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  Volume 96
Numero 3
maggio-giugno 2010 		I documenti sono in formato PDF, consultabili utilizzando Acrobat Reader
 
Dose per fraction and dose rate effect

To the Editor: We read with interest the clinical case reported by De Cicco et al. dealing with high dose rate (HDR) brachytherapy as a salvage treatment approach after external beam radiotherapy for locally recurrent prostate cancer1. The patient was given 4 fractions of 7 Gy each, administered bis in die in 2 consecutive days, up to a total nominal dose of 28 Gy, employing a remote after-loading unit. The definition of the optimal salvage strategy in this subset of patients represents an interesting medical challenge. The decision process is mainly based upon clinical, technological and expectational considerations, as pointed out by the authors.
Conversely, within a radiotherapeutic context, we would like to focus our attention on radiobiological issues supposedly influencing the preference between HDR bra­chy­therapy and low dose rate (LDR) bra­chy­the­rapy with permanent implants. The general assumption for prostate cancer is that it might show a low sensitivity to changes in fractionation. This characteristic would be depicted by a low α/β ratio (in the range of 1 to 4 Gy)2. Hence, we might suppose at least a comparable (some would say even smaller) sensitivity to fractionation between prostate cancer and the neighboring surrounding organs and tissues3.
Nullified in this context the rationale for conventionally fractionating the total dose, hypofractionated schedules thus would be able to achieve similar or even higher tumor control probability rates and comparable late-responding normal tissue control probability compared to classical schedules. HDR brachytherapy, with few delivered high-dose fractions, would thereby be a means to improve the ‘therapeutic index’ by escalating the biological equivalent dose.
On the contrary, the so-called ‘dose-rate effect’ is a biological process by which the radiosensitivity of cells decreases as the dose rate is lowered (compared to the common external beam radiotherapy range of 1-5 Gy min-1). This is due by the occurrence of repair, reassortment, repopulation and reoxygenation during a longer irradiation period. The range of influence upon cellular response depends on the speed of these events4. Repair is the fastest between these processes, thus affecting radiosensitivity over the dose-rate range of 1 to 0.1 cGy min-1. Conversely, repopulation takes much more time to occur, influencing cellular response below a lower range of dose rates (2 cGy min-1). Reoxygenation, as reassortment, might act over an intermediate dose-rate range5.
The dose-rate effect on cell survival might be extrapolated from cell survival curves for human cell lines, deriving radiation dose values at the same surviving fraction for different dose rates and calculating the so-called dose-recovery factor, using the ratio of the obtained radiation doses3. Using the incomplete repair model, it is possible to demonstrate the equivalence between dose per fraction within fractionated radiation therapy and dose rate within continuous radiation exposure6. Hence, as in fractionated radiation therapy diminishing the dose per fraction might be an option to spare late-responding normal tissues characterized by a low α/β ratio (such as rectal bleeding), so lowering the dose rate (thus the increasing dose-recovery factor) in a brachytherapy setting might be an equivalent possibility. This might be noteworthy dealing with re-treatment in order to minimize late effects, leading to the possibility of sparing normal tissues with the LDR brachytherapy treatment device.
In conclusion, the choice between the two brachy­therapy options (HDR or LDR) might also be driven by radiobiological considerations, influenced by the need of favoring tumor control probability over normal tissue control probability, or vice versa, according to the appropriate clinical context.

Pierfrancesco Franco, Debora Beldì, Marco Krengli 
Radiotherapy Department,
University Hospital Maggiore della Carità, Novara, Italy

References
1. De Cicco L, Vavassori A, Cattani F, Jereczek-Fossa BA, Orecchia R: Salvage high dose rate brachytherapy after primary external beam irradiation in localized prostate cancer: a case report. Tumori, 95: 553-556, 2009.
2. Brenner DJ: Hypofractionation for prostate cancer radiotherapy — What are the issues? Int J Radiat Oncol Biol Phys, 57: 912-914, 2003.
3. Brenner DJ: Toward optimal external-beam fractionation for prostate cancer. Int J Radiat Oncol Biol Phys, 48: 315-316, 2000.
4. Steel GG: The dose rate effect: brachytherapy and targeted radiotherapy. In: Basic Clinical Radiobiology, Steel GG (Ed), pp 134-146, Arnold, London, 2002.
5. Steel GG, Deacon JM, Duchesne GM, Horwich A, Kelland LR, Peacock JH: The dose-rate effect in human tumour cells. Radiother Oncol, 9: 299-310, 1987.
6. Thames HD: An ‘incomplete-repair’ model for survival after fractionated and continuous irradiation. Int J Radiat Biol, 47: 319-339, 1985.



 
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