5 Radiobiology of LDR, HDR, PDR and VLDR Brachytherapy

Radiobiology of LDR, HDR, PDR and VLDR Brachytherapy

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THE GEC ESTROHANDBOOKOF BRACHYTHERAPY | Part I: The Basics of Brachytherapy Version 1 - 22/10/2015

recovery half times for early and late responding normal tissues as well as tumours (Brenner 95, Fowler92-93). As stated previ- ously, available data on the kinetics of recovery are scanty. An important point is that in the early theoretical calculations (Brenner 91b, 95 97 Fowler 92) as well as in the animal exper- iments (Armour 1997,Brenner 1995,Haustermans 1997,Mason 1994) the ”pulses” were given with external beam equipment, e.g. 50 cGy in 10 minutes (with a dose rate of 5 cGy per min- ute, i.e. 300 cGy/hr or MDR), instead of with a stepping source that “walks through the target” delivering nearly all the dose to the target with a few dwell positions at dose rates higher than 20 cGy/minute or 1200 cGy/hr or definitely HDR.(see Fig 5.12) This has been called the “golf ball” effect by Fowler and Van Lim- bergen (Fowler 1997). Biologically equi-effective doses calculat- ed without accounting for this effect are usually underestimating the tissue toxicity and pulsed dose rate appears “hotter” than expected on the base of the older calculations and experiments. In summary, pulsed dose rate BT behaves biologically like «hy- per fractionated high dose rate with incomplete recovery be- tween the pulses. PDR mimics continuous low dose rate treat- ment only when pulse sizes are small (<0.5 Gy). In those cases, the differential effect to CLDR is less than 10 % (Fig 5.11). With larger pulse sizes and shorter recovery times, the effects in tissues with a lower α/β value are expected to be significantly larger. Mathematical modelling of the total effect E of repeated pulses taking into account incomplete recovery leads to the following equation (Thames 1985): where Hm is the incomplete repair factor which depends upon the number of fractions per day (m), the interval between frac- tions Δ T, the half time of repair T 1/2 and the repair constant μ (for details see Bentzen et al. 2012.) values for human tissues in situ is probably the biggest area of uncertainty of these estimations (Fowler 1993, Fowler 1995). Two regimens have been proposed: • The same total dose as with LDR irradiation, the same total duration, pulses repeated each hour or every two hours with an actual pulse size of not more than 1 Gy/h. This irradiation would reproduce the effects of low dose rate irradiation with a reduction in therapeutic ratio of not more than 10%, whatever the value of T 1/2 for late reacting normal tissues (Fowler 1997) • A fewer number of pulses per day, with intervals between puls- es as long as 3-4 hours (and sometimes a break at night), a sim- ilar total duration and reduced total dose. The equivalent dose was estimated to be acceptable, provided T 1/2 is short for early effects (0.5-1 hour), and long for late effects (3-4 hours) (Bren- ner 1997, Visser 1996). In contrast, a big reduction in therapeu- tic ratio would be observed if an unexpectedly short T 1/2 were observed in late responding normal tissues (compared with tumours) (Fig 5.11). Estimation of equivalent dose is much more complex for PDR treatment than for LDR and HDR treatments, and cannot be rea- sonably done manually. It assumes a constant dose rate during pulses, which may be low or medium according to ICRU defini- tions. It does not take into account the fact that the miniaturised source advances step by step inside the catheters. The dose rate The lack of knowledge for T 1/2 PDR = αD + βd . (1 + Hm). D [7]

in a given point in the target volume therefore varies between low and high values during the pulse, and PDR BT might behave more like HDR than LDR BT with incomplete recovery between the pulses and consequently pulse size rather than dose rate within the pulse will be the dominant factor (Fig 5.11) (Fowler 1997).

6.5 The EQD2 concept In order to compare the biological effects of the different dose rate and fractionation schedules that are used in HDR, PDR and LDR BT , and also to make dose additions to external beam radi- otherapy possible, the GEC-ESTRO promotes use of the equi-ef- fective dose concept of ICRU (Bentzen et al. 2012). Treatment schedules of external beam and BT are recalculated according to the LQ model (with incomplete recovery for PDR and LDR) and are expressed as an equi-effective total dose, as if it were given in 2 Gy fractions (EQD2). This leads to the use of a common language that has been shown to be very practical and useful in the comparisons of HDR, PDR and LDR BT for cervix cancer. The EQD2 formula is a simple formula based on the linear quad- ratic model of radiation effect and on the mono exponential model of recovery kinetics (see above). It includes the tissue- and endpoint-specific recovery parameters α/β and T 1/2 . Equieffectiv- ity can be calculated for each tissue of interest and each endpoint with the relevant parameters, when they are known. However most often average α/β and T 1/2 values are used for early (10 Gy and 1h) and for late reacting tissues (3 Gy and 1.5 h) without any concern for the inherent uncertainties. A fundamental warning is necessary when considering equi-ef- fect calculations based on the LQ model. There are almost no in vivo experimental data exploring the dose rate effect beyond 24 - 30 hours of continuous irradiation. Therefore the mathe- matical models, and more particularly the incomplete recovery model, have not yet been properly validated at dose rates rele- vant to classical LDR. There is also controversy about the validity of the LQ formalism at large doses per fraction (Brenner 2008, Kirkpatrick, et al . 2008), It is believed that the model adequately quantifies the biological effects in most tissues in the dose range of 0.5 Gy to 5 Gy to 6 Gy. At dose per fraction exceeding 6-10 Gy, the LQ formalism may overestimate the biological effect and the LQC model might be more appropriate (Bentzen, et al . 2012, Joiner 2009).These considerations must be taken into account by the clinician when prescribing high fraction sizes as in HDR BT for gynaecological tumours, prostate and breast where a trend to deliver fraction sizes of 6 Gy has become current practice. Moreover, equi-effectivities vary widely with variations of α/β and T 1/2 . Thus a simple “magical” formula equating HDR with LDR is probably a dangerous illusion. The responsible clinician must always make decisions with caution. Of course these parameters can be changed when new data and insights lead to another consensus. It is therefore important that the real physical data on absorbed dose distribution, dose rate, pulse and fraction sizes is available in the treatment report. In practice, starting from the total effect E of a particular frac- tionated external beam or HDR (see formula 1), an equi-effec-

E