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Clinical radiobiology of glioblastoma multiforme

Estimation of tumor control probability from various radiotherapy fractionation schemes

Klinische Strahlenbiologie des Glioblastoms

Schätzung der Tumorkontrollwahrscheinlichkeit von verschiedenen Radiotherapie-Fraktionierungsschemata

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Abstract

Background and purpose

The aim of this study was to estimate a radiobiological set of parameters from the available clinical data on glioblastoma (GB).

Patients and methods

A number of clinical trial outcomes from patients affected by GB and treated with surgery and adjuvant radiochemotherapy were analyzed to estimate a set of radiobiological parameters for a tumor control probability (TCP) model. The analytical/graphical method employed to fit the clinical data allowed us to estimate the intrinsic tumor radiosensitivity (α), repair capability (b), and repopulation doubling time (T d ) in a first phase, and subsequently the number of clonogens (N) and kick-off time for accelerated proliferation (T k ). The results were used to formulate a hypothesis for a scheduleexpected to significantly improve local control. The 95 % confidence intervals (CI95 %) of all parameters are also discussed.

Results

The pooled analysis employed to estimate the parameters summarizes the data of 559 patients, while the studies selected to verify the results summarize data of 104 patients. The best estimates and the CI95 % are α = 0.12 Gy−1 (0.10–0.14), b = 0.015 Gy−2 (0.013–0.020), α/b = 8 Gy (5.0–10.8), T d  = 15.4 days (13.2–19.5), N = 1 · 104 (1.2 · 103–1 · 105), and T k  = 37 days (29–46). The dose required to offset the repopulation occurring after 1 day (D prolif ) and starting after T k was estimated as 0.30 Gy/day (0.22–0.39).

Conclusion

The analysis confirms a high value for the α/b ratio. Moreover, a high intrinsic radiosensitivity together with a long kick-off time for accelerated repopulation and moderate repopulation kinetics were found. The results indicate a substantial independence of the duration of the overall treatment and an improvement in the treatment effectiveness by increasing the total dose without increasing the dose fraction.

Zusammenfassung

Hintergrund und Zweck

Schätzung eines strahlenbiologischen Parametersatzes auf der Grundlage klinischer Daten bei Patienten mit einem Glioblastom (GB).

Patienten und Methoden

Eine Reihe klinischer Ergebnisse von Patienten mit GB, die eine Operation sowie eine adjuvante Radiochemotherapie erhielten, wurde analysiert, um strahlenbiologische Parameter für das Tumorkontrollwahrscheinlichkeitsmodell („tumor control probability”, TCP) zu schätzen. Die angewandte analytische/graphische Methode ermöglichte eine Schätzung der intrinsischen Radiosensitivität des Tumors (α), der Regenerationsfähigkeit (b), der Re-Populationsverdopplungszeit (Td) in der ersten Phase und anschließend der Anzahl von clonogenen Zellen (N) sowie des Zeitpunkts einer beschleunigten Proliferation (Tk). Die Ergebnisse wurden verwendet, um eine Hypothese für die Fraktionierung der Strahlendosis zu erheben, welche die lokale Kontrolle erwartungsgemäß signifikant erhöht. Die 95 % Konfidenzintervalle (CI95 %) aller Parameter werden ebenfalls diskutiert.

Ergebnisse

Die angewandte gepoolte Analyse zur Schätzung der Parameter wurde bei insgesamt 559 Patienten durchgeführt, während die Überprüfung der Ergebnisse bei insgesamt 104-Patienten erfolgte. Die besten Schätzungen und CI95% sind α = 0,12 Gy−1 (0,10–0,14), b = 0,015 Gy−2 (0,013–0,020), α/b = 8 Gy (5,0–10,8), Td = 15,4 Tage (13,2–19,5), N = 1×104 (1,2×103–1×105), und Tk = 37 Tage (29–46). Die erforderliche Dosis für die Repopularisation, die nach 1 Tag (Dprolif) auftritt und nach Tk beginnt, wurde auf 0,30 Gy/Tag (0,22–0,39) geschätzt.

Schlussfolgerung

Die Analyse bestätigt einen hohen Wert für α/b. Darüber hinaus wurden eine hohe intrinsische Radiosensitivität und eine lange Dauer bis zum Beginn der beschleunigten Proliferation sowie eine moderate Repopularisationskinetik festgestellt. Die Ergebnisse zeigen ein hohes Maß an Unabhängigkeit von der Dauer der gesamten Behandlung und eine Verbesserung der Therapiewirksamkeit durch eine Erhöhung der Gesamtdosis, ohne dabei die Dosisfraktion zu erhöhen.

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References

  1. Balducci M, Apicella G, Manfrida S, Mangiola A, Fiorentino A, Azario L, D’Agostino GR, Frascino V, Dinapoli N, Mantini G, Albanese A, de Bonis P, Chiesa S, Valentini V, Anile C, Cellini N (2010) Single-Arm Phase II Study of Conformal Radiation Therapy and Temozolomide plus fractionated Stereotactic Conformal Boost in High grade Gliomas. Strahlen Onkol 186(10):558–564

    Article  Google Scholar 

  2. Balducci M, Chiesa S, Diletto B, D’Agostino GR, Mangiola A, Manfrida S, Mantini G, Albanese A, Fiorentino A, Frascino V, De Bari B, Micciche F, De Rose F, Morganti AG, Anile C, Valentini V (2012) Low-dose fractionated radiotherapy and concomitant chemotherapy in glioblastoma multiforme with poor prognosis: a feasibility study. Neuro Oncol 14(1):79–86

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Balducci M, Fiorentino A, De Bonis P, Chiesa S, Mangiola A, Mattiucci GC, D’Agostino GR, Frascino V, Mantini G, Alitto AR, Colosimo C, Anile C, Valentini V (2013) Concurrent and adjuvant temozolomide-based chemoradiotherapy schedules for glioblastoma. Hypotheses based on two prospective phase II trials. Strahlen Onkol 189(11):926–931

    Article  CAS  Google Scholar 

  4. Bao S, Wu Q, Mc Lendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760

    Article  PubMed  CAS  Google Scholar 

  5. Buckner JV, Ballman KV, Michalak JC, Burton GV, Cascino TL, Schomberg PJ, Hawkins RB, Scheithauer BW, Sandler HM, Marks RS, O’Fallon JR, North Central Cancer Treatment Group 93–72-52, Southwest Oncology Group 9503 Trials (2006) Phase III Trial of carmustine and cisplatin compared with carmustine alone and standard radiation therapy or accelerated radiation therapy in patients with glioblastoma multiforme: North Central Cancer Treatment Group 93–72-52 and Southwest Oncology Group 9503 Trials. J Clin Oncol 24(24):3871–3879

    Google Scholar 

  6. Ciammella P, Galeandro M, D’Abbiero N, Podgornii A, Pisanello A, Botti A, Cagni E, Iori M, Iotti C (2013) Hypo-fractionated IMRT for patients with newly diagnosed glioblastoma multiforme: a 6 year single institutional experience. Clin Neurol Neurosurg 115(9):1609–1614

    Article  PubMed  Google Scholar 

  7. Collett D (1994) Modelling survival data-in medical research. Chapman and Hall, London, pp 22–26

    Book  Google Scholar 

  8. Daşu A, Toma-Daşu I, Fowler JF (2003) Should single distributed parameters be used to explain the steepness of tumour control probability curves? Phys Med Biol 48:387–397

    Article  PubMed  Google Scholar 

  9. Efron B (1981) Censored data and the bootstrap. J Am Stat Ass 76:312–319

    Article  Google Scholar 

  10. Fietkau R, Putz F, Lahmer G, Semrau S, Buslei R (2013) Can MGMT promoter methylation status be used as a prognostic and predictive marker for glioblastomamultiforme at the present time?: a word of caution. Strahlenther Onkol 189(12):993–995

    Article  PubMed  CAS  Google Scholar 

  11. Guckenberger M, Mayer M, Buttmann M, Vince GH, Sweeney RA, Flentje M (2011) Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme. Strahlen Onkol 187(9):548–554

    Article  Google Scholar 

  12. 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(10):997–1003

    Article  PubMed  CAS  Google Scholar 

  13. Jones TS, Holland EC (2012) Standard of care therapy for malignant glioma and its effect on tumor and stromal cells. Oncogene 31:1995–2006

    Article  PubMed  CAS  Google Scholar 

  14. Lee SW, Fraass BA, Marsh LH, Herbort K, Gebarski SS, Martel MK, Radany EH, Lichter AS, Sandler HM (1999) Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. Int J Radiat Oncol Biol Phys 43:79–88

    Article  PubMed  CAS  Google Scholar 

  15. Massaccesi M, Ferro M, Cilla S, Balducci M, Deodato F, Macchia G, Valentini V, Morganti AG (2013) Accelerated intensity-modulated radiotherapy plus temozolomide in patients with glioblastoma: a phase I dose-escalation study (ISIDE-BT-1). Int J Clin Oncol 18(5):784–791

    Article  PubMed  CAS  Google Scholar 

  16. Mizumoto M, Okumura T, Ishikawa E, Yamamoto T, Takano S, Matsumura A, Oshiro Y, Ishikawa H, Sakurai H, Tsuboi K (2013) Reirradiation for recurrent malignant brain tumor with radiotherapy or proton beam therapy. Technical considerations based on experience at a single institution. Strahlenther Onkol 189(8):656–663

    Article  PubMed  CAS  Google Scholar 

  17. Morganti AG, Balducci M, Salvati M, Esposito V, Romanelli P, Ferro M, Calista F, Digesù C, Macchia G, Ianiri M, Deodato F, Cilla S, Piermattei A, Valentini V, Cellini N, Cantore GP (2010) A phase I dose-escalation study (ISIDE-BT-1) of accelerated IMRT with temozolomide in patients with glioblastoma. Int J Radiat Oncol Biol Phys 77(1):92–97

    Article  PubMed  CAS  Google Scholar 

  18. Nakagawa K, Aoki Y, Fujimaki T, Tago M, Terahara A, Karasawa K, Sakata K, Sasaki Y, Matsutani M, Akanuma A (1998) High-dose conformal radiotherapy influenced the pattern of failure but did not improve survival in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 40(5):1141–1149

    Article  PubMed  CAS  Google Scholar 

  19. Okunieff P, Morgan D, Niemierko A et al (1995) Radiation dose-response of human tumor. Int J Radiat Oncol Biol Phys 32:1227–1237

    Article  PubMed  CAS  Google Scholar 

  20. Panet-Raymond V, Souhami L, Roberge D, Kavan P, Shakibnia L, Muanza T, Lambert C, Leblanc R, Del Maestro R, Guiot MC, Shenouda G (2009) Accelerated hypofractionated intensity-modulated radiotherapy with concurrent and adjuvant temozolomide for patients with glioblastoma multiforme: a safety and efficacy. Int J Radiat Oncol Biol Phys 73(2):473–478

    Article  PubMed  CAS  Google Scholar 

  21. Pedicini P (2013) In regard to Pedicini et al. Int J Radiat Oncol Biol 87(5):858

    Article  Google Scholar 

  22. Pedicini P, Nappi A, Strigari L, Jereczek-Fossa BA, Alterio D, Cremonesi M, Botta F, Vischioni B, Caivano R, Fiorentino A, Improta G, Storto G, Benassi M, Orecchia R, Salvatore M (2012) Correlation between EGFR expression and accelerated proliferation during radiotherapy of head and neck squamous cell carcinoma. Radiat Oncol 7:143

    Article  PubMed  PubMed Central  Google Scholar 

  23. Pedicini P, Caivano R, Strigari L, Benassi M, Fiorentino A, Fusco V (2013) In regard to Miralbell et al. Re: Dose-fractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5969 patients in seven international institutional datasets: alpha/beta = 1.4 (0.9–2.2) Gy. Int J Radiat Oncol Biol Phys 85(1):10–11

    Article  PubMed  Google Scholar 

  24. Pedicini P, Fiorentino A, Improta G, Nappi A, Salvatore M, Storto G (2013) Estimate of the accelerated proliferation by protein tyrosine phosphatase (PTEN) over expression in postoperative radiotherapy of head and neck squamous cell carcinoma. Clin Transl Oncol 15(11):919–924

    Article  PubMed  CAS  Google Scholar 

  25. Pedicini P, Strigari L, Benassi M (2013) Estimation of a self-consistent set of radiobiological parameters from hypofractionated versus standard radiation therapy of prostate cancer. Int J Radiat Oncol Biol Phys 85(5):e231–e237

    Google Scholar 

  26. Roberts SA, Hendry JH (1998) A realistic closed-form radiobiological model of clinical tumor-control data incorporating intertumor heterogeneity. Int J Radiat Oncol Biol Phys 41(3):689–699

    Article  PubMed  CAS  Google Scholar 

  27. Souhami L, Seiferheld W, Brachman D, Podgorsak EB, Werner-Wasik M, Lustig R, Schultz CJ, Sause W, Okunieff P, Buckner J, Zamorano L, Mehta MP, Curran WJ Jr (2004) Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 60(3):853–860

    Article  PubMed  Google Scholar 

  28. Stupp R, Mason W, Van der Bent M, 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 glioblatoma. N Engl J Med 352(10):987–996

    Article  PubMed  CAS  Google Scholar 

  29. Terasaki M, Eto T, Nakashima S, Okada Y, Ogo E, Sugita Y, Tokutomi T, Shigemori M (2011) A pilot study of hypofractionated radiation therapy with temozolomide for adults with glioblastoma multiforme. J Neurooncol 102(2):247–253

    Article  PubMed  CAS  Google Scholar 

  30. Tsien C, Moughan J, Michalski JM, Gilbert MR, Purdy J, Simpson J, Kresel JJ, Curran WJ, Diaz A, Mehta MP, Radiation Therapy Oncology Group Trial 98-03 (2009) Phase I three-dimensional conformal radiation dose escalation study in newly diagnosed glioblastoma: Radiation Therapy Oncology Group Trial 98-03. Int J Radiat Oncol Biol Phys 73(3):699–708

    Google Scholar 

  31. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN, Cancer Genome Atlas Research Network (2010) An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1. Cancer Cell 17(1):98–110

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Walker MD, Strike TA (1976) An evaluation of methyl-CCNU, BCNU and radiotherapy in the treatment of malignant glioma. Proc Am Assoc Cancer Res 17:63

    CAS  Google Scholar 

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Authors and Affiliations

  1. Unit of Nuclear Medicine, Department of Radiation and Metabolic Therapies, I.R.C.C.S.-Regional-Cancer-Hospital-C.R.O.B, 1-Padre-Pio-Street, Rionero-in-Vulture, Italy

    Piernicola Pedicini Ph.D. & Giovanni Storto

  2. Radiation Oncology Department, Sacro Cuore – Don Calabria Hospital, Negrar, Verona, Italy

    Alba Fiorentino

  3. Laboratory of Preclinical and Translational Research, I.R.C.C.S.-Regional-Cancer-Hospital-C.R.O.B, Rionero-in-Vulture, Italy

    Vittorio Simeon

  4. Unit of Radiation Oncology, Department of Medicine Surgery and Neurological Sciences, University of Siena and Tuscany Tumor Institute, Siena, Italy

    Paolo Tini & Luigi Pirtoli

  5. Unit of Radiotherapy, Department of Radiation and Metabolic Therapies, I.R.C.C.S.-Regional-Cancer-Hospital-C.R.O.B, Rionero-in-Vulture, Italy

    Piernicola Pedicini Ph.D. & Costanza Chiumento

  6. Unit of Nuclear Medicine, I.R.C.C.S. SDN Foundation, Napoli, Italy

    Marco Salvatore

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  1. Piernicola Pedicini Ph.D.
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Correspondence to Piernicola Pedicini Ph.D..

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Pedicini, P., Fiorentino, A., Simeon, V. et al. Clinical radiobiology of glioblastoma multiforme. Strahlenther Onkol 190, 925–932 (2014). https://doi.org/10.1007/s00066-014-0638-9

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