Low Dose Chemo Part 3 – Holistic Cancer Treatments – An Oasis of Healing
 

Everything in excess is opposed to nature.”
—Hippocrates

Low-dose chemotherapy is a vital component of any holistic, integrative cancer treatment program. But, what constitutes a holistic, integrative cancer treatment?

I have previously written on the topic of holistic cancer treatments. Integrative cancer is slightly different. Unfortunately, there are many conventional physicians masquerading as integrative physicians, which creates a lot of confusion amongst conventional doctors and the general public at large. Integrative, as a term, is more than just a marketing term; it is a whole different way of thinking. An integrative approach to cancer treatment involves four levels of integration:

  • Simultaneous goals of the elimination of cancer and healing of the body
  • Use of holistic cancer and conventional cancer treatments
  • Therapies that integrate (work with) with the body’s physiology
  • Integration of the evidence into the use of holistic, natural, integrative cancer therapies

Low-dose chemotherapy is an integral treatment option in any holistic, integrative cancer treatment strategy.

 What is the origin of low-dose chemotherapy?

Contrary to what so many may think, this paradigm shift has its timeline origin well-published in the science. The concept of low-dose chemotherapy began with the search to find more effective, safer therapies to block the process of  angiogenesis. Angiogenesis is the abnormal blood vessel growth that is so characteristic and critical to the cancer process. The important contribution of angiogenesis to the carcinogenic process was first described back in 1971 [1]. The concept of low-dose chemotherapy’s anti-angiogenesis effect predates cancer. A 1989 study on rheumatoid arthritis found low-dose chemotherapy with methotrexate reduced angiogenesis and symptoms in patients with rheumatoid arthritis [2]. The big break with cancer came with the publication of two landmark studies. The fateful month was April of 2000. The first study, Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity [3], was published by Giannoula Klement and colleagues in April 2000. In this study, low-dose continuous chemotherapy with vinblastine significantly reduced tumor angiogenesis leading to tumor regression. The second study, Antiangiogenic Scheduling of Chemotherapy Improves Efficacy against Experimental Drug-resistant Cancer [4], published by Timothy Browder and colleagues was published in April 2000. In this study, the ‘anti-angiogenic’ dose scheduling of the chemotherapy drug, cyclophosphamide, overcame chemoresistance to inhibit angiogenesis and trigger programmed cell death (called apoptosis). The most commonly used term for the less is better approach of low-dose chemotherapy is metronomic chemotherapy. Metronomic chemotherapy was first described by Douglas Hanahan, Gabriele Bergers, and Emily Bergsland in the same April 2000 in the article, Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice [5]. This article was the first to define the concept of ‘metronomic’ dosing as either “continuous infusion or frequent administration without extended rest periods.” The authors advocated a fundamental shift in approach away from the tumor’s sole emphasis as the primary target. Yes, you did read that right. The idea that the tumor is the target, let alone the only target needs to change. Why? I will leave it to the author’s words to summarize:

  • “Drug regimens have been designed to kill as many tumor cells as possible by treating with ‘maximum tolerated doses’ (MTDs) of these cytotoxic agents”
  • Yet, “In rare cases, cures are achieved”
  • “…however, responses are short-lived, with relapses often marked by aggressive cancers that are resistant to the cytotoxic drug.”
  • “Furthermore, the standard MTD regimen as a rule seriously impairs quality of life.”

No summary is required. The author’s words say it all.

What is low-dose chemotherapy?

It is the next step in the less is better movement cancer treatment. It follows in the footsteps of less surgery and lower dose radiation in the treatment of cancer. Most importantly, it follows in the footsteps of science.

 To be specific, fractionated, metronomic dosing, insulin potentiated targeted low-dose chemotherapy (IPTLD), low-dose metronomic dosing, and multiple low-dose chemotherapy is defined as dosing of 10-30% [6] [7] [8] [9] [10] of the maximum tolerated to toxicity chemotherapy dosing. Ten to thirty percent of the maximum tolerated dose to toxicity seems like a good thing when the treatment involves toxic therapies like chemotherapy. Don’t forget that these drugs are designed and prescribed to kill. This point seems particularly obvious when the anti-cancer efficacy, due to the lower dose of chemotherapy, is maintained and even expanded. As quoted to Owen Barfield:

“The obvious is the hardest thing of all to point out to anyone who has genuinely lost sight of it.”

The obvious is obvious to everyone, except for those that it is not obvious too, but, is in fact, oblivious to.

Low—dose chemotherapy goes by many names:

  • Fractionated chemotherapy
  • metronomic chemotherapy
  • Metronomic low-dose chemotherapy
  • low-dose chemotherapy
  • Insulin Potentiated Targeted Low-Dose chemotherapy (IPTLD)
  • Multiple low-dose chemotherapy
  • Even ultra-low-dose chemotherapy

Metronomic chemotherapy is probably the most recognized, so I will use it to help provide a working definition for low-dose chemotherapy. According to a 2016 Nature Reviews in Clinical Oncology article, “The term ‘metronomic chemotherapy’ (MTC) is currently used for frequent and regular administration of lower doses of chemotherapeutic drugs with minimal drug-free time intervals, or only “lower doses, longer times”, to establish a prolonged and lower albeit an active range of plasma concentration enabling a favorable side-effect profile.” [11] Fractionated chemotherapy is merely a fraction of the maximum tolerated dose of chemotherapy. Low-dose is…well, lower dose. Chemotherapy that is lower in dose, lower in side effects, yet maintains efficacy…now that is something every physician should be able to get behind.

Insulin Potentiated targeted low-dose chemotherapy (IPTLD) is low-dose chemotherapy augmented by the biologic addition of insulin to take advantage of the increase in insulin receptors and binding affinity on cancer cells. Collectively, the combination targeting with insulin and a lower dose of chemotherapy gives insulin-potentiated targeted low-dose chemotherapy [12]. Insulin-potentiated targeted low-dose chemotherapy is like so many Integrative cancer treatments—it is misrepresented and misunderstood because of a general lack of understanding of the science. I don’t want to spend too much time here on IPTLD because I will discuss IPTLD in greater detail in future posts.

What is the purpose of low-dose chemotherapy?

The purpose of fractionated, metronomic dosing, IPTLD, low-dose metronomic dosing, and multiple low-dose chemotherapy is to administer low-dose, non-toxic chemotherapy at close, regular intervals without significant interruptions and complications [13], yet preserve anti-cancer treatment efficacy even in chemoresistant tumors [14]. Anti-cancer effects with less toxic effects would appear to be an obvious goal in the treatment of cancer. Instead, conventional medicine has circled the wagons around maximum tolerated chemotherapy. They just can’t let go of the war mentality that bore the very idea of chemotherapy. The obstinance in the face of the undeniable need for progression highlights the advocacy confusion prevalent in medicine today.

Is low-dose chemotherapy recognized?

In short,—yes! Fractionated [15] [16], metronomic dosing [17] [18] [19] [20], low-dose metronomic dosing [21] [22] [23], multiple low-dose chemotherapy 6 [24] [25], and IPTLD 2 [26]  are recognized world-wide as effective, low-dose chemotherapy dosing modification options in the treatment of cancer. These supportive articles are not published in some throw-away medical journals but are mainstream, well respected, conventional oncology journals. One just needs to take a little time to read.

Why low-dose?

The obvious seems… well… obvious. But, this appears to be lost on those who have lost sight of the obvious. Without getting into the specific mechanisms in this post, some of the obvious reasons for low-dose chemotherapy versus the maximum tolerated chemotherapy to toxicity approach includes:

The mounting accumulation of data on low-dose chemotherapy points to a significant reduction in unintended consequences compared to the maximum tolerated to toxicity chemotherapy approach.

If that wasn’t enough, except for those blind to the obvious, low-dose metronomic chemotherapy is equivalent to even more effective than the conventional maximum tolerated to toxicity approach [39] [40] [41]. Did I hear a mic drop? Even the American Society of Clinical Oncology (ASCO) President Monica Bertagnolli, MD, of Dana-Farber Cancer Institute in Boston, is quoted as saying “’Less is more’ is becoming a common refrain in some areas of cancer treatment, and one that is paying off for patients’ quality of life.” I believe that is a double mic drop.

This discussion of the broad benefits of low-dose metronomic chemotherapy could go on and on and on. At some point, one has to recognize the obvious evidence and…move on. In the coming posts, I will highlight the specific, evidence-based mechanisms of action of low-dose metronomic chemotherapy and even pull in an older article or two from the founder of An Oasis of Healing, Dr. Thomas Lodi, on Insulin Potentiated Chemotherapy.

_______________

[1] Folkman J. Tumor angiogenesis: therapeutic implications. NEJM. 1971;285:1182-1186.

[2] Hirata S, Matsubara T, Saura R, Hirohata K, Tateishi H. Inhibition of in vitro vascular endothelial cell proliferation and in vivo neovascularization by low‐dose methotrexate. Arthritis and Rheumatology. Sept 1989. https://doi.org/10.1002/anr.1780320903

[3] Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity [published correction appears in J Clin Invest. 2006 Nov;116(11):3084] [published correction appears in J Clin Invest. 2006 Oct;116(10):2827]. J Clin Invest. 2000;105(8):R15-R24. doi:10.1172/JCI8829

[4] Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O’Reilly MS, Folkman J. Antiangiogenic Scheduling of Chemotherapy Improves Efficacy against Experimental Drug-resistant Cancer. Cancer Res. April 2000;60(7):1878-1886.

[5] Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest. 2000;105(8):1045-1047. doi:10.1172/JCI9872

[6] Fernandes Neto, J.M., Nadal, E., Bosdriesz, E. et al. Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours. Nat Commun 11, 3157 (2020). https://doi.org/10.1038/s41467-020-16952-9

[7] Tesniere A., Apetoh L., Ghiringhelli F., et al. Immunogenic cancer cell death: a key-lock paradigm. Current Opinion in Immunology. 2008;20(5):504–511. doi: 10.1016/j.coi.2008.05.007.

[8] West J, Newton PK. Chemotherapeutic Dose Scheduling Based on Tumor Growth Rates Provides a Case for Low-Dose Metronomic High-Entropy Therapies. Cancer Res. 2017;77(23):6717-6728. doi:10.1158/0008-5472.CAN-17-1120

[9] Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004;4(6):423–36 [PubMed PMID: 15170445. Epub 2004/06/02.eng].

[10] Maraveyas A, Lam T, Hetherington JW, Greenman J. Can a rational design for metronomic chemotherapy dosing be devised? Br J Cancer 2005;92(8):1588–90 [PubMed PMID: 15846302. Pubmed Central PMCID: 2362004].

[11] Bocci G., Kerbel R. S. Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect. Nature Reviews Clinical Oncology. 2016;13(11):659–673. doi: 10.1038/nrclinonc.2016.64.

[12] Damyanov C, Gerasimova D, Maslev I, Gavrilov V. Low-dose chemotherapy with insulin (insulin potentiation therapy) in combination with hormone therapy for treatment of castration-resistant prostate cancer. ISRN Urol. 2012;2012:140182. doi:10.5402/2012/140182

[13] Shaked Y, Emmenegger U, Man S, et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood. 2005;106(9):3058-3061. doi:10.1182/blood-2005-04-1422

[14] Damyanov C, Radoslavova M, Gavrilov V, Stoeva D. Low dose chemotherapy in combination with insulin for the treatment of advanced metastatic tumors. Preliminary experience. Journal of B.U.ON. 2009;14(4):711–715.

[15] Smith AJ, Oertle J, Prato D. Genetically Targeted Fractionated Chemotherapy. Journal of Cancer Therapy.2015;6:182-198.

[16] Warman, P.I.; Kaznatcheev, A.; Araujo, A.; Lynch, C.C.; Basanta, D. Fractionated Follow-Up Chemotherapy Delays the Onset of Resistance in Bone Metastatic Prostate Cancer. Game Theory and Cancer 2018;9(2),19. https://doi.org/10.3390/g9020019

[17] El-Arab LR, Swellam M, El Mahdy MM. Metronomic chemotherapy in metastatic breast cancer: impact on VEGF. J Egypt Natl Canc Inst. 2012;24(1):15-22. doi:10.1016/j.jnci.2011.12.002

[18] Colleoni M, Orlando L, Sanna G, et al. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol. 2006;17(2):232-238. doi:10.1093/annonc/mdj066

[19] Orlando L, Cardillo A, Rocca A, et al. Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic breast cancer. Anticancer Drugs. 2006;17(8):961-967. doi:10.1097/01.cad.0000224454.46824.fc

[20] Chan TS, Hsu CC, Pai VC, et al. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells. J Exp Med. 2016;213(13):2967-2988. doi:10.1084/jem.20151665

[21] Krajnak S, Schnatz C, Almstedt K, et al. Low-dose metronomic chemotherapy as an efficient treatment option in metastatic breast cancer-results of an exploratory case-control study. Breast Cancer Res Treat. 2020;182(2):389-399. doi:10.1007/s10549-020-05711-5

[22] Krajnak S, Battista M, Brenner W, et al. Explorative Analysis of Low-Dose Metronomic Chemotherapy with Cyclophosphamide and Methotrexate in a Cohort of Metastatic Breast Cancer Patients. Breast Care (Basel). 2018;13(4):272-276. doi:10.1159/000487629

[23] Lien K, Georgsdottir S, Sivanathan L, Chan K, Emmenegger U. Low-dose metronomic chemotherapy: a systematic literature analysis. Eur J Cancer. 2013;49(16):3387-3395. doi:10.1016/j.ejca.2013.06.038

[24] Caumanns, J. J. et al. Low-dose triple drug combination targeting the PI3K/AKT/mTOR pathway and the MAPK pathway is an effective approach in ovarian clear cell carcinoma. Cancer Lett. 2019;461:102–111.

[25] Verschuur A, Heng-Maillard MA, Dory-Lautrec P, et al. Metronomic Four-Drug Regimen Has Anti-tumor Activity in Pediatric Low-Grade Glioma; The Results of a Phase II Clinical Trial. Front Pharmacol. 2018;9:00950. Published 2018 Sep 27. doi:10.3389/fphar.2018.00950

[26] Ayre SG, Perez Garcia y Bellon D, Perez Garcia D Jr. Neoadjuvant low-dose chemotherapy with insulin in breast carcinomas. Eur J Cancer. 1990;26(11-12):1262-1263. doi:10.1016/0277-5379(90)90284-z

[27] Szturz P, Wouters K, Kiyota N, et al. Weekly Low-Dose Versus Three-Weekly High-Dose Cisplatin for Concurrent Chemoradiation in Locoregionally Advanced Non-Nasopharyngeal Head and Neck Cancer: A Systematic Review and Meta-Analysis of Aggregate Data. Oncologist. 2017;22(9):1056-1066. doi:10.1634/theoncologist.2017-0015

[28] Mross K, Steinbild S. Metronomic anti-cancer therapy – An ongoing treatment option for advanced cancer patients. J Cancer Ther Res. 2012;1:32.

[29] André N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low-income and middle-income countries? The Lancet Oncology. 2013;14(6):e239–248.

[30] Munzone E, Colleoni M. Clinical overview of metronomic chemotherapy in breast cancer. Nat Rev Clin Oncol. 2015;12(11):631-644. doi:10.1038/nrclinonc.2015.131

[31] 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

[32] Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y, et al. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer research 2003;63:4342–6.

[33] Hasnis E., Alishekevitz D., Gingis-Veltski S., et al. Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy. Neoplasia. 2014;16(6):501–510. doi: 10.1016/j.neo.2014.05.011.

[34] Tran Cao H. S., Bouvet M., Kaushal S., et al. Metronomic gemcitabine in combination with sunitinib inhibits multisite metastasis and increases survival in an orthotopic model of pancreatic cancer. Molecular Cancer Therapeutics. 2010;9(7):2068–2078. doi: 10.1158/1535-7163.MCT-10-0201.

[35] Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays. 1991;13:31-36. doi:10.1002/bies.950130106

[36] Kandipalli S, Santhosh V, Voonna P. Impact of Metronomic Chemotherapy on Quality of Life in Recurrent, Residual and Metastatic Head & Neck Cancers. Journal of Medical Science and Clinical Research. Dec 2018;6(12):64-72.

[37] Noronha, V., Joshi, A., Marfatia, S. et al. Health-related quality of life in patients with metastatic, relapsed, or inoperable squamous cell carcinoma of the head and neck in India. Support Care Cancer. 2016; 24:1595–1602. https://doi.org/10.1007/s00520-015-2937-9

[38] Bahl A, Bakhshi S. Metronomic Chemotherapy in Progressive Pediatric Malignancies: Old Drugs in New Package. Indian J Pediatr. April 2012; DOI 10.1007/s12098-012-0759-z

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[41] Khan, K.A., Ponce de Léon, J.L., Benguigui, M. et al. Immunostimulatory and anti-tumor metronomic cyclophosphamide regimens assessed in primary orthotopic and metastatic murine breast cancer. npj Breast Cancer. 2020;6,29. https://doi.org/10.1038/s41523-020-0171-1

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