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 Cancer Res 2000, 60: 1878-86
Metronomic chemotherapy concept showing multiple mechanisms Nat Rev Clin Oncol 2015; 12: 631-44 3
Metronomic CT in breast cancer: number of published papers during years 18 16 14 12 10 8 6 4 2 0 2002-2005 2006-2009 2010-2011 2012-2014 Cancer Treatment Reviews 40 (2014) 942 950 4
Neoadjuvant treatment for early breast cancer
Trials with metronomic chemotherapy in the neoadjuvant setting Nat Rev Clin Oncol 2015; 12: 631-44 6
LET vs LET-CYC: Distribution of Disease Response According to Treatment Arm J Clin Oncol 2006; 24:3623-3628
Adjuvant treatment for early breast cancer
National Surgical Adjuvant Study for Breast Cancer 01 Trial 9 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 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 4-6 mos. Induction Chemotherapy CM Maintenance Chemotherapy (CMM) 12 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
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% IBCSG Triple Negative 75% 75% 75% *6% unknown local HER2
IBCSG Disease-Free Survival
Disease-Free Survival Triple Negative Node Positive and Triple Negative IBCSG
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 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 64 patients (14%) experienced at least one grade 3 or 4 AE attributable to CMM; no grade 5
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 Annals of Oncology Ann Oncol 2014; 25: 1871 1888 The Breast 2014, http://dx.doi.org/10.1016/j.breast.2014.08.009
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
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 22
Capecitabine Versus Classical Cyclophosphamide, Methotrexate, and Fluorouracil As First-Line Chemotherapy for Advanced Breast Cancer 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 J Clin Oncol 29:4498-4504
Trials with metronomic chemotherapy + biological agents in metastatic breast cancer 25 Nat Rev Clin Oncol 2015; 12: 631-44
Metronomic Cyclophosphamide + Methotrexate FIRST 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. SECOND STUDY Drug Dose Day 1 2 3 4 5 6 7 MTX 2,5 mg x 2 oral CTX 50 mg oral Clinical benefit (31-41%) Ann Oncol. 2006;17(2):232-8.
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) 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
Combinations of metronomic chemotherapy, bevacizumab and trastuzumab (or cetuximab) Clin Cancer Res, 2006 12; 904
Metronomic Chemotherapy + Bevacizumab (BEX): Bevacizumab Treatment Schedule 10 mg/kg iv every 2 weeks Cyclophosphamide (Endoxan ) Capecitabine meals (Xeloda ) 50 mg/day orally at 9 a.m. 500 mg x 3/day orally after J Clin Oncol 2008; 26 :4899-905
Metronomic Chemotherapy + Bevacizumab (BEX): Results Assessable patients 46 N % 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): Main Side Effects 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 Randomization Arm A Arm B Bevacizumab Paclitaxel (73 patients) Bevacizumab Cyclophos. Capecitabine (74 patients) until PD, unacc. toxicity or withdrawal Follow up 33 Name _ Datum ASCO,2014
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 16-34 Name _ Datum
Progression free survival stratified by treatment arm estimated survival probability 1 0.8 0.6 0.4 0.2 0 / / / // / //// / /// / / / / / / / / / / / / // / / / / / 0 4 8 12 16 20 24 28 32 36 // / Control: PB Treatment: CCB // / # at risk PB CCB months 73 64 38 16 7 4 3 2 0 0 74 46 33 20 14 8 3 3 1 0 35 Name _ Datum
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
Metronomic Chemotherapy (VEX): Treatment Schedule Vinorelbine 40 mg day 1, 3, 5 Cyclophosphamide (Endoxan ) Capecitabine (Xeloda ) 50 mg/day orally at 9 a.m. 500 mg x 3/day orally after meals
Metronomic Chemotherapy (VEX): Patients features at baseline Pretreated Number Untreated Number (46) (42) Metastatic site Metastatic site Not visceral 17 Not visceral 19 Visceral 3 Visceral 3 Multiple 26 Multiple 20 N of sites 3 4 13 3 N of sites 3 4 10 3 Previous line Chemotherapy ET Both 2 30 14 Previous Adj(neo)therapy Anthra Taxane 18 8 ECCO 2015
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
Metronomic Chemotherapy (VEX): Side Effects (untreated) G1 N pts G2 N pts Nausea 21 Diarrhea 19 HFS 5 Leucopenia 16 HFS 6 Transaminitis 6 Leucopenia 2 Alopecia none Transaminitis 9 G3:2 neutropenia,1 anemia, 1 diarrhea, 2 HFS, 2 Transaminitis
Metronomic Chemotherapy (VEX): Side effects (pretreated) G1 N pts G2 N pts Leucopenia 8 Transaminitis 17 Nausea 8 Transaminitis 2 HFS 5 Leucopenia 6 Diarrhea 14 Alopecia none Astenia 14 G3:1 leucopenia, 1 neutropenia, 1 nausea, 1 mucositis, 2 HFS
VICTOR 2 Multicenter Phase II (end of enrollment April 2015) Combination Schedule L M M G V S D Oral VNR 40 mg TD D1,3,5 weekly Capecitabine 500 x3 mg/daily Patients characteristics N 85 (100%) Median age 65 (38-85) Receptor status Luminal A 81 (95%) Visceral 55 (65%) involvement I line treatment 23 (27.1%) Primary objective: - CB 24 weeks Secondary objective: - Outcome (PFS, OS) - Tolerability -QoL - Compliance ABC3 Lisbona; EBCC 2016 Amsterdam.
SAFETY and EFFICACY Combination 669 cycles evaluable for toxicity 85 pts enrolled Toxicity G3/4 (%) Neutropenia 1.2% Thrombocytopenia 0.2% Diarrhoea 0.5% Mucositis 0.3% ACTIVITY % Clinical Benefit (CR+PR+SD 24 weeks) 80% ABC3 Lisbona; EBCC 2016 Amsterdam.
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
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