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A successful compartmental approach for the treatment of breast cancer brain metastases

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Abstract

Background

Brain metastases are challenging daily practice in oncology and remain a compartmental problem since most anti-cancer drugs do not cross the blood–brain barrier at relevant pharmacological concentrations.

Methods

In a young woman with HER2-overexpressing breast cancer resistant to standard treatments, at the time of brain metastases progression, a ventricular reservoir was implanted for intrathecal drug injections and detailed pharmacokinetic studies.

Results

A first association of intrathecal trastuzumab with intravenous cisplatin was offered to the patient. For trastuzumab, the mean cerebrospinal fluid trough concentration of 53.4 mg/L reached relevant levels, enabling the stabilization of the metastases. Adding intravenous cisplatin was not beneficial, since the cerebrospinal fluid exposure was almost undetectable under 0.08 mg/L. We then offered the patient an intrathecal combination of trastuzumab and methotrexate, because of their in vitro synergic cytotoxicity. The cerebrospinal fluid peak of methotrexate was 1037 µmol/L at 2 h, and the concentrations remained above the theoretical therapeutic concentration. After 2 months of this drug combination, we obtained an excellent response on the brain metastases.

Conclusion

Our preliminary study supports the interest of a compartmental approach through a direct administration of drugs into the cerebrospinal fluid for the treatment of breast cancer brain metastases.

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References

  1. Caroli M, Di Cristofori A, Lucarella F et al (2011) Surgical brain metastases: management and outcome related to prognostic indexes: a critical review of a ten-year series. In: Int. Sch. Res. Not. https://www.hindawi.com/archive/2011/207103/. Accessed 11 Dec 2017

  2. Swain SM, Baselga J, Kim S-B et al (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724–734. https://doi.org/10.1056/NEJMoa1413513

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792. https://doi.org/10.1056/NEJM200103153441101

    Article  PubMed  CAS  Google Scholar 

  4. Pestalozzi BC, Brignoli S (2000) Trastuzumab in CSF. J Clin Oncol Off J Am Soc Clin Oncol 18:2349–2351. https://doi.org/10.1200/JCO.2000.18.11.2349

    Article  CAS  Google Scholar 

  5. Bousquet G, Darrouzain F, Bazelaire C de et al (2016) Intrathecal trastuzumab halts progression of CNS metastases in breast cancer. J Clin Oncol. https://doi.org/10.1200/JCO.2012.44.8894

    Article  PubMed  Google Scholar 

  6. Vogel CL, Cobleigh MA, Tripathy D et al (2001) First-line herceptin monotherapy in metastatic breast cancer. Oncology 61(Suppl 2):37–42. https://doi.org/10.1159/000055400

    Article  PubMed  CAS  Google Scholar 

  7. Bernadou G, Campone M, Merlin J-L et al (2016) Influence of tumour burden on trastuzumab pharmacokinetics in HER2 positive non-metastatic breast cancer. Br J Clin Pharmacol 81:941–948. https://doi.org/10.1111/bcp.12875

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Zhang Q-H, Gong C, Yang H et al (2015) Pharmacokinetics of cisplatin in the absence or presence of Zengmian Yiliu granules (a traditional Chinese medicine compound) in rats determined via ICP-MS: an investigation on drug–herb interactions. Pharm Biol 53:159–166. https://doi.org/10.3109/13880209.2014.912241

    Article  PubMed  CAS  Google Scholar 

  9. Yamada K, Kato N, Takagi A et al (2005) One-milliliter wet-digestion for inductively coupled plasma mass spectrometry (ICP-MS): determination of platinum-DNA adducts in cells treated with platinum(II) complexes. Anal Bioanal Chem 382:1702–1707. https://doi.org/10.1007/s00216-005-3339-5

    Article  PubMed  CAS  Google Scholar 

  10. Chavan P, Bhat V, Karmore A et al (2017) Establishing Syva methotrexate assay on siemens dimension RxL analyzer: experience in a tertiary cancer care laboratory. J Lab Phys 9:67–68. https://doi.org/10.4103/0974-2727.187923

    Article  Google Scholar 

  11. Franciosi V, Cocconi G, Michiara M et al (1999) Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer 85:1599–1605

    Article  PubMed  CAS  Google Scholar 

  12. Christodoulou C, Bafaloukos D, Linardou H et al (2005) Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) Phase II study. J Neurooncol 71:61–65. https://doi.org/10.1007/s11060-004-9176-0

    Article  PubMed  CAS  Google Scholar 

  13. Pegram M, Hsu S, Lewis G et al (1999) Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18:2241–2251. https://doi.org/10.1038/sj.onc.1202526

    Article  PubMed  CAS  Google Scholar 

  14. Shapiro WR, Young DF, Mehta BM (1975) Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 293:161–166. https://doi.org/10.1056/NEJM197507242930402

    Article  PubMed  CAS  Google Scholar 

  15. Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer Oxf Engl (1990) 45:228–247. https://doi.org/10.1016/j.ejca.2008.10.026

    Article  CAS  Google Scholar 

  16. Laufman LR, Forsthoefel KF (2001) Use of intrathecal trastuzumab in a patient with carcinomatous meningitis. Clin Breast Cancer 2:235. https://doi.org/10.1016/S1526-8209(11)70419-0

    Article  PubMed  CAS  Google Scholar 

  17. Platini C, Long J, Walter S (2006) Meningeal carcinomatosis from breast cancer treated with intrathecal trastuzumab. Lancet Oncol 7:778–780. https://doi.org/10.1016/S1470-2045(06)70864-6

    Article  PubMed  Google Scholar 

  18. Zagouri F, Sergentanis TN, Bartsch R et al (2013) Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis. Breast Cancer Res Treat 139:13–22. https://doi.org/10.1007/s10549-013-2525-y

    Article  PubMed  CAS  Google Scholar 

  19. Pluchart H, Jacquet E, Charlety D et al (2016) Long-term survivor with intrathecal and intravenous trastuzumab treatment in metastatic breast cancer. Target Oncol 11:687–691. https://doi.org/10.1007/s11523-016-0429-6

    Article  PubMed  CAS  Google Scholar 

  20. Bonneau C, Paintaud G, Trédan O et al (2018) Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis. Eur J Cancer Oxf Engl (1990) 95:75–84. https://doi.org/10.1016/j.ejca.2018.02.032

    Article  CAS  Google Scholar 

  21. Jacobs SS, Fox E, Dennie C et al (2005) Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates. Clin Cancer Res Off J Am Assoc Cancer Res 11:1669–1674. https://doi.org/10.1158/1078-0432.CCR-04-1807

    Article  CAS  Google Scholar 

  22. Liu P, Gou M, Yi T et al (2012) The enhanced antitumor effects of biodegradable cationic heparin-polyethyleneimine nanogels delivering HSulf-1 gene combined with cisplatin on ovarian cancer. Int J Oncol 41:1504–1512. https://doi.org/10.3892/ijo.2012.1558

    Article  PubMed  CAS  Google Scholar 

  23. Jacobs S, McCully CL, Murphy RF et al (2010) Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates. Cancer Chemother Pharmacol 65:817–824. https://doi.org/10.1007/s00280-009-1085-7

    Article  PubMed  CAS  Google Scholar 

  24. Armand JP, Macquet JP, LeRoy AF (1983) Cerebrospinal fluid-platinum kinetics of cisplatin in man. Cancer Treat Rep 67:1035–1037

    PubMed  CAS  Google Scholar 

  25. DeGregorio MW, King OY, Holleran WM et al (1985) Ultrafiltrate and total platinum in plasma and cerebrospinal fluid in a patient with neuroblastoma. Cancer Treat Rep 69:1441–1442

    PubMed  CAS  Google Scholar 

  26. Nakagawa H, Fujita T, Kubo S et al (1996) Difference in CDDP penetration into CSF between selective intraarterial chemotherapy in patients with malignant glioma and intravenous or intracarotid administration in patients with metastatic brain tumor. Cancer Chemother Pharmacol 37:317–326. https://doi.org/10.1007/s002800050391

    Article  PubMed  CAS  Google Scholar 

  27. Braen APJM, Perron J, Tellier P et al (2010) A 4-week intrathecal toxicity and pharmacokinetic study with trastuzumab in cynomolgus monkeys. Int J Toxicol 29:259–267. https://doi.org/10.1177/1091581810361527

    Article  PubMed  CAS  Google Scholar 

  28. Rubenstein JL, Fridlyand J, Abrey L et al (2007) Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol Off J Am Soc Clin Oncol 25:1350–1356. https://doi.org/10.1200/JCO.2006.09.7311

    Article  CAS  Google Scholar 

  29. Zhang Y, Pardridge WM (2001) Mediated efflux of IgG molecules from brain to blood across the blood–brain barrier. J Neuroimmunol 114:168–172

    Article  PubMed  CAS  Google Scholar 

  30. Bleyer WA, Nelson JA, Kamen BA (1997) Accumulation of methotrexate in systemic tissues after intrathecal administration. J Pediatr Hematol Oncol 19:530–532

    Article  PubMed  CAS  Google Scholar 

  31. Bousquet G, Janin A (2015) Passage of humanized monoclonal antibodies across the blood–brain barrier: relevance in the treatment of cancer brain metastases? J Appl Biopharm Pharmacokinet 2:50–58

    Article  CAS  Google Scholar 

  32. Blanchette M, Michaud K, Fortin D (2012) A new method of quantitatively assessing the opening of the blood–brain barrier in murine animal models. J Neurosci Methods 207:125–129. https://doi.org/10.1016/j.jneumeth.2012.03.012

    Article  PubMed  CAS  Google Scholar 

  33. Boockvar JA, Tsiouris AJ, Hofstetter CP et al (2011) Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood–brain barrier disruption for recurrent malignant glioma. J Neurosurg 114:624–632. https://doi.org/10.3171/2010.9.JNS101223

    Article  PubMed  CAS  Google Scholar 

  34. Shin BJ, Burkhardt J-K, Riina HA, Boockvar JA (2012) Superselective intra-arterial cerebral infusion of novel agents after blood–brain disruption for the treatment of recurrent glioblastoma multiforme: a technical case series. Neurosurg Clin N Am 23:323–329. https://doi.org/10.1016/j.nec.2012.01.008

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Mrs. A. Swaine for revising the English language. We would also like to thank Dr. S. Szyldergemajn for his helpful advices. The study was supported by INSERM and University Paris 7.

Author information

Author notes

  1. Thuy T. Nguyen and Eurydice Angeli contributed equally.

  2. Anne Janin and Guilhem Bousquet are co-senior authors.

Authors and Affiliations

  1. U1165, Université Paris 7, INSERM, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010, Paris, France

    Thuy T. Nguyen, Eurydice Angeli, Anne Janin & Guilhem Bousquet

  2. AP-HP Hôpital Avicenne, Service d’Oncologie Médicale, 93000, Bobigny, France

    Thuy T. Nguyen, Sabine Winterman, Marie-Christine Pailler, Laurent Zelek & Guilhem Bousquet

  3. Medical Oncology Department A, National Cancer Hospital, Ha Noi, Viet Nam

    Thuy T. Nguyen & Quang T. Nguyen

  4. Université François-Rabelais de Tours, CNRS, GICC UMR 7292, 37000, Tours, France

    François Darrouzain & Gilles Paintaud

  5. CHRU de Tours, Pharmacologie-Toxicologie, 37000, Tours, France

    François Darrouzain, Céline Desvignes & Gilles Paintaud

  6. AP-HP Hôpital Avicenne, Pharmacie, 93000, Bobigny, France

    Marthe Rigal & Osman Nevine

  7. AP-HP Hôpital Avicenne, Service de Biochimie, 93000, Bobigny, France

    Patrick Nicolas

  8. Surgery Department A, National Cancer Hospital, Ha Noi, Viet Nam

    Quang V. Le

  9. Université Paris 13, 93430, Villetaneuse, France

    Laurent Zelek & Guilhem Bousquet

  10. AP-HP Hôpital Saint-Louis, Laboratoire de Pathologie, 75010, Paris, France

    Anne Janin

  11. Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1165, 75010, Paris, France

    Anne Janin & Guilhem Bousquet

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  1. Thuy T. Nguyen
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Contributions

TTN conceived and designed the study, provided the study material or patient, collected and assembled the data, provided data analysis and interpretation, and drafted the manuscript. EA provided data analysis and interpretation. FD provided data analysis and interpretation, provided the study material, provided administrative support and located financial support. QTN provided the study material and provided administrative support. CD provided the study material and provided administrative support. MR provided the study material and provided administrative support. ON provided the study material and provided administrative support. PN provided the study material, provided administrative support, provided data analysis and interpretation. QVL provided the study material and provided administrative support. SW provided the study material and provided administrative support. M-CP collected and assembled the data. LZ collected and assembled the data. GP provided the study material, provided administrative support, provided data analysis and interpretation. AJ conceived and designed the study, provided the study material, provided administrative support, provided data analysis and interpretation, drafted the manuscript and located financial support. GB conceived and designed the study, provided the study material, provided administrative support, collected and assembled the data, provided data analysis and interpretation, drafted the manuscript and located financial support.

Corresponding authors

Correspondence to Anne Janin or Guilhem Bousquet.

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The authors declare no conflict of interest.

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Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

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Nguyen, T.T., Angeli, E., Darrouzain, F. et al. A successful compartmental approach for the treatment of breast cancer brain metastases. Cancer Chemother Pharmacol 83, 573–580 (2019). https://doi.org/10.1007/s00280-018-3752-z

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