Skip to main content

Advertisement

SpringerLink
Log in

Pharmacodynamic biomarkers in metronomic chemotherapy: multiplex cytokine measurements in gastrointestinal cancer patients

  • Original Article
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

Metronomic chemotherapy has shown promising antitumor activity in a number of malignancies. We previously reported a phase II clinical trial of metronomic UFT (a 5-fluorouracil prodrug; 100 mg/twice per day p.o.) and cyclophosphamide (CTX; 500 mg/m2 i.v. bolus on day 1 and then 50 mg/day p.o.) plus celecoxib (200 mg/twice a day p.o.) in 38 patients with advanced refractory gastrointestinal tumors. The mechanisms of action of metronomic chemotherapy include inhibition of angiogenesis, direct cytotoxic effects on cancer cells, and, at least for drugs such as CTX, activation of the immune system. To further evaluate the latter, we carried out an immune system multiplex 14-cytokine profiling of plasma samples that were available (for day 0, day 28, and day 56) from 31 of the 38 patients in the above-noted clinical trial. Our results show that pre-treatment plasma-level cutoffs of interferon gamma (> 12.84 pg/ml), sCD40L (< 2168 pg/ml), interferon alpha 2 (> 55.11 pg/ml), and IL-17a (< 15.1 pg/ml) were predictive markers for those patients with better progression-free survival (p < .05 for each cytokine). After 28 days of metronomic therapy, the plasma levels of sCD40L, IL-17a, and IL-6 (< 130 pg/ml) could serve as predictors of improved progression-free survival, as could levels interferon gamma and sCD40L after 56 days of therapy. We observed minimal changes in cytokine profiles, from baseline, as a consequence of the metronomic therapy, with the exception of an elevation of IL-6 and IL-8 levels 28 days (and 56 days) after treatment started (p < 0.05). Our results indicate that a selective cytokine elevation involves IL-6 and IL-8, following metronomic chemotherapy administration. In addition, interferon gamma and sCD40L may be potential biomarkers for gastrointestinal cancer patients that are likely to benefit from metronomic chemotherapy. Our study contributes to our understanding of the mechanisms of action of metronomic chemotherapy, and the cytokine profiling we describe may guide future selection of gastrointestinal cancer patients for UFT/CTX/celecoxib combination metronomic chemotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Browder T, Butterfield CE, Kräling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000;60(7):1878–86.

    CAS  PubMed  Google Scholar 

  2. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4(6):423–36.

    Article  CAS  Google Scholar 

  3. Natale G, Bocci G. Does metronomic chemotherapy induce tumor angiogenic dormancy? A review of available preclinical and clinical data. Cancer Lett. 2018;432:28–37.

    Article  CAS  Google Scholar 

  4. Bocci G, Kerbel RS. Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect. Nat Rev Clin Oncol. 2016;13(11):659–73.

    Article  CAS  Google Scholar 

  5. Simkens LH, van Tinteren H, May A. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015;385(9980):1843–52.

    Article  CAS  Google Scholar 

  6. Wu J, Jordan M, Waxman DJ. Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators. BMC Cancer. 2016;16:623.

    Article  Google Scholar 

  7. Wu J, Waxman DJ. Metronomic cyclophosphamide schedule-dependence of innate immune cell recruitment and tumor regression in an implanted glioma model. Cancer Lett. 2014;353(2):272–80.

    Article  CAS  Google Scholar 

  8. Allegrini G, Di Desidero T, Barletta MT, et al. Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers. Angiogenesis. 2012;15(2):275–86.

    Article  CAS  Google Scholar 

  9. André N, Abed S, Orbach D, et al. Pilot study of a pediatric metronomic 4-drug regimen. Oncotarget. 2011;2(12):960–5.

    Article  Google Scholar 

  10. Derosa L, Galli L, Orlandi P, et al. Docetaxel plus oral metronomic cyclophosphamide: a phase II study with pharmacodynamic and pharmacogenetic analyses in castration-resistant prostate cancer patients. Cancer. 2014;120(24):3923–31.

    Article  CAS  Google Scholar 

  11. Di Desidero T, Derosa L, Galli L, et al. Clinical, pharmacodynamic and pharmacokinetic results of a prospective phase II study on oral metronomic vinorelbine and dexamethasone in castration-resistant prostate cancer patients. Invest New Drugs. 2016;34(6):760–70.

    Article  Google Scholar 

  12. Fontana A, Galli L, Fioravanti A, et al. Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res. 2009;15(15):4954–62.

    Article  CAS  Google Scholar 

  13. Kieran MW, Turner CD, Rubin JB, et al. A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J Pediatr Hematol Oncol. 2005;27(11):573–81.

    Article  Google Scholar 

  14. Rochlitz C, Bigler M, von Moos R, et al. 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. 2016;16(1):780.

    Article  Google Scholar 

  15. Lukaszewicz-Zając M, Mroczko B, Gryko M, et al. Comparison between clinical significance of serum proinflammatory proteins (IL-6 and CRP) and classic tumor markers (CEA and CA 19-9) in gastric cancer. Clin Exp Med. 2011;11(2):89–96.

    Article  Google Scholar 

  16. Jelski W, Orywal K, Laniewska M, et al. The diagnostic value of alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) measurement in the sera of gastric cancer patients. Clin Exp Med. 2010;10(4):215–9.

    Article  CAS  Google Scholar 

  17. Pasquier E, Kavallaris M, Andre N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol. 2010;7(8):455–65.

    Article  Google Scholar 

  18. Schwandt A, Garcia JA, Elson P, et al. Clinical and immunomodulatory effects of celecoxib plus interferon-alpha in metastatic renal cell carcinoma patients with COX-2 tumor immunostaining. J Clin Immunol. 2011;31(4):690–8.

    Article  CAS  Google Scholar 

  19. Peereboom DM, Alban TJ, Grabowski MM, et al., Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells. JCI Insight, 2019. 4(22).

  20. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.

    Article  Google Scholar 

  21. Bertolini F, Paul S, Mancuso P, et al. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res. 2003;63(15):4342–6.

    CAS  PubMed  Google Scholar 

  22. Shaked Y, Emmenegger U, Francia G, et al. Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy. Cancer Res. 2005;65(16):7045–51.

    Article  CAS  Google Scholar 

  23. Bocci G, Francia G, Man S, Lawler J, Kerbel RS. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA. 2003;100(22):12917–22.

    Article  CAS  Google Scholar 

  24. Daenen LG, Shaked Y, Man S, et al. Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models. Mol Cancer Ther. 2009;8(10):2872–81.

    Article  CAS  Google Scholar 

  25. Shaked Y. The pro-tumorigenic host response to cancer therapies. Nat Rev Cancer. 2019;19(12):667–85.

    Article  CAS  Google Scholar 

  26. Heinhuis KM, Ros W, Kok M, et al. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann Oncol. 2019;30(2):219–35.

    Article  CAS  Google Scholar 

  27. Mancuso P, Colleoni M, Calleri A, et al. Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood. 2006;108(2):452–9.

    Article  CAS  Google Scholar 

  28. Venetsanou K, Kaldis V, Kouzanidis N, et al. Measurement of tumour necrosis factor receptors for immune response in colon cancer patients. Clin Exp Med. 2012;12(4):225–31.

    Article  CAS  Google Scholar 

  29. Jelski W, Zalewski B, Chrostek L, et al. Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with colorectal cancer. Clin Exp Med. 2007;7(4):154–7.

    Article  CAS  Google Scholar 

  30. Burugu S, Asleh-Aburaya K, Nielsen TO. Immune infiltrates in the breast cancer microenvironment: detection, characterization and clinical implication. Breast Cancer. 2017;24(1):3–15.

    Article  Google Scholar 

  31. Lang C, Wang J, Chen L. CD25-expressing Th17 cells mediate CD8(+) T cell suppression in CTLA-4 dependent mechanisms in pancreatic ductal adenocarcinoma. Exp Cell Res. 2017;360(2):384–9.

    Article  CAS  Google Scholar 

  32. Parra K, Valenzuela P, Lerma N, et al. Impact of CTLA-4 blockade in conjunction with metronomic chemotherapy on preclinical breast cancer growth. Br J Cancer. 2017;116(3):324–34.

    Article  CAS  Google Scholar 

  33. Orlandi P, Fontana A, Fioravanti A, et al. VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide. Br J Cancer. 2013;109(4):957–64.

    Article  CAS  Google Scholar 

  34. Manciu M, Hosseini S, Di Desidero T, et al. Optimization of biomarkers-based classification scores as progression-free survival predictors: an intuitive graphical representation. Future Sci OA. 2018;4(10):FSO346.

    Article  Google Scholar 

Download references

Acknowledgements

Thanks to Jacopo Bocci for his assistance.

Funding

GF was supported by an SC1 GM136630-01 grant and an NIH-NCI SC2CA211029 grant and by the National Institute on Minority Health and Health Disparities of the NIH (via RTRN Pilots grants) under award number U54MD008149, as well as a RISE fellowship to KP.

Author information

Author notes

  1. Paloma Valenzuela, Derrick Oaxaca, and Teresa Di Desidero have contributed equally to this work.

Authors and Affiliations

  1. Border Biomedical Research Center, University of Texas at El Paso (UTEP), El Paso, TX, USA

    Paloma Valenzuela, Derrick Oaxaca, Karla Parra, Georgialina Rodriguez, Robert A. Kirken & Giulio Francia

  2. Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Teresa Di Desidero & Guido Bocci

  3. Department of Physics, UTEP, El Paso, TX, USA

    Marian Manciu

  4. Division of Medical Oncology, Pontedera Hospital, Azienda USL of Pisa, Pontedera, Italy

    Giacomo Allegrini

  5. Oncology Unit 2, University Hospital of Pisa, Pisa, Italy

    Alfredo Falcone

Authors
  1. Paloma Valenzuela
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Derrick Oaxaca
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Teresa Di Desidero
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karla Parra
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Georgialina Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marian Manciu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giacomo Allegrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alfredo Falcone
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guido Bocci
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Robert A. Kirken
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Giulio Francia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giulio Francia.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The plasma samples used in this study were collected as part of a previous study that was approved by the local ethics committee and registered in the European Clinical Trial Database EudraCT (http://eudract.emea.europa.eu; EudraCT registration number 2007-000065-38), and patients were informed of the investigational nature of the study, providing their written informed consent, including for the subsequent plasma biomarker analysis. All the experiments comply with the current Italian laws.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Appendices

Appendix 1

A number of factor suggested a correlation with PFS but were below the detection limit or were not significant at other time points following the start of treatment (Fig. 7).

Fig. 7
figure 7

Progression-free survival (PFS) according to patient plasma levels of a IL-2, b IP-10, c IL-13, d IL-6, as measured by luminex at day 0 of metronomic chemotherapy

Full size image

Appendix 2

See Fig. 8.

Fig. 8
figure 8

Progression-free survival (PFS) according to patient plasma levels of a IL-2, b IL-4, c IL-10, d IL-12p70, e IL-13, f IP-10, as measured by luminex at day 28 of metronomic chemotherapy

Full size image

Appendix 3

See Fig. 9.

Fig. 9
figure 9

Progression-free survival (PFS) according to patient plasma levels of a IL-13, b IL-12p70, c TNFa, as measured by luminex at day 56 of metronomic chemotherapy

Full size image

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Valenzuela, P., Oaxaca, D., Di Desidero, T. et al. Pharmacodynamic biomarkers in metronomic chemotherapy: multiplex cytokine measurements in gastrointestinal cancer patients. Clin Exp Med 21, 149–159 (2021). https://doi.org/10.1007/s10238-020-00666-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-020-00666-9

Keywords

Search

Navigation