A prospective phase II trial of response adapted whole brain radiotherapy after high dose methotrexate based chemotherapy in patients with newly diagnosed primary central nervous system lymphoma-analysis of acute toxicity profile and early clinical outcome

  • Narayan Adhikari
  • Ahitagni Biswas
  • Ajay Gogia
  • Ranjit Kumar Sahoo
  • Ajay Garg
  • Ashima Nehra
  • Mehar Chand Sharma
  • Suman Bhasker
  • Manmohan Singh
  • Vishnubhatla Sreenivas
  • Rohan Chawla
  • Garima Joshi
  • Lalit Kumar
  • Subhash Chander
Clinical Study

Abstract

Background

The treatment of primary CNS lymphoma (PCNSL) comprises high dose methotrexate (HDMTX) based chemotherapy followed by whole brain radiotherapy (WBRT), the major drawback of which is long term neurotoxicity. We intended to assess the feasibility of response adapted WBRT in PCNSL in the Indian setting.

Methods

We screened 32 patients and enrolled 22 eligible patients with PCNSL from 2015 to 2017 in a prospective phase II trial. The patients underwent five 2-weekly cycles of induction chemotherapy with rituximab, methotrexate, vincristine, procarbazine. Patients with complete response(CR) to induction chemotherapy were given reduced dose WBRT 23.4 Gy/13 fractions/2.5 weeks while those with partial response (PR), stable or progressive disease (SD or PD) were given standard dose WBRT 45 Gy/25 fractions/5 weeks. Thereafter two cycles of consolidation chemotherapy with cytarabine were given. The primary endpoints of the study were assessment of response rate (RR) and progression free survival (PFS). The secondary endpoints of the study were assessment of overall survival (OS), toxicity profile of treatment and serial changes in quality of life and neuropsychological parameters.

Results

Out of 19 patients who completed HDMTX based chemotherapy, 10 (52.63%) patients achieved CR, 8 (42.11%) patients had PR and 1 patient had PD. After a median follow-up period of 11.25 months, the estimated median OS was 19 months. The actuarial rates of PFS and OS were respectively 94.1 and 68.2% at 1 year and 50.2 and 48.5% at 2 years. Three patients in reduced dose WBRT arm had recurrence and two of them died of progressive disease, whereas there was no recurrence or disease related death in standard dose WBRT arm. On univariate analysis of PFS, age ≤ 50 years and use of standard dose WBRT (45 Gy) led to significantly improved outcome (p value 0.03 and 0.02 respectively).

Conclusion

In patients with PCNSL, reduced dose WBRT after CR to HDMTX based chemotherapy may lead to suboptimal clinical outcome due to higher risk of recurrence, progression and early death. Trial Registration No CTRI/2015/10/006268

Keywords

Primary CNS lymphoma High dose methotrexate Whole brain radiotherapy 

Notes

Acknowledgements

Financial assistance for research received from Indian Council of Medical Research (ICMR).

Compliance with ethical standards

Conflict of interest

The 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.

Informed consent

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

Research involving human and animal participants

This article does not contain any study with animals performed by any of the authors.

Supplementary material

11060_2018_2856_MOESM1_ESM.docx (1 mb)
Supplementary material 1 (DOCX 1054 KB)

References

  1. 1.
    Ricard D, Idbaih A, Ducray F et al (2012) Primary brain tumours in adults. Lancet 379:1984–1996.  https://doi.org/10.1016/S0140-6736(11)61346-9 CrossRefPubMedGoogle Scholar
  2. 2.
    Morris PG, Abrey LE (2009) Therapeutic challenges in primary CNS lymphoma. Lancet Neurol 8:581–592.  https://doi.org/10.1016/S1474-4422(09)70091-2 CrossRefPubMedGoogle Scholar
  3. 3.
    Ferreri AJM, DeAngelis L, Illerhaus G et al (2011) Whole-brain radiotherapy in primary CNS lymphoma. Lancet Oncol 12:118–119.  https://doi.org/10.1016/S1470-2045(11)70018-3 (author reply 119–120).CrossRefPubMedGoogle Scholar
  4. 4.
    Thiel E, Korfel A, Martus P et al (2010) High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 11:1036–1047.  https://doi.org/10.1016/S1470-2045(10)70229-1 CrossRefPubMedGoogle Scholar
  5. 5.
    Omuro A, Taillandier L, Chinot O et al (2011) Primary CNS lymphoma in patients younger than 60: can whole-brain radiotherapy be deferred? J Neurooncol 104:323–330.  https://doi.org/10.1007/s11060-010-0497-x CrossRefPubMedGoogle Scholar
  6. 6.
    Batchelor T, Carson K, O’Neill A et al (2003) Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol 21:1044–1049CrossRefPubMedGoogle Scholar
  7. 7.
    Abrey LE, Yahalom J, DeAngelis LM (2000) Treatment for primary CNS lymphoma: the next step. J Clin Oncol 18:3144–3150CrossRefPubMedGoogle Scholar
  8. 8.
    Omuro AMP, Ben-Porat LS, Panageas KS et al (2005) Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol 62:1595–1600.  https://doi.org/10.1001/archneur.62.10.1595 CrossRefPubMedGoogle Scholar
  9. 9.
    Abrey LE, DeAngelis LM, Yahalom J (1998) Long-term survival in primary CNS lymphoma. J Clin Oncol 16:859–863CrossRefPubMedGoogle Scholar
  10. 10.
    Ferreri AJM, Reni M, Pasini F et al (2002) A multicenter study of treatment of primary CNS lymphoma. Neurology 58:1513–1520CrossRefPubMedGoogle Scholar
  11. 11.
    Rubenstein JL, Hsi ED, Johnson JL et al (2013) Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 31:3061–3068.  https://doi.org/10.1200/JCO.2012.46.9957 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ekenel M, Iwamoto FM, Ben-Porat LS et al (2008) Primary central nervous system lymphoma: the role of consolidation treatment after a complete response to high-dose methotrexate-based chemotherapy. Cancer 113:1025–1031.  https://doi.org/10.1002/cncr.23670 CrossRefPubMedGoogle Scholar
  13. 13.
    Shibamoto Y, Hayabuchi N, Hiratsuka J et al (2003) Is whole-brain irradiation necessary for primary central nervous system lymphoma? Patterns of recurrence after partial-brain irradiation. Cancer 97:128–133CrossRefPubMedGoogle Scholar
  14. 14.
    Bessell EM, López-Guillermo A, Villá S et al (2002) Importance of radiotherapy in the outcome of patients with primary CNS lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy treatments. J Clin Oncol 20:231–236CrossRefPubMedGoogle Scholar
  15. 15.
    DeAngelis LM, Seiferheld W, Schold SC et al (2002) Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: radiation therapy oncology group study 93-10. J Clin Oncol 20:4643–4648CrossRefPubMedGoogle Scholar
  16. 16.
    Shah GD, Yahalom J, Correa DD et al (2007) Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 25:4730–4735.  https://doi.org/10.1200/JCO.2007.12.5062 CrossRefPubMedGoogle Scholar
  17. 17.
    Morris PG, Correa DD, Yahalom J et al (2013) Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol 31:3971–3979.  https://doi.org/10.1200/JCO.2013.50.4910 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Abrey LE, Batchelor TT, Ferreri AJM et al (2005) Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034–5043.  https://doi.org/10.1200/JCO.2005.13.524 CrossRefPubMedGoogle Scholar
  19. 19.
    Ferreri AJM, Verona C, Politi LS et al (2011) Consolidation radiotherapy in primary central nervous system lymphomas: impact on outcome of different fields and doses in patients in complete remission after upfront chemotherapy. Int J Radiat Oncol Biol Phys 80:169–175.  https://doi.org/10.1016/j.ijrobp.2010.01.066 CrossRefPubMedGoogle Scholar
  20. 20.
    Ferreri AJ, Cwynarski K, Pulczynski E et al (2016) Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International extranodal lymphoma study group-32 (IELSG32) phase 2 trial. Lancet Haematol 3:e217–e227.  https://doi.org/10.1016/S2352-3026(16)00036-3 CrossRefPubMedGoogle Scholar
  21. 21.
    Bromberg J, Issa S, Bukanina K et al (2017) Effect of rituximab in primary central nervous system lymphoma: results of the randomized phase III HOVON 105/ALLG NHL 24 Study. Blood 130:582Google Scholar
  22. 22.
    Shibamoto Y, Sumi M, Takemoto M et al (2014) Analysis of radiotherapy in 1054 patients with primary central nervous system lymphoma treated from 1985 to 2009. Clin Oncol 26:653–660.  https://doi.org/10.1016/j.clon.2014.06.011 CrossRefGoogle Scholar
  23. 23.
    Alvarez-pinzon AM, Wolf AL, Swedberg H et al (2016) Primary central nervous system lymphoma (PCNSL): analysis of treatment by gamma knife radiosurgery and chemotherapy in a prospective, observational study. Cureus 8:e697.  https://doi.org/10.7759/cureus.697 PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Narayan Adhikari
    • 1
  • Ahitagni Biswas
    • 1
  • Ajay Gogia
    • 2
  • Ranjit Kumar Sahoo
    • 2
  • Ajay Garg
    • 3
  • Ashima Nehra
    • 4
  • Mehar Chand Sharma
    • 5
  • Suman Bhasker
    • 1
  • Manmohan Singh
    • 6
  • Vishnubhatla Sreenivas
    • 7
  • Rohan Chawla
    • 8
  • Garima Joshi
    • 4
  • Lalit Kumar
    • 2
  • Subhash Chander
    • 1
  1. 1.Department of Radiation OncologyAll India Institute of Medical SciencesNew DelhiIndia
  2. 2.Department of Medical OncologyAll India Institute of Medical SciencesNew DelhiIndia
  3. 3.Department of NeuroradiologyAll India Institute of Medical SciencesNew DelhiIndia
  4. 4.Department of Clinical NeuropsychologyAll India Institute of Medical SciencesNew DelhiIndia
  5. 5.Department of PathologyAll India Institute of Medical SciencesNew DelhiIndia
  6. 6.Department of NeurosurgeryAll India Institute of Medical SciencesNew DelhiIndia
  7. 7.Department of BiostatisticsAll India Institute of Medical SciencesNew DelhiIndia
  8. 8.Department of OphthalmologyAll India Institute of Medical SciencesNew DelhiIndia

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