Skip to main content

Advertisement

Springer Nature Link
Log in

Can anticancer chemotherapy promote the progression of brain metastases?

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Brain metastases natural history from one primary tumor type might be accelerated or favored by using certain systemic chemotherapy. A great deal was described in mice and suggested in human with antiangiogenic drugs, but little is known about the metastatic progression generated by the perverse effect of anticancer drugs. A total of 413 patients who underwent treatment for brain metastasis (2013–2016) were included. The identification of all previous anticancer drugs received by patients from primary tumor diagnosis to brain metastases diagnosis was collated. The median value for the time of first appearance of brain metastasis in all patients was 13.1 months (SD 1.77). The values of brain metastasis-free survival (bMFS) for each primary cancer were: 50.9 months (SD 8.8) for breast, 28.5 months (SD 11.4) for digestive, 27.7 months (SD 18.3) for melanoma, 12.3 months (SD 8.3) for kidney, 1.5 months (SD 0.1) for lung and 26.9 months (SD 18.3) for others (p < 0.009). Through Cox multivariate proportional hazard model, we identified that the only independent factors associated with short bMFS were: lung primary tumor [odd ratio (OR) 0.234, CI 95% 0.16–0.42; p < 0.0001] and mitotic spindle inhibitor (taxanes) chemotherapy [OR 0.609, CI 95% 0.50–0.93; p < 0.001]. Contrariwise, breast primary tumor [odd ratio (OR) 2.372, CI 95% 1.29–4.3; p < 0.005] was an independent factor that proved a significantly longer bMFS. We suggest that anticancer drugs, especially taxane and its derivatives, could promote brain metastases, decreasing free survival. Mechanisms are discussed but still need to be determined.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics. CA Cancer J Clin. 2008;58:71–96.

    Article  PubMed  Google Scholar 

  2. Zimm S, Wampler GL, Stablein D, Hazra T, Young HF. Intracerebral metastases in solid-tumor patients: natural history and results of treatment. Cancer. 1981;48:384–94.

    Article  CAS  PubMed  Google Scholar 

  3. Posner JB. Neurologic complications of cancer. Philadelphia: FA Davies; 1995.

    Google Scholar 

  4. Barnholtz-Sloan J, Sloan A, Davis F, Vigneau F, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004;22(14):2865–72.

    Article  PubMed  Google Scholar 

  5. Gupta G, Massague J. Cancer metastasis: building a framework. Cell. 2006;127:679–95.

    Article  CAS  PubMed  Google Scholar 

  6. von Essen CF. Radiation enhancement of metastasis: a review. Clin Exp Metastasis. 1991;9:77–104.

    Article  Google Scholar 

  7. Kargiotis O, Geka A, Rao JS, Kyritsis AP. Effects of irradiation on tumor cell survival, invasion and angiogenesis. J Neurooncol. 2010;100:323–38.

    Article  PubMed  Google Scholar 

  8. Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220–31.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15:232–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37(4):745–51.

    Article  CAS  PubMed  Google Scholar 

  11. Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010;77(3):655–61. https://doi.org/10.1016/j.ijrobp.2009.08.025 Epub 2009 Nov 26.

    Article  PubMed  Google Scholar 

  12. Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012;30(4):419–25. https://doi.org/10.1200/JCO.2011.38.0527 Epub 2011 Dec 27.

    Article  PubMed  Google Scholar 

  13. Krewski D, Rao JNK. Inference from stratified samples: properties of the linearization, jackknife and balanced repeated replication methods. Ann Stat. 1981;9:1010–9.

    Article  Google Scholar 

  14. Niwińska A, Rudnicka H, Murawska M. Breast cancer leptomeningeal metastasis: propensity of breast cancer subtypes for leptomeninges and the analysis of factors influencing survival. Med Oncol. 2013;30(1):408. https://doi.org/10.1007/s12032-012-0408-4 Epub 2013 Jan 16.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Enders F, Geisenberger C, Jungk C, Bermejo JL, Warta R, von Deimling A, et al. Prognostic factors and long-term survival in surgically treated brain metastases from non-small cell lung cancer. Clin Neurol Neurosurg. 2016;142:72–80. https://doi.org/10.1016/j.clineuro.2016.01.011 Epub 2016 Jan 14.

    Article  PubMed  Google Scholar 

  16. Amelot A, Terrier LM, Mazeron JJ, Valery CA, Cornu P, Carpentier A, et al. Timeline metastatic progression: in the wake of the « seed and soil » theory. Med Oncol. 2017;34(11):185. https://doi.org/10.1007/s12032-017-1045-8.

    Article  PubMed  Google Scholar 

  17. Niwińska A. Brain metastases as site of first and isolated recurrence of breast cancer: the role of systemic therapy after local treatment. Clin Exp Metastasis. 2016;33(7):677–85. https://doi.org/10.1007/s10585-016-9802-1 Epub 2016 May 25.

    Article  PubMed  Google Scholar 

  18. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205:275–92.

    Article  CAS  PubMed  Google Scholar 

  19. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;133:571–3.

    Article  Google Scholar 

  20. Fidler I. The biology of brain metastasis: challenges for therapy. Cancer J. 2015;21(4):284–93. https://doi.org/10.1097/PPO.0000000000000126.

    Article  CAS  PubMed  Google Scholar 

  21. Cairns RA, Hill RP. Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res. 2004;64:2054–61.

    Article  CAS  PubMed  Google Scholar 

  22. Cairns RA, Kalliomaki T, Hill RP. Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res. 2001;61:8903–8.

    CAS  PubMed  Google Scholar 

  23. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299–309.

    Article  CAS  PubMed  Google Scholar 

  24. Saidi A, Hagedorn M, Allain N, Verpelli C, Sala C, Bello L, et al. Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness. Int J Cancer. 2009;125:1054–64.

    Article  CAS  PubMed  Google Scholar 

  25. Rofstad EK, Halsør EF. Hypoxia-associated spontaneous pulmonary metastasis in human melanoma xenografts: involvement of microvascular hot spots induced in hypoxic foci by interleukin 8. Br J Cancer. 2002;86:301–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rofstad EK, Rasmussen H, Galappathi K, Mathiesen B, Nilsen K, Graff BA. Hypoxia promotes lymph node metastasis in human melanoma xenografts by up-regulating the urokinase-type plasminogen activator receptor. Cancer Res. 2002;62:1847–53.

    CAS  PubMed  Google Scholar 

  27. Heath VL, Bicknell R. Anticancer strategies involving the vasculature. Nat Rev Clin Oncol. 2009;6:395–404.

    Article  CAS  PubMed  Google Scholar 

  28. Gingis-Velitski S, Loven D, Benayoun L, Munster M, Bril R, Voloshin T, et al. Host response to short-term, single-agent chemotherapy induces matrix metalloproteinase-9 expression and accelerates metastasis in mice. Cancer Res. 2011;71:6986–96.

    Article  CAS  PubMed  Google Scholar 

  29. Shree T, Olson O, Elie B, Kester J, Garfall A, Simpson K, et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 2011;25:2465–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Timaner M, Bril R, Kaidar-Person O, Rachman-Tzemah C, Alishekevitz D, Kotsofruk R, et al. De-qualinium blocks macrophage-induced metastasis following local radiation. Oncotarget. 2015;6:27537–54.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD, Raviv Z, et al. Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3. Cell Rep. 2016;17(5):1344–56. https://doi.org/10.1016/j.celrep.2016.09.083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Olson EM, Abdel-Rasoul M, Maly J, Wu CS, Lin NU, Shapiro CL. Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab. Ann Oncol. 2013;24:1526–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Spielmann M, Roche H, Delozier T, Canon JL, Romieu G, Bourgeois H, et al. Trastuzumab for patients with axillary- node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol. 2009;27:6129–34.

    Article  CAS  PubMed  Google Scholar 

  34. Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomized controlled trials. Lancet Oncol. 2011;12:236–44.

    Article  CAS  PubMed  Google Scholar 

  35. Lee HH, Bellat V, Law B. Chemotherapy induces adaptive drug resistance and metastatic potentials via phenotypic CXCR4-expressing cell state transition in ovarian cancer. PLoS ONE. 2017;12(2):e0171044. https://doi.org/10.1371/journal.pone.0171044.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was not funded.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Groupe Hospitalier Pitié-Salpétrière, APHP, 47-83 Boulevard de l’Hôpital, Batiment Babinski, 75013, Paris, France

    Aymeric Amelot, Bertrand Mathon, Charles-Ambroise Valery, Philippe Cornu, Marc Leveque & Alexandre Carpentier

  2. Department of Neurosurgery, Hopital Bretonneau, Tours, France

    Louis-Marie Terrier & Ann-Rose Cook

  3. Université Paris VI – Pierre et Marie Curie, Paris, France

    Aymeric Amelot, Bertrand Mathon, Jean-Jacques Mazeron, Charles-Ambroise Valery, Philippe Cornu, Marc Leveque & Alexandre Carpentier

  4. Department of Radiotherapy, Groupe Hospitalier Pitié-Salpétrière, APHP, Paris, France

    Jean-Jacques Mazeron

Authors
  1. Aymeric Amelot
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Louis-Marie Terrier
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Bertrand Mathon
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Ann-Rose Cook
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Jean-Jacques Mazeron
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Charles-Ambroise Valery
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Philippe Cornu
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Marc Leveque
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Alexandre Carpentier
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

AA, LMT, BM, CAV, AC, ML and JJM contributed to design and conceptualization of the study; AA, LMT, ARC, CAV and PC analyzed the data; AA, BM, ARC, LMT, AC, ML and JJM interpreted the data; AA, LMT, AC, ML, JJM and PC drafted the manuscript; AA, LMT, AC, ML and ARC wrote the manuscript; AA, BM, ARC, LMT, CAV, AC, ML, JJM and ARC contributed to manuscript revision for intellectual content. The guarantors, AA and ML are responsible for the overall content.

Corresponding author

Correspondence to Aymeric Amelot.

Ethics declarations

Conflict of interest

AA, LMT, BM, JJM, CAV, PC, AC and ML declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amelot, A., Terrier, LM., Mathon, B. et al. Can anticancer chemotherapy promote the progression of brain metastases?. Med Oncol 35, 35 (2018). https://doi.org/10.1007/s12032-018-1097-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-018-1097-4

Keywords