34. Uncommon indications for brachytherapy - The GEC-ESTRO Handbook of Brachytherapy

Uncommon indications for brachytherapy

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THE GEC ESTRO HANDBOOK OF BRACHYTHERAPY | Part II Clinical Practice Version 1 - 30/04/2025

6. RESULTS AND ADVERSE SIDE EFFECTS

The majority of the reported adverse events can be divided for ease of description into wound healing complications, osteoradionecrosis and neural damage. Wound Healing Complications (WHC) WHC are the most common adverse events in patients treated with adjuvant brachytherapy and have been reported in 2.3% to 59.0% of patients. Severe grade 3-4 complications leading to reoperation occur in 10 to 15% of cases [25,26]. Risk factors leading to complications include time, volume, dose/volume and technical factors. Time-associated factors (time to loading) were the first variables associated with WHC. In the MSKCC trial, the significant wound complication rates were 24% in the BT monotherapy group and 14% in the control group (p =ns). However, WHC significantly increased (48%) with BT delivered prior to postoperative 5 day, whereas patients treated with BT monotherapy >5 days postoperatively had wound complication rates comparable to surgery alone (17% vs. 15%, p=ns) [27]. More recent studies however, have not described such correlation [25]. Volume-associated factors in the form of tumour volume, tumour location, extent of resection, width of skin resected, CTV size, implant volume, number of catheters, etc. are all associated with a greater risk of WHC and should be taken into consideration [20] at the time of surgical closure, brachytherapy and adjuvant EBRT. Dose-volume - associated factors have been increasingly gaining attention in the sarcoma literature. A recent report [28] described a correlation between WHC and CTV larger than 50 cm 3 (p = 0.02) and CTV 2cm 3 physical dose > 110 Gy (p = 0.02) in a multivariate analysis of a series of 139 unirradiated soft tissue sarcomas treated with adjuvant brachytherapy in combination with EBRT. When used in combination, patients with CTV volume and CTV 2cm 3 values below the constraints had a WHC rate of 13.2%. This figure increased to 44% and 77.8% with one or two values above the constraints. Hence, WHC seems to result mainly from high-dose irradiation of large tissue volumes. The goal of obtaining a suitable CTV size can only be accomplished through strict case selection. Similarly, suitable CTV 2cm 3 values can be achieved using shorter intercatheter spacing (10–12 mm) and meticulous treatment planning to minimize high- dose areas. Technical factors related to the surgical procedure, closure and postoperative play an important role in the development of WHC. In the MSKCC trial, it was noted that wound reoperation was related to the width of the excised skin (WES) [1% (WES < 4 cm) vs. 10% (WES > 4 cm), p = 0.02][26]. WHC can be also minimized with the use of free tissue closure, negative pressure wound therapy (NPWT) or temporary closure and delayed reconstruction [20]. Osteoradionecrosis (ORN) ORN is a rare complication after adjuvant brachytherapy (median 1.4%, range, 0–4.5%). ORN has been associated with periosteal stripping [29] that decreases bone viability. A recent report in 139 patients treated with adjuvant brachytherapy and EBRT described an ORN rate of 5% with a time to appearance of 59 months. ORN was associated in multivariate analysis with bone dose with a cut-off level at EQD2 3 Bone 2cm 3 of 67 Gy (p = 0.01). ORN was not observed below this constraint. Bone 2cm 3 EQD2 should be closely monitored or lowered in cases in which periosteal stripping has been performed.

6.1. Unirradiated Cases 6.1.1. Local Control

BT monotherapy has shown 5-year local control rates greater than 75% in the majority of the reports [5,17-19]. Of note, the Memorial Sloan Kettering Cancer Center (MSKCC) phase III trial showed a 5-year local control of 82% in the LDR brachytherapy group compared to 67% in the surgery-only group (p=0.049) [5]. Brachytherapy was delivered with Ir-192 LDR to a total dose of 42 45Gy over 4-6 days. Total hospital stay from the date of surgery was 10-14 days. This difference was due to the marked improvement in high grade tumours (90% vs. 65%; p=0.013) while the difference in low grade tumours was not significant. This local control advantage did not translate into improved disease-specific survival. In a later update with 202 patients, the 5-year local control remained stable at 84% [17]. The rest of the BT monotherapy literature comprises a mix of LDR, HDR and PDR series with smaller number of patients and/or shorter follow-up [20]. BT in combination with EBRT is the most common use of brachytherapy in soft tissue sarcomas, especially in those cases at higher risk of local relapse. A subgroup analysis from MSKCC [9] comparing brachytherapy alone vs. brachytherapy + EBRT in margin-positive patients showed superiority of the combined treatment with 5-year local control rates of 59% vs. 90% (p=0.08), suggesting a dose-escalation effect in high-risk patients without an increase in complications. Most series report 5-year local control results greater than 80-85% with a combination of EBRT of 45-50Gy delivered with standard fractionation and 10 to 25 Gy of LDR or pulsed-dose rate (PDR) or an HDR equivalent [21-24]. Different factors have been implicated in local control after brachytherapy alone or combined with EBRT although margin status remains the most influential prognostic factor for local control [21,22,25]. Gimeno et al. [25] showed that margin status, as defined by the MSKCC classification, was the only factor predictive of local control after multivariate analysis of a series of 106 patients treated with HDR brachytherapy of 16-24Gy and 45Gy of EBRT. The 10-year local control decreased from 95% to 74% (p=0.013) when the surgical margins were positive. 6.1.2. Adverse effects Complications are multifactorial in origin and are related to patient (age, comorbidities, ), tumour (size, location, proximity to sensitive structures, ) and treatment factors (extent of surgery, periosteal bone stripping, reconstruction, dosimetry). An exhaustive list of factors related to adverse effects can be found elsewhere [20]. A recent detailed summary published by the American Brachytherapy Society describes an all-type grade >2 complication rate of of 5 to 10% for brachytherapy monotherapy and of 25-30% for combined brachytherapy and EBRT [20]. These numbers must be taken only as an approximation due to the different systems for scoring and reporting used in the literature.