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 processes, which occur – with a certain tissue specif- ic half-time – between radiation fractions, or during exposure with low dose rates. In vivo, these processes are mainly, but definitely not exclusively, based on DNA repair activities. These processes are dominant in late responding tissues. • Repopulation is a process that is occurring in turnover tissues and in some tumour entities, as soon as a certain level of cell depletion has been accumulated (Dörr 2009, Hopewell 2003). The underlying mechanisms are complex (Dörr 1997, 2003). Repopulation is based on an additional production of stem cells, through a switch to symmetrical divisions resulting in two daughter stem cells, an acceleration of these stem cell divi- sions, and a substantial rate of “abortive”, residual divisions of doomed cells. • Redistribution relates to cell cycle effects of IR, with a pre- dominant kill in sensitive cycle phases, synchronisation at check-points, etc. These effects have been extensively studied in in-vitro systems but the relevance of these phenomena for in-vivo tissue effects is highly questionable. • Reoxygenation describes an improvement of the oxygen status of tumour (stem) cells during radiotherapy. In many tumours, hypoxia develops, based mainly on the increasing distance of the tumour cells from their related vessels/capillaries and increasing intratumoral pressure (chronic, diffusion-related hypoxia), and on the inadequate function (e.g. temporary oc- clusion) of the capillaries (acute, perfusion-related hypoxia). During treatment, temporarily occluded vessels re-open, and with tumour shrinkage, the interstitial pressure decreases and the surviving tumour cells move back closer to their vessels. These complex processes promote an increasing radiosensitiv- ity of the hypoxic – and hence cure- and recurrence- relevant – areas with increasing overall treatment time. • Modern EBRT and established techniques such as BT are asso- ciated with an increase in dose inhomogeneity in the OAR; this is frequently depicted as the “volume effect” although this term can be misleading. The response of individual tissues and or- gans, and importantly also their individual response endpoints, to such dose inhomogeneity can be highly varied and complex. The QUANTEC initiative [Marks 2010] made an attempt to summarize current knowledge about volume-related organ tolerance, and a series of studies and analyses has extended this knowledge since then. However, different endpoints of re- sponse in a particular OAR, such as incontinence vs. bleeding after exposure of the rectum, do have different target subvol- umes, radiopathologies, and radiobiological characteristics. These need to be studied experimentally and particularly clini- cally in forthcoming years. There are different time frames for the relevance of these factors. (Fig 5.4) Recovery of sublethal damage (see above) is the fastest process that starts within one hour. Its consequences can be detected af- ter only15-30 minutes and it is completed approximately 6 hours after an exposure, but may take as long as 1 day (e.g. in spinal cord). It is the most significant factor altering radiation effects between 1 Gy/min and 0.3 Gy/h. Half-times of recovery for hu- man tissues and tumours are estimated to be >2-4 h. The possibility of recovery for various tissue responses is de- pendent on the capacity of the tissue (in the linear-quadratic sys- tem described by the α/β ratio) and its time kinetics (halftime, T½). It is effective in the dose ranges between 100 cGy/min (60 Gy/hr) and 0.1 cGy/min (6 cGy/hr). The higher the dose rate,

Fig 5.3: Definitions of time-dose patterns used in brachytherapy for cervix treatment. Overall treatment times (blue) and irradiation times (red) are presented for different types of treatment. (ICRU Report 88, 2015)

• Very Low Dose Rate (VLDR) irradiation by permanent im- plants delivers a high total dose (for example 150 Gy) over several weeks to months. It is evident that the biological effects resulting from the different dose–time patterns will lead to different biological effects. How- ever, they may have the same biological efficacy.

5. THE FOUR R’S OF RADIOBIOLOGY AND THE DOSE RATE EFFECT

Several factors influence the response of normal tissues and tu- mours to therapeutic radiation exposure, which are often sum- marized as the Rs of radiotherapy [Withers 1975, Steel, Dörr and Van der Kogel 2009, Dörr 2015, Dörr and Schmidt 2014). • The intrinsic radiosensitivity of a given organ, which mainly depends on the number and sensitivity of the tissue specific stem cells (the stem cell hypothesis), but also on the sensitivity and interaction of other cell populations (e.g. endothelial cells, fibroblasts) in a complex way.