 The University of Texas: MD Anderson Cancer Center. Hyperthermic intraperitoneal chemotherapy. The University of Texas: MD Anderson Cancer Center. https://www.mdanderson.org/treatment-options/hyperthermic-intraperitoneal-chemotherapy.html/. Accessed April 30, 2022.

21 Hyperthermia Cancer Institute. Insurance coverage. Hyperthermia Cancer Institute. https://hcioncology.com/insurance-coverage/. Updated 2022. Accessed April 30, 2022.

22 Angeles Health International. Hyperthermia: functional oncology alternative cancer treatment. Angeles Health International. https://www.angeleshealth.com/hyperthermia-therapy-for-cancer/. Accessed April 30, 2022.

23 Loyola Medicine. Hyperthermia: regional or local heat therapy for cancer treatment. Loyola Medicine. https://www.loyolamedicine.org/find-a-condition-or-service/cancer/cancer-treatments/radiation-therapy/hyperthermia/. Accessed April 30, 2022.