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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 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 © 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 25 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 SD24 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+SD24 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