Chapter 24.3 metronomic chemotherapy

general oncology from devita presentation

1. Concepts of Metronomic
Chemotherapy

2. Metronomic Chemotherapy
Should we change our thinking
in the treatment of advanced tumors?
Mauch C. Metronomic Chemotherapy. Should we change our thinking in the treatment of advanced tumors? J Dtsch Dermatol Ges 2005;3(1):3-4.

3. Cancer facts & Figures
In 2008, 72% of cancer deaths occurred in low-income and middle-income
countries, where, although there is a lower incidence of cancer than in high-
income countries, survival rates are also low. Many patients are sent home to
die, & an even larger number of patients do not have access to treatment
facilities.
New constraint-adapted therapeutic strategies are therefore urgently needed.
Metronomic chemotherapy—the chronic administration of chemotherapy at
low, minimally toxic doses on a frequent schedule of administration, with no
prolonged drug-free breaks—has recently emerged as a potential strategy to
control advanced or refractory cancer.
This low-cost, well-tolerated, and easy to access strategy is an attractive
therapeutic option in resource-limited countries. Moreover, combined with
drug repositioning, additional anticancer effects can be achieved, ultimately
resulting in improved cancer control while maintaining minimum cost of
treatment.
Andre et al Lancet Oncol 2013; 14: e239–48

4. Cytotoxic Chemotherapy
Most of these drugs are DNA damaging agents or microtubule inhibitors
Designed to kill rapidly dividing cells –direct killing OR inhibit growth of cycling
tumour cells
DNA synthesis
Antimetabolites
DNA
DNA transcription DNA duplication
Mitosis
Alkylating agents
Spindle poisons
Intercalating agents
Kerbel RS et al. The anti-angiogenic basis of metronomic chemotherapy. Nature Reviews Cancer 2004;4:423-436.
Laquente B et al. metronomic chemotherapy: an antiangiogenic scheduling. Clin Transl Oncol 2007;9(2):93-8.

5. Conventional Chemotherapy
Dosage:
Based on ‘Log-dose survival
curve for cancer-cell kill’
Leading model for
chemotherapy dose
calculation
Maximum Tolerated Dose
(MTD)
Short courses of therapy at
highest possible doses
without causing life
threatening levels of toxicity
Kerbel RS et al. The anti-angiogenic basis of metronomic chemotherapy. Nature Reviews Cancer 2004;4:423-436.
Baruchel S et al. Low-dose metronomic chemotherapy: Myth or truth? Onkologie 2006;29:305-307.
Hanahan D et al. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. The J ClinInves 2000;105(8):1045-47.

6. Conventional Chemotherapy
MTD Therapy:
Usually associated with toxic side effects
Acute side effects
Myelosuppression
Hair loss
Damage to intestinal mucosa
Chronic side effects
Long term cardiac / renal / neurological / reproductive
consequences
Need to administer supportive care drugs
Kerbel RS et al. The anti-angiogenic basis of metronomic chemotherapy. Nature Reviews Cancer 2004;4:423-436.
Hanahan D et al. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. The J ClinInves 2000;105(8):1045-47.
Stempak D et al. Metronomic dosing of chemotherapy: Applications in pediatric oncology. Cancer Investigation 2006;24:432-443.

7. Conventional Chemotherapy
EFFICACY TOXICITY
Require prolonged breaks during successive cycles of
therapy (generally 2-3 weeks)
Allow for recovery of normal tissues
To balance toxicity and efficacy
Tonini G et al. Antiangiogenic properties of metronomic chemotherapy in breast cancer. Future Oncol 2007;3:183-90.
Hanahan D et al. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. The J ClinInves 2000;105(8):1045-47.
Gasparini G. Metronomic scheduling: the future of chemotherapy. Lancet Oncology 2001;2:733-739.
MTD Goal:
To obtain total eradication of cancer cells

8. Conventional Chemotherapy
Limitations:
Standard MTD regimen seriously impairs QOL
Initially efficacious
Tumour regression or stabilization
Prolonged survival
Short lived responses
Relapse (recurrence or regrowth) often marked by
aggressive cancers
Resistant to cytotoxic chemotherapy
Tonini G et al. Antiangiogenic properties of metronomic chemotherapy in breast cancer. Future Oncol 2007;3:183-90.
Baruchel S et al. Low-dose metronomic chemotherapy: Myth or truth? Onkologie 2006;29:305-307.
Hanahan D et al. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. The J ClinInves 2000;105(8):1045-47.
Stempak D et al. Metronomic dosing of chemotherapy: Applications in pediatric oncology. Cancer Investigation 2006;24:432-443.

9. Concept of Dose Intensity
Relates to the amount& frequencyof
administration with which a drug is given
Dose intensity correlates with outcomes
Norton L. Evolving concepts in the systemic drug therapy of breast cancer. Semin Oncol 1997;24(4, Suppl 10):S3-S10.

10. Dose Intensity
vs
↑ dose
Constant frequency
Option 1:Dose Escalation
(Increase amount of drug)
If increasing the amount of a drug has practical limitations, what if we
increase the frequency of administration?
Greater impact on clinical outcomes (+ use of CSF for hemopoietic
recovery)
Norton L. Evolving concepts in the systemic drug therapy of breast cancer. Semin Oncol 1997;24(4, Suppl 10):S3-S10.
vs
Option 2:Dose Density
(Increase frequency)
Constant dose
↑ frequency

11. Metronomic Chemotherapy
Chronic administration of chemotherapeutics at relatively low doses
(non-toxic, significantly below MTD), on a frequent schedule of
administration, with no prolonged drug-free break periods
Also termed ‘Low dose chemotherapy’ OR ‘Low dose metronomic
chemotherapy’ OR ‘Anti-angiogenic chemotherapy’
Dose 1/10 to 1/3 of MTD
Kerbel RS et al. The anti-angiogenic basis of metronomic chemotherapy. Nature Reviews Cancer 2004;4:423-436.
Kerbel RS. Improving conventional or low dose metronomic chemotherapy with targeted antiangiogenic drugs. Cancer Res Treat 2007;39(4):150-159.
Stempak D et al. Metronomic dosing of chemotherapy: Applications in pediatric oncology. Cancer Investigation 2006;24:432-443.
Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncology 2001;2:733-739.

12. What it means……….
Hanahan D et al. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. The J ClinInves 2000;105(8):1045-47.

13. Metronomic Chemotherapy
Metronomic Chemotherapy Dose Dense Chemotherapy
Dosing Frequency More frequent More frequent
Dose Used
Individual Doses < Conventional MTD regimes< Conventional MTD regimes
Cumulative Doses < Conventional MTD regimes>Conventional MTD regimes
Target Endothelial cells in growing
vasculature of the tumour
Proliferating tumour cells
Host Toxicity Significantly less toxicity
Reduced need for supportive
therapy (e.g. G-CSF)
Toxicity is a concern
Supportive therapy is
required to control
symptoms
Form of dose dense chemotherapy, with some
differences
Kerbel RS. Improving conventional or low dose metronomic chemotherapy with targeted antiangiogenic drugs. Cancer Res Treat 2007;39(4):150-159.
Kerbel RS et al. The anti-angiogenic basis of metronomic chemotherapy. Nature Reviews Cancer 2004;4:423-436.
Stempak D et al. Metronomic dosing of chemotherapy: Applications in pediatric oncology. Cancer Investigation 2006;24:432-443.
Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncology 2001;2:733-739.

14. Mathematical models of tumor cytoreduction
and regrowth
Luck HJ et al. Weekly paclitaxel: an effective and well-tolerated treatment in patients with advanced breast cancer. Crit Rev Onco Hemat 2002;44:S15-S30.

15. Metronomic Chemotherapy
Rationale
Novel therapeutic anticancer treatment
strategy:
To manage cancer as a chronic but stable
disease
Total tumour burden is kept at the lowest
possible level
Targeting of tumor vasculature [Anti-
angiogenic activity]
Sarmiento R et al. Antiangiogenic metronomic chemotherapy. Onkologie 2008;31:161-162.
Maraveyas A et al. Can a rational design for metronomic chemotherapy dosing be devised? Br J Cancer 2005;92:1588-1590.
Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncology 2001;2:733-739.

16. By combining metronomic chemotherapy and drug repositioning, metronomics can target
the three main compartments of the tumour microenvironment (cancer cells, tumour
vasculature, and the immune system), ultimately leading to cancer control. Arrow sizes
are proportional to the potential difference in intensity of effect on the different targets
Mechanisms of action of metronomics
Andre et al Lancet Oncol 2013; 14: e239–48

17. Tumour Angiogenesis
Multi step process
Pro angiogenic factors
secreted by both tumor and
host cells
Angiogenesis –sustain growth
of both primary tumor,
progression and development
of metastasis
Sarmiento R et al. Antiangiogenic metronomic chemotherapy. Onkologie 2008;31:161-162.
Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncology 2001;2:733-739.
Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992; 267(16):10931-4.
Basement membrane
VEGF
receptor
Endothelial
cell migration
Endothelial cell
proliferation
Tube formation
VEGF VEGF binds to
receptor activating
endothelial cells
Elongation
Remodelling
ANGIOGENIC TIMELINE

18. Mechanisms of action of metronomic chemotherapy

19. Angiogenesis Chemotherapy Model
Proliferation of intra-tumoural vascular
endothelial cells:
Less than Tumor cells
Weakly disrupted by episodic regimens of standard CT
protocols
Long interval between cycles of conventional CT
Permits survival and re-growth
Allows tumor angiogenesis to persist
Metronomic CT optimizes anti-angiogenic
properties
Shortening interval between cycles
Prevents effective recovery of damaged tumor vasculature
Kamat AA et al. Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer. Cancer Res 2007;67(1):281-8.
Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncology 2001;2:733-739.
Hanahan D et al. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. The J ClinInves 2000;105(8):1045-47.

20. Metronomic Chemotherapy
Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncology 2001;2:733-739.
Stempak D et al. Metronomic dosing of chemotherapy: Applications in pediatric oncology. Cancer Investigation 2006;24:432-443.
Sarmiento R et al. Antiangiogenic metronomic chemotherapy. Onkologie 2008;31:161-162.
Kerbel RS. Improving conventional or low dose metronomic chemotherapy with targeted antiangiogenic drugs. Cancer Res Treat 2007;39(4):150-159.

21. Metronomic Chemotherapy
Opportunities:
Combination with:
Targeted antiangiogenic drug like bevacizumab
Synergistic anti tumor activity
Targeted therapies like target specific signal
transduction molecules
Chemo-switching protocols
Integrated and sequenced with standard MTD type
chemotherapy where brief courses of such induction
therapy, given ‘upfront', is followed by long term
maintenance / metronomic low-dose chemotherapy
Kerbel RS. Improving conventional or low dose metronomic chemotherapy with targeted antiangiogenic drugs. Cancer Res Treat 2007;39(4):150-159.
Kerbel RS et al. The anti-angiogenic basis of metronomic chemotherapy. Nature Reviews Cancer 2004;4:423-436.
Sarmiento R et al. Antiangiogenic metronomic chemotherapy. Onkologie 2008;31:161-162.
Munoz R et al. Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy. The Breast 2005;14:466–479.
Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncology 2001;2:733-739.

22. Metronomic Chemotherapy
Challenges and Concerns:
Determining the optimal biologic dose (OBD)
Lowest possible toxicity to non-neoplastic tissue without
compromising its anti angiogenic effect
If combined with MTD regimes, important not to completely
eradicate tumor vasculature (else, impair delivery of cytotoxic drugs
to its target)
Pharmacokinetic evaluation needed
Identify and validate surrogate markers
To select the OBD
Monitor before and after therapy
May cause delayed toxicities
Kerbel RS. Improving conventional or low dose metronomic chemotherapy with targeted antiangiogenic drugs. Cancer Res Treat 2007;39(4):150-159.
Stempak D et al. Metronomic dosing of chemotherapy: Applications in pediatric oncology. Cancer Investigation 2006;24:432-443.
Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncology 2001;2:733-739.

23. Classical q3w schedule at the MTD
Continuous infusion at the MTD
Metronomic (daily) oral therapy
Continuous infusion and
q3w IV Chemotherapy (e.g. ECF)
q3w iv chemotherapy+ metronomic
low –dose concept (e.g. XELOX)
Weekly chemotherapy
(e.g. Paclitaxel)
Mross et al. Journal of Cancer therapeutics & Research 2012,

24. Dose-response curves for different effects of
cyclophosphamide.
Mross et al. Journal of Cancer therapeutics & Research 2012,

25. Lancet Oncol 2013; 14: e239–48

26. Drug repositioning
Using old drugs for new indications. Testing drugs already
approved for nonmalignant diseases on the basis of newly
identified anticancer properties presents several advantages.
Side-effects (moderate & well documented) that are known.
Phase 1 studies are therefore not mandatory and further
clinical development can often start directly with phase 2
trials.
Celecoxib –antiangiogenic,
Valproic acid as a histone deacetylase inhibitor
Metformin-AMP kinase and mTOR inhibitor
Itraconazole-sonic hedgehog inhibitor
Nifurtimox -inhibitor of tyrosine-related kinase B.
Propranolol -immunomodulatory & anti angiogenic properties
Andre et al Lancet Oncol 2013; 14: e239–48

27. Potential advantages of metronomics
in LMICs
1.Low direct cost
2.Usually available in oral form
3.Can be taken at home
4.Minimal risk of infections or additional nutrition problems
5.Minimal blood product support
6.Complex infrastructure/highly trained human resources not
required
7.Basic oncology units can be introduced even in rural areas
Andre et al Lancet Oncol 2013; 14: e239–48

28. Potential disadvantages of metronomics
No validated biomarkers for minimal effective dose
Compliance decreases with treatment duration
New technologies using daily mobile phone alerts

29. Examples of published metronomic studies undertaken in high-income countries

30. Metronomic studies undertaken in Low & Middle income countries

32. Conclusions
1.Metronomic chemotherapy is useful in many advanced
cancers.
2.Older and cheaper drugs have good repositioning
benefits for use in cancers.
3.Combination is often used than single drug.
4.It may be effective in prolonged control of disease.
5.Usually safe & well tolerated, with minimal side effects.
6.Optimizing a metronomic anticancer therapy (which
drugs ?, which tumors ? and when at which time point
?) is still an open question?
7.It is highly cost effective in developing world.

33. Metronomic Chemotherapy
Teaching Old Drugs…
Vogelzang N. Metronomic Chemotherapy. Teaching old drugs new tricks? Clin Adv Hematol Oncol 2004;2(7):432-3.
…The New Tricks