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© IEO 2009
Metronomic chemotherapy for breast cancer
M. Colleoni International Breast Cancer Study Group
(IBCSG), Division of Medical Senology,
European Institute of Oncology
© IEO 2009
Metronomic Scheduling and Inhibition of Tumor Growth: In Vivo Models
Cancer Res 2000, 60: 1878-86
© IEO 2009
Metronomic chemotherapy concept showing multiple mechanisms
3Nat Rev Clin Oncol 2015; 12: 631-44
© IEO 2009
Metronomic CT in breast cancer: number of published papers during
years
4
02468
1012141618
2002-20052006-20092010-20112012-2014
Cancer Treatment Reviews 40 (2014) 942–950
© IEO 2009
Neoadjuvant treatment for early breast cancer
© IEO 2009
Trials with metronomic chemotherapy in the neoadjuvant setting
6
Nat Rev Clin Oncol 2015; 12: 631-44
© IEO 2009
LET vs LET-CYC: Distribution of DiseaseResponse According to Treatment Arm
J Clin Oncol 2006; 24:3623-3628
© IEO 2009
Adjuvant treatment for early breast cancer
© IEO 2009
National Surgical Adjuvant Study for Breast Cancer 01 Trial
9 J Clin Oncol 27:1368-1374. 2009
© IEO 2009
Relapse-free survival, overall survival of the total patients treated with uracil and tegafur (UFT) or
cyclophosphamide, methotrexate, and fluorouracil
10J Clin Oncol 27:1368‐1374. 2009
Similar RFS and OS with oral UFT to those with classical CMF Higher QOL scores
IBCSG
CM Maintenance Chemotherapy (CMM)
IBCSG Trial 22-00 (CM Maintenance)
SURGERY
4-6 mos.
12 mos.
Stratify•Institution•Menopausal status
•Induction regimen
Induction Chemotherapy
4-6 mos.
*Any time from start of induction to within 8 weeks after first day of last course of induction
Observation (OBS)
1081 patients in ITT population; Median follow-up 6.9 years
Hormone receptor negative (< 10% positive cells by IHC) by locally-determined ER and PgR
Induction Chemotherapy
1086 patients enrolled Jan 2001 - Dec 2012RANDOMIZE*
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
IBCSG
Patient/Disease CharacteristicsCMM
(N=542)OBS
(N=539)Overall
(N=1081)
Median age (range) 52 (28, 79) 52 (23, 80) 52 (23, 80)
Premenopausal 44% 46% 45%
Tumor > 2 cm 57% 52% 54%
Grade 3 84% 85% 84%
Lymph Node +ve 43% 42% 42%
HER2+ve* 19% 19% 19%
Triple Negative 75% 75% 75%
*6% unknown local HER2
IBCSG
Disease-Free Survival
IBCSG
Disease-Free SurvivalTriple Negative Node Positive and Triple Negative
Adherence with CMM and Disease-Free Survival
Landmark: patients alive and disease-free approximately 1 year from cessation of induction chemotherapy, when CMM would be finished.
All Patients Triple Negative
IBCSG
Select AEs Grade 3 Grade 4Leukopenia 8 1Neutropenia 2 4Elevated SGPT 9 -Elevated SGOT 32 1Nausea 4 -Vomiting 3 -Dysuria 2 -Infection 4 -Pain 3 -Cardiovascular 3 -Neurologic 3 -Ocular/Visual - 1
Adverse Events CMM (N=473*)
64 patients (14%) experienced at least one grade 3 or 4 AE attributable to CMM; no grade 5
*Safety Population:Received some CMM:471 assigned CMM2 assigned OBS
Possibly, probably, definitely due to CMM
© IEO 2009
Treatment of advanced breast cancer
© IEO 2009
ESO-ESMO 2nd international consensus guidelines for advanced breast cancer
(ABC2)
Advanced breast cancer (ABC) is a treatable but still generally incurable disease. The goals of care are to optimize both length and quality of life
Annals of Oncology Ann Oncol 2014; 25: 1871–1888 The Breast 2014, http://dx.doi.org/10.1016/j.breast.2014.08.009
© IEO 2009
Strenghts and weakeness of oral CT
• Surveys have shown that most patients prefer oral to i.v.
• A minority prefer i.v. due to possible less effectiveness of oral therapies (last resort)
• Robust data are required to convince the full benefit of ora chemotherapy
J Clin Oncol 1997; 15: 110–115Ann Oncol 2006; 17: 205–210Breast Cancer Res Treat 2005; 92: 265–272
© IEO 2009
Metronomic chemotherapy
• Attractive to consider a therapeutic strategy with good toxicity profile
• Good tumor control
• Not expensive for the health system
© IEO 2009
Trials with metronomic chemotherapy in metastatic breast cancer
22
© IEO 2009
Capecitabine Versus Classical Cyclophosphamide, Methotrexate, and Fluorouracil As First-Line Chemotherapy for Advanced Breast Cancer
J Clin Oncol 29:4498-4504
© IEO 2009
Capecitabine Versus Classical Cyclophosphamide, Methotrexate, and Fluorouracil As First-Line Chemotherapy for Advanced Breast Cancer:
PFS and OS
J Clin Oncol 29:4498-4504
The average duration of chemotherapy was longer in those assignedcapecitabine than in those assigned CMF
© IEO 2009
Trials with metronomic chemotherapy + biological agents in metastatic breast cancer
25Nat Rev Clin Oncol 2015; 12: 631-44
© IEO 2009Clinical benefit (31-41%)
FIRST STUDYDrug Dose Day
1 2 3 4 5 6 7MTX 2,5 mg x 2 oral
CTX 50 mg oral
SECOND STUDYDrug Dose Day
1 2 3 4 5 6 7MTX 2,5 mg x 2 oral
CTX 50 mg oral
Ann Oncol. 2002 ;13(1):73-80.
Metronomic Cyclophosphamide + Methotrexate
Ann Oncol. 2006;17(2):232-8.
© IEO 2009
PCB = no disease progression (CRs, PRs, or SDs) for ≥ 12 months
24/153 pts with PBC (15.7%)
Median duration of response: 20.7 months (range, 1.5-44.6)
Prolonged clinical benefit (PCB) with metronomic chemotherapy (CM) in MBC
Anticancer Drugs. 2006;17:961-7.
© IEO 2009
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
© IEO 2009
Combinations of metronomic chemotherapy, bevacizumab and trastuzumab (or cetuximab)
Clin Cancer Res, 2006 12; 904
© IEO 2009
Bevacizumab 10 mg/kg iv every 2 weeks
Cyclophosphamide 50 mg/day orally at 9 a.m. (Endoxan®)Capecitabine 500 mg x 3/day orally after
meals(Xeloda®)
Metronomic Chemotherapy + Bevacizumab(BEX):
Treatment Schedule
J Clin Oncol 2008; 26 :4899-905
© IEO 2009
N %
Assessable patients 46CR 1 3PR 18 45SD24 weeks 8 20SD<24 weeks 8 20PD 5 13
Overall response (CR+PR) 19 48%Clinical benefit (CR+PR+SD24 weeks) 27 68%
J Clin Oncol 2008; 26 :4899‐905
Metronomic Chemotherapy + Bevacizumab (BEX):
Results
© IEO 2009
All Grades ≥ Grade 3
Mucositis 36 ‐Leucopenia 25 2Asthenia 25 ‐Nausea 24 1HFS 24 ‐Hypertension 22 8Neurology (paresthesias) 20 ‐Neutropenia 15 2Constipation 17 ‐Transaminitis 17 2Headache 16 ‐Diarrhea 16 ‐Proteinuria 15 1Vomiting 8 1Cystitis 7 ‐
J Clin Oncol 2008; 26 :4899‐905
Metronomic Chemotherapy + Bevacizumab (BEX):
Main Side Effects
© IEO 2009Name _ Datum33
SAKK 24‐09: Study Design
Randomiza-tion Bevacizumab
Cyclophos.Capecitabine(74 patients)
BevacizumabPaclitaxel
(73 patients)Arm A
Arm B
until PD, unacc.
toxicity or withdrawal
Follow up
ASCO,2014
© IEO 2009Name _ Datum34
Toxicities defining primary endpoint
Arm A (n=71) Arm B (n=68)Grade 3 Grade 4 Grade 3 Grade 4
Arthralgia 2 - 2 -Headache - - 2 -Infection 5 - 4 -Neuropathy 7 - - -Thromboembolic 2 1 4 -Nausea 1 - 3 -Mucositis - - 1 -Total 17 1 16 -
© IEO 2009Name _ Datum35
Progression free survival stratified by treatment arm
months
estim
ated
sur
viva
l pro
babi
lity /
/ / //////////
/
///
/
//
//
/ /
//
///
/ // / /
// /
/ / /
/ / /
/
0 4 8 12 16 20 24 28 32 360
0.2
0.4
0.6
0.8
1
# at riskPBCCB
73 64 38 16 7 4 3 2 0 074 46 33 20 14 8 3 3 1 0
Control: PBTreatment: CCB
© IEO 2009Name _ Datum36
Less hair loss in arm B was the onlyclinically relevant and statistically significant difference in QoL
Objective response rates:
• 58% (42/73; 95% CI 0.46–0.69)• 50% (37/74; 95% CI 0.39–0.61)
Activity and tolerability
© IEO 2009
Vinorelbine 40 mg day 1, 3, 5
Cyclophosphamide 50 mg/day orally at 9 a.m. (Endoxan®)Capecitabine 500 mg x 3/day orally after meals(Xeloda®)
Metronomic Chemotherapy (VEX):Treatment Schedule
© IEO 2009
Metronomic Chemotherapy (VEX):Patients’ features at baseline
Pretreated Number(46)
Metastatic siteNot visceralVisceralMultiple
17326
N° of sites34
133
Previous lineChemotherapyETBoth
23014
Untreated Number(42)
Metastatic siteNot visceralVisceralMultiple
19320
N° of sites34
103
Previous Adj(neo)therapyAnthraTaxane
188
ECCO 2015
© IEO 2009
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
© IEO 2009
Metronomic Chemotherapy (VEX):Side Effects (untreated)
G1 N° pts
Nausea 21
Diarrhea 19
HFS 5
Leucopenia 2
Transaminitis 9
G2 N° pts
Leucopenia 16
HFS 6
Transaminitis 6
Alopecia none
G3:2 neutropenia,1 anemia, 1 diarrhea, 2 HFS, 2 Transaminitis
© IEO 2009
Metronomic Chemotherapy (VEX):Side effects (pretreated)
G1 N° pts
Leucopenia 8
Transaminitis 17
Nausea 8
Diarrhea 14
Astenia 14
G2 N° pts
Transaminitis 2
HFS 5
Leucopenia 6
Alopecia none
G3:1 leucopenia, 1 neutropenia, 1 nausea, 1 mucositis, 2 HFS
© IEO 2009
VICTOR 2Multicenter Phase II
(end of enrollment April 2015)
Combination
ABC3 Lisbona; EBCC 2016 Amsterdam.
L M M G V S D
Capecitabine 500 x3 mg/daily
Oral VNR 40 mg TD D1,3,5 weekly
Schedule
Primary objective: - CB ≥24 weeks
Secondary objective:- Outcome (PFS, OS)- Tolerability- QoL- Compliance
Patients’ characteristicsN 85 (100%)Median age 65 (38-85)Receptor status
Luminal A 81 (95%)Visceralinvolvement
55 (65%)
I° line treatment 23 (27.1%)
© IEO 2009
SAFETY and EFFICACYCombination
85 pts enrolled
Toxicity G3/4 (%)Neutropenia 1.2%Thrombocytopenia 0.2%Diarrhoea 0.5%Mucositis 0.3%
669 cycles evaluable for toxicity
ACTIVITY %
Clinical Benefit(CR+PR+SD≧24 weeks) 80%
ABC3 Lisbona; EBCC 2016 Amsterdam.
© IEO 2009
CONCLUSIONS Metronomic chemotherapy demonstrated activity
in BC
Provided disease control for a significant proportion of patients with MBC
The low burden of personal costs to the patient and the possibility to continue the treatment for several months support the use of metronomic CT as an additional therapeutic tool
Metronomic combinations in early stages key for future trials
Trend toward a benefit as maintenance in high risk triple negative breast cancer
© IEO 2009
CONCLUSIONS
• Despite the published literature, metronomic chemotherapy approaches are currently not widely used in everyday practice
• This emphasizes the need for new large studies comparing this approach with more conventional therapies
45
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