16. Cervix cancer - The GEC-ESTRO Handbook of Brachytherapy

Cervix cancer

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THE GEC ESTRO HANDBOOK OF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 01/09/2023

<20cc), >93% in intermediate size targets (CTV-T_HR 20-30 cc) and >86% in large targets (CTV-T_HR 31-70 cc). For the CTV-T_IR and GTV-T res , D98% doses of ≥60 Gy and ≥95 Gy respectively, are required to assure similar levels of local control [27]. A recent analysis of EMBRACE I data showed that a D90 of 85 Gy to the CTVHR led to 95% local control at 3 years for squamous cell compared to 86% for adeno/adenosquamous carcinoma histology [67] (Figure 22b). A detailed summary of the evidence for the dose effect on tumour control from IGABT studies was published by Tanderup et al. in 2020 [28]. 12.2 Impact of BT technique The high doses required to sterilise larger tumours can only be achieved with the addition of additional IS needles. In the Retro EMBRACE study, systematic usage of combined IC/IS techniques was associated with an increase in CTV-T_HR D90% from 83 +/- 14Gy to 92 +/- 13Gy [71]. The 3-year local control rate in patients with a CTV-T_HR volume ≥30 cm 3 was 10% higher in the IC/IS group (Figure 23). No improvement in local control was found for smaller tumours at the time of brachytherapy with CTV-T_HR<30 cm 3 (p=0.50) treated with the IC/IS technique (Fig 23). The benefit of additional oblique needles was demonstrated for very large residual tumours at brachytherapy by Mahantshetty et al. [72]; the 5-year local control rate was 72% in 69 patients with a mean CTV-T_HR of 71 ± 34 cm 3 at the time of first BT. The recording and reporting of early and late adverse events after radiotherapy for gynaecological tumours is an important aspect of treatment. Prospective evaluation for morbidity is preferable to minimise under-reporting; reporting of both actuarial and crude rates as well as prevalence allows more meaningful assessment of morbidity and comparison between centres. Crude, actuarial and prevalence rates for G1-G4 gastrointestinal (GI), genitourinary (GU) and vaginal morbidity have been reported for a large patient cohort treated in the EMBRACE-I study [73-77]. For any given organ system, it seems essential to assess various morbidity endpoints as the pathophysiology (e.g. fibrous tissue, vasculature, nerve structures) and the outcome may differ significantly. The prevalence rates for GU and GI morbidity are often much lower than the actuarial incidence [75, 76]. In addition, there are considerable differences between physician-assessed morbidity and patient-reported outcomes, particularly for G1 and G2 morbidity [75, 76]. It is beyond the scope of this paragraph to provide detailed information about the important comprehensive morbidity outcome data from the EMBRACE studies but figures for vaginal [73], rectal [74] and urinary [75] morbidity have been provided as examples (Figure 24-26). Morbidity assessment and reporting appears to be more straightforward in regard to severe (G3-G5) adverse effects. Vittrup et al. [78] recently reported the overall severe morbidity data seen in the EMBRACE-I study. In total, 534 severe events (all endpoints) occurred in 270/1416 patients; 429 events were G3 events and 105 were G4 events. For organ-related morbidity (GI, 13. ADVERSE EVENTS

GU, vaginal, or fistula), 330 G≥3 events occurred in 183 patients. The 5-year actuarial estimate for G≥3 events was 8.5% for GI (117 events in 81 patients), 6.5% for GU (112 events in 75 patients), 5.7% for vagina (59 events in 55 patients) and 3.2% for fistula (42 events in 34 patients). The 5-year actuarial estimate for all organ related events (GI, GU, vaginal, or fistula) was 18.4%. The 5-year actuarial estimate when aggregating all G≥3 endpoints (GI, GU, vaginal, fistulas, and non-GI/GU/vaginal) was 26.6%. Thirteen patients had a treatment-related death, 8 of which were associated with GI morbidity (actuarial risk at 5 years 1.2%). Vittrup et al. [73] compared the severe morbidity outcomes in EMBRACE-I with large historical series - the rate of adverse effects was lower for GI, vaginal and fistula events and similar for GU events. When comparing specific brachytherapy-associated G≥3 morbidity such as fistula and ureteric strictures, these seem to be limited in MRI-based IGABT (EMBRACE-I: 3.2%, 2.9% respectively). G≥3 brachytherapy-associated morbidity such as fistula and ureteric stricture is especially low for patients with stage I-II disease (1.3%, 0,7%). Overall, severe brachytherapy-related morbidity with IGABT is also low for other organ-related endpoints (e.g. GI bleeding, urinary incontinence, vaginal obliteration), Fistulae and ureteric strictures remain a therapeutic challenge in stage IIIA-B (10,2%, 10,8%) and IVA (18,6%, 21,3%) patients, which may reflect tumour extension at diagnosis. The diversity and severity of early and late adverse effects after radiotherapy for gynaecological tumours have led to the development of several scoring systems over the decades (e.g. RTOG-EORTC, LENT-SOMA, Franco-Italian glossary, CTCAE). Most systems are based on assessment of symptoms at single time points which may or may not be relevant to patient quality of life. The grading of severity of different endpoints for each OAR may not reflect the impact on the patient. As already mentioned, there is often significant discrepancy between the severity of symptoms as reported by the physician and the patient. Mild and moderate symptoms which have an impact on quality of life are often under-reported. The EMBRACE group has therefore proposed a new methodological approach (LAPERS) [79, 80] to identify clinically relevant, long-lasting treatment-related symptoms based on patient-reported symptoms which may address some of the limitations of previous methodologies to summarise morbidity after radiotherapy. The amount of LAPERS symptoms often differs considerably from physician reported morbidity and also from patient-reported outcomes (less for physician reported morbidity). Up to now, most series have tended to only report late adverse events affecting the bowel and urinary tract. In contrast, the symptoms with LAPERS rates of >10% in the EMBRACE cohort after cisplatin based chemo-radiotherapy and IGABT were urinary frequency, neuropathy, fatigue, insomnia, and menopausal symptoms [80]. While these symptoms are often treatment-related, they are also influenced by other factors such as previous pelvic surgery, and comorbidity such as diabetes. 13.1 Impact of dose and volume on risk of morbidity The impact of dose of irradiation on incidence of complications has long been recognised. For example, Perez et al. [81] reported that the incidence of complications significantly increased when the dose to point A exceeded 80 Gy. In their analysis of 1456 patients, a dose below 80 Gy to point A correlated with a 3% bladder morbidity compared to 5% with higher doses. In the rectosigmoid, the incidence of morbidity significantly increased