Skip to main content

Advertisement

SpringerLink
Log in

Pseudoprogression in patients with malignant gliomas treated with concurrent temozolomide and radiotherapy: potential role of p53

  • Clinical Study - Patient Studies
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

We investigated pseudoprogression (psPD) in patients with malignant gliomas treated with radiotherapy (RT) and maintenance temozolomide (TMZ) in terms of incidence, outcomes, and predictive and prognostic factors. We evaluated p53 overexpression by immunohistochemical analysis of thirty-five tumor samples as a predictor for psPD. The time to progression and overall survival were compared between subgroups, psPD versus early progression (ePD) versus nonprogression (nonPD). Eight patients developed psPD among eighteen patients with lesion enlargement at the first MRI scan, and the others were classified as ePD. The remaining stable or improved patients were classified as nonPD. All patients with psPD were alive at last follow-up (median follow-up period was 12 months; range 5.8–58.5 months). Overall survival of psPD patients was significantly higher than ePD patients (P < 0.01). There was no significant survival difference between the psPD group and nonPD group (P = 0.25). Seven (87.5%) of eight tumors with psPD showed p53 overexpression, as compared to 3 (30%) of the ten tumors with ePD (P = 0.03). Our study indicates that psPD following chemoradiotherapy with TMZ is associated with significantly better overall survival compared to that of ePD, and is comparable to nonPD group. Overexpression of p53 was identified as a potential biomarker for predicting the development of psPD.

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

Similar content being viewed by others

References

  1. Chamberlain MC, Glantz MJ, Chalmers L, van Horn A, Sloan AE (2007) Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. J Neurooncol 82:81–83

    Article  PubMed  Google Scholar 

  2. Jefferies S, Burton K, Jones P, Burnet N (2007) Interpretation of early imaging after concurrent radiotherapy and temozolomide for glioblastoma. Clin Oncol (R Coll Radiol) 19:S33

    Google Scholar 

  3. Taal W, Brandsma D, de Bruin HG, Bromberg JE, Swaak-Kragten AT, Smitt PA, van Es CA, van den Bent MJ (2008) Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer 113:405–410

    Article  CAS  PubMed  Google Scholar 

  4. Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, Bertorelle R, Bartolini S, Calbucci F, Andreoli A, Frezza G, Leonardi M, Spagnolli F, Ermani M (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 

  5. Takahashi A, Ohnishi K, Wang X, Kobayashi M, Matsumoto H, Tamamoto T, Aoki H, Furusawa Y, Yukawa O, Ohnishi T (2000) The dependence of p53 on the radiation enhancement of thermosensitivity at different let. Int J Radiat Oncol Biol Phys 47:489–494

    Article  CAS  PubMed  Google Scholar 

  6. Kock H, Harris MP, Anderson SC, Machemer T, Hancock W, Sutjipto S, Wills KN, Gregory RJ, Shepard HM, Westphal M, Maneval DC (1996) Adenovirus-mediated p53 gene transfer suppresses growth of human glioblastoma cells in vitro and in vivo. Int J Cancer 67:808–815

    Article  CAS  PubMed  Google Scholar 

  7. Srivenugopal KS, Shou J, Mullapudi SR, Lang FF Jr, Rao JS, Ali-Osman F (2001) Enforced expression of wild-type p53 curtails the transcription of the O(6)-methylguanine-DNA methyltransferase gene in human tumor cells and enhances their sensitivity to alkylating agents. Clin Cancer Res 7:1398–1409

    CAS  PubMed  Google Scholar 

  8. Batista LF, Roos WP, Kaina B, Menck CF (2009) p53 mutant human glioma cells are sensitive to UV-C-induced apoptosis due to impaired cyclobutane pyrimidine dimer removal. Mol Cancer Res 7:237–246

    Article  CAS  PubMed  Google Scholar 

  9. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280

    CAS  PubMed  Google Scholar 

  10. Henson JW, Ulmer S, Harris GJ (2008) Brain tumor imaging in clinical trials. AJNR Am J Neuroradiol 29:419–424

    Article  CAS  PubMed  Google Scholar 

  11. Wiewrodt D, Nagel G, Dreimuller N, Hundsberger T, Perneczky A, Kaina B (2008) MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome. Int J Cancer 122:1391–1399

    Article  CAS  PubMed  Google Scholar 

  12. Curtin K, Slattery ML, Holubkov R, Edwards S, Holden JA, Samowitz WS (2004) p53 alterations in colon tumors: a comparison of SSCP/sequencing and immunohistochemistry. Appl Immunohistochem Mol Morphol 12:380–386

    CAS  PubMed  Google Scholar 

  13. Sarkar C, Karak AK, Nath N, Sharma MC, Mahapatra AK, Chattopadhyay P, Sinha S (2005) Apoptosis and proliferation: correlation with p53 in astrocytic tumors. J Neurooncol 73:93–100

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. de Wit MC, de Bruin HG, Eijkenboom W, Sillevis Smitt PA, van den Bent MJ (2004) Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression. Neurology 63:535–537

    PubMed  Google Scholar 

  16. Jensen RL (2009) Brain tumor hypoxia: tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target. J Neurooncol 92:317–335

    Article  CAS  PubMed  Google Scholar 

  17. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ (2008) Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9:453–461

    Article  PubMed  Google Scholar 

  18. Khodarev NN, Labay E, Darga T, Yu J, Mauceri H, Gupta N, Kataoka Y, Weichselbaum RR (2004) Endothelial cells co-cultured with wild-type and dominant/negative p53-transfected glioblastoma cells exhibit differential sensitivity to radiation-induced apoptosis. Int J Cancer 109:214–219

    Article  CAS  PubMed  Google Scholar 

  19. Schmidt MC, Antweiler S, Urban N, Mueller W, Kuklik A, Meyer-Puttlitz B, Wiestler OD, Louis DN, Fimmers R, von Deimling A (2002) Impact of genotype and morphology on the prognosis of glioblastoma. J Neuropathol Exp Neurol 61:321–328

    CAS  PubMed  Google Scholar 

  20. Simmons ML, Lamborn KR, Takahashi M, Chen P, Israel MA, Berger MS, Godfrey T, Nigro J, Prados M, Chang S, Barker FG 2nd, Aldape K (2001) Analysis of complex relationships between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients. Cancer Res 61:1122–1128

    CAS  PubMed  Google Scholar 

  21. Tada M, Matsumoto R, Iggo RD, Onimaru R, Shirato H, Sawamura Y, Shinohe Y (1998) Selective sensitivity to radiation of cerebral glioblastomas harboring p53 mutations. Cancer Res 58:1793–1797

    CAS  PubMed  Google Scholar 

  22. Shiraishi S, Tada K, Nakamura H, Makino K, Kochi M, Saya H, Kuratsu J, Ushio Y (2002) Influence of p53 mutations on prognosis of patients with glioblastoma. Cancer 95:249–257

    Article  CAS  PubMed  Google Scholar 

  23. Hermisson M, Klumpp A, Wick W, Wischhusen J, Nagel G, Roos W, Kaina B, Weller M (2006) O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells. J Neurochem 96:766–776

    Article  CAS  PubMed  Google Scholar 

  24. Roos WP, Batista LF, Naumann SC, Wick W, Weller M, Menck CF, Kaina B (2007) Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 26:186–197

    Article  CAS  PubMed  Google Scholar 

  25. Watanabe T, Katayama Y, Komine C, Yoshino A, Ogino A, Ohta T, Fukushima T (2005) O6-methylguanine-DNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course. Int J Cancer 113:581–587

    Article  CAS  PubMed  Google Scholar 

  26. Shamsara J, Sharif S, Afsharnezhad S, Lotfi M, Raziee HR, Ghaffarzadegan K, Moradi A, Rahighi S, Behravan J (2009) Association between MGMT promoter hypermethylation and p53 mutation in glioblastoma. Cancer Invest 27(8):825–829

    Article  CAS  PubMed  Google Scholar 

  27. Jesien-Lewandowicz E, Jesionek-Kupnicka D, Zawlik I, Szybka M, Kulczycka-Wojdala D, Rieske P, Sieruta M, Jaskolski D, Och W, Skowronski W, Sikorska B, Potemski P, Papierz W, Liberski PP, Kordek R (2009) High incidence of MGMT promoter methylation in primary glioblastomas without correlation with TP53 gene mutations. Cancer Genet Cytogenet 188:77–82

    Article  CAS  PubMed  Google Scholar 

  28. Bouchet BP, de Fromentel CC, Puisieux A, Galmarini CM (2006) p53 as a target for anti-cancer drug development. Crit Rev Oncol Hematol 58:190–207

    Article  PubMed  Google Scholar 

  29. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the grants from Korean Ministry of Education, Science & Technology (BAERI # 2007-2001198) to IAK.

Conflict of interest statement

None.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Seoul National University Bundang Hospital, 300 Gumidong Seongnamsi, Kyeonggido, 463-707, Republic of Korea

    Hyun-Cheol Kang & In Ah Kim

  2. Department of Neurosurgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea

    Chae-Yong Kim & Jung Ho Han

  3. Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea

    Ghee Young Choe

  4. Department of Radiology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea

    Jae Hyoung Kim

  5. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea

    Jee Hyun Kim

  6. Cancer Research Institute, Seoul National University, Seoul, Republic of Korea

    In Ah Kim

Authors
  1. Hyun-Cheol Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chae-Yong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jung Ho Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ghee Young Choe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jae Hyoung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jee Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. In Ah Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to In Ah Kim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kang, HC., Kim, CY., Han, J.H. et al. Pseudoprogression in patients with malignant gliomas treated with concurrent temozolomide and radiotherapy: potential role of p53. J Neurooncol 102, 157–162 (2011). https://doi.org/10.1007/s11060-010-0305-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-010-0305-7

Keywords

Search

Navigation