Cancer tumour

Integrative Hyperthermia

Hyperthermia (HT) is a useful treatment to use alongside most chemotherapy (CT) regimens, as well as radiotherapy (RT) schedules, in the management of most solid tumours. I will summarize some of the best evidence available today, in support of Loco-Regional HT and it’s sensitizing effects on both these crucial standard of care treatments. In most randomized studies to date, HT makes both these treatments significantly more effective in the local control of the disease, it improves quality of life, and it increases overall survival.

Very generally, I prescribe the use of HT alongside each IV chemotherapy treatment (ideally within the first half-life/same day of chemo infusion), and three times weekly during RT protocols. If a chemotherapeutic is being used orally, it is taken by mouth an hour before each HT treatment, to allow it to circulate. HT is then applied to direct the chemotherapeutic to target. Here are some of the mechanisms we know that make these combination treatments more effective than either alone.

HT + CT

HT makes many chemotherapy and molecularly targeted agents more effective, mainly by accelerating their primary mode of action (1-10);

  1. Improves the Alkylating action of this class of drugs
  2. Induces protein damage & DNA strand breaks
  3. Production of oxygen radicals

HT improves the vascular perfusion of tumours as well as the oxygenation of the tissue. Since the blood vessels grown in tumours are weak and disordered, HT causes the drugs to “leak” out into the tumour. This improves delivery of the drug into target tissue, and the improved oxygenation allows the drugs to work better.

Many CT agents have been shown to have improved effects when combined with HT, including; melphalan, cyclophosphamide, nitrogen mustards, anthracyclines, nitrosureas, bleomycin and mitomycin C (11-13). To date, a lack of Interaction has been found with etoposide and vinca alkaloids (11)

HT + RT

There are a number of complimentary effects between RT and HT including (14-22);

  1. Cancer cells in S-phase are relatively resistant to RT, but are also the most sensitive to HT. The combination therefore allows more cells, in various stages of their life cycles, to be killed.
  2. Hypoxic cells are 3 times more resistant to RT than aerobic cells. This means that if cells are not receiving adequate oxygen through adequate circulation and other factors, they do not respond as well to RT. Conversely, there is no difference in the thermal sensitivity to HT between aerobic and hypoxic cells.
  3. There is good evidence in human soft tissue sarcoma and locally advanced breast cancer, that HT causes the re-oxygenation of the target tissue, further improving RT response (15,19)
  4. HT inhibits the repair of protein damage caused by itself, RT or CT, by inactivating crucial DNA repair pathways and mechanisms (21,22)

Any treatment that is able to maximize the potential of today’s best standards of practice while improving quality of life is worthy of further study. It is my sincere expectation that HT will one day be used alongside most CT and RT schedules, because of it’s ability to make them work better without adding much more in the way of toxicity and complications. This has been our experience over the past two years at IHC, where we have now completed over 3,000 treatments. Having experience treating most of today’s most prevalent solid tumour types. We are collecting this critical information and hope to publish some initial data on our patient’s outcomes late this year.

In Health,

Gurdev Parmar, B.Sc., ND

References

  1. Issels RD, et al. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 2010 Jun;11(6):561-70.
  2. Jones EL, et al. A pilot Phase II trial of concurrent radiotherapy, chemotherapy, and hyperthermia for locally advanced cervical carcinoma. Cancer. 2003;98:277–282.
  3. Issels RD, Abdel-Rahman S, Wendtner C, et al. Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk adult soft- tissue sarcomas (STS) of adults: long-term results of a phase II study. Eur J Cancer. 2001;37:1599–1608.
  4. Rau B, et al. Phase II study on preoperative radio-chemo- thermotherapy in locally advanced rectal carcinoma. Strahlenther Onkol. 1998;174:556–565.
  5. 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. 1998;40:287–295.
  6. Bornstein BA, et al. Pilot study of local hyperthermia, radiation therapy, etanidazole, and cisplatin for advanced superficial tumours. Int J Hyperthermia. 1995;11:489–499.
  7. Vaden SL, et al. Effect of hyperthermia on cisplatin and carboplatin disposition in the isolated, perfused tumour and skin flap. Int J Hyperthermia. 1994;10:563–572.
  8. Herman TS, et al. Effect of hypoxia and acidosis on the cytotoxicity of mitoxantrone, bisantrene and amsacrine and their platinum complexes at normal and hyperthermic temperatures. Anticancer Res. 1992;12:827–836.
  9. Urano M, et al. The effect of 5-fluorouracil at elevated temperatures on a spontaneous mouse tumour: Arrhenius analysis and tumour response. Int J Radiat Biol. 1991;59:239–249.
  10. Herman TS, et al. Rationale for use of local hyperthermia with radiation therapy and selected anticancer drugs in locally advanced human malignancies. Int J Hyperthermia. 1988;4:143–158.
  11. Dahl O. Interaction of heat and drugs in vitro and in vivo. In: Seegenschmiedt M, Fessenden P, Vernon C, eds. Thermoradiotherapy and Thermochemotherapy. Berlin: Springer Verlag; 1995:103–155.
  12. Herman TS, et al. Effect of hypoxia and acidosis on the cytotoxicity of mitoxantrone, bisantrene and amsacrine and their platinum complexes at normal and hyperthermic temperatures. Anticancer Res. 1992;12:827–836.
  13. Herman TS, Teicher BA, Jochelson M, Clark J, Svensson G, Coleman CN. Rationale for use of local hyperthermia with radiation therapy and selected anticancer drugs in locally advanced human malignancies. Int J Hyperthermia. 1988;4:143–158.
  14. Van der Zee J, 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. 2000;355:1119–1125.
  15. Prosnitz LR, et al. The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy. Int J Radiat Oncol Biol Phys. 1999;45:941–949
  16. Vernon CC, 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. 1996;35:731– 744.
  17. Emami B, 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. 1996;34:1097–1104.
  18. Overgaard J, et al. Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology. Lancet. 1995;345:540–543.
  19. Perez CA, 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. 1991;14:133– 141.
  20. Datta NR, et al. Head and neck cancers: results of thermoradiotherapy versus radiotherapy. Int J Hyperthermia. 1990;6:479–486.
  21. Raaphorst GP, Ng CE, Yang DP. Thermal radiosensitization and repair inhibition in human melanoma cells: a comparison of survival and DNA double strand breaks. Int J Hyperthermia. 1999;15:17–27.
  22. Overgaard J. The current and potential role of hyperthermia in radiotherapy. Int J Radiat Oncol Biol Phys. 1989;16:535–549.

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