This Article Abstract Full Text Full Text (PDF) Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Stamatakos, G S Articles by Dale, R G Search for Related Content PubMed PubMed Citation Articles by Stamatakos, G S Articles by Dale, R G

A four-dimensional computer simulation model of the in vivo response to radiotherapy of glioblastoma multiforme: studies on the effect of clonogenic cell density

¹ In Silico Oncology Group, Microwave and Fibre Optics Laboratory, School of Electrical and Computer Engineering, National Technical University of Athens, 9 Iroon Polytechniou St., GR 157 80 Greece, ² Department of Radiation Physics and Radiobiology, Hammersmith Hospitals NHS Trust and Faculty of Medicine, Imperial College, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK

View larger version (9K): [in a new window]   Figure 1. (a) Total number of proliferating and dormant tumour cells as a function of time for the hyperfractionated (1.2 Gy twice daily, 5 days per week to the dose of 81.6 Gy, "HF-81.6") and accelerated hyperfractionated (1.6 Gy twice daily, 5 days per week to the dose of 54.4 Gy, "AHF-54.4") radiotherapy schedules. HF-81.6 is completed on day 46 after initiation of treatment whereas AHF-54.4 is completed on day 23. In all fractionation schedules considered in this paper, no radiation is administered on Saturdays or Sundays. (b) Total number of proliferating and dormant tumour cells as a function of time for the hyperfractionated (1.2 Gy twice daily, 5 days per week to the dose of 76.8 Gy, "HF-76.8") and accelerated hyperfractionated (1.6 Gy twice daily, 5 days per week to the dose of 48 Gy, "AHF-48") radiotherapy schedules. Both irradiation schedules start on the first day of the first week of treatment. HF-76.8 is completed on day 44 after initiation of treatment whereas AHF-48 is completed on day 19.

View larger version (8K): [in a new window]   Figure 2. (a) Total number of proliferating and dormant tumour cells as a function of time for the hyperfractionated (1.2 Gy twice daily, 5 days per week to the dose of 72 Gy, "HF-72") and accelerated hyperfractionated (1.6 Gy twice daily, 5 days per week to the dose of 48 Gy, "AHF-48") radiotherapy schedules. HF-72 is completed on day 40 after initiation of treatment whereas AHF-48 is completed on day 19. (b) Total number of proliferating and dormant tumour cells as a function of time for the hyperfractionated (1.2 Gy twice daily, 5 days per week to the dose of 64.8 Gy, "HF-64.8") and accelerated hyperfractionated (1.6 Gy twice daily, 5 days per week to the dose of 48 Gy, "AHF-48") radiotherapy schedules. HF-64.8 is completed on day 37 after initiation of treatment whereas AHF-48 is completed on day 19. Both irradiation schedules start on the first day of the first week of treatment.

View larger version (9K): [in a new window]   Figure 3. Total number of tumour cells(proliferating, dormant and dead cells) as a function of time for the hyperfractionated (1.2 Gy twice daily, 5 days per week to the dose of 76.8 Gy, "HF-76.8") and accelerated hyperfractionated (1.6 Gy twice daily, 5 days per week to the dose of 48 Gy, "AHF-48") radiotherapy schedules. Irradiation starts on the first day of the first week. HF-76.8 is completed on day 44 after initiation of treatment whereas AHF-48 is completed on day 19. Both irradiation schedules start on the first day of the first week of treatment.

View larger version (17K): [in a new window]   Figure 4. Simulation predictions of(a) the number of proliferating and (b) the total number of proliferating, dormant and dead mt p53 tumour cells in the case of the standard fractionation scheme (2 Gy once a day, 5 days per week, 60 Gy in total) for different clonogenic cells densities (CCD = 104 cells mm–3). Irradiation schedule starts on the first day of the first week of treatment. It should be stressed that reproductively dead cells and their offspring that are still cycling are considered proliferating until their ultimate biological death. The periodicity noticed on all graphs reflects the weekly irradiation periodicity. It is noted that no irradiation takes place during the weekend.

View larger version (31K): [in a new window]   Figure 5. Two-dimensional visualization of the simulated response of a radiosensitive clinical glioblastoma multiforme tumour to the standard fractionation scheme, for a range of clonogenic cell density (CCD). The figure shows a centrally located horizontal slice of a tumour with clonogenic cell density equal to 1xCCD( = 104 cells mm–3) (a) 3 fictitious days after the beginning of the radiotherapy course (e) 5 fictitious days after the beginning of the radiotherapy course, (i) 8 fictitious days after the beginning of the radiotherapy course. A centrally located horizontal slice of a tumour with clonogenic cell density equal to 2xCCD (b) 3 fictitious days after the beginning of the radiotherapy course (f) 5 fictitious days after the beginning of the radiotherapy course (j) 8 fictitious days after the beginning of the radiotherapy course. A centrally located horizontal slice of a tumour with clonogenic cell density equal to 3xCCD, (c) 3 fictitious days after the beginning of the radiotherapy course, (g) 5 fictitious days after the beginning of the radiotherapy course, (k) 8 fictitious days after the beginning of the radiotherapy course. A centrally located horizontal slice of a tumour with clonogenic cell density equal to 4xCCD, (d) 3 fictitious days after the beginning of the radiotherapy course, (h) 5 fictitious days after the beginning of the radiotherapy course, (l) 8 fictitious days after the beginning of the radiotherapy course. For this specific case, the LQ model parameters of the tumour are in accordance with a GBM cell line with known mt p53 gene. Irradiation schedule starts on the first day of the first week of treatment. Colour Code: dark grey: proliferating cell layer, light grey: dormant cell layer (G0), white: dead cell layer. The colouring criterion "99.8%" used to visualize the predictions has been defined as follows. "For a geometrical cell of the discretising mesh, if the percentage of dead cells is lower than 99.8% then {if percentage of proliferating cells > percentage of G0 cells, then paint the geometrical cell dark grey (proliferating cell layer)}, else paint the geometrical cell light grey (G0 cell layer) else paint the geometrical cell white (dead cell layer)".

View larger version (9K): [in a new window]   Figure 6. Simulation predictions of the number of(a) proliferating and (b) dormant mt p53 tumour cells in the case of standard fractionation for different OER (1.0, 2.0, 3.0) values. It is stressed that reproductively dead cells and their offspring that are still cycling are considered proliferating until their ultimate biological death. Irradiation schedule starts on the first day of the first week of treatment.

View larger version (15K): [in a new window]   Figure 7. Simulation predictions of the number of(a) proliferating and (b) dormant mt p53 tumour cells in the case of standard fractionation for different Tc (cell cycle time) values. It is stressed that reproductively dead cells and their offspring that are still cycling are considered proliferating until their ultimate biological death. Irradiation schedule starts on the first day of the first week of treatment.

View larger version (25K): [in a new window]   Figure 8. Three-dimensional visualization of the simulated response of a radiosensitive clinical glioblastoma multiforme tumour to the standard fractionation scheme, for (a) Tc = 24 h and (b) Tc = 72 h at the end of day 8. It is pointed out that total tumour cells include all morphologically existing cells, living (proliferating and quiescent) and dead (but not yet lysed or fragmented) alike. Irradiation schedule starts on the first day of the first week of treatment. Colour Code: red: proliferating cell layer, green: G0 layer, blue: dead cell layer. The colouring criterion "99.8%" was used to visualize the predictions (Figure 5).