This is the first ever presentation on slideshare regarding basics of Metronomic Chemotherapy.

1. Dr Sonali R. Karekar
PGY-2,
Dept. of Pharmacology &
Therapeutics,
Seth GSMC & KEMH.
Metronomic Chemotherapy

2. Flow Of Seminar
2
Background
What is Metronomic Chemotherapy?
Differences from Conventional Chemotherapy
Mechanism of action
Drugs used in Adults & Paediatrics
Optimal Biological Dose
Clinical trials
Toxicity
Resistance
Cost comparison
Limitations
Summary

3. Cancer
• Every year globally 8.2 million people die from cancer
• ICMR in 2016 said that the total number of new cancer
cases in India is likely to reach nearly 17.3 lakh by 2020
• Acc to a study, 7.5% of patient deaths occurred within 30
days of chemotherapy, were related to treatment rather
than disease progression
O’Brien MER, Borthwick A, Rigg A, et al. Mortality within 30 days of chemotherapy: a clinical
governance benchmarking issue for oncology patients. British Journal of Cancer.
2006;95(12):1632-1636. doi:10.1038/sj.bjc.6603498.
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4. Current challenges to Maximum
Tolerated Dose (MTD)
Chemotherapy
Chemotherapy and Side effects
Collateral damage
Certain malignancies do not have a cure
Time interval between cycles - Emerging resistance
R. S. Kerbel,G. Klement, K. I. Pritchard, B. Kamen; Continuous low-dose anti-angiogenic/metronomic chemotherapy: from
the research laboratory into the oncology clinic. Annals of Oncology. 2002;31(1): 12–15. 4
Targeting endothelial cells present in a tumor’s growing
vasculature  Potential Benefit
What would be the advantage of using
chemotherapeutics as possible angiogenesis inhibitors?

5. What would be the advantage of
using chemotherapeutics as possible
angiogenesis inhibitors?
• Massive and diverse genetic instabilities present in cancer
cells
• Targeting of a normal, terminally differentiated and
genetically stable endothelial cell presents the theoretical
possibility of avoiding, or at least delaying, the onset of
acquired drug resistance
• Might be more effective in metastasis
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6. Pioneer of angiogenesis theory
• 1970s – Judah Folkman
• Tumor angiogenesis was recognized as a key driver of cancer
growth and an important target for chemotherapy.
6

7. Why not routine angiogenesis
inhibitors?
Shortcomings of anti-vascular tumor therapy:
(i) most tumors are inherently resistant to VEGFi and other
anti-vascular therapies used alone;
(ii) even when used in combinations that increase the initial
response rate, responsive tumors typically develop acquired
resistance within a few months; and
(iii)Adjuvant use of these agents did not increase cure rates
7
However, the frequent and sustained use of low doses
of conventional chemotherapeutics mimics the long-
term antiangiogenic activities of VEGFi.

8. Browder, et al. Antiangiogenic Scheduling of Chemotherapy Improves Efficacy against Experimental
Drug-resistant Cancer. Cancer research. 2000. 8
Concept of Metronomic Chemotherapy
In the year 2000, Browder et al. reported that :
• Cyclophosphamide given to tumor-bearing mice
• Maximum Tolerated Dose (MTD)
• Breaks at every 3 weeks
• Little therapeutic benefit
• Transient anti-angiogenic effect.

9. • Cyclophosphamide administered chronically once a week
without breaks
• At a lower dose (e.g. one third of the MTD)
• Repair process was compromised and anti-angiogenic
effects of the drug were not lost.
9
Concept of Metronomic Chemotherapy
This method of administrating chemotherapy
was named ‘anti-angiogenic chemotherapy’ by
Browder et al and ‘metronomic’ dosing by
Hanahan et al

10. What is Metronomic Chemotherapy?
Metronomic chemotherapy is the chronic administration
of chemotherapy at low, minimally toxic doses on a
frequent schedule of administration, with no prolonged
drug-free breaks.
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-e248. 10

11. ‘Metronome’ = musical instrument that produces regular,
metrical ticks representing fixed, regular aural pulse.
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12. Mechanism of action
Pasquier E, Kavallaris M,André N. Metronomic chemotherapy: new rationale for new
directions. Nature Reviews Clinical Oncology. 2010;7(8):455-465.
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Stimulates immune response
Inhibits tumor angiogenesis
Treg cell
Tumor cell

13. 4 D Effect
Andre et al., have postulated a ‘drug-driven
dependency/ deprivation’ or a 4-dimensional
(4D) phenomenon
•Tumor cells become dependent on the
chemotherapy during long exposure
•Sudden cessation or replacement of therapy
might lead to cell death.
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14. Mechanism of action
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15. Conventional Chemotherapy
Vs.
Metronomic Chemotherapy
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16. Conventional
Chemotherapy
Metronomic
Chemotherapy
Maximum tolerated
doses(MTD) used
Lower dose than MTD
Therapy at defined intervals
depending on recovery of bone
marrow. Eg: 3 weekly
Dosing frequency is
continuous. Eg: Weekly, daily,
alternate days
Rise and fall of plasma conc Sustained plasma conc
Targets proliferating tumor
cells
Targets endothelial cells of
vasculature of the tumour
Toxicity concern Less toxicity
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17. The main characteristics of metronomic
chemotherapy are:
Frequent (dose-dense) administration of chemotherapy
without any interruptions
Using a biological optimized dose instead MTD
Preference for oral drugs
Low incidence of treatment related side-effects
Potential for delayed development of resistance.
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18. Criteria of an anti-angiogenic
agent for MCT
• Strong differential cytotoxicity between cancer cells and
endothelial cells
• Changes of mechanistic effects (e.g., biomarker changes:IL-1
and 6, VEGF, VEGFR1 and 2, bFGF, MMP-2 and 9, vessel density
etc.)
• Inhibition of angiogenesis in-vivo and in-vitro (in-vivo models at
best only with spontaneous, slow growing tumors)
Maiti R. Metronomic chemotherapy. J Pharmacol Pharmacother 2014;5:186-92. 18

19. Which Patients Are
Candidates?
• Does not benefit every patient as is clear
from the clinical data gathered to date.
• Need to identify the right context and the
right patient group to benefit from
metronomic chemotherapy
19

20. The use of Metronomic Chemotherapy in the clinical practice
has been mainly limited to :
Palliative purposes in relapse/refractory diseases
and metastatic cases
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When to use?

21. When to use?
•Particularly appropriate for maintenance strategies
•Can be delivered as a continuation of the induction
regimen, where one or two drugs already used in the
induction regimen are carried on as maintenance;
or
• As switch maintenance, where short periods of
conventional chemotherapy are followed by long courses of
non cross-resistant cytotoxic drugs.
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22. Toxicity
• Generally well tolerated
• Most common toxic effects of this treatment are:
• Grade 1 nausea and/or vomiting,
• Grade 1 and 2 anemia, neutropenia, leucopenia and
lymphopenia as well as low-grade fatigue
• Cumulative effects can lead to secondary leukemia, or
myelodysplastic syndrome (MDS)
Gnoni A, Silvestris N, Licchetta A, Santini D, Scartozzi M, Ria R et al. Metronomic chemotherapy
from rationale to clinical studies: A dream or reality?. Critical Reviews in Oncology/Hematology.
2015;95(1):46-61.
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23. Biomarkers for evaluation
• Shaked et al., have investigated some cellular pharmacodynamic
biomarkers :
(i) previous observations showing significant and sustained decline in
circulating VEGFR-2+ Endothelial Progenitor Cells (CEP);
(ii) preclinical validation of measuring levels of such cells as a surrogate
blood-based marker of angiogenesis
Maiti R. Metronomic chemotherapy. J Pharmacol Pharmacother 2014;5:186-92.

24. Biomarkers for evaluation
• Circulating blood biomarkers (cytokines such as VEGF,
thrombospondin-1/2 and circulating endothelial cells)
• Functional imaging (e.g. DCE-MRI, or DCE-CT - utilized in early
phase clinical trials)
T. Rajasekaran, et al., Metronomic chemotherapy: A relook at its basis and rationale. Cancer
Letters. 2016.
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However, these biomarkers have not shown to
consistently correlate with response or
survival outcome.

25. Trials in Metronomic CT
• Metronomic doses are nearly 1/10th of MTD of conventional
chemotherapy – Toxicity not a concern
• Therefore the aims of phase 1 clinical trial is to obtain the
Optimum Biological Dose (OBD) of a drug
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26. Study designs in Metronomic
trials
• Phase I standard '3+3' design to observe pre-defined DLT 
Failed to detect the OBD.
• The OBD is determined based on the performance of desired
level of Surrogate Marker(SM).
• Single arm studies
• Majority of these are Phase I and Phase II studies, with small
patient numbers
• Often when standard of care has been exhausted.
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27. involving
Metronomic CT
Breast CA
27%
Colon CA
18%
Ovarian CA
9%
Prostate CA
9%
Hematologic,
CNS,Soft
tissue
37%
Trials
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28. Drugs used in Metronomic trials
•Totally 18 drugs were used as single drug and in combinations
•Most commonly employed drugs were cyclophosphamide,
methotrexate, capecitabine, bevacizumab, vinorelbine
•Cyclophosphamide and methotrexate were employed in
doses of 50mg once daily and 2.5mg twice daily respectively.
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Metronomic Chemotherapy: Seems Prowess
to Battle against Cancer in Current Scenario

29. Metronomic CT in TNBC – Phase III
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30. Metronomic CT inTNBC – Phase
III results
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The mean OS for groups 1  37.3 months
Group 2  29.3 months
4-year OS were 74% for group 1 v/s 55% for group 2

31. Adult regimens
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32. Paediatric
Regimens
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33. Issues in metronomic trials
Lack of studies regarding pharmacokinetics and the
pharmacodynamic properties
To detect cumulative side effects
Long duration of trials– How long?
Metronomic chemotherapy studies should be adopted only
after strong preclinical data indicating –
Which drugs should be used, how long, and at which doses?
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34. Metronomic Resistance
• Shares a number of mechanisms of resistance that are also
functional in VEGFi therapy
• Some mechanisms are –
Endothelial cell-driven resistance – Vascular remodeling
Drug efflux pump positive endothelial progenitor cells
Riesco-Martinez M, Parra K, Saluja R, Francia G, Emmenegger U. Resistance to metronomic
chemotherapy and ways to overcome it. Cancer Letters. 2017;400:311-318.
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35. Cost Comparison
• According to a pharmacoeconomic evaluation by Bocci et al.
in metastatic breast cancer, metronomic regimen is a cost-
effective alternative to intravenous infusion chemotherapy
regimens
• Concluded that the MCT scheme could reduce health care
costs
Bocci G, Tuccori M, Emmenegger U, et al. Cyclophosphamide–methotrexate “metronomic”
chemotherapy for the palliative treatment of metastatic breast cancer. A comparative
pharmacoeconomic evaluation. Ann Oncol 2005;16:1243–52.
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36. Drug repositioning
• Using drugs already approved for non-malignant diseases on
the basis of newly identified anticancer properties
• Data available on pharmacokinetics, bioavailability, toxicities
• Truncates drug development process
• Repurposing Drugs in Oncology (ReDO) project
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-e248.
36

37. Successful Drug repositioning
examples
• Celecoxib  Anti-angiogenic
• Propranolol  Immunomodulatory and anti-
angiogenic properties
• Valproic acid  Histone deacetylase inhibitor
• Metformin  AMP kinase and mTOR
inhibitor or epithelial–mesenchymal
transition inhibitor
• Itraconazole  Sonic hedgehog inhibitor
• Nifurtimox  inhibitor of tyrosine-related
kinase B
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38. In vitro assays - Metformin and
Propranolol
Conventional
Chemotherapy
Metronomic
Chemotherapy
Cell Type IC50
Metformin
(µM)
IC50
Propranolol
(µM)
IC50
Metformin
(µM)
IC50
Propranolol
(µm)
4T1 5.87 5.20 0.16 0.10
MDA-
MB-231
5.90 7.91 0.27 0.21
MCF7 1.08 7.97 0.07 0.17
Rico M, Baglioni M, Bondarenko M, Laluce N, Rozados V, André N et al. Metformin and propranolol
combination prevents cancer progression and metastasis in different breast cancer models.
Oncotarget. 2016;8(2).
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39. Limitations
• Most effective dose and schedule have yet to be defined
• May not benefit every patient as is clear from the clinical
data gathered to date
• Need to identify the right context and the right patient
group to benefit from metronomic chemotherapy
• Time lag between anti-tumor effect and a visible reduction
in tumor bulk may in some cases decrease the utility in
advanced disease
T. Rajasekaran, et al., Metronomic chemotherapy: A relook at its basis and rationale.
Cancer Letters .2016. 39

40. • There is a need to delineate patient subsets in which
metronomic will prove useful
• Need for studies regarding pharmacokinetics and the
pharmacodynamic properties of metronomic chemotherapy
• Most promising applications of metronomic chemotherapy
may be in the maintenance treatment setting after induction
therapy
40
Future Directions

41. • Chronic administration of chemotherapy at low, minimally
toxic doses on a frequent schedule of administration, with
no prolonged drug-free breaks.
• Multi-directional mechanisms – Anti-angiogenesis,
Increased immune response
• Low incidence of treatment related side-effects
• Need to identify the right context and the right patient
group to benefit from metronomic chemotherapy
• Most promising applications of metronomic chemotherapy
may be in the maintenance treatment setting after
induction therapy
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42. Thank you!
There is a ‘CAN’ in
‘CANCER’ because we
can beat it!
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