metronomic chemotherapy

1. METRONOMIC
CHEMOTHERAPY IN MBC
DR. R. RAJKUMAR D.M.
CONSULTANT MEDICAL ONCOLOGIST
VELAMMAL MEDICAL COLLEGE &
SPECIALITY HOSPITALS

2. METRONOMIC CHEMOTHERAPY
• Metronomic chemotherapy involves
administering lower doses of
chemotherapeutic drugs at more frequent
intervals
• Lower dosage allows targeting supporting
tumor stroma without selecting for resistant
cells, unlike in case of antibiotic resistance
• Lower dosage and more frequent
administration allow preservation and
maintenance of anti-tumor immunity
• Metronomic chemotherapy yields long-term
improved clinical outcome despite slower
initial decreases in tumor size
Predicted response to changes in tumor size over time after
MTD compared to metronomic chemotherapy
*

3. METRONOMIC CHEMOTHERAPY
• Possible mechanisms of action
for metronomic chemotherapy
include
• Inhibition of angiogenesis
• Stimulation of the immune
system
• Direct targeting of tumor cells
André et al. Nat Rev Clin Oncol 2014; 11: 413–431. Potential mechanisms of action of metronomic chemotherapy.

4. METRONOMIC CHEMOTHERAPY VS MTD
*Cancer Lett. 2015 Mar 28; 358(2): 100–106

5. MTD regimens
Vascular repair activity during the drug-free
periods because of up-regulation of pro-
angiogenic factors
Antivascular effects of MTD & Metronomic CHT
Metronomic regimens
Increase of the antivascular effects by
blocking the recovery of new vascularization
without increasing adverse events

6. TUMOR DORMANCY
 Cellular dormancy (G0-G1 arrest)
 Angiogenic dormancy
 Immunosurveillance
 Adaptative therapy

7. INVOLVING
METRONOMIC CT
Breast
CA
27%
7
Colon
CA
18%
Ovarian
CA
9%
Prostate
CA
9%
Hematologi
c,
CNS,Soft
tissue
37%
Trial
s

8. 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.
28

9. SUCCESSFUL DRUG REPOSITIONING
9
 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

11. TRIALS OF METRONOMIC CHEMOTHERAPY AS
MONOTHERAPY IN ADVANCED BREAST CANCER

12. TRIALS OF METRONOMIC CHEMOTHERAPY
COMBINATIONS IN ADVANCED BREAST CANCER

13.  Delivery of a multitargeted antiangiogenic regimen with significant anticancer
activity without the side effects typically associated with chemotherapy
 Rationale of treating patients using combinations of metronomic
chemotherapy plus targeted therapeutics, such as:
- Targeted antiangiogenic agents
- HER-2/HER-1 inhibitors
NEW STRATEGIES: METRONOMIC CT +
TARGETED THERAPEUTICS

14. TRIALS OF METRONOMIC CHEMOTHERAPY
COMBINATIONS IN ADVANCED BREAST CANCER

15. ORIGINAL ARTICLE
METRONOMIC CHEMOTHERAPY WITH ORAL VINORELBINE (mVNR) AND CAPECITABINE (mCAPE)
IN ADVANCED HER2-NEGATIVE BREAST CANCER PATIENTS: IS IT A WAY TO OPTIMIZE DISEASE CONTROL?
FINAL RESULTS OF THE VICTOR-2 STUDY
M.E. Cazzaniga1, L. Cortesi2, A. Ferzi3, L. Scaltriti4, F. Cicchiello1, M. Ciccarese M5, S. Della Torre6, F. Villa7, M. Giordano8, C. Verusio9, M. Nicolini10, A.R. Gambaro11, L. Zanlorenzi12, E. Biraghi13, L. Legramandi14, E. Rulli14
on behalf of the VICTOR Study Group
VICTOR-2 STUDY
1 Primary end point
CBR=OR+SD≥24 weeks
2 Secondary end points
ORR=CR+PR
DCR=OR+SD
PFS, TTP
Cazzaniga ME, Cortesi L, Ferzi A et Al. Breast Cancer Res Treat, 2016

16. Cazzaniga ME, Cortesi L, Ferzi A et Al. Breast Cancer Res Treat, 2016
Median time to response: 2.0 months
VICTOR-2 STUDY
Primary end point CBR = OR+SD ≥ 6 months
Clinical Benefit
n/N
Clinica Benefit
% (95% CI)
Chemotherapy line
First line 16/35 45.7 [28.8 – 63.4]
Second line 23/45 51.1 [35.8 – 66.3]
Overall 39/80 48.8 [37.4 – 60.2]
First line
Receptor status
HR+ve 11/22 50.0 [28.2 – 71.8]
TNBC 5/13 38.5 [13.9 – 68.4]
Tumor site
Visceral 10/23 43.5 [23.2 – 65.6]
Non visceral 6/12 50.0 [21.1 – 80.0]
Second line
Receptor status
HR+ve 18/30 60.0 [40.6 – 77.3]
TNBC 5/15 33.3[11.8 – 61.6]
Tumor site
Visceral 16/35 45.7 [28.8 – 63.3]
Non visceral 7/10 70.0 [34.8 – 93.3]
Overall
Receptor status
HR+ve 29/52 55.8 [41.3 – 69.5]
TNBC 10/28 35.7 [18.6 – 55.9]
Tumor site
Visceral 26/58 44.8 [31.7 – 58.5]
Non visceral 13/22 59.1 [36.4 – 79.3]
CBR=48.8%
CBR=55.8%

17. Cazzaniga ME, Cortesi L, Ferzi A et Al. Breast Cancer Res Treat, 2016
PFS rate at 1 year: 1st-line=24.3% - 2nd-line=22.2%
PFS according to treatment line and hormone receptor status
VICTOR 2 STUDY – EFFICACY RESULTS

18. Vinorelbine
Cyclophosphamide
(Endoxan®)
Capecitabine
(Xeloda®)
40 mg day 1, 3, 5
50 mg/day orally at 9 a.m.
500 mg x 3/day orally after meals
METRONOMIC CHEMOTHERAPY (VEX):
TREATMENT SCHEDULE

19. METRONOMIC CHEMOTHERAPY (VEX):
MEDIAN TIME TO PROGRESSION
Untreated Pretreated
Median TTP 26.5 mo 9.6 mo
1-yr PFS 73% 38%
2-yr PFS 52% 28%
Response Rate (PR+CR) 35% 30%
ECCO 2015

22. NAME TRIAL

23. METRONOMIC MONOTHERAPY AND
COMBINATIONS
• Numerous phase II clinical trials have demonstrated activity for oral
chemotherapeutic agents as metronomic monotherapy in patients with MBC
• First-line capecitabine, administered at standard doses or continuously, improved
OS and was better tolerated than classical cyclophosphamide, methotrexate, and
fluorouracil (CMF) in women with MBC unsuitable for more intensive chemotherapy
regimens
• Metronomic oral vinorelbine has demonstrated promising activity and safety as a
single agent
• Combination metronomic regimens have also demonstrated activity and excellent
tolerability in MBC

24. Cazzaniga et al. The PENELOPE Project. Adv Ther 2019; 36: 381–406.

25. THE PENELOPE PROJECT
• October 2017, a consensus meeting of ten international experts in the management of
breast cancer
• To develop an expert report that described the current status of the use of metronomic
chemotherapy (mCHT) for the treatment of advanced breast cancer.
• Metronomic chemotherapy was defined as the frequent, regular administration of drug
doses that maintain a low, prolonged, and pharmacologically active range of plasma
concentrations of drugs with a favorable toxicity profile or as the minimum biologically
effective dose of a chemotherapy agent that can be administered in a continuous
dosing regimen with no prolonged drug-free breaks.
Cazzaniga et al. The PENELOPE Project. Adv Ther 2019; 36: 381–406.

26. THE PENELOPE PROJECT
• 85 unique references were included in the final list and served as support to develop this report.
• Following are main findings of this expert consensus meeting.
1. A full consensus was reached concerning the acknowledgement that mCHT is not simply a different way of
administering chemotherapy but a truly new treatment option.
2. Most of the experts agree that mCHT has multiple mechanisms of action, such as anti-angiogenic and
immune-mediated effects.
3. The best-known effect of mCHT is on angiogenesis inhibition, but exciting new data are on the way
regarding potential activity on immune system activation.
Cazzaniga et al. The PENELOPE Project. Adv Ther 2019; 36: 381–406.

27. PENELOPE PROJECT
4. The experts strongly suggest that the ideal patients for mCHT are those with hormone receptor (HR)-
positive tumors or those with triple-negative disease.
5. Independently of HR status, mCHT could be an advantageous option for elderly patients, who are often
under-treated simply because of their age.
6. Panel experts concluded that the large amount of preclinical and clinical data for mCHT is robust enough to
recommend considering this kind of therapy as a treatment option in patients with MBC.
Cazzaniga et al. The PENELOPE Project. Adv Ther 2019; 36: 381–406.

29. ChT component of HER2 positive ABC treatment

30. WHAT’S NEXT
L O O K I N G A H E A D
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33. TRIALS WITH METRONOMIC CHEMOTHERAPY IN
THE NEOADJUVANT SETTING

34. CM Maintenance Chemotherapy (CMM)
IBCSG TRIAL 22-00 (CM MAINTENANCE)
S
U
R
G
E
R
Y
12 mos.
Stratify
•Institution
•Menopausal
status
•Induction
regimen
Induction Chemotherapy
4-6 mos.
Observation (OBS)
4-6 mos.
*Any time from start of induction to within 8 weeks after first day of last course of induction
1081 patients in ITT population; Median follow-up 6.9 years
IBCSG
Induction Chemotherapy
Hormone receptor negative (< 10% positive cells by IHC) by locally-determined ER and PgR
1086 patients enrolled Jan 2001 - Dec 2012
R
A
N
D
O
M
I
Z
E
*

35. IBCSG
TRIAL TREATMENT
• Low dose oral CM
– C, cyclophosphamide 50 mg/day orally continuously
– M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week
• CM Maintenance (CMM)
– CM after induction chemotherapy for 12 months duration
• Cost of CMM: 10 €/month

36. IBCSG
DISEASE-FREE
SURVIVAL

37. IBCSG
DISEASE-FREE
SURVIVAL
Triple Negative Node Positive and Triple Negative

38. 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
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39. • 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
FUTURE
DIRECTIONS
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40. THANK YOU
D R . R . R A J K U M A R 9 6 7 7 7 2 2 0 2 4 d r r a j 1 2 3 1 9 @ g m a i l . c o m