Holistic Cancer Treatment: Low Dose Chemo – Part 6

Immune system effects of low-dose, metronomic chemotherapy

I often tell patients that the best answer to cancer is to never get cancer. Of course, that is an obvious point. However, according to the statistics, that target is proving difficult as the current estimates are that 1:2 women will develop cancer in their lifetime, and 1:3 men will develop cancer in their lifetime [1]. Not to pile on, but according to a recent study, the Prospective Urban Rural Epidemiology study published in March 2020, cancer is now responsible for twice as many deaths as cardiovascular disease (CVD) in high income countries. Think about that for a moment. If one gets cancer, the best answer is the immune system. No need to recreate the wheel here. No need to play god. The immune system design is to protect the body from all enemies, both foreign and domestic. We know the foreign enemies well, i.e., bacteria, viruses’, parasites. It is the domestic enemies that we don’t recognize yet often pose the most risk, i.e., autoimmune disease and cancer.

To understand how to use the immune system to heal from cancer, it is important to recognize how cancer manipulates the immune system. To a growing tumor, the immune defense is the greatest threat to survival. At the same time, the immune defense is an opportunity. Cancer affects the immune system in 3 broad ways:

  • Immune system dysregulation
  • Immune system suppression
  • Immune system evasion

The goal of using the immune system to fight cancer is to move from a balance that favors immune system suppression to a balance that favors immune system stimulation. It is about changing the environment within the body, and the immune system is front and center in this endeavor. Ground zero is the tumor microenvironment. Interestingly, this immune system activation, particularly the innate immunity, occurs with low-dose, metronomic chemotherapy, but not with the maximum to tolerated toxicity approach [2]. One supports, and one destroys.

Conventional medicine research likes to use fancy words to impress. Just as lawyers have their legalese, physicians have their medical lingo. Take the use of the immune system in the fight against cancer, for example. Immunotherapy is the word used for the conventional medicine use of the new class of drugs, i.e., keytruda, opdivo, herceptin. These are the new drugs (monoclonal antibodies, checkpoint inhibitors, inhibitory drugs) that dominate advertising these days which are designed to work within the immune system—thus, the label immunotherapy. However, these new drugs use the same approach as the conventional paradigm of chemotherapy drugs. It is the same dog and pony show, but just with new names and new flashy objects. Even though immunotherapy is targeting the immune system, the approach is simply just modern-day chemotherapy under a different name.

Then there is immunomodulatory therapy. These therapies are designed to modulate the immune system for an intended effect. Essentially, immunomodulatory therapy is the modulation of the already present, though dysfunctional, immune system to redirect and repurpose the immune system back to doing its job correctly. No need to tear everything down to then try and rebuild the immune system better. No need to anticipate that throwing a monkey wrench into the immune system’s cogwheels will solve the immune system disruptions present in cancer. No reason to recreate the wheel here.

Are immunotherapy or immunomodulatory therapies that much different? If I have to be honest, not really. Their difference is just semantics. But, they are regularly and interchangeably used and are important to know and understand; one is primarily a conventional medicine therapy and the other is a more integrative, holistic medicine therapy. And don’t forget that one is very, very profitable.

Why the need to develop a new therapy at all? If chemotherapy, radiation, and surgery are the panacea of cancer cure, why the need for an addition? First, patents and thus profitability run out. Second, chemotherapy drugs don’t work as well as advertised. Third, therapies that are worse than the disease they are intended to treat is not a viable treatment strategy.

What about the repurposing of chemotherapy? One day, the goal is the treatment of cancer without chemotherapy. The idea is to have therapies that focus on healing, a salutogenic approach, rather than disease, which is a pathogenic approach. Salutogenic is the support of health and wellness. But, until that goal is achieved, what about using chemotherapy safer, smarter, and better? As a result, I give you maximum to tolerated toxicity chemotherapy (MTTC) versus low-dose, metronomic, or ultra-low dose chemotherapy. Maximum to tolerated toxicity is associated with well-known adverse effects of increased morbidity, mortality, metastasis, and significant toxicity (neurotoxic, immunotoxic, myeloid toxic). Also, it aggressively drives early chemoresistance. That is in addition to the fact, that it just doesn’t work very well. According to a 2004 study, The Contribution of Cytotoxic Chemotherapy to 5-year survival in Adult Malignancies, a benefit of 5 year survival was found in only 13 of 22 cancer types evaluated [3]. That may sound good, but when you dive deeper it really is not. In only 3 of those 13 did the benefit in 5 year survival reach 10%. Yikes!!!  No better evidence than in breast cancer, where the 5-year survival benefit from adjuvant chemo was only 3.5%. Let me repeat that 3.5%!  Try getting on your next flight with those kind of percentages. The authors conclusion statement says it all, “The overall contribution of curative and adjuvant cytotoxic chemotherapy to 5-year survival in adults was estimated to be 2.3% in Australia and 2.1% in the USA.” As the name implies, low-dose, metronomic chemotherapy is lower in dose. It is associated with a reduction in side effects, an increase in quality of life (QOL), and has expanded anti-cancer effects. In the previous blog post series, I focused on the effects of low-dose, metronomic chemotherapy in angiogenesis. This blogpost series will focus on the profound impact of low-dose, metronomic chemotherapy on the immune system.

Immunogenic cell death

Most cell death that occurs in the body does so without the stimulation of any significant inflammation. Think about, millions of cells in the body die every day as the body cleans and recycles old or dysfunctional cells through the process of autophagy.  The concept of immunogenic cell death was born out of chemotherapy and radiation-induced cancer cell death. It was, however, first described in conjunction with chemotherapy [4]. For general purposes, immunogenic cell death can be defined as chemotherapy or radiation induced cancer cell death, cancer cell antigen presentation, which leads to specific immune system activation to the original cancer antigen. An antigen is typically something foreign to the body, whether foreign or domestic. Foreign antigens are the obvious: bacteria, viruses’, parasites, environmental toxicants. Domestic antigens, such as cancer, originate within the body but are foreign to the body from a normal, healthy function perspective. Restated and described in relation to radiation treatment of cancer, immunogenic cell death is the induction of “…immune-stimulating tumor antigens released from dying tumor cells into the surrounding milieu…that contributes to the propagation of anti-tumor immunity” [5]. The main take-home point is that immunogenic cell death is the awakening and activation of the immune system against cancer. It is the stimulation of the immune system that results from cell death. The immune system is the key to cancer destruction, not chemotherapy. Leave it to conventional medicine to lose the forest for the trees and step in, play god, and take all credit from the creator for the real answer—the immune system. I often tell patients that the best answer to cancer is to never get it; but, if one does get cancer, the best answer is the immune system.

What is the relevance to low-dose, metronomic chemotherapy? I am so glad you asked. Low-dose, metronomic chemotherapy stimulates immunogenic cell death [6] [7] [8]. It does have direct cancer cytotoxic effects, but its main point of action is through the stimulation and activation of the immune system. The real powerhouse in any anti-cancer attack is the immune system. The dose and the chemotherapy drug used, however, are critical in the elicitation of the anti-cancer effect [9]. The more immunogenic chemotherapies include cyclophosphamide, doxorubicin, epirubicin, idarubicin, mitoxantrone, and oxaliplatin [10] [11] [12]. Low-dose, metronomic chemotherapy provides just enough direct cancer cell death to activate the immune system [13], yet not destroy it. In contrast, maximum to tolerated toxicity chemotherapy does not elicit immunogenic cell death of cancer cells, because of the massive immune system suppression of T cells, NK cells, and dendritic cells 4 [14]. One of the primary activation targets is the hand-to-hand combat capability of the innate immune system. Low-dose, metronomic chemotherapy stimulates tumor regression via a significant anti-cancer immune response through innate immune system activation 2 [15]. Though the expanded effects and the lower toxicities provided through the low-dose, metronomic chemotherapy are the primary benefits, evidence exists to support its superiority to maximum tolerated chemotherapy in direct cytotoxic effects [16]. In contrast, the bigger is the better approach found in maximum to tolerated toxicity often leads to an overwhelming inflammatory burst, called cytokine storm, which can lead to significant complications such as Tumor Lysis Syndrome (TLS), even recurrence and metastasis [17] [18] [19] [20]; both of which leads to a significant increase in mortality. It doesn’t take a rocket scientist or a conventional physician to see that is not good!

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[1] Ahmad AS, Ormiston-Smith N, Sasieni PD. Trends in the lifetime risk of developing cancer in Great Britain: comparison of risk for those born from 1930 to 1960. Br J Cancer. 2015;112(5):943-947. doi:10.1038/bjc.2014.606

[2] Doloff JC, Waxman DJ: VEGF receptor inhibitors block the ability of metronomically dosed cyclophosphamide to activate innate immunity-induced tumor regression. Cancer Res. 2012. 72:1103-1115.

[3] Morgan G, Ward R, Barton M. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clin Oncol (R Coll Radiol). 2004 Dec;16(8):549-60. doi: 10.1016/j.clon.2004.06.007. PMID: 15630849.

[4] Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat. Rev. Clin Oncol. 2011;8:151–60.

[5] Golden EB, Apetoh L. Radiotherapy and Immunogenic Cell Death. Sem Rad Onc. Jan 2015;25(1):11-17.

[6] Fares JE, Tomb PE, Khalil LE, Atwani RW, Moukaem HA, Awada A, Saghir NS. Metronomic chemotherapy for patients with metastatic breast cancer: Review of effectiveness and potential use during pandemics. Cancer Treatment Reviews. Sept 2020;89. https://doi.org/10.1016/j.ctrv.2020.102066

[7] Tran AP, Al-Radhawi MA, Kareva I, Wu J, Waxman DJ, Sontag ED. Delicate Balances in Cancer Chemotherapy: Modeling Immune Recruitment and Emergence of Systemic Drug Resistance. From Immunol. Jun 2020; https://doi.org/10.3389/fimmu.2020.01376

[8] Wu J, Jordan M, Waxman DJ. Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators. BMC Cancer. 2016;16,623. https://doi.org/10.1186/s12885-016-2597-2

[9] Wu J, Waxman DJ. Immunogenic chemotherapy: Dose and schedule dependence and combination with immunotherapy. Cancer letters. 2018;419:210-221.

[10] Pol J, Vacchelli E, Aranda F, Castoldi F, Eggermont A, Cremer I, Sautes- Fridman C, Fucikova J, Galon J, Spisek R, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: immunogenic cell death inducers for anticancer chemotherapy, Oncoimmunology. 2015;4. e1008866

[11] Bracci L, Schiavoni G, Sistigu A. et al. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21:15–25. https://doi.org/10.1038/cdd.2013.67

[12] Vacchelli E, Aranda F, Eggermont A, Galon J, Sautes-Fridman C, Cremer I, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: chemotherapy with immunogenic cell death inducers, Oncoimmunology. 2014;3. e27878

[13] André N, Tsai K, Carré M, Pasquier E. Metronomic Chemotherapy: Direct Targeting of Cancer

Cells after all? Trends in Cancer. 2017;166. http://dx.doi.org/10.1016/j.trecan.2017.03.011

[14]  Shurin MR, Naiditch H, Gutkin DW, Umansky V, Shurin GV. Chemo- ImmunoModulation: immune regulation by the antineoplastic chemotherapeutic agents, Curr. Med. Chem. 2012;19:1792e1803.

[15] Chen CS, Doloff JC, Waxman DJ: Intermittent metronomic drug schedule is essential for activating antitumor innate immunity and tumor xenograft regression. Neoplasia. 2014;16: 84-96.

[16] Gerrits C, de Jonge M, Schellens J, et al. Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development. Br J Cancer.1997;76: 952–962. https://doi.org/10.1038/bjc.1997.491

[17] Fillippou PS, Karagiannis GS. Cytokine storm during chemotherapy: a new companion diagnostic emerges? Oncotarget. 2020;11(3):213-215.

[18] Gartung A, Yang J, Sukhatme VP, Bielenberg DR, Fernandes D, Chang J, Schmidt BA, Hwang SH, Zurakowski D, Huang S, Kieran MW, Hammock BD, Panigrahy D. Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor. Proceedings of the National Academy of Sciences. Jan 2019;116(5):1698-1703. DOI: 10.1073/pnas.1803999116

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

[20] Pusztai L, TR Mendoza, JR Monica, M Martinez et al. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine. Feb 2007;25(3):94-102. https://doi.org/10.1016/j.cyto.2003.10.004

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