Skip to main content
SpringerLink
Log in

Early platelet variation during concomitant chemo-radiotherapy predicts adjuvant temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma patients

  • Original Article
  • Published:
Supportive Care in Cancer Aims and scope Submit manuscript

Abstract

Purpose

Temozolomide (TMZ) is known to induce thrombocytopenia but no early predictive test has yet been clearly established. The aim of the study was to retrospectively identify and validate a threshold of early platelet variation predicting TMZ-induced thrombocytopenia during the TMZ phase in patients treated according to the Stupp protocol for glioblastoma.

Methods

A training set was used to analyze variations in platelet count occurring from the first week (W1) to week 6 (W6) during radiotherapy. Our aim was to identify the most relevant platelet decrease associated with TMZ-induced thrombocytopenia ≤ 100 G/L at day 28 during the TMZ phase. The performance of the threshold was confirmed in an independent validation set.

Results

Overall, 147 patients were included, 85 and 62 in the training and validation sets, respectively. Twenty-seven patients (18%) experienced at least one TMZ-induced thrombocytopenia in the TMZ phase. A platelet decrease at W6 ≥ 35% (∆W6 ≥ 35%) was identified as the best predictive variation with an AUC of 0.83, a sensitivity of 65%, and a specificity of 96%. In the validation set, ∆W6 ≥ 35% platelet variation was identified as an independent marker of TMZ-induced thrombocytopenia during the TMZ phase (OR 15.23 (95% CI 3.5–107.5)) corresponding to sensitivity of 77% (66–87%), specificity of 73% (62–84%), a positive predictive value of 42% (29–54%), and a negative predictive value of 92% (86–99%).

Conclusion

Platelet decrease at W6 ≥ 35% during the RT-TMZ phase is an early and simple predictive marker of clinically relevant TMZ-induced thrombocytopenia during TMZ maintenance.

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

Similar content being viewed by others

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. https://doi.org/10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  2. Chinot OL, Nishikawa R, Mason W, Henriksson R, Saran F, Cloughesy T, Garcia J, Revil C, Abrey L, Wick W (2016) Upfront bevacizumab may extend survival for glioblastoma patients who do not receive second-line therapy: an exploratory analysis of AVAglio. Neuro-Oncology 18:1313–1318. https://doi.org/10.1093/neuonc/now046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z (2015) Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA 314:2535–2543. https://doi.org/10.1001/jama.2015.16669

    Article  CAS  PubMed  Google Scholar 

  4. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708. https://doi.org/10.1056/NEJMoa1308573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31:4085–4091. https://doi.org/10.1200/JCO.2013.49.6968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gupta T, Mohanty S, Moiyadi A, Jalali R (2013) Factors predicting temozolomide induced clinically significant acute hematologic toxicity in patients with high-grade gliomas: a clinical audit. Clin Neurol Neurosurg 115:1814–1819. https://doi.org/10.1016/j.clineuro.2013.05.015

    Article  PubMed  Google Scholar 

  7. U.S. Department of Health and Human Services National Institutes of Health National Cancer Institute (2010) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03

  8. Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R, Nordic Clinical Brain Tumour Study Group (NCBTSG) (2012) Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 13:916–926. https://doi.org/10.1016/S1470-2045(12)70265-6

    Article  CAS  PubMed  Google Scholar 

  9. Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, Steinbach JP, Wick W, Tarnawski R, Nam DH, Hau P, Weyerbrock A, Taphoorn MJ, Shen CC, Rao N, Thurzo L, Herrlinger U, Gupta T, Kortmann RD, Adamska K, McBain C, Brandes AA, Tonn JC, Schnell O, Wiegel T, Kim CY, Nabors LB, Reardon DA, van den Bent M, Hicking C, Markivskyy A, Picard M, Weller M, European Organisation for Research and Treatment of Cancer (EORTC), Canadian Brain Tumor Consortium, CENTRIC study team (2014) Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 15:1100–1108. https://doi.org/10.1016/S1470-2045(14)70379-1

    Article  CAS  PubMed  Google Scholar 

  10. Sure D, Dunn I, Norden A, Anderson WS (2010) Intracerebral hemorrhage secondary to thrombocytopenia in a patient treated with temozolomide. Clin Neurol Neurosurg 112:741–742. https://doi.org/10.1016/j.clineuro.2010.04.005

    Article  PubMed  Google Scholar 

  11. Armstrong TS, Cao Y, Scheurer ME, Vera-Bolaños E, Manning R, Okcu MF, Bondy M, Zhou R, Gilbert MR (2009) Risk analysis of severe myelotoxicity with temozolomide: the effects of clinical and genetic factors. Neuro-Oncology 11:825–832. https://doi.org/10.1215/15228517-2008-120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lombardi G, Rumiato E, Bertorelle R, et al (2013) Clinical and genetic factors associated with severe hematological toxicity in glioblastoma patients during radiation plus Temozolomide treatment: a prospective study. Am J Clin Oncol. doi: https://doi.org/10.1097/COC.0b013e3182a790ea

  13. Altinoz MA, Elmaci I, Bolukbasi FH, Ekmekci CG, Yenmis G, Sari R, Sav A (2017) MGMT gene variants, temozolomide myelotoxicity and glioma risk. A concise literature survey including an illustrative case. J Chemother 29:1–7. https://doi.org/10.1080/1120009X.2017.1312752

    Article  Google Scholar 

  14. Scaringi C, De Sanctis V, Minniti G, Enrici RM (2013) Temozolomide-related hematologic toxicity. Onkologie 36:444–449. https://doi.org/10.1159/000353752

    Article  CAS  PubMed  Google Scholar 

  15. Preusser M, Elandt K, Schwarzinger I, Marosi C, Heinzl H (2011) Immature and absolute platelet count changes and thrombocytopenia in malignant glioma. Eur J Clin Investig 41:539–545. https://doi.org/10.1111/j.1365-2362.2010.02442.x

    Article  Google Scholar 

  16. Mirimanoff R-O, Gorlia T, Mason W, van den Bent MJ, Kortmann RD, Fisher B, Reni M, Brandes AA, Curschmann J, Villa S, Cairncross G, Allgeier A, Lacombe D, Stupp R (2006) Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 24:2563–2569. https://doi.org/10.1200/JCO.2005.04.5963

    Article  CAS  PubMed  Google Scholar 

  17. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709–722. https://doi.org/10.1056/NEJMoa1308345

    Article  CAS  PubMed  Google Scholar 

  18. Yovino S, Kleinberg L, Grossman SA, Narayanan M, Ford E (2013) The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Investig 31:140–144. https://doi.org/10.3109/07357907.2012.762780

    Article  CAS  Google Scholar 

  19. Sabharwal A, Waters R, Danson S, Clamp A, Lorigan P, Thatcher N, Margison GP, Middleton MR (2011) Predicting the myelotoxicity of chemotherapy: the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mononuclear cells. Melanoma Res 21:502–508. https://doi.org/10.1097/CMR.0b013e32832ccd58

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Frédéric Di Fiore and Florian Clatot contributed equally to this work.

Authors and Affiliations

  1. Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Normandy Centre for Genomic and Personalized Medicine, Rouen University Hospital, F-76031, Rouen, France

    Maxime Fontanilles, Frédéric Di Fiore & Florian Clatot

  2. Department of Medical Oncology, Cancer Centre Henri Becquerel, 1 Rue d’Amiens, 76000, Rouen Cedex, France

    Maxime Fontanilles, Cristina Alexandru, Isabelle Tennevet, Frédéric Di Fiore & Florian Clatot

  3. Normandie Univ, UNIROUEN, Inserm U1245, Normandy Centre for Genomic and Personalized Medicine, Department of Pathology, Rouen University Hospital, F-76031, Rouen, France

    Florent Marguet & Annie Laquerriere

  4. Department of Neurosurgery, Rouen University Hospital, F-76031, Rouen, France

    Olivier Langlois, Vianney Gilard & Chantal Hanzen

  5. Department of Radiation Oncology and Medical Physics, Cancer Centre Henri Becquerel, F-76000, Rouen, France

    Ovidiu Veresezan

  6. Department of Biopathology, Cancer Centre Henri Becquerel, F-76000, Rouen, France

    Marion David

  7. Department of Hepatogastroenterology, Rouen University Hospital, F-76031, Rouen, France

    Frédéric Di Fiore

Authors
  1. Maxime Fontanilles
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Florent Marguet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristina Alexandru
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Olivier Langlois
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ovidiu Veresezan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vianney Gilard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marion David
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Annie Laquerriere
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chantal Hanzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Isabelle Tennevet
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Frédéric Di Fiore
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Florian Clatot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maxime Fontanilles.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fontanilles, M., Marguet, F., Alexandru, C. et al. Early platelet variation during concomitant chemo-radiotherapy predicts adjuvant temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma patients. Support Care Cancer 27, 477–484 (2019). https://doi.org/10.1007/s00520-018-4336-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00520-018-4336-5

Keywords

Search

Navigation