METRONOMIC CHEMOTHERAPY

1. .
Metronomic Chemotherapy

2. Introduction
 Conventional chemotherapy–
Maximum tolerated dose (MTD).
 Success in many hematological
malignancies ,early stage solid
tumors.
 Failed to demonstrate sustained
response in majority of common
advanced solid tumors.

3. Current challenges toMaximum
Tolerated Dose (MTD)
Chemotherapy
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Chemotherapy and Side effects
Collateral damage
Certain malignancies do not haveacure
Time interval between cycles- Emerging resistance

4. Gatenby hypothesis
 controlling tumor growth rather
than eradicating it and treating it like a
chronic disease may be more
meaningful.

5. The endothelium of tumor vasculature
has been recognized as clinically
validated therapeutic target.
Targeting endothelial cells present in a
tumor’s growing vasculature -- Potential
Benefit
Angiogenesis is the key factor in the
local and metastatic growth of cancer.

6. What would be the advantage of
using chemotherapeutics as
possible angogenesis inhibitors
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• Massive and diverse genetic instabilities present incancer
cells
• Targeting of anormal, terminally differentiated and
genetically stable endothelial cell presents thetheoretical
possibility of avoiding, or at least delaying, the onset of
acquired drug resistance.
• Might be more effective inmetastasis

7. 7
Conventional
chemotherapy
Metronomic
chemotherap
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
Riseand fall of plasmaconc Sustained plasma conc
Targetsproliferating tumor
cells
Targetsendothelial cells of
vasculature of thetumour
Toxicity concern Lesstoxicity

8. Concept – Metronomic
chemotherapy
 Conventional chemotherapy – anti
cancer drugs are administered in
cycles at the maximum tolerated dose.
 Alternate with long drug free period.
 Recurrence – metastatic and high risk
cancers.
 Rationale and effectiveness of
conventional MTD based therapy -??
In metastatic and poor prognosis
patients

9. Pioneer of angiogenesis theory –
JUDAH FOLKMANN

10. Pioneer of angiogenesis theory
• 1970s – Judah Folkman
• Tumor angiogenesis wasrecognized asakey driver of cancer
growth and an important target forchemotherapy.
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11.  Browder et al published pre clinical
data in year2000 from Judah
Folksmann laboratory.
 For demonstrating the anti angiogenic
effects they used transplantable
tumors and xenograft models.

12.  Study revealed that metronomic
regimen of cyclophosphamide was
more effective than conventional
therapy and could overcome drug
resistance.
 Browder et al – antiangiogenic
chemotherapy.
 Hanahan et al – metronomic

13.  Metronomic chemotherapy is the
frequent administration of
chemotherapy drugs at doses below
the MTD and with no prolonged drug
free break.

14. ???

15. ‘Metronome’ =musical instrument that producesregular,
metrical ticks representing fixed, regular auralpulse.
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16. Metronomic chemotherapy is the chronicadministration
of chemotherapy at low, minimally toxic doseson a
frequent schedule of administration, with no prolonged
drug-free breaks.
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What is metronomic
chemotherapy

17. The main characteristics of
metronomic chemotherapy are:
Frequent (dose-dense) administration of chemotherapy
without anyinterruptions
Using abiological optimized dose instead MTD
Preference for oraldrugs
Low incidence of treatment relatedside-effects
Potential for delayed development ofresistance.
No application of hematopoietic growth factors
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18. Mechanism of action
 Anti angiogenic effects
 Activation of immunity
 Induction of tumor dormancy
 Induction of senescence
 Four-dimensional effects

19. Criteria of ananti-angiogenic
agent forMCT
• Strong differential cytotoxicity between cancer cellsand
endothelial cells
• Changes of mechanistic effects (e.g., biomarker changes:IL-1
and 6, VEGF
,VEGFR1and 2, bFGF
,MMP-2 and 9, vesseldensity
etc.)
• Inhibition of angiogenesis in-vivoand in-vitro (in-vivo modelsat
best only with spontaneous, slow growingtumors)
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20. Mechanism of action
PasquierE,Kavallaris M,AndréN. Metronomic chemotherapy: newrationalefor new
directions. Nature ReviewsClinicalOncology. 2010;7(8):455-465.
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Stimulates immuneresponse
Inhibits tumorangiogenesis
Treg cell
Tumorcell

21. Mechanism of action
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22. 4 DEffect
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Andre et al., have postulated a‘drug-driven
dependency/ deprivation’or a4-dimensional
(4D) phenomenon
• Tumor cells become dependent onthe
chemotherapy during longexposure
• Suddencessation or replacement of therapy
might lead to celldeath.

23. Which PatientsAre
Candidates?
• Doesnot benefit every patient asisclear
from the clinical data gathered todate.
• Need to identify the right context and the
right patient group to benefit from
metronomic chemotherapy
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24. Theuseof Metronomic Chemotherapy in the clinical practice
hasbeen mainly limited to :
Palliative purposes in relapse/refractorydiseases
and metastatic cases
When touse?
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25. When touse?
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• 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 asmaintenance;
or
• Asswitch maintenance, where short periods of
conventional chemotherapy are followed by long coursesof
non cross-resistant cytotoxicdrugs.

26. Metronomic chemotherapy
in adults- various regimens

27. Metastatic breast cancer
previously treated with
conventional chemotherapy
 Cyclophosphamide
 Methotrexate

28. Untreated or previously treated
breast cancer with conventional
chemotherapy
 Cyclophosphamide
 Methotrexate
OR
• Cyclophosphamide
• Methotrexate
• Thalidomide

29. HER2 +metastatic breast cancer
previously treated with
transtuzumab and conventional
chemotherapy
 Cyclophosphamide
 Methotrexate
 Transtuzumab

30. Recurrent ovarian cancer
previously treated with
conventional chemotherapy.
 Cyclophosphomide
 Bevacizumab

31. Hormone refractory prostate
cancer,previously treated by
androgen deprivation
 Cyclophosphamide
 Dexamethasone
 or
 Dexamethasone
 Celecoxib

32. Aggressive relapsed or refractory
Non hodgkin lymphoma.
 Cyclophosphamide
 Celecoxib

33. Progressive multiple myeloma
previously treated with
conventional chemotherapy
 Cyclophosphomide
 Prednisolone

34. Metastatic or locally advanced
neuroendocrine carcinoma
 Long acting release octreotide
monthly
 5 FU

35. Pediatrics – regimens
Relapsed refractory high risk
tumors of various types.

36.  Etoposide alternating with
Temozolomide
 Celecoxib
 Retinoic acid
 Etoposide ,alternating with
cyclophosphomide
 Thalidomide

37. OMC REGIMENS ,CANCER
INSTITUTE(W.I.A)
 Cyclophosphamide
 Etoposide
 Prednisolone

38. Toxicity
• Generally well tolerated
• Most common toxic effects of this treatment are:
• Grade1 nauseaand/or vomiting,
• Grade1 and 2 anemia, neutropenia, leucopenia and
lymphopenia aswell aslow-grade fatigue
• Cumulative effects canlead to secondary leukemia,or
myelodysplastic syndrome(MDS)
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39. Biomarkers forevaluation
• Shakedet al., have investigated some cellular pharmacodynamic
biomarkers :
(i)previous observations showing significant and sustained declinein
circulating VEGFR-2+Endothelial Progenitor Cells(CEP);
(ii)preclinical validation of measuring levels of such cells asasurrogate
blood-based marker of angiogenesis
2

40. Biomarkers forevaluation
.
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• Circulating blood biomarkers (cytokines suchasVEGF
,
thrombospondin-1/2 and circulating endothelial cells)
• Functional imaging (e.g. DCE-MRI,or DCE-CT- utilized in early
phase clinical trials)
However, these biomarkers have not shownto
consistently correlate with response or
survival outcome.

41. Trialsin MetronomicCT
• Metronomic dosesare nearly 1/10th of MTDof conventional
chemotherapy –Toxicity not aconcern
• Therefore the aims of phase 1 clinical trial is to obtain the
Optimum Biological Dose(OBD)of adrug
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42. Metronomic Resistance
• Sharesanumber of mechanisms of resistance that arealso
functional in VEGFi therapy
• Somemechanisms are –
Endothelial cell-driven resistance – Vascular remodeling
Drug efflux pump positive endothelial progenitorcells
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43. Cost
Comparison
• According to apharmacoeconomic evaluation by Bocci etal.
in metastatic breast cancer, metronomic regimen is acost-
effective alternative to intravenous infusion chemotherapy
regimens
• Concluded that the MCTscheme could reduce healthcare
costs
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44. Drugrepositioning
• Using drugs already approved for non-malignant diseaseson
the basisof newly identified anticancerproperties
• Data available on pharmacokinetics, bioavailability,toxicities
• Truncates drug development process
• Repurposing Drugsin Oncology (ReDO)project
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45. Successful Drugrepositioning
examples
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• Celecoxib  Anti-angiogenic
• Propranolol  Immunomodulatory andanti-
angiogenic properties
• Valproic acid  Histone deacetylaseinhibitor
• Metformin  AMPkinase andmTOR
inhibitor or epithelial–mesenchymal
transition inhibitor
• Itraconazole  Sonichedgehog inhibitor
• Nifurtimox  inhibitor oftyrosine-related
kinase B

46. Limitations
• Most effective dose and schedule have yet tobe defined
• May not benefit every patient asis clear from the clinical
data gathered to date
• Need to identify the right context and the right patient
group tobenefit from metronomic chemotherapy
• Time lag between anti-tumor effect and avisiblereduction
in tumor bulk may in some casesdecrease the utility in
advanced disease
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47. • There is aneed to delineate patient subsets inwhich
metronomic will proveuseful
• Need for studies regarding pharmacokinetics and the
pharmacodynamic properties of metronomicchemotherapy
• Most promising applications of metronomic chemotherapy
may be in the maintenance treatment setting after induction
therapy
Future Directions
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48. • Chronic administration of chemotherapy at low, minimally
toxic doses on a frequent schedule of administration, with
no prolonged drug-freebreaks.
• Multi-directional mechanisms –Anti-angiogenesis,
Increased immune response
• Low incidence of treatment relatedside-effects
• Need to identify the right context and the right patient
group tobenefit from metronomic chemotherapy
• Most promising applications of metronomicchemotherapy
may be in the maintenance treatment setting after
induction therapy
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49. Thankyou!
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There is a‘CAN’in
‘CANCER’becausewe
canbeat it!