Immunotherapy Series – Anti-Cancer Benefits of Hyperthermia

Anti-Cancer Benefits of Hyperthermia

I recently had a patient that told me that her Oncologist was uncomfortable with the course of her treatment. What was the Oncologist doing that stirred such concern? The Oncologist had to use lower and lower doses of chemotherapy secondary to side effects and poor tolerability encountered by the patient due to treatment. Yet, the Oncologist was perfectly comfortable with the high-dose, side-effect-laden, toxic doses of chemotherapy. Where are we now in a place in medicine where toxicity is the directed and intending goal of treatment; but, the lower side effects and expanded anti-cancer effects of low-dose metronomic chemotherapy are not? Hmmm. Up is down, and down is up. Crazy times!

Surgery, chemotherapy, and radiation are the original trinity of conventional cancer treatment. I call them the unholy trinity of cancer treatment. Unholy, because there is nothing holy in the individual and collective destruction to the body that they cause. None have brought the answer to the treatment and healing of cancer. Sure, each has provided some targeted benefit, and they have their role. That being said, they are unholy. How could I make such a statement? The answer is relatively easy. Research clearly and repeatedly points to the facts that surgery ^{[1] [2] [3]}, chemotherapy ^{[4] [5] [6] [7] [8]}, and radiation ^{[9] [10] [11]} cause the metastatic spread of cancer. It is ok to re-read that sentence, and you did read that right. This statement is a significant point because 90% of mortality and morbidity of cancer are the result of metastasis ^{[12] [13] [14] [15]}. Metastasis is the spread of cancer cells from the place where they first formed to another part of the body. Beyond the obvious direct harm of surgery, chemotherapy, and radiation, there is the absolute harm in the morbidity and mortality of metastasis.

In steps conventional immunotherapy to try and answer the question of cancer. Now we have the trinity + 1. Immunotherapy is really just modern-day chemotherapy that works within the immune system. Its paradigm and mode of action are a mere modern-day upgrade of chemotherapy. The target is just the immune system disaffected by cancer and not the growth cycle of the cancer cell. I discussed immunotherapy in the first post in this series, so check that out here.

As I said above, chemotherapy and radiation can have a beneficial role in cancer treatment strategy. Those of us in the Holistic, Integrative cancer movement have to recognize these therapies’ contributions when they are required. Of course, Dr. Lodi and I prefer low-dose chemotherapy if chemotherapy is required. We prefer no radiation, but if major organ function is compromised or threatened and radiation is indicated, then limit the exposure. The same applies to conventional immunotherapy; when needed, target its delivery and limit the exposure. Just as surgery, chemotherapy, and radiation were not the answer, conventional immunotherapy is not the answer to cancer.

According to a 2013 Clinical Cancer Research article—Exposure-response relationships of the efficacy and safety of ipilumumab in patients with advanced melanoma published in Clinical Cancer Research:

“Accumulating evidence suggests that only a fraction of cancer patients benefit from checkpoint inhibitors, and severe immune-related adverse events (irAEs) are seen in some patients undergoing ICI (immune checkpoint inhibitor) therapy” ^[16].

Time for some evidence—the receipts, please. The good news is that hyperthermia augments chemotherapy. In addition, hyperthermia augments radiation and conventional immunotherapy—more on these topics later. This augmentation increases the individual therapy effectiveness, yet allows the lowering of chemotherapy, radiation, and immunotherapy dose to limit side effects. Now that is a novel concept—augmentation of efficacy, yet reduction in side effects. Even though chemotherapy, radiation, and conventional immunotherapy are not the final answers to cancer, hyperthermia still augments their anti-cancer effects ^[17].

Hyperthermia augments chemotherapy

Chemoresistance and the production of Cancer Stem Cells (CSCs) are crucial steps in the metastatic spread of cancer and are significant problems with the conventional mindset to full-dose chemotherapy. If you keep going back to the same well over and over again, eventually, that well is going to dry up. The result is more than one dry well; this approach leads to the drying up of all other treatment wells because of the cancer treatment resistance that results. This is one of the many risks associated with the high-dose approach of chemotherapy. Too many times, I have seen patients that have received twelve plus consecutive months of chemotherapy. The result of this over-the-top dosing of chemotherapy is chemoresistance—a cancerous tumor that no longer responds to treatment with chemotherapy. Cancer rarely responds to any treatment at the point that resistance develops. The literature is repetitive and very clear on how this chemoresistance happens ^[18]. A few examples include:

• Low oxygen in the tumor microenvironment—called hypoxia
• Acidosis of the tumor microenvironment—not the whole body
• Nutrient depletion
• Increased interstitial fluid pressure within the tumor microenvironment
• Low delivery of drug concentrations
• Low intra-tumoral concentrations of drug
• Reduced effectiveness of intra-tumoral drugs
• Increased elimination of drug

Hyperthermia to the prevention and rescue of chemoresistance! This rescue occurs in a multitude of ways.

Hyperthermia overcomes chemoresistance

Hyperthermia overcomes tumor chemoresistance and restores chemosensitivity ^{[19] [20]}. Chemoresistance is when a tumor and cancer cells become resistant to chemotherapy. Chemosensitivity is any treatment that increases the sensitivity and susceptibility of a tumor and cancer cells to chemotherapy. Chemoresistance is a significant obstacle in any cancer treatment strategy. It is one thing to prevent chemoresistance or to augment chemosensitivity when no resistance exists. It is quite another to overcome chemoresistance and to restore chemosensitivity where it is lost.

Hypoxia is one of the key, primary holistic causes of cancer. I discussed this topic in great detail in a previous blog post series. In addition, hypoxia is a major driving force behind chemoresistance. The hypoxia-induced oncogenic transformation has been shown to lead to treatment resistance with many chemotherapy agents (cisplatin, doxorubicin, etoposide, melphalan, 5-fluorouracil, gemcitabine, vincristine, methotrexate, and docetaxel) ^{7 [21] [22] [23]}. Interestingly enough, it is the high dose delivery of chemotherapy that is a significant contributor to the development of this potential resistance ^[24]. This process occurs through the activation of several hypoxia signals. Hypoxia-Inducible Factor-1 (HIF-1) is one of these critical signals activated by hypoxic conditions within the tumor microenvironment. A 2015 article, entitled Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1, eloquently states this point:

“It is the result of imbalances in the intake and consumption of oxygen. This results from vascularization that is structurally and functionally abnormal, coupled with high proliferation rates in tumor cells.” ⁷

In response to hypoxic conditions, tumors express HIF-1, particularly HIF-1alpha (α). Hypoxia-Inducible factor-1α is stabilized in these hypoxic conditions, whereas in normal oxygen conditions (normoxia), it is broken down. The stabilized HIF-1α then is transported to the cell nucleus where it combines with HIF-1beta (β), and it is this complex that triggers genetic transcription of hundreds of genes that promote oncogenic transformation, oncogenic metabolism, and immune system dysfunction. Also, HIF-1 stabilization under hypoxia leads to the expression of PDK1 protein that phosphorylates and inactivates pyruvate dehydrogenase (PDH), and limits the conversion of pyruvate to acetyl-CoA in the mitochondria. Consequently, PDK1 induction decreases the citric acid cycle (TCA cycle) activity and reduces oxygen consumption. Amazingly, all this impact only affects  approximately 1% of human genes ^[25]. So, it is the alteration of the 1% by hypoxia that drives the process called cancer. The result is an increase in cancer aggressiveness, and you guessed it—chemoresistance.

Just a few examples of how HIF-1 induces chemoresistance ⁷:

• Increase Multidrug Resistance 1 proteins (MDR1) which protect the cancer cells by transporting chemotherapy out of the cell
• Decrease in Topoisomerase II
• Reduce chemotherapy-induced program cell death—a process called apoptosis
• Reduce chemotherapy-induced senescence
• Chemotherapy-induced autophagy
• Reduction in Reactive Oxygen Species (ROS)
• Reduction in cancer DNA damage by treatment

The best way to counter the tumor microenvironment’s lack of oxygen (hypoxia) is to deliver oxygen. Hyperthermia counters the tumor’s hypoxia environment and its associated tumor microenvironment through the increase in the delivery of oxygen to the tumor microenvironment. The result is a decrease in HIF-1 signaling and a reduction in chemoresistance ^[26]. This approach is the same objective for other holistic cancer treatments such as hyperbaric oxygen therapy and Ozone therapy.

Hyperthermia augments Chemosensitivity

Regardless of the presence of chemoresistance, hyperthermia augments the chemosensitivity of a variety of different chemotherapy agents ^{[27] [28] [29]} .  Hyperthermia has been shown to augment the direct cancer-killing effects (cytotoxicity) of radiation and chemotherapy. This hyperthermic effect is called thermal radiosensitization and thermal chemosensitization, respectively ^[30]. Hyperthermia, in close sequence or simultaneous, to many chemotherapy agents has been shown to augment the chemosensitivity ^{[31] [32]} of cancer cells with improved treatment outcomes ^[33]. To be specific, hyperthermia has been shown to increase the effectiveness of cisplatin and other platinum-based chemotherapies by up to 10 fold and increase the effectiveness of the metronomic delivery of cisplatin ^{[34] [35]}. Now that is a novel concept—a treatment that improves sensitivity, enables a lower dose, reduces toxicities, and maintains the effectiveness of treatment. Better yet, the lower dose and metronomic delivery of chemotherapy actually expands its therapeutic effects. The previous series on Low-dose metronomic chemotherapy (LDMC) shows that LDMC actually expands the anti-cancer effects compared to full-dose chemotherapy. One day soon, Dr. Lodi and I hope that the treatment of cancer will no longer require chemotherapy. That will be a great day! However, until that time, we can lower the dose, augment with hyperthermia and other holistic, integrative therapies that improve chemosensitivity, like high-dose IV vitamin C ^[36], and limit the side effects.

Hyperthermia affects tumor accumulation

Hyperthermia increases the accumulation and distribution of chemotherapy within tumors ^[37]. In this way, hyperthermia is acting as a cancer-targeting mechanism. Hyperthermia is the funnel to flood cancer and its local tumor microenvironment with targeted therapy. This targeting is similar to the targeting of cancer via insulin with low-dose, metronomic chemotherapy. Both target perceived cancer advantages to turn into a cancer disadvantage for a patient healing advantage.

The question is, how does hyperthermia flood the tumor microenvironment zone? It does this in several ways. First, it increases the blood flow into the tumor microenvironment ^[38]. Think of this process as a super lane highway. Hyperthermia creates a six-lane superhighway into the tumor and associated microenvironment. One caveat to this point, it is only at the lower temperatures, < 42 °C, that this increase in blood flow occurs.

In contrast, temperatures > 42 °C actually decrease the tumor blood flow. Second, it increases vascular permeability. It is one thing to increase the blood flow via the super lane highway analogy, and it is quite another also to increase the exit ramps off to deliver treatment. The increase in delivery is exactly what increasing vascular permeability accomplishes. The third mechanism targets the acidic nature of the tumor microenvironment. This point hits at the heart of the oncogenic metabolic transformation of cancer. As Otto Warburg described, via aerobic glycolysis, cancer increases the production of lactic acid via the altered metabolism common to cancer. This lactic acid is pumped out of the cancer cells into the tumor microenvironment to create an acidic barrier to block immune infiltration. In a counter to the acidic environment, hyperthermia increases the pH of the tumor microenvironment. Restated, hyperthermia counters the lactic acid rich, acidic environment through the alkalinization of the tumor microenvironment ²⁶. This weakens part of the protective shell around cancer and the local tumor microenvironment to allow penetration of the immune system and other therapeutics. Lastly, hyperthermia at temperatures < 41 °C increases the tissue oxygen tension (TpO2) of the tumor microenvironment ^[39]. Restated, it increases the oxygen delivery into the tumor tissue. Cancer loves hypoxia. In many ways, hypoxia is the driving force behind the oncogenic metabolic transformation, oncogenic epigenetic changes,  oncogenic signaling, and oncogenic immune disruption characteristics of cancer. The hyperthermia induced increase in TpO2 disrupts the dominant hypoxia and eases targeted therapies’ delivery into the tumor microenvironment.

Hyperthermia increases cytotoxicity

It is one thing to increase the lanes to the tumor, increase the exit ramps to the tumor, and increase the tumor accumulation of the drugs. It is another to increase the anti-cancer cytotoxic (cancer-killing) effects. The assumption is that all this will increase treatment effects. We have all heard the idiom, you can lead a horse to water, but you can’t make it drink. If the targeted therapies reach the cancer and local tumor microenvironment targets and have little to no effect, what really has been done? But, if hyperthermia increases the delivery and increases the anti-cancer effects—now that is something. In fact, that is the case. Hyperthermia facilitates the cancer-killing effects of chemotherapy once it arrives and accumulates in the tumor and tumor microenvironment ^{[40] [41]}.

What is the final result? The result is an increase in overall chemotherapy effectiveness. Add in low-dose metronomic chemotherapy, other holistic, integrative therapies like high-dose IV vitamin C, and the stage is set for some serious anti-cancer fireworks.

---

^[1] Dillekås H, Demicheli R, Ardoino I et al. The recurrence pattern following delayed breast reconstruction after mastectomy for breast cancer suggests a systemic effect of surgery on occult dormant micrometastases. Breast Cancer Res Treat. 2016;158:169–178. https://doi.org/10.1007/s10549-016-3857-1

^[2] Yang W, Cai J, Zabkiewicz C, Zhang H, Ruge F, Jiang WG. The Effects of Anesthetics on Recurrence and Metastasis of Cancer, and Clinical Implications. World J Oncol. 2017;8(3):63-70. doi:10.14740/wjon1031e

^[3] Coffey JC, Wang JH, Bouchier-Hayes D, Cotter TG, Redmond HP. The targeting of phosphoinositide-3 kinase attenuates pulmonary metastatic tumor growth following laparotomy. Ann Surg. 2006;243(2):250-256. doi:10.1097/01.sla.0000197712.71055.12

^[4] D’Alterio C, Scala S, Sozzi G, Roz L, Bertolini G. Paradoxical effects of chemotherapy on tumor relapse and metastasis promotion. Semin Cancer Biol. Feb 2020;60:351-361. doi: 10.1016/j.semcancer.2019.08.019.

^[5] Karagiannis GS, Condeelis JS, Oktay MH. Chemotherapy-induced metastasis: mechanisms and translational opportunities. Clin Exp Metastasis. 2018;35(4):269-284. doi:10.1007/s10585-017-9870-x

^[6] Karagiannis GS, Condeelis JS, Oktay MH. Chemotherapy-induced metastasis in breast cancer. Oncotarget. 2017;8(67):110733-110734. doi:10.18632/oncotarget.22717

^[7] Liu K, Min XL, Peng J, Yang K, Yang L, Zhang XM. The Changes of HIF-1α and VEGF Expression After TACE in Patients With Hepatocellular Carcinoma. J Clin Med Res. 2016;8(4):297-302. doi:10.14740/jocmr2496w

^[8] Karagiannis GS, Condeelis JS, Oktay MH. Chemotherapy-Induced Metastasis: Molecular Mechanisms, Clinical Manifestations, Therapeutic Interventions. Cancer Res. 2019 Sep 15;79(18):4567-4576. doi: 10.1158/0008-5472.CAN-19-1147.

^[9] Lee SY, Jeong EK, Ju MK, et al. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol Cancer. Jan 2017;16(1):10. doi:10.1186/s12943-016-0577-4

^[10] Li D, Qu C, Ning Z, et al. Radiation promotes epithelial-to-mesenchymal transition and invasion of pancreatic cancer cell by activating carcinoma-associated fibroblasts. Am J Cancer Res. Oct 2016;6(10):2192-2206.

^[11] De Bacco F, Luraghi P, Medico E, Reato G, Girolami F, Perera T, Gabriele P, Comoglio PM, Boccaccio C. Induction of MET by Ionizing Radiation and Its Role in Radioresistance and Invasive Growth of Cancer. JNCI: Journal of the National Cancer Institute. Apr 2011;103(8):645–661. https://doi.org/10.1093/jnci/djr093

^[12] Bogenrieder T, Herlyn M. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene. 2003;22(42):6524‐6536.

^[13] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57‐70.

^[14] Dillekås H, Demicheli R, Ardoino I, Jensen SA, Biganzoli E, Straume O. The recurrence pattern following delayed breast reconstruction after mastectomy for breast cancer suggests a systemic effect of surgery on occult dormant micrometastases. Breast Cancer Res Treat. 2016;158(1):169‐178.

^[15] Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127(4):679‐695.

^[16] Feng Y. et al. Exposure–response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin. Can. Res. 2013;19,3977.

^[17] Frampton JE. Catumaxomab: in malignant ascites. Drugs. 2012;72:1399-1410.

^[18] Doktorova H, Hrabeta J, Khalil MA, Eckschlager T. Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. Jun 2015;159(2):166-77. doi: 10.5507/bp.2015.025

^[19] Raoof M, Zhu C, Cisneros BT, et al. Hyperthermia inhibits recombination repair of gemcitabine-stalled replication forks. J Natl Cancer Inst. 2014;106(8):dju183. Published 2014 Aug 15. doi:10.1093/jnci/dju183

^[20] Masunaga S, Ono K, Akaboshi M, Kawai K, Suzuki M, Kinashi Y, Takagaki M. Augmentation in Chemosensitivity of Intratumor Quiescent Cells by Combined Treatment with Nicotinamide and Mild Hyperthermia. Japanese Journal of Cancer Research. Aug 2005. https://doi.org/10.1111/j.1349-7006.1997.tb00449.x

^[21] Wust P, Hildebrandt B, Sreenivasa G, Rau B, Gellermann J, Riess H, Felix R, Schlag PM. Hyperthermia in combined treatment of cancer. Lancet Oncol. Aug 2002;3(8):487-97. doi: 10.1016/s1470-2045(02)00818-5.

^[22] Li DW, Dong P, Wang F, Chen XW, Xu CZ, Zhou L. Hypoxia induced multidrug resistance of laryngeal cancer cells via hypoxia-inducible factor-1α. Asian Pacific J. Cancer Prev. 2013;14:4853-8

^[23] Frolova O, Samudio I, Benito J, Jacamo R, Kornblau SM, Markovic A, Schober W, Lu H, Qiu YH, Buglio D, McQueen T, Pierce S, Shpall E, Konoplev S, Thomas D, Kantarjian H, Lock R, Andreeff M, Konopleva M. Regulation of HIF-1α signaling and chemoresistance in acute lymphocytic leukemia under hypoxic conditions of the bone mar- row microenvironment. Cancer Biol. Ther. 2012;13:858-70

^[24] Wang CY, Cusack JC Jr, Liu R, Baldwin AS Jr. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nat Med. Apr 1999;5(4):412-7. doi: 10.1038/7410.

^[25] Denko NC, Fontana LA, Hudson KM, Sutphin PD, Raychaudhuri S, Altman R, Giaccia AJ. Investigating hypoxic tumor physiology through gene expression patterns. Oncogene 2003;22:5907-1

^[26] Song CW, Park HJ, Lee CK, Griffin R. Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment. Int J Hyperthermia. Dec 2005;21(8):761-767.

^[27] Abiko T, Kawamura M, Izumi Y, Oyama T, Saito Y, Kobayashi K. Prediction of anti-tumour effect of thermochemotherapy with in vitro thermochemosensitivity testing for non-small cell lung cancer, International Journal of Hyperthermia. 2007;23(3):267-275. DOI: 10.1080/02656730701286333

^[28] Paroni R, Salonia A, Lev A, et al. Effect of local hyperthermia of the bladder on mitomycin C pharmacokinetics during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma. Br J Clin Pharmacol. 2001;52(3):273-278. doi:10.1046/j.0306-5251.2001.01449.x

^[29] Issels RD. Hyperthermia adds to chemotherapy. European Journal of Cancer. Nov 2008;44(17):2546-2554. https://doi.org/10.1016/j.ejca.2008.07.038

^[30] Hildebrandt B, Wust P, Ahlers O, Dieing A, Sreenivasa G, Kerner T, Felix R, Riess H. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol. Jul 2002;43(1):33-56. doi: 10.1016/s1040-8428(01)00179-2.

^[31] Hettinga JV, Lemstra W, Meijer C, Dam WA, Uges DR, Konings AW, De Vries EG, Kampinga HH. Mechanism of hyperthermic potentiation of cisplatin action in cisplatin- sensitive and -resistant tumour cells. Br J Cancer. 1997;75(12):1735-43.

^[32] de Wit R, van der Zee J, van der Burg ME, Kruit WH, Logmans A, van Rhoon GC, Verweij J. A phase I/II study of combined weekly systemic cisplatin and locoregional hyperthermia in patients with previously irradiated recurrent carcinoma of the uterine cervix. Br J Cancer. Jul 1999;80(9):1387-91. doi: 10.1038/sj.bjc.6690533.

^[33] Lee SY, Lee NR, Cho D, Kim JS. Treatment outcome analysis of chemotherapy combined with modulated electro-hyperthermia compared with chemotherapy alone for recurrent cervical cancer, following irradiation. Oncology Letters. 2017;14:73-78. https://doi.org/10.3892/ol.2017.6117

^[34] Rietbroek RC, van de Vaart PJM, Haveman J et al. Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation of lobaplatin and oxaliplatin in cultured SW 1573 cells. J Cancer Res Clin Oncol. 1997;123:6–12. https://doi.org/10.1007/BF01212608

^[35] Franckena M, De Wit R, Ansink AC, Notenboom A, Canters RA, Fatehi D, Van Rhoon GC, Van Der Zee J. Weekly systemic cisplatin plus locoregional hyperthermia: an effective treatment for patients with recurrent cervical carcinoma in a previously irradiated area. Int J Hyperthermia. Aug 2007;23(5):443-50. doi: 10.1080/02656730701549359.

^[36] Aboelella NS, Brandle C, Kim T, Ding ZC, Zhou G. Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy. Cancers (Basel). 2021;13(5):986. doi:10.3390/cancers13050986

^[37] Dunne M, Regenold M, Allen C. Hyperthermia can alter tumor physiology and improve chemo- and radio-therapy efficacy. Advanced Drug Delivery Reviews. 2020;163-164:98-124.

^[38] Seynhaeve ALB, Amin M, Haemmerich D, van Rhoon GC, Ten Hagen TLM. Hyperthermia and smart drug delivery systems for solid tumor therapy. Adv Drug Deliv Rev. 2020;163-164:125-144. doi: 10.1016/j.addr.2020.02.004.

^[39] Bicher HI, Hetzel FW, Sandhu TS, Frinak S, Vaupel P, O’Hara MD, O’Brien T. Effects of hyperthermia on normal and tumor microenvironment. Radiology. Nov 1980;137(2):523-30. doi: 10.1148/radiology.137.2.7433686.

^[40] Wismeth C, Dudel C, Pascher C, Ramm P, Pietsch T, Hirschmann B, Reinert C, Proescholdt M, Rümmele P, Schuierer G, et al: Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas: Phase I clinical results. J Neurooncol. 2010;98:395–405.

^[41] Sahinbas H, Grönemeyer DH, Böcher E and Szasz A: Retrospective clinical study of adjuvant electro-hyperthermia treatment for advanced brain-gliomas. Dtsch Z Onkol. 2007;39:154–160.