Top

Published in:

01-07-2020 | Metastasis | Clinical trial

Low-dose metronomic chemotherapy as an efficient treatment option in metastatic breast cancer—results of an exploratory case–control study

Authors: S. Krajnak, C. Schnatz, K. Almstedt, W. Brenner, F. Haertner, A.-S. Heimes, A. Lebrecht, G.-M. Makris, R. Schwab, A. Hasenburg, M. Schmidt, M. J. Battista

Published in: Breast Cancer Research and Treatment | Issue 2/2020

Abstract

Purpose

There is growing interest in low-dose metronomic chemotherapy (LDMC) in metastatic breast cancer (MBC). In this retrospective case–control analysis, we compared the efficacy of LDMC and conventional chemotherapy (CCT) in MBC.

Methods

Each LDMC patient receiving oral cyclophosphamide (CTX) (50 mg daily) and methotrexate (MTX) (2.5 mg every other day) was matched with two controls who received CCT. Age, number of chemotherapy lines and metastatic sites as well as hormone receptor (HR) status were considered as matching criteria. Primary endpoint was disease control rate longer than 24 weeks (DCR). Secondary endpoints were progression-free survival (PFS), duration of response (DoR) and subgroup analyses using the matching criteria.

Results

40 cases and 80 controls entered the study. 30.0% patients with LDMC and 22.5% patients with CCT showed DCR (p = 0.380). The median PFS was 12.0 weeks in both groups (p = 0.218) and the median DoR was 31.0 vs. 20.5 weeks (p = 0.383), respectively. Among younger patients, DCR was 40.0% in LDMC vs. 25.0% in the CCT group (p = 0.249). DCR was achieved in 33.3% vs. 26.2% non-heavily pretreated patients (p = 0.568) and in 36.0% vs. 18.0% patients without multiple metastases (p = 0.096), respectively. In the HR-positive group, 30.0% LDMC vs. 28.3% CCT patients showed DCR (p = 1.000). Among triple-negative patients, DCR was achieved in 30.0% LDMC and 5.0% CCT patients (p = 0.095).

Conclusions

We demonstrated a similar efficacy of LDMC compared to CCT in the treatment of MBC. Thus, LDMC may be a valuable treatment option in selected MBC patients.

Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, Andre F, Harbeck N, Aguilar Lopez B, Barrios CH, Bergh J, Biganzoli L, Boers-Doets CB, Cardoso MJ, Carey LA, Cortes J, Curigliano G, Dieras V, El Saghir NS, Eniu A, Fallowfield L, Francis PA, Gelmon K, Johnston SRD, Kaufman B, Koppikar S, Krop IE, Mayer M, Nakigudde G, Offersen BV, Ohno S, Pagani O, Paluch-Shimon S, Penault-Llorca F, Prat A, Rugo HS, Sledge GW, Spence D, Thomssen C, Vorobiof DA, Xu B, Norton L, Winer EP (2018) 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)dagger. Ann Oncol 29(8):1634–1657. https://doi.org/10.1093/annonc/mdy192 CrossRefPubMed

Cazzaniga ME, Pinotti G, Montagna E, Amoroso D, Berardi R, Butera A, Cagossi K, Cavanna L, Ciccarese M, Cinieri S, Cretella E, De Conciliis E, Febbraro A, Ferrau F, Ferzi A, Fiorentini G, Fontana A, Gambaro AR, Garrone O, Gebbia V, Generali D, Gianni L, Giovanardi F, Grassadonia A, Leonardi V, Marchetti P, Melegari E, Musolino A, Nicolini M, Putzu C, Riccardi F, Santini D, Saracchini S, Sarobba MG, Schintu MG, Scognamiglio G, Spadaro P, Taverniti C, Toniolo D, Tralongo P, Turletti A, Valenza R, Valerio MR, Vici P, Clivio L, Torri V, Group VS (2019) Metronomic chemotherapy for advanced breast cancer patients in the real world practice: final results of the VICTOR-6 study. Breast 48:7–16. https://doi.org/10.1016/j.breast.2019.07.006 CrossRefPubMed

Simsek C, Esin E, Yalcin S (2019) Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience. J Oncol 2019:5483791. https://doi.org/10.1155/2019/5483791 CrossRefPubMedPubMedCentral

Hanahan D, Bergers G, Bergsland E (2000) Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105(8):1045–1047. https://doi.org/10.1172/JCI9872 CrossRefPubMedPubMedCentral

Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nole F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, Viale BF, Goldhirsch G (2002) Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13(1):73–80CrossRefPubMed

Gebbia V, Boussen H, Valerio MR (2012) Oral metronomic cyclophosphamide with and without methotrexate as palliative treatment for patients with metastatic breast carcinoma. Anticancer Res 32(2):529–536PubMed

Perroud HA, Alasino CM, Rico MJ, Mainetti LE, Queralt F, Pezzotto SM, Rozados VR, Scharovsky OG (2016) Metastatic breast cancer patients treated with low-dose metronomic chemotherapy with cyclophosphamide and celecoxib: clinical outcomes and biomarkers of response. Cancer Chemother Pharmacol 77(2):365–374. https://doi.org/10.1007/s00280-015-2947-9 CrossRefPubMed

Cazzaniga ME, Munzone E, Bocci G, Afonso N, Gomez P, Langkjer S, Petru E, Pivot X, Sanchez Rovira P, Wysocki P, Torri V (2019) Pan-European Expert Meeting on the Use of Metronomic Chemotherapy in Advanced Breast Cancer Patients: The PENELOPE Project. Adv Ther 36(2):381–406. https://doi.org/10.1007/s12325-018-0844-4 CrossRefPubMed

Schmidt M (2016) Dose-Dense Chemotherapy in Metastatic Breast Cancer: Shortening the Time Interval for a Better Therapeutic Index. Breast Care (Basel) 11(1):22–26. https://doi.org/10.1159/000442726 CrossRef

10.

Krajnak S, Battista M, Brenner W, Almstedt K, Elger T, Heimes AS, Hasenburg A, Schmidt M (2018) Explorative Analysis of Low-Dose Metronomic Chemotherapy with Cyclophosphamide and Methotrexate in a Cohort of Metastatic Breast Cancer Patients. Breast Care (Basel) 13(4):272–276. https://doi.org/10.1159/000487629 CrossRef

11.

Aurilio G, Munzone E, Botteri E, Sciandivasci A, Adamoli L, Minchella I, Esposito A, Cullura D, Curigliano G, Colleoni M, Goldhirsch A, Nole F (2012) Oral metronomic cyclophosphamide and methotrexate plus fulvestrant in advanced breast cancer patients: a mono-institutional case-cohort report. Breast J 18(5):470–474. https://doi.org/10.1111/j.1524-4741.2012.01278.x CrossRefPubMed

12.

Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, Ghisini R, Sandri MT, Zorzino L, Nole F, Viale G, Goldhirsch A (2006) Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol 17(2):232–238. https://doi.org/10.1093/annonc/mdj066 CrossRefPubMed

13.

Li JW, Zuo WJ, Ivanova D, Jia XQ, Lei L, Liu GY (2019) Metronomic capecitabine combined with aromatase inhibitors for new chemoendocrine treatment of advanced breast cancer: a phase II clinical trial. Breast Cancer Res Treat 173(2):407–415. https://doi.org/10.1007/s10549-018-5024-3 CrossRefPubMed

14.

Romiti A, Falcone R, Roberto M, Marchetti P (2016) Current achievements and future perspectives of metronomic chemotherapy. Invest New Drugs. https://doi.org/10.1007/s10637-016-0408-x CrossRefPubMed

15.

Liu Y, Gu F, Liang J, Dai X, Wan C, Hong X, Zhang K, Liu L (2017) The efficacy and toxicity profile of metronomic chemotherapy for metastatic breast cancer: a meta-analysis. PLoS ONE 12(3):e0173693. https://doi.org/10.1371/journal.pone.0173693 CrossRefPubMedPubMedCentral

16.

Cazzaniga ME, Biganzoli L, Cortesi L, De Placido S, Donadio M, Fabi A, Ferro A, Generali D, Lorusso V, Milani A, Montagna E, Munzone E, Orlando L, Pizzuti L, Simoncini E, Zamagni C, Pappagallo GL, Metronomic Chemotherapy in Advanced Breast Cancer" Study G (2019) Treating advanced breast cancer with metronomic chemotherapy: what is known, what is new and what is the future? Onco Targets Ther 12:2989–2997. https://doi.org/10.2147/OTT.S189163 CrossRefPubMedPubMedCentral

17.

Montagna E, Palazzo A, Maisonneuve P, Cancello G, Iorfida M, Sciandivasci A, Esposito A, Cardillo A, Mazza M, Munzone E, Lai A, Goldhirsch A, Colleoni M (2017) Safety and efficacy study of metronomic vinorelbine, cyclophosphamide plus capecitabine in metastatic breast cancer: A phase II trial. Cancer Lett 400:276–281. https://doi.org/10.1016/j.canlet.2017.01.027 CrossRefPubMed

18.

Addeo R, Sgambato A, Cennamo G, Montella L, Faiola V, Abbruzzese A, Capasso E, Leo L, Botti G, Caraglia M, Del Prete S (2010) Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer. Clin Breast Cancer 10(4):301–306. https://doi.org/10.3816/CBC.2010.n.039 CrossRefPubMed

19.

Yoshimoto M, Takao S, Hirata M, Okamoto Y, Yamashita S, Kawaguchi Y, Takami M, Furusawa H, Morita S, Abe C, Sakamoto J (2012) Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: a phase II study in patients with HER2-negative metastatic breast cancer. Cancer Chemother Pharmacol 70(2):331–338. https://doi.org/10.1007/s00280-012-1826-x CrossRefPubMed

20.

Dufresne A, Pivot X, Tournigand C, Facchini T, Altweegg T, Chaigneau L, De Gramont A (2008) Impact of chemotherapy beyond the first line in patients with metastatic breast cancer. Breast Cancer Res Treat 107(2):275–279. https://doi.org/10.1007/s10549-007-9550-7 CrossRefPubMed

21.

Cazzaniga ME, Cortesi L, Ferzi A, Scaltriti L, Cicchiello F, Ciccarese M, Della Torre S, Villa F, Giordano M, Verusio C, Nicolini M, Gambaro AR, Zanlorenzi L, Biraghi E, Legramandi L, Rulli E, Group VS (2016) Metronomic chemotherapy with oral vinorelbine (mVNR) and capecitabine (mCAPE) in advanced HER2-negative breast cancer patients: is it a way to optimize disease control? Final results of the VICTOR-2 study. Breast Cancer Res Treat 160(3):501–509. https://doi.org/10.1007/s10549-016-4009-3 CrossRefPubMedPubMedCentral

22.

Lu Q, Lee K, Xu F, Xia W, Zheng Q, Hong R, Jiang K, Zhai Q, Li Y, Shi Y, Yuan Z, Wang S (2020) Metronomic chemotherapy of cyclophosphamide plus methotrexate for advanced breast cancer: real-world data analyses and experience of one center. Cancer Commun (Lond). https://doi.org/10.1002/cac2.12029 CrossRef

23.

Thill M, Liedtke C, Muller V, Janni W, Schmidt M, Committee AGOB (2018) AGO recommendations for the diagnosis and treatment of patients with advanced and metastatic breast cancer: update 2018. Breast Care (Basel) 13(3):209–215. https://doi.org/10.1159/000489331 CrossRef

24.

Harbeck N, Gnant M (2017) Breast cancer. Lancet 389(10074):1134–1150. https://doi.org/10.1016/S0140-6736(16)31891-8 CrossRefPubMed

25.

Masoud V, Pages G (2017) Targeted therapies in breast cancer: New challenges to fight against resistance. World J Clin Oncol 8(2):120–134. https://doi.org/10.5306/wjco.v8.i2.120 CrossRefPubMedPubMedCentral

26.

Murphy CG (2019) The Role of CDK4/6 inhibitors in breast cancer. Curr Treat Options Oncol 20(6):52. https://doi.org/10.1007/s11864-019-0651-4 CrossRefPubMed

27.

Andre N, Tsai K, Carre M, Pasquier E (2017) Metronomic chemotherapy: direct targeting of cancer cells after all? Trends Cancer 3(5):319–325. https://doi.org/10.1016/j.trecan.2017.03.011 CrossRefPubMed

28.

Kerbel RS, Shaked Y (2017) The potential clinical promise of 'multimodality' metronomic chemotherapy revealed by preclinical studies of metastatic disease. Cancer Lett 400:293–304. https://doi.org/10.1016/j.canlet.2017.02.005 CrossRefPubMed

29.

Munoz R, Hileeto D, Cruz-Munoz W, Wood GA, Xu P, Man S, Viloria-Petit A, Kerbel RS (2019) Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion. PLoS ONE 14(9):e0222580. https://doi.org/10.1371/journal.pone.0222580 CrossRefPubMedPubMedCentral

30.

Kareva I, Waxman DJ, Lakka Klement G (2015) Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance. Cancer Lett 358(2):100–106. https://doi.org/10.1016/j.canlet.2014.12.039 CrossRefPubMed

31.

Bocci G, Tuccori M, Emmenegger U, Liguori V, Falcone A, Kerbel RS, Del Tacca M (2005) Cyclophosphamide-methotrexate 'metronomic' chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation Ann Oncol 16(8):1243–1252. https://doi.org/10.1093/annonc/mdi240 CrossRefPubMed

32.

Thanki K, Gangwal RP, Sangamwar AT, Jain S (2013) Oral delivery of anticancer drugs: challenges and opportunities. J Control Release 170(1):15–40. https://doi.org/10.1016/j.jconrel.2013.04.020 CrossRefPubMed

33.

Lien K, Georgsdottir S, Sivanathan L, Chan K, Emmenegger U (2013) Low-dose metronomic chemotherapy: a systematic literature analysis. Eur J Cancer 49(16):3387–3395. https://doi.org/10.1016/j.ejca.2013.06.038 CrossRefPubMed

34.

Thill M, Jackisch C, Janni W, Muller V, Albert US, Bauerfeind I, Blohmer J, Budach W, Dall P, Diel I, Fasching PA, Fehm T, Friedrich M, Gerber B, Hanf V, Harbeck N, Huober J, Kolberg-Liedtke C, Kreipe HH, Krug D, Kuhn T, Kummel S, Loibl S, Luftner D, Lux MP, Maass N, Mobus V, Muller-Schimpfle M, Mundhenke C, Nitz U, Rhiem K, Rody A, Schmidt M, Schneeweiss A, Schutz F, Sinn HP, Solbach C, Solomayer EF, Stickeler E, Thomssen C, Untch M, Wenz F, Witzel I, Wockel A, Ditsch N (2019) AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2019. Breast Care (Basel) 14(4):247–255. https://doi.org/10.1159/000500999 CrossRef

35.

Thomssen C, Luftner D, Untch M, Haidinger R, Wurstlein R, Harbeck N, Augustin D, Briest S, Ettl J, Fasching PA, Forster F, Kurbacher CM, Luck HJ, Marschner N, Muller L, Muller V, Perlova-Griff L, Radke I, Ruckhaberle E, Scheffen I, Schumacher-Wulf E, Schwoerer M, Steinfeld-Birg D, Ziegler-Lohr K (2020) International Consensus Conference for Advanced Breast Cancer, Lisbon 2019: ABC5 Consensus - Assessment by a German Group of Experts. Breast Care (Basel) 15(1):82–95. https://doi.org/10.1159/000505957 CrossRef

36.

Hao YB, Yi SY, Ruan J, Zhao L, Nan KJ (2014) New insights into metronomic chemotherapy-induced immunoregulation. Cancer Lett 354(2):220–226. https://doi.org/10.1016/j.canlet.2014.08.028 CrossRefPubMed

37.

Kareva I (2017) A Combination of Immune Checkpoint Inhibition with Metronomic Chemotherapy as a Way of Targeting Therapy-Resistant Cancer Cells. Int J Mol Sci. https://doi.org/10.3390/ijms18102134 CrossRefPubMedPubMedCentral

38.

Mayer EL, Isakoff SJ, Klement G, Downing SR, Chen WY, Hannagan K, Gelman R, Winer EP, Burstein HJ (2012) Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics. Breast Cancer Res Treat 136(1):169–178. https://doi.org/10.1007/s10549-012-2256-5 CrossRefPubMedPubMedCentral

39.

Petrizzo A, Mauriello A, Luciano A, Rea D, Barbieri A, Arra C, Maiolino P, Tornesello M, Gigantino V, Botti G, Ciliberto G, Buonaguro FM, Tagliamonte M, Buonaguro L (2018) Inhibition of tumor growth by cancer vaccine combined with metronomic chemotherapy and anti-PD-1 in a pre-clinical setting. Oncotarget 9(3):3576–3589. https://doi.org/10.18632/oncotarget.23181 CrossRefPubMed

40.

Rochlitz C, Bigler M, von Moos R, Bernhard J, Matter-Walstra K, Wicki A, Zaman K, Anchisi S, Kung M, Na KJ, Bartschi D, Borner M, Rordorf T, Rauch D, Muller A, Ruhstaller T, Vetter M, Trojan A, Hasler-Strub U, Cathomas R, Winterhalder R (2016) SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs. bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial. BMC Cancer 16(1):780. https://doi.org/10.1186/s12885-016-2823-y CrossRefPubMedPubMedCentral

Title: Low-dose metronomic chemotherapy as an efficient treatment option in metastatic breast cancer—results of an exploratory case–control study
Authors: S. Krajnak
C. Schnatz
K. Almstedt
W. Brenner
F. Haertner
A.-S. Heimes
A. Lebrecht
G.-M. Makris
R. Schwab
A. Hasenburg
M. Schmidt
M. J. Battista
Publication date: 01-07-2020
Publisher: Springer US
Keywords: Metastasis
Breast Cancer
Methotrexate
Methotrexate
Breast Cancer
Cytostatic Therapy
Published in: Breast Cancer Research and Treatment / Issue 2/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-020-05711-5

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2020

Reply to letters to the editor: Discordance in estrogen receptor and change of Ki67 between primary site and metastatic site of recurrent breast cancer

Cost-effectiveness analysis of endocrine therapy alone versus partial-breast irradiation alone versus combined treatment for low-risk hormone-positive early-stage breast cancer in women aged 70 years or older

A comparison of two non-radioactive alternatives to wire for the localization of non-palpable breast cancers

Metabolic syndrome and early stage breast cancer outcome: results from a prospective observational study

Evolution in the risk of adverse events of adjuvant endocrine therapy in postmenopausal women with early-stage breast cancer

Does oncoplastic surgery increase immediate (30-day) postoperative complications? An analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database

Keynote webinar | Spotlight on antibody–drug conjugates in cancer