Skip to main content

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

Journal of Neuro-Oncology volume 139, pages 153–166 (2018)Cite this article

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

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

Data availability

Data generated or analysed during this study are included in this published article [and its supplementary information files] and remaining datasets are available from the corresponding author on reasonable request.

References

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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 21:1044–1049

    Article  PubMed  CAS  Google Scholar 

  7. Abrey LE, Yahalom J, DeAngelis LM (2000) Treatment for primary CNS lymphoma: the next step. J Clin Oncol 18:3144–3150

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  9. Abrey LE, DeAngelis LM, Yahalom J (1998) Long-term survival in primary CNS lymphoma. J Clin Oncol 16:859–863

    Article  PubMed  CAS  Google Scholar 

  10. Ferreri AJM, Reni M, Pasini F et al (2002) A multicenter study of treatment of primary CNS lymphoma. Neurology 58:1513–1520

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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 97:128–133

    Article  PubMed  Google Scholar 

  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 20:231–236

    Article  PubMed  CAS  Google Scholar 

  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 20:4643–4648

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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 130:582

    Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

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

Funding

Dr. N. Adhikari received financial assistance for research from Indian Council of Medical Research (ICMR). This was an investigator initiated prospective phase II trial. The cost of imaging(MRI) and other investigations, chemotherapy (but not Rituximab) and radiotherapy in patients in this clinical trial was exempted by the competent authority at All India Institute of Medical Sciences, New Delhi.

Author information

Affiliations

  1. Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India

    Narayan Adhikari, Ahitagni Biswas, Suman Bhasker & Subhash Chander

  2. Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India

    Ajay Gogia, Ranjit Kumar Sahoo & Lalit Kumar

  3. Department of Neuroradiology, All India Institute of Medical Sciences, New Delhi, India

    Ajay Garg

  4. Department of Clinical Neuropsychology, All India Institute of Medical Sciences, New Delhi, India

    Ashima Nehra & Garima Joshi

  5. Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

    Mehar Chand Sharma

  6. Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India

    Manmohan Singh

  7. Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India

    Vishnubhatla Sreenivas

  8. Department of Ophthalmology, All India Institute of Medical Sciences, New Delhi, India

    Rohan Chawla

Authors
  1. Narayan Adhikari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahitagni Biswas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ajay Gogia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ranjit Kumar Sahoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ajay Garg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ashima Nehra
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mehar Chand Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Suman Bhasker
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Manmohan Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vishnubhatla Sreenivas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rohan Chawla
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Garima Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Lalit Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Subhash Chander
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ahitagni Biswas.

Ethics declarations

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.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 1054 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Adhikari, N., Biswas, A., Gogia, A. et al. 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. J Neurooncol 139, 153–166 (2018). https://doi.org/10.1007/s11060-018-2856-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-018-2856-y

Keywords

  • Primary CNS lymphoma
  • High dose methotrexate
  • Whole brain radiotherapy