Download Metronomic chemotherapy for breast cancer

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
Nat Rev Clin Oncol 2015; 12: 631-44
© IEO 2009
3
Metronomic CT in breast cancer:
number of published papers during
years
18
16
14
12
10
8
6
2002-2005
2006-2009
2010-2011
2012-2014
4
2
0
© IEO 2009
Cancer Treatment
Reviews 40 (2014) 942–950
4
Neoadjuvant treatment
for early breast cancer
© IEO 2009
Trials with metronomic chemotherapy
in the neoadjuvant setting
Nat Rev Clin Oncol 2015; 12: 631-44
© IEO 2009
6
LET vs LET-CYC: Distribution of Disease
Response 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
© IEO 2009
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J Clin Oncol 27:1368-1374. 2009
Relapse-free survival, overall survival of the total
patients treated with uracil and tegafur (UFT) or
cyclophosphamide, methotrexate, and fluorouracil
Similar RFS and OS with oral UFT to those with classical CMF
Higher QOL scores
© IEO 2009
10
J Clin Oncol 27:1368‐1374. 2009
IBCSG Trial 22-00 (CM Maintenance)
Hormone receptor negative (< 10% positive cells by IHC) by locally-determined ER and PgR
1086 patients enrolled Jan 2001 - Dec 2012
S
U
R
G
E
R
Y
Stratify
•Institution
•Menopausal
status
•Induction
regimen
R
A
N
D
O
M
I
Z
E
*
Induction Chemotherapy
CM Maintenance Chemotherapy (CMM)
4-6 mos.
12 mos.
Induction Chemotherapy
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
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 Characteristics
CMM
(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%
IBCSG
*6% unknown local HER2
Disease-Free Survival
IBCSG
Disease-Free Survival
Triple Negative
IBCSG
Node Positive and Triple Negative
Adherence with CMM and Disease-Free Survival
All Patients
Triple Negative
Landmark: patients alive and disease-free approximately 1 year from cessation of induction
chemotherapy, when CMM would be finished.
Adverse Events CMM (N=473*)
Possibly, probably, definitely due to CMM
*Safety Population:
Received some CMM:
471 assigned CMM
2 assigned OBS
IBCSG
Select AEs
Leukopenia
Neutropenia
Elevated SGPT
Elevated SGOT
Nausea
Vomiting
Dysuria
Infection
Pain
Cardiovascular
Neurologic
Ocular/Visual
Grade 3
8
2
9
32
4
3
2
4
3
3
3
-
Grade 4
1
4
1
1
64 patients (14%) experienced at least one grade 3 or
4 AE attributable to CMM; no grade 5
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: 110–115
Ann Oncol 2006; 17: 205–210
Breast 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
© IEO 2009
22
Capecitabine Versus Classical Cyclophosphamide,
Methotrexate, and Fluorouracil As First-Line
Chemotherapy for Advanced Breast Cancer
© IEO 2009
J Clin Oncol 29:4498-4504
Capecitabine Versus Classical Cyclophosphamide,
Methotrexate, and Fluorouracil As First-Line
Chemotherapy for Advanced Breast Cancer:
PFS and OS
The average duration of chemotherapy was longer in those assigned
capecitabine than in those assigned CMF
© IEO 2009
J Clin Oncol 29:4498-4504
Trials with metronomic chemotherapy + biological
agents in metastatic breast cancer
© IEO 2009
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Nat Rev Clin Oncol 2015; 12: 631-44
Metronomic Cyclophosphamide + Methotrexate
FIRST STUDY
Drug
Dose
Day
1234567
MTX
CTX
2,5 mg x 2 oral
50 mg oral


Ann Oncol. 2002 ;13(1):73-80.
SECOND STUDY
Drug
Dose
Day
1234567
MTX
CTX
2,5 mg x 2 oral
50 mg oral



Ann Oncol. 2006;17(2):232-8.
Clinical benefit (31-41%)
© IEO 2009
Prolonged clinical benefit (PCB)
with metronomic chemotherapy (CM) in MBC
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)
© IEO 2009
Anticancer Drugs. 2006;17:961-7.
New strategies:
metronomic CT + targeted therapeutics
 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
© IEO 2009
Combinations of metronomic chemotherapy,
bevacizumab and trastuzumab (or cetuximab)
© IEO 2009
Clin Cancer Res, 2006 12; 904
Metronomic Chemotherapy + Bevacizumab
(BEX):
Treatment Schedule
Bevacizumab
10 mg/kg iv every 2 weeks
Cyclophosphamide
(Endoxan®)
Capecitabine
meals
(Xeloda®)
50 mg/day orally at 9 a.m.
© IEO 2009
500 mg x 3/day orally after
J Clin Oncol 2008; 26 :4899-905
Metronomic Chemotherapy + Bevacizumab (BEX):
Results
N
Assessable patients
CR
PR
SD24 weeks
SD<24 weeks
PD
%
46
1
18
8
8
5
3
45
20
20
13
Overall response (CR+PR)
19
48%
Clinical benefit (CR+PR+SD24
weeks)
27
68%
© IEO 2009
J Clin Oncol 2008; 26 :4899‐905
Metronomic Chemotherapy + Bevacizumab (BEX):
Main Side Effects
© IEO 2009
All Grades
≥ Grade 3
Mucositis
36
‐
Leucopenia
25
2
Asthenia
25
‐
Nausea
24
1
HFS
24
‐
Hypertension
22
8
Neurology (paresthesias)
20
‐
Neutropenia
15
2
Constipation
17
‐
Transaminitis
17
2
Headache
16
‐
Diarrhea
16
‐
Proteinuria
15
1
Vomiting
8
1
Cystitis
7
‐
J Clin Oncol 2008; 26 :4899‐905
SAKK 24‐09: Study Design
Arm A
Randomization
Arm B
33
Name _ Datum
© IEO 2009
Bevacizumab
Paclitaxel
(73 patients)
Bevacizumab
Cyclophos.
Capecitabine
(74 patients)
until PD,
unacc.
toxicity or
withdrawal
ASCO,2014
Follow
up
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
-
17
1
16
-
Total
34
Name _ Datum
© IEO 2009
estimated survival probability
Progression free survival stratified by treatment arm
1
/ /
//
0.8
35
Name _ Datum
//
0.6
Control: PB
Treatment: CCB
/////
///
/ /
/
/
/
/
/
//
/
0.4
/
//
//
/
/
0.2
//
/
//
/
//
0
0
# at risk
PB
73
CCB
74
© IEO 2009
/
/
4
8
12
16
20
/
24
28
32
36
3
3
2
3
0
1
0
0
months
64
46
38
33
16
20
7
14
4
8
Activity and tolerability
Less hair loss in arm B was the only
clinically 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)
36
Name _ Datum
© IEO 2009
Metronomic Chemotherapy (VEX):
Treatment Schedule
Vinorelbine
40 mg day 1, 3, 5
Cyclophosphamide
(Endoxan®)
Capecitabine
(Xeloda®)
50 mg/day orally at 9 a.m.
© IEO 2009
500 mg x 3/day orally after meals
Metronomic Chemotherapy (VEX):
Patients’ features at baseline
Pretreated
Metastatic site
Not visceral
Visceral
Multiple
N° of sites
3
4
Previous line
Chemotherapy
ET
Both
© IEO 2009
Number
(46)
Untreated
Number
(42)
17
3
26
Metastatic site
Not visceral
Visceral
Multiple
19
3
20
13
3
N° of sites
3
4
10
3
2
30
14
Previous
Adj(neo)therapy
Anthra
Taxane
18
8
ECCO 2015
Metronomic Chemotherapy (VEX):
Median Time to progression
Untreated
Pretreated
26.5 mo
9.6 mo
1-yr PFS
73%
38%
2-yr PFS
52%
28%
Response Rate (PR+CR)
35%
30%
Median TTP
ECCO 2015
© IEO 2009
Metronomic Chemotherapy (VEX):
Side Effects (untreated)
G1
N° pts
G2
N° pts
Nausea
21
Leucopenia
16
Diarrhea
19
HFS
6
HFS
5
Transaminitis
6
Leucopenia
2
Alopecia
none
Transaminitis
9
G3:2 neutropenia,1 anemia, 1 diarrhea, 2 HFS, 2 Transaminitis
© IEO 2009
Metronomic Chemotherapy (VEX):
Side effects (pretreated)
G1
N° pts
G2
N° pts
Leucopenia
8
Transaminitis
2
Transaminitis
17
HFS
5
Nausea
8
Leucopenia
6
Diarrhea
14
Alopecia
none
Astenia
14
G3:1 leucopenia, 1 neutropenia, 1 nausea, 1 mucositis, 2 HFS
© IEO 2009
VICTOR 2
Combination
Multicenter Phase II
(end of enrollment April 2015)
Schedule
L
M
M
G
V
S
Oral VNR 40 mg TD D1,3,5 weekly
D
Primary objective:
- CB ≥24 weeks
Capecitabine 500 x3 mg/daily
Patients’ characteristics
N
85 (100%)
Median age
65 (38-85)
Receptor status
Luminal A
81 (95%)
Visceral
involvement
55 (65%)
I° line treatment
23 (27.1%)
© IEO 2009
Secondary objective:
- Outcome (PFS, OS)
- Tolerability
- QoL
- Compliance
ABC3 Lisbona; EBCC 2016 Amsterdam.
Combination
SAFETY and EFFICACY
85 pts enrolled
669 cycles evaluable for toxicity
Toxicity
G3/4 (%)
ACTIVITY
Neutropenia
1.2%
Clinical Benefit
Thrombocytopenia
0.2%
(CR+PR+SD≧24 weeks)
Diarrhoea
0.5%
Mucositis
0.3%
ABC3 Lisbona; EBCC 2016 Amsterdam.
© IEO 2009
%
80%
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
© IEO 2009
45