17 Endometrial Cancer

Endometrial Cancer

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THE GEC ESTRO HANDBOOK OF BRACHYTHERAPY | Part II: Clinical Practice Version 1 - 25/04/2016

pared to TAH-BSO [64,65,66]. However, pelvic lymphadenectomy increases the risk of complications, especially in the sub-group of patients who receive additional external irradiation. In multivari- ate analysis, pelvic lymphadenectomy was an independent signifi- cant factor for complications (p=0.0049) [67]. The risk of compli- cations with a treatment combining pelvic lymphadenectomy and irradiation has been shown to increase with age [68]. External BeamTherapy alone The risk of severe complications mostly gastro-intestinal after treatments combining external irradiation and surgery ranges between 5.5% [54] and 7.8% [69]. In the PORTEC 1 randomized study assessing the value of postoperative irradiation, an overall rate of late complications, 25%, occurred in the radiation group, 3% of them being grade 3 or 4 [70]. All patients with severe complications had symptoms from the gastro-intestinal tract. Acute toxicity was the most important factor predisposing to late complications. The radiation technique was also a predic- tive factor, with a significant increase in complications when a two field technique was used. In this trial, no complementary brachytherapy was given and the patients were not submitted to a routine lymphadenectomy. Detailed quality of life was prospectively studied in the PORTEC 2 trial [22] comparing external beam radiotherapy with vaginal vault brachytherapy in intermediate risk patients. After external beam 15.4% of patients reported ‘quite a bit’ of diarrhoea and 7.3% ‘very much’ diarrhoea compared to 2.8% and 2.8% with VBT. The rates of diarrhoea decrease with longer follow-up but remained at a higher level compared to EBRT and to an age-controlled Dutch normal population. In addition, 10% of EBRT patients reported an increase in faecal leakage and 22% had limitation of daily activities because of bowel symptoms compared to 2% and 6% of the patients treated with VBT. The Swedish trial that randomised patients between VBT and EBRT combined with the same VBT found a similar negative effect of EBRT on gastro-intestinal symptoms. Long-term quality of life was investigated in the PORTEC-1 trial with a median follow-up of 13.3 years [71]. This analysis confirmed increased gastrointestinal symptoms impacting on limitations in daily activities and physical functioning with longer follow-up after EBRT. In addition there was an increased rate of urinary incontinence and increased use of pads after EBRT (day and night use 43% vs 15% after no additional thera- py). Of importance approximately 30% of patients were treated with parallel opposing fields in this trial. So far no increased rate of urinary incontinence was found with shorter follow-up in PORTEC-2 in which all patients received 3D conformal EBRT Vaginal brachytherapy Acute side effects are limited and may result from vaginitis, mild cystitis and/or proctitis during or immediately following brachytherapy, complaints which may in part be caused by the applicator or urinary catheter insertion itself, particularly in PDR where they will be retained for a long period. These symp- toms usually disappear spontaneously within a few days. The main late side effects are mild to moderate vaginal dryness, shortening and less frequently consequential stenosis. Chronic cystitis, proctitis, sigmoiditis and enteritis are less frequently reported, and only rarely have grade 3 events such as bowel ob- struction, necrosis and fistula (between bladder, vagina, rectum) been reported.

When HDR brachytherapy is used the dose per fraction appears to be a significant factor for complications. In an older study that used different dose fractionation schedules, 404 patients treated by HDR brachytherapy alone, with different doses per fraction, vaginal complications increased with the dose per fraction: 31% in the group of patients treated 6 x 4.5 Gy, 50% in the 6 x 5 Gy group, 60% in the 5 x 6 Gy group, and 79% in the 4 x 9 Gy group; all doses are at 5mm.. The overall complication rate also increased, ranging from 11.2% in the lowest dose per fraction group to 87.5% in the highest dose per fraction group [24]. In another series of 141 patients treated with HDR brachytherapy alone, with 4 frac- tions of 8.5 Gy calculated at the surface of the vaginal mucosa, no grade 3, 4, or 5 complications were observed [58]. The incidence of grade 1 and 2 vaginal complications was 15.3%, bladder com- plications 5.6% and rectal complications 2.1%. The individualization of the depth of the prescription dose ac- cording to the vaginal thickness reduces the risk of late compli- cations as discussed in section 7.1.4. Another important factor is the length of the vagina treated, with a significant increase in complications seen when the whole va- gina is included [72]. The change in the mean age of this popu- lation towards younger and sexually active patients may high- light the importance of vaginal changes after brachytherapy and counseling for post-treatment vaginal dilatation. In the PORTEC 2 trial 3 fractions of 7 Gy were prescribed at 5 mm from the surface of the cylinder and the target volume con- sisted of the proximal half of the vagina. One year after treatment mild to moderate mucosal atrophy on gynaecological examina- tion was found in 36% of the patients treated with VBT com- pared to 14% after EBRT, and grade 3 atrophy with shortening was seen in 2% after VBT and <1% after EBRT. This higher rate of vaginal atrophy with vaginal brachytherapy can be explained by the higher dose at the surface of the cylinder (EQD2 approxi- mately 63 Gy). Importantly the increased rate of mucosal changes did not lead to a difference in sexual activity or patient reported vaginal symptoms between both arms of the trial. In fact sexual activity increased in the first six months in most patients except those older than 75 years. It should be noted that the majority of these patients are elderly and quite a few indicated they were widowed. When compared to an age matched Dutch normal population, sexual activity in both treatment groups was a little lower, which might be explained by the diagnosis and surgery for a gynaecological malignancy. In contrast, mild to moderate gastro-intestinal toxicity was more frequent after EBRT 21% at one year compared to 9% after VBT (remaining at baseline level) , and grade 3 toxicity was found in 2% after EBRT compared to <1% after VBT. The increase rate of gastro-intestinal toxicity with EBRT compared to VBT was confirmed by the Swedish trial which reported an incidence of all grades GI toxicity in 14.5% in the external beam arm and only 2.7% in the brachytherapy arm [24]. If external beam radiotherapy is combined with a vaginal brachytherapy boost, the dose to the vagina and surrounding organs at risk (rectum, sigmoid, bowel and bladder) is higher. Although there is no randomised trial that has compared EBRT and EBRT with a VBT boost, cohort studies do suggest a higher rate of complications with the combined EBRT with VBT boost. However, complications from the small and large bowel (except the rectum) reported in different series are usually related to the dose and volume treated by external beam therapy.