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Increase of pseudoprogression and other treatment related effects in low-grade glioma patients treated with proton radiation and temozolomide

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Abstract

Introduction

Concurrent radiotherapy and temozolomide (TMZ) is associated with radiographic pseudoprogression (PsP) in glioblastoma. The occurrence of PsP and other treatment effects is less well understood in low-grade gliomas (LGG). The purpose of this study is to evaluate whether the addition of TMZ to radiotherapy increases the incidence of PsP in adults with LGG treated with proton radiotherapy (PRT).

Methods

Chart review and volumetric MRI-analysis was performed on radiotherapy-naive adults with WHO grade II or IDH mutant WHO grade III gliomas treated with PRT between 2005 and 2015. Progression was defined by histology, new chemotherapy initiation, or progressive increase in lesion volume beyond 40% from baseline. Post treatment related effects (PTRE) were defined as new/increased T2/FLAIR or abnormal enhancement which eventually resolved or stabilized without evidence of progression for a period of 6–12 months. PsP was defined as the subset of PRTE suspicious for progression or volumetrically increased at least 40% from baseline. Pearson’s chi-squared test and Cox-proportional hazards models were used for statistical analysis.

Results

There were 119 patients meeting inclusion criteria. There was an increased risk of PsP following PRT + TMZ versus PRT-alone (HR = 2.2, p = 0.006, on Cox univariate analysis). Presence of PsP was associated with improved OS (p = 0.02 with PsP as time-varying covariate).

Conclusions

TMZ use, when added to PRT, was associated with increased PsP in patients with LGG; however, patients with PsP tended to achieve longer survival.

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References

  1. Louis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820

    Article  PubMed  Google Scholar 

  2. Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW (2007) From the archives of the AFIP: patterns of contrast enhancement in the brain and meninges. Radiographics 27:525–551

    Article  PubMed  Google Scholar 

  3. Wen PY, Reardon DA (2016) Neuro-oncology in 2015: progress in glioma diagnosis, classification and treatment. Nat Rev Neurol 12:69

    Article  PubMed  CAS  Google Scholar 

  4. Van den Bent M, Smits M, Kros J, Chang S (2017) Diffuse infiltrating oligodendroglioma and astrocytoma. J Clin Oncol 35:2394–2394

    Article  PubMed  Google Scholar 

  5. Brat D, Verhaak R et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481–2498

    Article  PubMed  CAS  Google Scholar 

  6. Kruser TJ, Mehta MP, Robins HI (2013) Pseudoprogression after glioma therapy: a comprehensive review. Expert Rev Neurother 13:389–403

    Article  PubMed  CAS  Google Scholar 

  7. Hoffman WF, Levin VA, Wilson CB (1979) Evaluation of malignant glioma patients during the postirradiation period. J Neurosurg 50:624–628

    Article  PubMed  CAS  Google Scholar 

  8. Wen PY, Macdonald DR, Reardon DA et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972

    Article  PubMed  Google Scholar 

  9. Van den Bent MJ, Wefel JS, Schiff D et al (2011) Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol 12(6):583–593

    Article  PubMed  Google Scholar 

  10. Brandes AA, Franceschi E, Tosoni A et al (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 26:2192–2197

    Article  PubMed  Google Scholar 

  11. Chamberlain MC, Glantz MJ, Chalmers L et al (2007) Early necrosis following concurrent temodar and radiotherapy in patients with glioblastoma. J Neurooncol 82(1):81–83

    Article  PubMed  Google Scholar 

  12. Taal W, Brandsma D, de Bruin HG et al (2008) Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer 113(2):405–410

    Article  PubMed  CAS  Google Scholar 

  13. Gerstner ER, McNamara MB, Norden AD, Lafrankie D, Wen PY (2009) Effect of adding temozolomide to radiation therapy on the incidence of pseudo-progression. J Neurooncol 94(1):97–101. https://doi.org/10.1007/s11060-009-9809-4

    Article  PubMed  CAS  Google Scholar 

  14. Gunjur A, Lau E, Taouk Y, Ryan G (2011) Early post-treatment pseudo-progression amongst glioblastoma multiforme patients treated with radiotherapy and temozolomide: a retrospective analysis. J Med Imaging Radiat Oncol 55:603–610

    Article  PubMed  Google Scholar 

  15. Kang H, Kim C, Han JH et al (2011) Pseudoprogression in patients with malignant gliomas treated with concurrent temozolomide and radiotherapy: potential role of p53. J Neuro-Oncol 102:157–162

    Article  CAS  Google Scholar 

  16. Roldán GB, Scott JN, McIntyre JB et al (2009) Population-based study of pseudoprogression after chemoradiotherapy in GBM. Can J Neurol Sci 36:617–622

    Article  PubMed  Google Scholar 

  17. Sanghera P, Perry J, Sahgal A et al (2010) Pseudoprogression following chemoradiotherapy for glioblastoma multiforme. Can J Neurol Sci 37:36–42

    Article  PubMed  Google Scholar 

  18. Brandsma D et al (2008) Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9:453–461

    Article  PubMed  Google Scholar 

  19. Langen K, Galldiks N, Hattingen E, Shah N (2017) Advances in neuro-oncology imaging. Nat Rev Neurol 13:279–289

    Article  PubMed  Google Scholar 

  20. Melguizo-Gavilanes I, Bruner JM, Guha-Thakurta N, Hess KR, Puduvalli VK (2015) Characterization of pseudoprogression in patients with glioblastoma: is histology the gold standard? J Neuro-Oncol 123:141–150

    Article  CAS  Google Scholar 

  21. Hygino Da Cruz LC Jr, Rodriguez I, Domingues RC, Gasparetto EL, Sorensen AG (2011) Pseudoprogression and pseudoresponse: imaging challenges in the assessment of posttreatment glioma. Am J Neuroradiol 32:1978–1985

    Article  PubMed  Google Scholar 

  22. Van West S, de Bruin H, van de Langerijt B, Swaak-Kragten A, van den Bent M, Taal W (2016) Incidence of pseudoprogression in low-grade gliomas treated with radiotherapy. Neuro-Oncology 19:719–725

    PubMed Central  Google Scholar 

  23. De Wit MCY, De Bruin HG, Eijkenboom W, Sillevis Smitt PAE, Van Den Bent MJ (2004) Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression. Neurology 63:535–537

    Article  PubMed  Google Scholar 

  24. Lin A, Liu J, Evans J et al (2014) Codeletions at 1p and 19q predict a lower risk of pseudoprogression in oligodendrogliomas and mixed oligoastrocytomas. Neuro-Oncology 16:123–130

    Article  PubMed  CAS  Google Scholar 

  25. Lin AL, White M, Miller-Thomas MM, Fulton RS, Tsien CI, Rich KM et al (2016) Molecular and histologic characteristics of pseudoprogression in diffuse gliomas. J Neurooncol 130:529–533

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Meyzer C, Dhermain F, Ducreux D et al (2010) A case report of pseudoprogression followed by complete remission after proton-beam irradiation for a low-grade glioma in a teenager: the value of dynamic contrast-enhanced MRI. Radiat Oncol 5:9

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hauswald H, Rieken S, Swantje E, Kessel KA, Herfarth K, Debus J, Combs SE (2012) First experiences in treatment of low-grade glioma grade I and II with proton therapy. Radiat Oncol 7:189

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lassen-Ramshad Y, Petersen JB, Tietze A, Borghammer P, Mahajan A, McGovern SL (2015) Pseudoprogression after proton radiotherapy for pediatric low grade glioma. Acta Oncol 54(9):1701–1702 https://doi.org/10.3109/0284186X.2015.1078498

    Article  PubMed  Google Scholar 

  29. Naftel RP, Pollack IF, Zuccoli G, Deutsch M, Jakacki RI (2015) Pseudoprogression of low-grade gliomas after radiotherapy. Pediatr Blood Cancer 62:35–39

    Article  PubMed  Google Scholar 

  30. Bronk JK, Guha-Thakurta N, Allen PK, Mahajan A, Grosshans DR, McGovern SL (2018) Analysis of pseudoprogression after proton or photon therapy of 99 patients with low grade and anaplastic glioma. Clin Transl Radiat Oncol 9:30–34

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chappell R, Miranpuri SS, Mehta MP (1998) Dimension in defining tumor response. J Clin Oncol 16(3):1234

    Article  PubMed  CAS  Google Scholar 

  32. Ellingson BM, Wen PY, Cloughesy TF (2017) Modified criteria for radiographic response assessment in glioblastoma clinical trials. Neurotherapeutics 14:307–320

    Article  PubMed  PubMed Central  Google Scholar 

  33. Motegi H, Kamoshima Y, Terasaka S, Kobayashi H, Yamaguchi S, Tanino M et al (2013) IDH1 mutation as a potential novel biomarker for distinguishing pseudoprogression from true progression in patients with glioblastoma treated with temozolomide and radiotherapy. Brain Tumor Pathol 30:67–72

    Article  PubMed  CAS  Google Scholar 

  34. McGovern SL, Okcu MF, Munsell MF, Kumbalasseriyil N, Grosshans DR, McAleer MF et al (2014) Outcomes and acute toxicities of proton therapy for pediatric atypical teratoid/rhabdoid tumor of the central nervous system. Int J Radiat Oncol Biol Phys 90:1143–1152

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gunther JR, Sato M, Chintagumpala M, Ketonen L, Jones JY, Allen PK et al (2015) Imaging changes in pediatric intracranial ependymoma patients treated with proton beam radiation therapy compared to intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys 93:54–63

    Article  PubMed  Google Scholar 

  36. Ruben JD, Dally M, Bailey M, Smith R, McLean CA, Fedele P (2006) Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys 65(2):499–508

    Article  PubMed  Google Scholar 

  37. Chawla S, Korones DN, Milano MT et al (2012) Spurious progression in pediatric brain tumors. J Neuro-Oncol 107:651–657

    Article  Google Scholar 

  38. Bakardjiev AI, Barnes PD, Goumnerova LC et al (1996) Magnetic resonance imaging changes after stereotactic radiation therapy for childhood low grade astrocytoma. Cancer 78:864–873

    Article  PubMed  CAS  Google Scholar 

  39. Carceller F, Mandeville H, Mackinnon AD, Saran F (2017) Facing pseudoprogression after radiotherapy in low grade gliomas. Transl Cancer Res 6(Suppl 2):S254–S258

    Article  Google Scholar 

  40. Carceller F, Fowkes LA, Khabra K et al (2016) Pseudoprogression in children, adolescents and young adults with non-brainstem high grade glioma and diffuse intrinsic pontine glioma. J Neurooncol 129:109–121

    Article  PubMed  Google Scholar 

  41. Clarke JL, Iwamoto FM, Sul J et al (2009) Randomized phase II trial of chemoradiotherapy followed by either dosedense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol 27:3861–3867

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Linhares P, Carvalho B, Figueiredo R et al (2013) Early pseudoprogression following chemoradiotherapy in glioblastoma patients: the value of RANO evaluation. J Oncol 2013:690585

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. MacDonald SM, Sethi R, Lavally B et al (2013) Proton radiotherapy for pediatric central nervous system ependymoma: clinical outcomes for 70 patients. Neuro Oncol 15:1552–1559

    Article  PubMed  PubMed Central  Google Scholar 

  44. Indelicato DJ, Flampouri S, Rotondo RL et al (2014) Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy. Acta Oncol 53:1298–1304

    Article  PubMed  CAS  Google Scholar 

  45. McGovern SL, Okcu MF, Munsell MF et al (2014) Outcomes and acute toxicities of proton therapy for pediatric atypical teratoid/rhabdoid tumor of the central nervous system. Int J Radiat Oncol Biol Phys 90:1143–1152

    Article  PubMed  PubMed Central  Google Scholar 

  46. Giantsoudi D, Sethi RV, Yeap BY et al (2015) Incidence of CNS injury for a cohort of 111 patients treated with proton therapy for medulloblastoma: LET and RBE associations for areas of injury. Int J Radiat Oncol Biol Phys 95:287–296

    Article  PubMed  Google Scholar 

  47. Ares C, Albertini F, Frei-Welte M et al (2016) Pencil beam scanning proton therapy for pediatric intracranial ependymoma. J Neurooncol 128:137–145

    Article  PubMed  CAS  Google Scholar 

  48. Gentile MS, Yeap BY, Paganetti H et al (2018) Brainstem injury in pediatric patients with posterior fossa tumors treated with proton beam therapy and associated dosimetric factors. Int J Radiat Oncol Biol Phys 100(3):719–729

    Article  PubMed  Google Scholar 

  49. Fouladi M, Chintagumpala M, Laningham FH et al (2004) White matter lesions detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 22:4551–4560

    Article  PubMed  Google Scholar 

  50. Merchant TE, Li C, Xiong X et al (2009) Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol 10:258–266

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Radiation Oncology, Massachusetts General Hospital, 30 Fruit Street, Boston, MA, 02114, USA

    Andrzej Niemierko, Kevin S. Oh, Jay S. Loeffler & Helen A. Shih

  2. Duke University School of Medicine, Durham, NC, USA

    Michael Dworkin

  3. Department of Radiology, Massachusetts General Hospital, Boston, MA, USA

    William Mehan

  4. Harvard Radiation Oncology Program, Boston, MA, USA

    Sophia C. Kamran

  5. Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA

    Jorg Dietrich & Tracy T. Batchelor

  6. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Maria Martinez-Lage

  7. Dana-Farber Cancer Institute, Boston, MA, USA

    Patrick Y. Wen

  8. Harvard Medical School, Boston, MA, USA

    Nayan Lamba

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  1. Michael Dworkin
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Correspondence to Helen A. Shih.

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Dworkin, M., Mehan, W., Niemierko, A. et al. Increase of pseudoprogression and other treatment related effects in low-grade glioma patients treated with proton radiation and temozolomide. J Neurooncol 142, 69–77 (2019). https://doi.org/10.1007/s11060-018-03063-1

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  • DOI: https://doi.org/10.1007/s11060-018-03063-1

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