Radiobiology of LDR, HDR, PDR and VLDR Brachytherapy - GEC-ESTRO Handbook of 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

In early responding, turnover tissues (hierarchically structured), such as the bone marrow or the gastrointestinal mucosae, the above mentioned stem cells produce transit cells, which are re- sponsible for overall cell production, which is then counteracted by the physiological cell loss. In late responding tissues, the tissue specific stem cells produce differentiating cells that may also be recruited into proliferation if there is a demand (flexible tissues). In all tissues, there is a combined and complex response of all exposed cell populations at the cellular level. In early respond- ing tissues, the clinical radiation response is largely based on the changes in the proliferating compartment (stem cell loss, defi- cit in transit cells, hypoplasia, ulceration). Therefore, the time to onset of early effects depends mainly on the turnover time of the proliferative compartment, and is largely independent of the radiation dose. For example, oral mucositis occurs at 9 days after the accumulation of a radiation dose of 20 Gy (Van der Schueren et al . 1990). Based on the number of surviving tissue stem cells, early radiation effects usually heal after a (biologically effective) dose-dependent time interval. The more aggressive the treat- ment, the earlier the effect and the longer it takes to heal. In contrast, for late radiation effects, the parenchymal (i.e. stem cell based) response is of varying importance. Here, endotheli- al/vascular changes, such as dose dependent loss of capillaries, vascular occlusions and telangiectasia – all associated with an impairment of perfusion – are one major component. Radia- tion- induced differentiation of fibroblasts, associated with a substantial increase in connective tissue production, is another predominant factor in radiation-induced tissue fibrosis. It must be emphasized that these late tissue reactions are hence based on changes in cellular functions in a complex way, rather than (exclusively) on cell death. With BT, treatment can be delivered in completely different time patterns: either continuously at lower (VLDR/LDR) or medium dose rates (MDR) or fractionated with smaller or larger fraction sizes and intervals (HDR/ PDR) (Fig 5.3) • Low Dose Rate (LDR) BT applies dose rates in the range be- tween 0.4 and 2 Gy/h. However, in routine clinical practice, LDR BT is usually delivered at dose rates between 0.3 and 1 Gy/h. This is compatible with manual or automatic afterload- ing techniques. • Medium Dose Rate (MDR) BT administers doses in the range between 2 Gy/h and 12 Gy/h. MDR can also be delivered by manual or automatic afterloading, • High Dose Rate (HDR) BT delivers the dose at dose rates of 12 Gy/h and more (>20 cGy per minute), and only remote after- loading is feasible because of the high source activity. Two other dose rate schedules are also used in BT at present. • Pulsed Dose Rate (PDR) BT delivers the dose in a large num- ber of small fractions, called pulses, at short intervals, allowing only for incomplete recovery in between. This aims to achieve a radiobiological effect similar to low dose rate over the same treatment time, typically a few days. 4. DOSE - TIME PATTERNS IN BT

inactivate the free radicals, and fixation reactions that eventu- ally lead to stable chemical changes in the DNA. Even at this point, some repair occurs. For example, the restoration of vari- ous DNA lesions, like DNA-strand or DNA-protein crosslinks, base damages, single- (SSB) or double-strand breaks (DSB) can be induced. Multiply damaged sites, i.e. combinations of these damages, appear to be the basic changes leading to critical bio- logical effects, e.g. cell death. • A third, biological phase , much longer (seconds to years and decades), during which the cells react to the inflicted chemi- cal damage and interact with neighbouring cells, but also with the immune system. It begins with the DNA Damage Response (DDR) which is a highly complex and coordinated system of enzymatic reactions that respond to the existing DNA damage. It is estimated that 1 Gy, resulting in around 10 5 ionisations, causes more than 5000 DNA base damages, about 1000 single strand breaks and 20-80 double strand breaks, but will lead only to a 30 % clonogenic cell kill in an average mammalian cell line. This clearly indicates that in order to cope with different types of radiation damage, mammalian cells have a variety of very effec- tive DNA repair systems such as Base Excision Repair (BER) for base damages, Single Strand Break Repair (SSBR) for SSB, and – for DSB - Homologous Recombination (HR), Non Homologous End Joining (NHEJ), and Single Strand Annealing (SSA), which work with varying efficacy and fidelity (Wouters et al. ). These repair processes successfully repair the vast majority of lesions in DNA. Thus only a few lesions are not or inadequately repaired, and may lead to clonogenic cell death. Multiple damaged sites, including DSB, are the main changes contributingto cell death. Clonogenic cell death is defined as loss of the potential of a cell to undergo an unlimited number of divisions. Clonogenic cells may hence be considered as either normal tissue or tumour stem cells. Clonogenic cell death after radiation exposure can occur in various ways and at various times. Three pathways are dominant. Mitotic death may occur at the first or at (3-4) subsequent cell divisions, when the amount of accumulated DNA damage does not allow for completion of the mitosis. Apoptosis is prominent in only a few cell types, such as lympho- cytes and seminal epithelium, as well as in endothelial cells irra- diated at high doses (> 15 Gy). Thirdly, radiation induced differentiation (e.g. of epithelial cells) or senescence (e.g. transformation of fibroblasts into fibrocytes) can occur, which renders the cells non-clonogenic, although still metabolically active, but with different metabolic and also cell-interactive pathways. The “stem cell hypothesis” postulates that the radiosensitivity of a tissue is based on the number and the intrinsic radiosensitivity of the tissue specific stem cells. Whenever these cells divide (in a normal state), they produce a new stem cell (“self-renewal”) and one other cell, which may either have a limited proliferative capacity (“transit cell”) or directly undergo differentiation. With regard to the time course, early (rather than acute) radia- tion effects – by definition occurring during the first 90 days after the onset of radiotherapy – are distinguished from late (chronic) radiation effects that occur after months to many years.