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

combined with external beam radiation therapy, acting as boost, notably in cancer of the cervix. In other situations, such as for small cancers of the mobile tongue, attempts to replace exclu- sive low dose rate BT by combined external radiotherapy and BT boost led to a decrease in local control, and sometimes to an increase in complications (Benk 1990, Pernot 1994,Pernot 1997,Wendt 1989). One randomised trial has compared a boost with EBRT or BT in breast cancer. Fourquet et al . reported on 255 patients present- ing with large (3 - 7 cm) breast tumours, who were treated with EBRT to the whole breast (58 Gy) with a 20 Gy boost to the tu- mour bed, either with conventional cobalt -60 irradiation or with an interstitial iridium 192 implant (mean dose rate: 0.64 Gy/h) (Fourquet 1995). The 8-year local control rates were 61% and 76%, respectively (p = 0.02). These and other retrospective data confirm the dose effect of the higher EUD resulting from BT as compared to external beam treatments to the same nominal pre- scription dose (see table 5.1) 9.2 Dose rate effects in low dose rate BT It has become clear that dose rate effects are strongly depend- ent on repair capacity and kinetics and that there exist strong differences in dose rate effects between tumour responses and complication rates. Tumour control In squamous cell carcinoma, a tumour assumed to have a high α/β ratio of about 10 Gy, no strong dose rate effects have been reported Pierquin et al . reviewed the local outcome of 263 squamous cell carcinomas of the oral cavity, the lower lip, the skin, and the pe- nis, implanted with iridium 192, to deliver a dose of 70 Gy in 3 to 8 days (Pierquin 1973). They did not find an effect of overall treatment duration on either probability of local control or com- plications within this range. Similar conclusions were drawn by Fu et al. in oral tongue cancers (Fu1976). Larra et al . did not find an effect of overall time between 1 and 10 days on the control of 121 skin carcinomas implanted to a dose of 60 Gy (Larra 1977). The same was concluded in the GEC-ESTRO survey on BT for lip cancer, where no significant dose rate effect was noted in the dose rate range from <40 to >120 cGy/hr. Van Limbergen et al. also observed no strong dose rate effect with differences in local control between 3 and 6 days with tu- mours of the uterine cervix treated with a dose of 60 Gy (Van Limbergen 1985).This observation was confirmed later, by a ran- domised trial in cervix cancer (Haie1994) where no dose rate effect was seen either in tumour cell sterilisation in the postoper- ative specimen or in relapse free survival. Different observations were seen for breast cancer by Mazeron et al . who observed an effect of dose rate on local control in a population of 340 patients with a T1-3 adenocarcinoma of breast treated with a 37 Gy iridium -192 boost. Recurrence rates varied from 31% at dose rates 0.3 – 0.4 Gy/h to 0 % at dose rates 0.8 - 0.9 Gy/h (Mazeron 1991).These findings are compatible with radiobiological modelling from later data of breast cancer hypof- ractionation studies which estimate a lower α/β ratio of about 4.1 Gy for breast cancer. (Yarnold 1994)

For the same CTV, the treated volume in BT is significantly smaller than with EBRT, since in principle no PTV margins have to be taken to cover the target. Assuming a CTV of 4 x 4 x 2 cm, this would need a PTV of 32 cm 3 in case of BT, but would be expanded to 75 cm 3 if a 0.5 cm margin and 144 cm 3 when a 1 cm PTV margin is chosen in EBRT. Thus, treated volumes will increase by a factor 2.3 to 4.3 depending on the chosen PTV margin. This corresponds with clinical data from breast boost implants where the average treat- ed volume is 3 times smaller (50 cm 3 versus 150 cm 3 ) for external beam boosts. However these smaller volumes have not been as- sociated with lower local control rates (Table 5.1). The probability of late effects also depends upon the type of tis- sue involved (see above, e.g. QUANTEC). For example, the same technique of BT applied to oral tongue and floor of mouth carci- nomas leads to a rate of soft tissue necrosis more than two times higher in the floor of mouth than in the oral tongue [Mazeron 1991]. This may be related to the different radiopathologies of the individual tissues/tissue components. Table 5.1 Local recurrence rates of breast cancer treated with RT only or Breast Conserving surgery and RT, either with external beam boost (EBB) with photons or electrons versus interstitial BT boost (BTB). * Randomized phase III trial. Retrospective non randomized data. RT ONLY* EBB BTB Fourquet 1995 5y 30% 16% BCS + RT** Mansfield 1990 10y 18% 8% p= 0.2 Touboul 1995 5y 8.8% 5.5% p= 0.32 Hammer 1995 5y 8.2% 4.3% p= 0.03 Polgar 2001 5y 5.8% 7.7% p= 0.69 Poortmans 2004 5y 4.5% 2.5% p= 0.09 Verhoeven 2015 10y 2.5% 0.7 % p= 0.11

9. CLINICAL RESULTS: LDR, MDR, HDR AND PDR BT

Many clinical data have been accumulated over the years in BT, but there have been very few randomised trials. Nevertheless, these retrospective studies help us understand better the biolog- ical background of BT and devise rules that can be followed in clinical practice.

9.1 BT versus external beam radiation therapy While BT has been a very popular treatment for about a centu- ry, most studies are retrospective. In fact, BT has been used as a standard treatment since the 1920s in many tumours, such as cancers of the cervix, oral cavity, lip, penis, etc. It was originally delivered as the only treatment. Later, it was often successfully