Breast cancer

(1)

Metronomic chemotherapy for breast cancer

M. Colleoni

International Breast Cancer Study Group (IBCSG),

Division of Medical Senology,

European Institute of Oncology

(2)

Metronomic Scheduling and Inhibition of Tumor Growth: In Vivo Models

Cancer Res 2000, 60: 1878-86

(3)

Metronomic chemotherapy concept showing multiple mechanisms

3

Nat Rev Clin Oncol 2015; 12: 631-44

(4)

Metronomic CT in breast cancer:

number of published papers during years

4

0 2 4 6 8 10 12 14 16 18

2002-2005 2006-2009 2010-2011 2012-2014

Cancer Treatment Reviews 40 (2014) 942–950

(5)

Neoadjuvant treatment

for early breast cancer

(6)

Trials with metronomic chemotherapy in the neoadjuvant setting

6

Nat Rev Clin Oncol 2015; 12: 631-44

(7)

LET vs LET-CYC: Distribution of Disease Response According to Treatment Arm

J Clin Oncol 2006; 24:3623-3628

(8)

Adjuvant treatment

for early breast cancer

(9)

National Surgical Adjuvant Study for Breast Cancer 01 Trial

9 J Clin Oncol 27:1368-1374. 2009

(10)

Relapse-free survival, overall survival of the total patients treated with uracil and tegafur (UFT) or cyclophosphamide, methotrexate, and fluorouracil

10 J Clin Oncol 27:1368‐1374. 2009 Similar RFS and OS with oral UFT to those with classical CMF

Higher QOL scores

(11)

I B C S G

CM Maintenance Chemotherapy (CMM)

IBCSG Trial 22-00 (CM Maintenance)

S U R G E R Y

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 2012 R

A N D O M I Z E

*

(12)

I B C S G

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

(13)

I B C S G

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%

*6% unknown local HER2

(14)

I B C S G

Disease-Free Survival

(15)

I B C S G

Disease-Free Survival

Triple Negative Node Positive and Triple Negative

(16)

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

(17)

I B C S G

Select AEs Grade 3 Grade 4

Leukopenia 8 1

Neutropenia 2 4

Elevated SGPT 9 -

Elevated SGOT 32 1

Nausea 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 CMM 2 assigned OBS

Possibly, probably, definitely due to CMM

(18)

Treatment

of advanced breast cancer

(19)

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

(20)

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

(21)

Metronomic chemotherapy

• Attractive to consider a

therapeutic strategy with good toxicity profile

• Good tumor control

• Not expensive for the health

system

(22)

Trials with metronomic chemotherapy in metastatic breast cancer

22

(23)

Capecitabine Versus Classical Cyclophosphamide, Methotrexate, and Fluorouracil As First-Line

Chemotherapy for Advanced Breast Cancer

J Clin Oncol 29:4498-4504

(24)

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 assigned

capecitabine than in those assigned CMF

(25)

Trials with metronomic chemotherapy + biological agents in metastatic breast cancer

25 Nat Rev Clin Oncol 2015; 12: 631-44

(26)

Clinical benefit (31-41%)

FIRST STUDY

Drug Dose Day

1 2 3 4 5 6 7

MTX 2,5 mg x 2 oral  

CTX 50 mg oral       

SECOND STUDY

Drug Dose Day

1 2 3 4 5 6 7

MTX 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.

(27)

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.

(28)

 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

(29)

Combinations of metronomic chemotherapy, bevacizumab and trastuzumab (or cetuximab)

Clin Cancer Res, 2006 12; 904

(30)

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

(31)

N %

Assessable patients 46

CR 1 3

PR 18 45

SD24 weeks 8 20

SD<24 weeks 8 20

PD 5 13

Overall response (CR+PR) 19 48%

Clinical benefit (CR+PR+SD24

weeks) 27 68%

J Clin Oncol 2008; 26 :4899‐905

Metronomic Chemotherapy + Bevacizumab (BEX):

Results

(32)

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

Metronomic Chemotherapy + Bevacizumab (BEX):

Main Side Effects

(33)

SAKK 24‐09: Study Design

Randomiza-

tion Bevacizumab

Cyclophos.

Capecitabine (74 patients) Bevacizumab

Paclitaxel (73 patients) Arm A

Arm B

until PD, unacc.

toxicity or withdrawal

Follow up

ASCO,2014

(34)

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 -

(35)

Progression free survival stratified by treatment arm

months

estimated survival probability ^/

/ / / /////////

/ /

//

/ //

/ /

/ / /

/ ///

/ / /

//

/ / /

/

0 4 8 12 16 20 24 28 32 36

0 0.2 0.4 0.6 0.8 1

# at risk

PBCCB 73 64 38 16 7 4 3 2 0 0

74 46 33 20 14 8 3 3 1 0

Control: PB

Treatment: CCB

(36)

Less hair loss in arm B was the only clinically relevant and statistically

significant difference in QoL

O bjective response rates:

• 58% (42/73; 95% CI 0.46–0.69)

• 50% (37/74; 95% CI 0.39–0.61 ⁾

Activity and tolerability

(37)

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

(38)

Metronomic Chemotherapy (VEX):

Patients’ features at baseline

Pretreated Number (46) Metastatic site

Not visceral Visceral Multiple

17 3 26

N° of sites 3

4

13 3

Previous line Chemotherapy ET

Both

2 30 14

Untreated Number (42) Metastatic site

Not visceral Visceral Multiple

19 3 20

N° of sites 3

4

10 3

Previous

Adj(neo)therapy Anthra

Taxane

18 8

ECCO 2015

(39)

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

(40)

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

(41)

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

(42)

VICTOR 2

Multicenter 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’ 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%)

(43)

SAFETY and EFFICACY

Combination

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.

(44)

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

(45)

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

Breast cancer

Metronomic chemotherapy for breast cancer

M. Colleoni

International Breast Cancer Study Group (IBCSG),

Division of Medical Senology,

European Institute of Oncology

Metronomic Scheduling and Inhibition of Tumor Growth: In Vivo Models

Metronomic chemotherapy concept showing multiple mechanisms

Metronomic CT in breast cancer:

number of published papers during years

Neoadjuvant treatment

for early breast cancer

Trials with metronomic chemotherapy in the neoadjuvant setting

LET vs LET-CYC: Distribution of Disease Response According to Treatment Arm

Adjuvant treatment

for early breast cancer

National Surgical Adjuvant Study for Breast Cancer 01 Trial

Relapse-free survival, overall survival of the total patients treated with uracil and tegafur (UFT) or cyclophosphamide, methotrexate, and fluorouracil

Treatment

of advanced breast cancer

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

Strenghts and weakeness of oral CT

Metronomic chemotherapy

• Attractive to consider a

therapeutic strategy with good toxicity profile

• Good tumor control

• Not expensive for the health

system

Trials with metronomic chemotherapy in metastatic breast cancer

Metronomic Cyclophosphamide + Methotrexate

Prolonged clinical benefit (PCB)

with metronomic chemotherapy (CM) in MBC

New strategies:

metronomic CT + targeted therapeutics

Combinations of metronomic chemotherapy, bevacizumab and trastuzumab (or cetuximab)

Metronomic Chemotherapy + Bevacizumab (BEX):

Treatment Schedule

Metronomic Chemotherapy + Bevacizumab (BEX):

Results

Metronomic Chemotherapy + Bevacizumab (BEX):

Main Side Effects

SAKK 24‐09: Study Design

Toxicities defining primary endpoint

Less hair loss in arm B was the only clinically relevant and statistically

significant difference in QoL

O bjective response rates:

• 58% (42/73; 95% CI 0.46–0.69)

• 50% (37/74; 95% CI 0.39–0.61 )

Activity and tolerability

Metronomic Chemotherapy (VEX):

Treatment Schedule

Metronomic Chemotherapy (VEX):

Patients’ features at baseline

Metronomic Chemotherapy (VEX):

Median Time to progression

Metronomic Chemotherapy (VEX):

Side Effects (untreated)

Metronomic Chemotherapy (VEX):

Side effects (pretreated)

SAFETY and EFFICACY

CONCLUSIONS

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

• 50% (37/74; 95% CI 0.39–0.61 ⁾