Metronome Chemotherapiekonzepte

Zusammenfassung

Erfolgreichere Therapien für Patienten mit metastasierten Karzinomen zu entwickeln, bleibt eine Herausforderung. In der palliativen Situation ist bei allen Wünschen an die Wirksamkeit immer auch die Lebensqualität zu berücksichtigen. Hier bietet das Konzept der metronomen Chemotherapie einen guten Ansatz, da hierdurch eine bessere Balance zwischen Wirksamkeit und Verträglichkeit erreicht werden kann. Grundelemente der metronomen Chemotherapie sind die regelmäßige Gabe von Zytostatika in niedriger Dosis mit dem Ziel einer wirksamen und gut verträglichen Therapie. Studien mit metronomer Chemotherapie bei metastasiertem Mammakarzinom weisen sogar auf eine vergleichbare Effektivität wie mit konventioneller Chemotherapie und eine geringere Toxizität hin. Dieser Übersichtsartikel fasst das Wissen um diese Form der Therapie zusammen und bezieht auch wesentliche Mechanismen des Tumorgeschehens – der Metastasierung, der Interaktion von Tumor und Stroma sowie der körpereigenen Tumorabwehr – mit ein, um die Wirkungsweise der metronomen Chemotherapie besser verstehen zu lernen.

ABSTRACT

It is still a challenging endeavour to develop more successful therapies for patients with metastatic carcinoma. Especially during the palliative stage, the desire for more effective therapy also has to take into account the quality of life of the patient. In this regard, the concept of metronomic chemotherapy offers a good approach because it enables the achievement of a better balance between efficacy and tolerability. The basic elements of metronomic chemotherapy are the regular administration of cytotoxic drugs in low doses with the objective of an effective and well-tolerated treatment. Studies of metronomic chemotherapy in metastatic breast cancer have exhibited the same effectiveness as well as lower toxicity compared with conventional chemotherapy. This review article summarizes the current state of knowledge of this form of therapy. This includes the significant mechanisms of tumour activity (i. e. metastasis, the interaction between tumour and stromal cells as well as the body's tumour defence) in order to better understand the mechanism of action of metronomic chemotherapy.

Schlüsselwörter

metronome Chemotherapie - Palliation - Antiangiogenese - Immunstimulation - Mammakarzinom

Key words

metronomic chemotherapy - palliative care - anti-angiogenesis - immune stimulation - breast cancer

• Literatur

• 1 Pötzi PV, Aiginger P, Kühböck J. Ixoten-Therapie bei malignen Lymphomen. Acta Med Austriaca 1979; 6: 247-249
• 2 Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000; 105: 1045-1047
• 3 Klement G, Baruchel S, Rak J. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000; 105: R15-R24
• 4 Emmenegger U, Chow A, Bocci G. The Biomodulatory Capacities of Low-Dose Metronomic Chemotherapy: Complex Modulation of the Tumor Microenvironment. In: Reichle A. ed. From Molecular to Modular Tumor Therapy. Dordrecht, Heidelberg, London, New York: Springer; 2010: 243-260
• 5 Browder T, Butterfield CE, Kräling BM. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000; 60: 1878-1886
• 6 Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004; 4: 423-436
• 7 Ghiringhelli F, Menard C, Puig PE. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 2007; 56: 641-648
• 8 Ge Y, Domschke C, Stoiber N. et al. Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunol Immunother 2012; 61: 353-362
• 9 Schmidt M, Gütz S. Metronome Chemotherapie – Gute Gründe für ein niedrig dosiertes Therapiekonzept. http://cme-medipoint.de/fortbildungen/151202_Metronome-Chemotherapie_WEB.pdf (Besucht: 7.6.2016)
• 10 Floren I. et al. Transmission of malignancy by corneal transplantation. Brussels, Belgium: 15th Conference of European Eye Bank Association; 2003
• 11 Vanharanta S, Massagué J. Origins of metastatic traits. Cancer Cell 2013; 24: 410-421
• 12 Fidler IJ. Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125 I-5-iodo-2'-deoxyuridine. J Natl Cancer Inst 1970; 45: 773-782
• 13 Luzzi KJ, MacDonald IC, Schmidt EE. et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 1998; 153: 865-873
• 14 Brastianos PK, Carter SL, Santagata S. et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov 2015; 5: 1164-1177
• 15 Paik PK, Shen R, Won H. et al. Next-generation sequencing of stage IV squamous cell lung cancers reveals an association of PI3K aberrations and evidence of clonal heterogeneity in patients with brain metastases. Cancer Discov 2015; 5: 610-621
• 16 Pukrop T, Dehghani F, Chuang HN. et al. Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way. Glia 2010; 58: 1477-1489
• 17 Kim SJ, Kim JS, Park ES. et al. Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia 2011; 13: 286-298
• 18 Rietkötter E, Menck K, Bleckmann A. et al. Zoledronic acid inhibits macrophage/microglia-assisted breast cancer cell invasion. Oncotarget 2013; 4: 1449-1460
• 19 Rietkötter E, Bleckmann A, Bayerlova M. et al. Anti-CSF-1 treatment is effective to prevent carcinoma invasion induced by monocyte-derived cells but scarcely by microglia. Oncotarget 2015; 6: 15482-1593
• 20 Valiente M, Obenauf AC, Jin X. et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 2014; 156: 1002-1016
• 21 Siam L, Bleckmann A, Chaung HN. et al. The metastatic infiltration at the metastasis/brain parenchyma-interface is very heterogeneous and has a significant impact on survival in a prospective study. Oncotarget 2015; 6: 29254-29267
• 22 Malladi S, Macalinao DG, Jin X. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 2016; 165: 45-60
• 23 Bocci G, Kerbel RS. Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect. Nat Rev Clin Oncol 2016; 13: 659-673
• 24 Papi A, De Carolis S, Bertoni S. PPARγ and RXR ligands disrupt the inflammatory cross-talk in the hypoxic breast cancer stem cells niche. J Cell Physiol 2014; 229: 1595-1606
• 25 Hart C, Vogelhuber M, Wolff D. et al. Anakoinosis: Communicative reprogramming of tumor systems - for rescuing from chemorefractory neoplasia. Cancer Microenviron 2015; 8: 75-92
• 26 Biziota E, Briasoulis E, Mavroeidis L. et al. Cellular and molecular effects of metronomic vinorelbine and 4-O-deacetylvinorelbine on human umbilical vein endothelial cells. Anticancer Drugs 2016; 27: 216-224
• 27 Jedeszko C, Paez-Ribes M, Di Desidero T. et al. Postsurgical adjuvant or metastatic renal cell carcinoma therapy models reveal potent antitumor activity of metronomic oral topotecan with pazopanib. Sci Transl Med 2015; 7: 282ra50
• 28 Ghibelli L, Maresca V, Coppola S. et al. Protease inhibitors block apoptosis at intermediate stages: a compared analysis of DNA fragmentation and apoptotic nuclear morphology. FEBS Lett 1995; 377: 9-14
• 29 Kummar S, Raffeld M, Juwara L. et al. Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1alpha in advanced solid tumors. Clin Cancer Res 2011; 17: 5123-5131
• 30 Munzone E, Colleoni M. Clinical overview of metronomic chemotherapy in breast cancer. Nat Rev Clin Oncol 2015; 12: 631-644
• 31 Teresi RE, Shaiu CW, Chen CS. et al. Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone. Int J Cancer 2006; 118: 2390-2398
• 32 Teresi RE, Waite KA. PPARgamma, PTEN, and the fight against cancer. PPAR Res 2008; 2008: 932632
• 33 Ugocsai P, Wolff D, Menhart K. et al. Biomodulatory metronomic therapy induces PET-negative remission in chemo- and brentuximab-refractory Hodgkin lymphoma. Br J Haematol 2016; 172: 290-293
• 34 Lu J, Zhang F, Yuan Y. et al. All-trans retinoic acid upregulates the expression of p53 via Axin and inhibits the proliferation of glioma cells. Oncol Rep 2013; 29: 2269-2274
• 35 Melarangi T, Zhuang J, Lin K. et al. Glucocorticoid resistance in chronic lymphocytic leukaemia is associated with a failure of upregulated Bim/Bcl-2 complexes to activate Bax and Bak. Cell Death Dis 2012; 3: e372
• 36 Tissing WJ, den Boer ML, Meijerink JP. et al. Genomewide identification of prednisolone-responsive genes in acute lymphoblastic leukemia cells. Blood 2007; 109: 3929-3935
• 37 Berger AH, Knudson AG, Pandolfi PP. A continuum model for tumour suppression. Nature 2011; 476: 163-169
• 38 McClellan JS, Dove C. Gentles AJ et al. Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages. Proc Natl Acad Sci USA 2015; 112: 4074-4079
• 39 Thomas S, Schelker R, Klobuch S. et al. Biomodulatory therapy induces complete molecular remission in chemorefractory acute myeloid leukemia. Haematologica 2015; 100: e4-e6
• 40 Colleoni M, Rocca A, Sandri MT. et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 2002; 13: 73-80
• 41 Wong NS, Buckman RA, Clemons M. et al. Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response. J Clin Oncol 2010; 28: 723-730
• 42 Stockler MR, Harvey VJ, Francis PA. et al. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol 2011; 29: 4498-4504
• 43 Briasoulis E, Aravantinos G, Kouvatseas G. et al. Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer: a hellenic cooperative oncology group clinical translational study. BMC Cancer 2013; 13: 263
• 44 Addeo R, Sgambato A, Cennamo G. et al. Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer. Clin Breast Cancer 2010; 10: 301-306
• 45 Cazzaniga ME, Torri V, Villa F. et al. Efficacy and safety of the all-oral schedule of metronomic vinorelbine and capecitabine in locally advanced or metastatic breast cancer patients: The Phase I-II VICTOR-1 Study. Int J Breast Cancer 2014; 2014: 769790
• 46 Thomssen C, Augustin D, Ettl J. et al. ABC3 Consensus: assessment by a German group of experts. Breast Care (Basel) 2016; 11: 61-70
• 47 AGO (Arbeitsgemeinschaft Gynäkologische Onkologie) e. V.. Kommission Mamma, Hrsg. Diagnostik und Therapie von Patientinnen mit primärem und metastasiertem Brustkrebs. http://www.ago-online.de/fileadmin/downloads/leitlinien/mamma/Maerz2016/de/Alle_aktuellen_Empfehlungen_2016.pdf (besucht am 9.6.2016)
• 48 Hirnmetastasen. https://www.hirntumorhilfe.de/hirntumor/tumorarten/hirnmetastasen/ (besucht am 9.6.2016)
• 49 Bachelot T, Romieu G, Campone M. et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol 2013; 14: 64-71
• 50 Chuang HN, van Rossum D, Sieger D. et al. Carcinoma cells misuse the host tissue damage response to invade the brain. Glia 2013; 61: 1331-1346