Paradoxical Pro-Metastatic Effects of Chemotherapy by Jeffrey Dach MD
One of my patients underwent chemotherapy for lymphoma with a good result. The chemotherapy induced a complete remission. The para-aortic and mediastinal nodal masses melted away, and the follow up PET scan was completely clean, a complete remission. However only 3 months later, the lymphoma returned with a vengeance, even more aggressive than before. Over the next 3 years this was repeated three times. Each remission was followed by a relapse with more aggressive cancer behavior.
Above header image : Killer T cells Surround a Cancer Cell, Courtesy of University of Basel and National Institute of Health (NIH)
Pro-metastatic Effects of Chemotherapy
In 2020, Dr. Crescenzo D’Alterio reviewed the medical literature on this effect, writing chemotherapy has paradoxical pro-metastatic effects:
This review highlights the paradoxical pro-metastatic effects of chemotherapy linking reactive responses to treatment to tumor relapse and metastasis formation through primary tumor remodeling and generation of a favorable pro-metastatic niche.(1)
Dr. Crescenzo D’Alterio goes on to explain the mechanism of at play. The chemotherapy kills the “bulk” tumor cells, yet leaves behind chemo-resistant cancer stem cells, which repopulate with greater metastatic potential.The cancer stem cells repopulate under the intense stimulation of a massive systemic inflammatory response characterized by massive cytokine and chemokine release.
Breast Cancer Example
In the below quote, Dr. Crescenzo D’Alterio describes chemotherapy induced cytokine release which activates both the Wnt/β-catenin and NF-κB pathways creating an inflammatory feedback loop in breast cancer:
In breast cancer, cytokines released by tumor cells after chemotherapy can activate both Wnt/β-catenin and NF-κB pathways that amplify the secretion of further cytokines able to establish an autocrine inflammatory forward-feedback loop enriching for chemoresistant CSCs.(1)
Lung Cancer Example
A common chemotherapy drug for lung cancer is cisplatin, which kills bulk cancer cells, yet triggers massive IL-6 cytokine release which contributes to chemoresistance and prometastatic effects, resulting in increased distant metastatic disease formation. Dr. Crescenzo D’Alterio writes:
For instance, cisplatin treatment of lung cancer cell lines and xenografts triggers an increased release of the pro-inflammatory cytokine IL-6 [Interleukin-6] , that contributes to chemoresistance of cancer cells by activating EMT [epithelial to mesenchymal transition] and up-regulating anti-apoptotic proteins and DNA repair associated molecules [55]… Interestingly, despite primary tumor shrinkage, cisplatin-selection and priming of chemoresistant and metastatic CD133+CXCR4+ cells [Cancer Stem cells] results in increased distant metastasis formation.(1)
Above image : Fig. 2. Mechanisms mediating pro-metastatic effects of chemotherapy at different tumor districts. Courtesy of Dr. Crescenzo D’Alterio.(1)
Dr. Crescenzo D’Alterio concludes that chemotherapy is overall unsatisfactory for control of metastatic cancer spread throughout the body, and actually induces this effect:
In several tumor types, chemotherapy has so far demonstrated an overall unsatisfactory potential to counteract and control metastatic dissemination even when a partial or complete response has been achieved at the primary tumor site [4]. This clinical issue could be in part related to host responses to chemotherapy activating reactive and reparatory mechanisms able to foster generation of CSCs [Cancer Stem Cells], primary tumor cells escape and distant site colonization. (1)
Chemotherapy 97 Percent Failure Rate.
It is well known that chemotherapy has a paradoxical pro-metastatic effect, thus the high failure rate. In the video clip below, Dr. Peter Glidden’s claims a “97% failure rate” for chemotherapy, and then suggests it is still being used because of the financial incentive called “the chemotherapy concession”. The medical literature shows that Morgan et al. (2004) provides the 2–3% survival contribution figure (hence “97%”), while Maeda et al, 2018 gives the closest direct failure-rate statistic (90% ±5%).
CHEMO HAS A 97% FAILURE RATE. Dr. Peter Glidden:
“Chemotherapeutic drugs are the only classification of drugs where the prescribing doctor gets a direct cut. So if your doctor prescribes chemo for you, here’s how it goes. The doctor buys it from the pharmaceutical company for… pic.twitter.com/dVR0DywQ2F
— healthbot (@thehealthb0t) May 16, 2026
Conclusion: it is clear that cytotoxic chemotherapy only makes a minor contribution to cancer survival. The pro-metastatic effects of chemotherapy could explain its high failure rate. The chemotherapy concession and associated profit incentives are well-documented in the literature as a structural issue in U.S. oncology practice. There are some cancer cell types in which chemotherapy should be used. Chemotherapy is highly curative in some lymphomas, leukemias, testicular cancers and marginal efficacy in many advanced solid tumors. Always consult a knowledgeable integrative oncologist or mainstream oncologist for personalized advice.
=======================================
Cracking Cancer Toolkit by Jeffrey Dach MD
Did you like this article? You may wish to read my book: Cracking Cancer Toolkit available on on multiple platforms.
Articles With Related Interest:
Ivermectin, Antiparasitic, Anticancer Wonder Drug
Artemisinin Our Best Cancer Weapon
All Cancer Articles on This Blog
Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Fl 33314
954-792-4663
References
D’Alterio, Crescenzo, et al. “Paradoxical effects of chemotherapy on tumor relapse and metastasis promotion.” Seminars in cancer biology. Vol. 60. Academic Press, 2020.
At the primary tumor site, chemotherapy has been reported to promote selection of chemoresistant and disseminating tumor cells endowed with properties of cancer stem cells (CSCs) through activation of autocrine and paracrine self-renewing/survival pathways promoted jointly by therapy-selected tumor and stromal cells. Resistant CSCs represent seeds for tumor relapse and increased infiltration by immune cells, together with enhanced vascular permeability induced by chemotherapy, facilitates tumor cells intravasation, the first step of the metastatic cascade. As a consequence of primary tumor/metastasis re-shaping induced by chemotherapy, circulating tumor cells (CTCs) detected during therapy can display a shift towards a more mesenchymal and stem-like phenotype, conductive to increased ability to survive in the circulation and seed distant organs. At the metastatic site, host responses to therapy activate inflammatory pathways that ultimately facilitate tumor cells extravasation and metastatic colonization. Finally, cooperation of immune cells and endothelial cells at perivascular niches favors the extravasation of tumor cells endowed with high potential for metastasis initiation and protects them from chemotherapy.This review highlights the paradoxical pro-metastatic effects of chemotherapy linking reactive responses to treatment to tumor relapse and metastasis formation through primary tumor remodeling and generation of a favorable pro-metastatic niche.
He, Dasa, et al. “Chemotherapy awakens dormant cancer cells in lung by inducing neutrophil extracellular traps.” Cancer Cell (2025).
Disseminated tumor cells (DTCs) can remain in a non-proliferative, dormant state for years in distant organs, but the exogenous causes triggering their reactivation and metastatic colonization are unclear. Here, we demonstrate that chemotherapeutic drugs, including doxorubicin and cisplatin, enhance proliferation and lung metastasis of dormant breast cancer cells. Using a recombinase-based dormancy tracing system, DormTracer, we confirm chemotherapy-induced reactivation of dormant DTCs leading to metastatic relapse. Mechanistically, chemotherapy induces fibroblast senescence, which promotes formation of neutrophil extracellular traps (NETs) through secreted proteins. NETs promote dormant DTC proliferation through extracellular matrix remodeling. Importantly, combining senolytic drugs, dasatinib and quercetin, with doxorubicin inhibits post-therapy DTC reactivation and suppresses metastatic relapse. This study provides direct evidence of dormancy awakening and reveals a mechanism underlying detrimental effect of chemotherapy on metastasis, highlighting potential strategies to improve cancer treatment.
D’Alterio, Crescenzo, et al. “Paradoxical Effects of Chemotherapy on Tumor Relapse and Metastasis Promotion.” Seminars in Cancer Biology, vol. 60, Feb. 2020, pp. 351–361. ScienceDirect, https://doi.org/10.1016/j.semcancer.2019.08.019. PubMed: https://pubmed.ncbi.nlm.nih.gov/31454672/.
A Breast cancer cytokine/Wnt/β-catenin/NF-κB inflammatory feedback loop enriches chemoresistant Cancer stem cells (CSCs)
Jia, Dongya, et al. “An Autocrine Inflammatory Forward-Feedback Loop after Chemotherapy Withdrawal Facilitates the Enrichment of Breast Cancer Stem Cells.” Cell Death & Disease, vol. 8, no. 12, Dec. 2017, p. e3165. Nature, https://doi.org/10.1038/cddis.2017.560. 3.
Lung cancer / cisplatin example of IL-6 release, EMT, chemoresistance, CD133+CXCR4+ CSC enrichment, and increased distant metastasis despite primary tumor shrinkage.
Duan, Zhijun, et al. “IL-6 Signaling Contributes to Cisplatin Resistance in Non-Small Cell Lung Cancer.” Oncotarget, vol. 6, no. 36, 2015, pp. 39051–39060. PMC, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695015/ (free full text).
Karagiannis, George S., et al. “Chemotherapy-Induced Metastasis: Molecular Mechanisms, Clinical Manifestations, Therapeutic Interventions.” Cancer Research, vol. 79, no. 18, Sept. 2019, pp. 4567–4576. PMC, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744993/
References:
Maeda, Hiroshi, and Mahin Khatami. “Analyses of Repeated Failures in Cancer Therapy for Solid Tumors: Poor Tumor-Selective Drug Delivery, Low Therapeutic Efficacy and Unsustainable Costs.” Clinical and Translational Medicine, vol. 7, no. 1, 1 Mar. 2018, p. 11.
https://doi.org/10.1186/s40169-018-0185-6.
URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC5852245/ (full text free).Summary of the study:
Study summary: This review analyzes why reductionist cancer therapies (including traditional cytotoxic chemotherapy, molecular targeted drugs, and immunotherapy) have repeatedly failed for solid tumors over six decades. The authors cite governmental agencies and industry data showing outcome failure rates of 90% (±5%) (with ranges of 85–95% in many trials). Key reasons include poor tumor-selective drug delivery (e.g., classic low-molecular-weight chemotherapeutics distribute systemically, causing toxicity without adequate tumor targeting; issues with the enhanced permeability and retention (EPR) effect in nanoparticles), infinite genetic mutations/heterogeneity in tumors, drug resistance/relapse, induction of further mutations via reactive oxygen/nitrogen species from inflammation, and life-threatening side effects (e.g., multiple organ failure). It also highlights unsustainable costs ($100,000–$1,000,000+ per course for “designer” drugs with minimal survival gains). The paper calls the outcomes “very bleak and disappointing” for solid tumors (vs. better results in leukemias) and criticizes reliance on animal models that do not reflect human tumor complexity.
For over six decades reductionist approaches to cancer chemotherapies including recent immunotherapy for solid tumors produced outcome failure-rates of 90% (±5) according to governmental agencies and industry. Despite tremendous public and private funding and initial enthusiasm about missile-therapy for site-specific cancers, molecular targeting drugs for specific enzymes such as kinases or inhibitors of growth factor receptors, the outcomes are very bleak and disappointing. Major scientific reasons for repeated failures of such therapeutic approaches are attributed to reductionist approaches to research and infinite numbers of genetic mutations in chaotic molecular environment of solid tumors that are bases of drug development. Safety and efficacy of candidate drugs tested in test tubes or experimental tumor models of rats or mice are usually evaluated and approved by FDA. Cost-benefit ratios of such ‘targeted’ therapies are also far from ideal as compared with antibiotics half a century ago.
——————-
2. Morgan et al. 2004 (the study most frequently cited/misrepresented as the source of the “97% failure” claim)
Morgan, Graeme, et al. “The Contribution of Cytotoxic Chemotherapy to 5-Year Survival in Adult Malignancies.” Clinical Oncology, vol. 16, no. 8, Dec. 2004, pp. 549–60. https://doi.org/10.1016/j.clon.2004.06.007.
URL: https://pubmed.ncbi.nlm.nih.gov/15630849/ (abstract; full text available via journal or libraries).
Summary of the study: This systematic literature review examined randomized clinical trials reporting 5-year survival benefits attributable solely to cytotoxic chemotherapy (curative or adjuvant) in adult malignancies. Using Australian cancer registry data and U.S. SEER data, it estimated that chemotherapy contributes only 2.3% to 5-year survival in Australia and 2.1% in the USA. (Overall 5-year relative survival for all cancers was ~60%+, so most survival benefit comes from surgery, radiation, etc.) The authors conclude that cytotoxic chemotherapy makes “a minor contribution to cancer survival” despite widespread use. This paper is often cited in alternative-medicine contexts to argue extremely low effectiveness (i.e., ~97–98% “failure” in terms of survival contribution), though the original study does not frame it as a “97% failure rate” or claim chemo is useless—it highlights limited added benefit across adult solid tumors.
——————————-
Abstract
Aims: The debate on the funding and availability of cytotoxic drugs raises questions about the contribution of curative or adjuvant cytotoxic chemotherapy to survival in adult cancer patients.
Materials and methods: We undertook a literature search for randomised clinical trials reporting a 5-year survival benefit attributable solely to cytotoxic chemotherapy in adult malignancies. The total number of newly diagnosed cancer patients for 22 major adult malignancies was determined from cancer registry data in Australia and from the Surveillance Epidemiology and End Results data in the USA for 1998. For each malignancy, the absolute number to benefit was the product of (a) the total number of persons with that malignancy; (b) the proportion or subgroup(s) of that malignancy showing a benefit; and (c) the percentage increase in 5-year survival due solely to cytotoxic chemotherapy. The overall contribution was the sum total of the absolute numbers showing a 5-year survival benefit expressed as a percentage of the total number for the 22 malignancies.
Results: 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.
Conclusion: As the 5-year relative survival rate for cancer in Australia is now over 60%, it is clear that cytotoxic chemotherapy only makes a minor contribution to cancer survival. To justify the continued funding and availability of drugs used in cytotoxic chemotherapy, a rigorous evaluation of the cost-effectiveness and impact on quality of life is urgently required.
———————————-
3. Malin et al. 2013 (supports the “driven by profit (the chemotherapy concession)” part)
Malin, Jennifer L., et al. “Medical Oncologists’ Perceptions of Financial Incentives in Cancer Care.” Journal of Clinical Oncology, vol. 31, no. 5, 10 Feb. 2013, pp. 530–35. https://doi.org/10.1200/JCO.2012.43.6063. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC3565179/ (full text free) or https://ascopubs.org/doi/10.1200/JCO.2012.43.6063.
Summary of the study: This survey (part of the Cancer Outcomes Research and Surveillance study) of 480 U.S. medical oncologists examined how compensation structures affect perceived financial incentives for prescribing chemotherapy or growth factors. It explicitly discusses the “chemotherapy concession” (the buy-and-bill model where oncologists purchase chemotherapy drugs at a discount and bill insurers/payers at a markup, often accounting for ~65% of oncology practice revenue). Non-salaried oncologists (fee-for-service or salary-plus-productivity incentives) were far more likely to report that their income increases when they administer chemotherapy (odds ratios 7.05–7.52) or growth factors compared to fixed-salary physicians. The authors raise concerns that these financial incentives may influence treatment recommendations and contribute to rising cancer care costs, though most oncologists reported no income effect overall. It supports the idea that the current reimbursement system creates profit motives tied to chemotherapy volume.
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
954-792-4663
www.jeffreydachmd.com
http://www.drdach.com
http://www.naturalmedicine101.com
http://www.bioidenticalhormones101.com
http://www.truemedmd.com
Disclaimer click here: http://www.drdach.com/wst_page20.html
The reader is advised to discuss the comments on these pages with his/her personal physicians and to only act upon the advice of his/her personal physician. Also note that concerning an answer which appears as an electronically posted question, I am NOT creating a physician — patient relationship. Although identities will remain confidential as much as possible, as I can not control the media, I can not take responsibility for any breaches of confidentiality that may occur.
Copyright (c) 2024 Jeffrey Dach MD All Rights Reserved. This article may be reproduced on the internet without permission, provided there is a link to this page and proper credit is given.
FAIR USE NOTICE: This site contains copyrighted material the use of which has not always been specifically authorized by the copyright owner. We are making such material available in our efforts to advance understanding of issues of significance. We believe this constitutes a ‘fair use’ of any such copyrighted material as provided for in section 107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section 107, the material on this site is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.
Serving Areas of: Hollywood, Aventura, Miami, Fort Lauderdale, Pembroke Pines, Miramar, Davie, Coral Springs, Cooper City, Sunshine Ranches, Hallandale, Surfside, Miami Beach, Sunny Isles, Normandy Isles, Coral Gables, Hialeah, Golden Beach ,Kendall,sunrise, coral springs, parkland,pompano, boca raton, palm beach, weston, dania beach, tamarac, oakland park, boynton beach, delray,lake worth,wellington,plantation.zzzz
Discover more from Jeffrey Dach MD
Subscribe to get the latest posts sent to your email.
Leave a Reply
You must be logged in to post a comment.