Raadpleeg ook de literatuurlijsten van niet-toxische middelen en behandelingen van arts-bioloog drs. Engelbert Valstar

1 mei 2019: Bron: . 2019 Feb; 54(2): 407–419

De afgelopen tientallen jaren hebben oncologen zich gefocust op het behandelen van de tumoren, maar de behandelingen kunnen resulteren in schade aan de tumor dragende gastheer (de kankerpatiënt) en zijn immuunsysteem, oftewel een verslechterende kwaliteit van leven, die soms zo slecht is dat mensen het amper nog kunnen dragen. De bijwerkingen van systemische chemotherapie voor de behandeling van kanker zijn namelijk vaak ernstig en soms chronisch.

Om er een paar te noemen alleen al bij borstkankerpatienten die chemotherapie krijgen bevestigen onderstaande studies dat chemotherapie soms chronische ernstige bijwerkingen kan veroorzaken. (met dank aan Jolanda die ons hierop wees): 

(1) https://www.theguardian.com/society/2014/apr/25/having-cancer-not-fight-or-battle

(2) https://www.sciencedirect.com/science/article/pii/S152682091170297X

(3) https://ascopubs.org/doi/full/10.1200/JCO.2016.68.5826

(4) https://www.ncbi.nlm.nih.gov/pubmed/21430504

(5) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256170/

(6) https://www.ncbi.nlm.nih.gov/pubmed/15630849 

De laatste jaren is er veel aandacht besteed aan het immuunsysteem van patiënten en de activering ervan via biologische therapieën. Biologische therapieën, waaronder immuuntherapie en behandelingen met gemoduleerde oncolytische virussen (OV- therapie),. Deze vormen van behandelingen zijn vaak meer fysiologisch en worden beter verdragen door kankerpatiënten.

Waarbij opvalt dat immuuntherapie met gemoduleerde virussen veruit de minste bijwerkingen geeft met graad 0 tot 2. En ook vaak de beste resultaten, indien ingezet in een vroeg stadium van de ziekte.

Chemotherapeutische cytostatica (chemokuren) en SMI's zijn chemische behandelingen, terwijl de andere behandelingen biologisch zijn. De werkingsmechanismen en bijwerkingen van deze geneesmiddelen worden gepresenteerd in onderstaande Table I.

Table I

Overview of chemotherapy and biological cancer therapy.

Type of therapyC or BMechanism of actionPhysiologicalSide effects
1. Cytostatic drugs C Interfere with cell proliferation No Grade 1-4
2. Small molecule inhibitorsa C Targeted therapy: Interfere with oncogenic signal transduction Yes Grade 1-4
3. Antitumor MAbsb B Targeted immunotherapy Yes Grade 1-3
4. Anti-angiogenesis MAbsc B Inhibit angiogenesis Yes Grade 1-3
5. Checkpoint inhibitor MAbsd B Immune regulation No Grade 1-4
6. CAR-T cells B Targeted cytotoxic T lymphocytes No Grade 1-3
7. Antitumor vaccines B Active specific vaccination Yes Grade 0-2
8. Oncolytic virusese B Oncolysis, induction of immunogenic cell death Yes Grade 0-2
ae.g. KIT inhibitors, such as sunitinib, imatinib, sorafenib and lapatinib;
be.g. cetuximab, trastuzumab, panitumumab (targets include HER-1, HER-2 and RAS);
ce.g. bevacizumab (Avastin; targets VEGF-L), ramucirumab (Cyramza; targets VEGF receptor 2);
de.g. ipilimumab (targets cytotoxic T-lymphocyte-associated protein 4), nivolumab (targets programmed cell death protein 1), atezolizumab and durvalumab (targets programmed death-ligand 1);
ee.g. RNA viruses, including Newcastle Disease Virus from attenuated natural wild type strains. B, biological therapy; C, chemoteherapy; HER, human epidermal growth factor receptor; VEGF, vascular endothelial growth factor.

Met betrekking tot SMI's werd geconcludeerd dat ze fysiologisch waren, aangezien SMI's een op tumoren gerichte aanpak voorstellen; toch kunnen normale cellen ook worden beïnvloed. Met betrekking tot anti-PD medicijnen , de MAbs, werd geconcludeerd dat ze niet fysiologisch waren, omdat interferentie met immuunregulatie ook interfereert met auto-immuunreactiviteit. Met betrekking tot CAR-T-cellen werd geconcludeerd dat ze niet fysiologisch waren, omdat de receptor kunstmatig is en alle cellen dezelfde receptor hebben.

Het veranderen van de manier hoe kanker te behandelen is echter niet eenvoudig, want de gezondheidszorg is een enorme markt. En het systeem van evidence based medicine is nog te weinig aangepast aan niuewere vormen van behandelen, waardoor het te leveren bewijs van efectiviteit veel te lang duurt en te duur wordt. 
Op dit moment zijn er medicijnen met een immuuntherapeutische werking, zoals MAbs en anti-PD medicijnen - checkpointremmers met succes op de markt gekomen; echter ook tegen bijna onbetaalbare prijzen. dit is echter maar een klein deel van het potentieel van wat mogelijk is met immuuntherapie.

In de toekomst kan immuuntherapie een op zichzelf staande discipline worden, waaronder immuundiagnose, immunotherapie, immuunbewaking en immunologische follow-up. Verder zijn twee kankervaccins, ATV-NDV en VOL-DC, die OV's combineren met TAA's, in de klinische toepassing opgenomen. Na> 30 jaar kan integratie van OV's in kankerimmuuntherapie snel mainstream worden ()

Bovenstaande teksten komen uit een grote reviewstudie: From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review) welke volledig gratis is in te zien. 

Het studierapport geeft een uitstekend gedocumenteerd beeld met een waardevolle referentielijst. Hier de conclusie / toelichting en abstract. Klik op de verschillende hoofdstukken om het studierapport door te bladeren

Biological and physiological therapies, which support the immune system, may therefore benefit cancer treatment. The present review focused on immunotherapy, with the aim of reducing side effects and increasing long-lasting efficacy in cancer therapy.

. 2019 Feb; 54(2): 407–419.
Published online 2018 Dec 10. doi: 10.3892/ijo.2018.4661
PMCID: PMC6317661
PMID: 30570109

From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review)

Abstract

The side effects of systemic chemotherapy used to treat cancer are often severe. For decades, oncologists have focused on treating the tumor, which may result in damage to the tumor-bearing host and its immune system. Recently, much attention has been paid to the immune system of patients and its activation via biological therapies. Biological therapies, including immunotherapy and oncolytic virus (OV) therapy, are often more physiological and well tolerated. The present review elucidated how these therapies work and why these therapies may be better tolerated: i) In contrast to chemotherapy, immunotherapies induce a memory function of the adaptive immunity system; ii) immunotherapies aim to specifically activate the immune system against cancer; side effects are low due to immune tolerance mechanisms, which maintain the integrity of the body in the presence of B and T lymphocytes with their antigen-receptor specificities and; iii) the type I interferon response, which is evoked by OVs, is an ancient innate immune defense system. Biological and physiological therapies, which support the immune system, may therefore benefit cancer treatment. The present review focused on immunotherapy, with the aim of reducing side effects and increasing long-lasting efficacy in cancer therapy.

10. Discussion

In spite of its severe side effects, chemotherapy remains a main treatment option for cancer. As early as 1963, the disappointing efficacy of chemotherapy was reported (). However, between 1984 and 1985, at the peak of aggressive chemotherapy, >6,000 articles were published in medical journals regarding treatment of cancer with chemotherapy; none of these studies reported on novel strategies that could cure advanced solid tumors in combination with chemotherapy (). Grade 3 and 4 side effects can be life threatening. One of the many types of cytostatic drug that produce such side effects are molecular derivatives of nitrogen mustard, which is a toxin that was used during World War I. Examples, still in use, are melphalan, chlorambucil, cyclophosphamide, ifosfamid and others.

Evidence-based medicine is currently the gold standard for the approval of novel drugs. The quality of criteria for clinical studies has steadily increased since the introduction of cytostatic drugs; however, some drugs originally approved many years ago are still in use. Recommendations for updates of standard therapy come from medical oncology societies. There is no guarantee, however, that such recommendations are devoid of conflicts of interest; therefore, it remains the individual responsibility of a medical oncologist to decide which drugs to apply or not. Medical ethics should be respected.

To change the direction of cancer therapy is not easy, as healthcare is a huge market. At present, immunological products, such as MAbs and checkpoint inhibitors have successfully entered the market; however, this is only a small portion of the potential of immunotherapy. In the future, immunotherapy may be a discipline in its own right, including immune diagnosis, immunotherapy, immune monitoring and immunological follow-up. Furthermore, two cancer vaccines, ATV-NDV and VOL-DC, which combine OVs with TAAs, have been entered into clinical application. After >30 years, integrating OVs into cancer immunotherapy may soon become mainstream ().

11. Conclusions

The present review compared chemotherapy and biological therapies, including immunotherapy and OV therapy.

Systemic forms of cancer treatment are necessary at the transition phase of cancer, when it turns from a localized into a systemic form of disease with metastases. Systemic forms of cancer treatment can be prophylactic (e.g. in a post-operative situation) or therapeutic. The primary aim of chemotherapy is to reduce tumor burden, whereas the aim of immunotherapy is to generate systemic protective anticancer immunity. The focus is either on the tumor or on the tumor-bearing host organism and its immune system.

The aim of this review was to present novel concepts, which may reduce side effects from systemic cancer treatment. This is necessary because chemotherapy often exhibits relatively low tumor specificity and high toxicity. Targeted therapy with chemically designed SMIs has higher tumor specificity than conventional chemotherapy; however, the side effects are similar. The majority of novel concepts are derived from biological types of therapy (Tables IIII); some of these biological therapies exert considerable side effects. Conversely, conventional immunotherapy, including vaccination and OV therapy, exerts only mild side effects and is well tolerated. It is suggested that the reason for this difference is physiological: Immunological self-tolerance and immunological memory.

An important difference between chemotherapy and immunotherapy or OV therapy is the dose-response curve. While in the case of cytostatic drugs the curve is linear, in the case of biological and physiological therapies it is bell-shaped. The reason for this difference appears to be due to the complementarity of specific cognate molecular lock-and-key interactions. This is exemplified with interactions between antigens and antibodies, as well as between pMHC and TCR in cases of T-cell-mediated immune responses.

Notably, a combination of cancer immunotherapy and OV therapy was successful in a randomized controlled study (,). This previous study evaluated the efficacy of post-operative vaccination with ATV-NDV in patients with stage IV CRC following resection of liver metastases. The results revealed that in patients with colon cancer a significant 10-year survival benefit of as much as 30% was detected. The magnitude of the effect is similar to that obtained in patients with melanoma treated with ICB (). The side effects of these two approaches, however, were different: Grade 0-2 for the vaccination study compared with grade 1-4 for the ICB study.

With regards to future developments, it has been suggested to combine vaccines, OVs and immune checkpoint inhibitors to prime, expand and facilitate effective tumor immunotherapy (,). The main conclusions of this review are: i) It may be beneficial for immunotherapy to be included in standard care. Rules of evidence-based medicine should be adjusted to the needs of individualized immunotherapy studies, as well as to multimodal therapy studies in general. ii) Recommendations for the use of cytostatic drugs that produce severe side effects and low efficacy should be reviewed by societies of internal medicine.

Acknowledgments

Chapter 6 on central immunological self-tolerance in the thymus is dedicated to the author’s former colleague at the DKFZ (Heidelberg, Germany), the late Professor Bruno Kyewski (1950-2018). The author also wishes to acknowledge Dr Wilfried Stuecker and Dr Stefaan van Gool (IOZK, Cologne, Germany) for their support in translational immunotherapy.

Funding

This review was supported by IOZK, Cologne, Germany.

Availability of data and materials

Not applicable.

Author contributions

VS contributed the idea, wrote the text, and generated the tables.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The author declares that they have no competing interests.

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