VCB AS A BOOST
No randomized trial has evaluated the value of VCB boost after EBRT, but two studies have evaluated the effect of EBRT added to VCB.40,45 While the older study45 did not find any statistically significant difference by adding EBRT, after a median of 20.5 years of follow-up, Sorbe et al40 observed a significant improvement in the locoregional relapses (Table 2), although no differences in survival were achieved. A SEER database analysis demonstrated a significant survival advantage among 1333 early stage uterine papillary serous (UPSC) and CC carcinoma patients who had undergone adjuvant radiotherapy (106 vs. 151 months for observation and radiotherapy, respectively [p = 0.006]).46 Nevertheless, a later analysis of 1653 patients who had high-risk stages I–II, high-grade endometrioid carcinoma and non-endometrioid histologies was unable to find any improvement in cancer survival by adding VCB after EBRT.47 Similar results were found after an analysis of 3395 high-risk stages I and II EC patients retrieved from the same database.48 Lack of patient selection and control of confounding variables, such as pathological factors or chemotherapy among patients at a high risk of distant relapses, might explain it because the SEER database does not record specific pathological information, site of relapse or chemotherapy administration. Bingham et al43 who analyzed stage III EC reported an improvement in survival only with the addition of VCB to EBRT among the subgroup with cervical involvement. In a multivariate Cox analysis, chemotherapy has been shown to reduce the crude percentage of initial extra-abdominal failure from 19% to 10%49 compared with whole-abdominal irradiation and improve survival significantly.43 An increase in late toxicity linked to the use of VCB as a boost has been described. Despite these facts, 28% of the respondents of a recent survey stated to use this approach only in a high-risk disease, and 6.3% of the respondents always use it.50
HIGH-RISK AND UNFAVORABLE HISTOLOGY TUMORS
This group of patients include those with high-risk endometrioid carcinomas (grade 3 and locally advanced tumors) and high-risk histologies (UPSC and CC tumors). Stages III–IV of UPSC and CC tumors have a more aggressive natural history and lower overall survival than grade 3 endometrioid carcinomas (55%, 68% and 77%, respectively).51 Patients at stage IC G3 recruited in the Norwegian trial52 had lower survival rates than lower risk patients. A retrospective analysis of 125 patients treated for stage IA unfavorable histology endometrial carcinoma indicated an improved 5-year locoregional control and overall survival with postoperative irradiation compared with no irradiation (97.8% vs 80.1%, p = 0.018, and 84.9% vs 68.1%, p = 0.0062, respectively).53 The GOG-122 trial demonstrated, in spite of the reduction in local relapses, a detrimental effect in 5-year survival with postoperative radiotherapy (abdominal irradiation [30 Gy] followed by an external pelvic boost up to 45 Gy) compared with the group treated with chemotherapy (38% vs 50%, respectively).49 Two other trials54,55 included 385 and 345 patients, respectively, and were unable to demonstrate differences between the radiotherapy arm and chemotherapy arm.
A retrospective analysis of 37 patients treated with postoperative VCB without EBRT for early-stage UPSC and CC was carried out at the Dana-Farber Cancer Institute. Only four patients relapsed; the 2-year vaginal control rate and 2-year disease-free and overall survival were 96.8%, 89.3% and 100%, respectively.56 A retrospective analysis of 84 women with stage I UPSC or CC compared postoperative EBRT + VCB with VCB alone. No significant differences were observed in disease-free survival or in overall survival (88% vs 84%, p = 0.6, and 100% vs 94%, p = 0.6, respectively).57 A SEER database analysis found a median survival improvement with the use of postoperative irradiation (106 vs 151 months, p = 0.006).46 The analysis of 1653 patients with UPSC, CC and high-grade endometrioid carcinoma, from the same database, found no statistically significant cause-specific survival differences between patients treated with postoperative EBRT and EBRT + VCB (85.3% vs 86.5%, p = 0.72).47 No comparisons with a large number of patients treated with VCB alone have been reported.
The widespread use of HDR brachytherapy has allowed for a greater flexibility in the irradiation delivery. The 2014 American Brachytherapy Society (ABS) update survey34 reports that 7 Gy for three fractions is the most common schedule for postoperative VCB alone and 5 Gy for three fractions is the most common schedule for VCB as a boost after EBRT, both delivered to a depth of 0.5 cm. Nevertheless, a wide variation in the dose schedules was noted; 24 regimens for monotherapy and 22 as a boost were recorded. Because comparative studies of dose fractionation are scarce,59,60 the schedule used depends on the doctors’ experience, preference or workload. No clear optimal dose for VCB has been established; the reported doses for VCB alone range from 35 to 48 Gy EQD2 and 57 to 69 Gy EQD2 after EBRT.39 Sorbe et al59 randomized 290 low-risk EC patients to six fractions of 2.5 Gy (total dose of 15.0 Gy) or 5.0 Gy (total dose of 30.0 Gy). No differences on locoregional control were observed, but mucosal atrophy, bleeding and vaginal shortening were significantly more frequent in the 5.0-Gy group. Rovirosa et al60 compared two VCB schedules in 319 patients (three fractions after EBRT and six fractions in the exclusive VCB at a dose of 4–6 Gy/fraction, three to four fractions per week vs two fractions after EBRT and four fractions in the exclusive VCB at a dose per fraction of 5–6 Gy daily). No differences in relapses or toxicity were observed. Large doses per fraction have been related to vaginal shortening;59 2.5 Gy per fraction did not produce a statistically significant vaginal shortening (0.3 cm, 3%) compared with the pre-VCB measure, while 5 Gy per fraction produced a significant mean vaginal shortening (2.1 cm, 25%). The percentage of late vagina complications can vary widely depending on the treatment schedule, the length of treated vagina and the score system used for their recording. Owing to the low toxicity associated with the procedure, assays have been carried out to minimize the number of fractions or to reduce the total length of its administration.60–62 No significant differences in late toxicity or VC relapses were observed with the accelerated schedules.
APPLICATOR TYPE AND POSITION, PATIENT POSITION AND VOLUME TO TREAT
The majority of the treatments are carried out with a single-channel cylinder (83.2%) due to its simplicity and resources compared to the use of colpostats or vaginal molds.63 However, this technique is not without its drawbacks. In spite of using the largest cylinder that can comfortably fit into the vagina, there can still be air gaps on the vaginal surface.64 This can increase when the vaginal introitus is smaller than the apex. Avoiding the smaller cylinder diameters reduces toxicity. A multichannel cylinder allows a better conformal dosimetry and reduces bladder and rectum doses.65 Compared to cylinders, vaginal colpostats can reduce percentage depth doses in the anterior/posterior and lateral directions as well as the dose falloff along the longitudinal axis.66 The main drawback is the possibility of producing cold spots due to the vaginal packing. Ring applicators have also been used, with similar clinical results to cylinders.67 The 5-year overall survival of 100 patients was 84%, and 6% of the patients showed failure (one isolate in the vaginal vault and two in the vaginal vault and pelvis simultaneously; three other patients relapsed out of the field or distant). “Dog-ear” vaginal vaults can be underdosed with standard cylinders and are best irradiated with vaginal molds68 or ovoids.69 Molds do not need vaginal packaging compared with ovoids and provide a good solution in irregular vaults where a good contact between cylinders and mucosa may not be achievable. The classic technique is to create it from a vaginal impression, which can optimize catheter configuration with the aid of computed tomography (CT) imaging70 The growing use of the three-dimensional (3D) printing technologies in the brachytherapy field71 improves mold design and creates highly personalized applicators. These 3D printing applicators made from 3D images might improve dose deposition by conforming to the patient’s anatomy and optimizing the range of catheter sources to the individual anatomy.72 Intravaginal balloons have also been used for postoperative VCB.73
Humphrey et al74 assessed 103 CT scans, and air gaps were visible in 38 patients accounting for a total of 67 air gaps. However, air gaps of >2 mm that lead to repositioning or use of large cylinders were only reported in 11 out of 103 patients. After correction, only 7% of the patients had air gaps of >2 mm. Two other reports have reported 32% and 72% of air gaps of >2 mm, respectively,64,75 but the majority are not clinically significant64 and only represent 0.86% of the vaginal surface. The ratio of patients to air pockets has been as high as 58% (29/50) of the patients or 33% (45/135) of the VCB plans.76 Their volume can reach up to 2.1 cm3, and the displacement of the vaginal mucosa from the cylinder surface can be up to 1.09 cm. The relationship between the cylinder applicator diameter and air gaps forces the selection of the largest applicator diameter that will comfortably fit into the vagina. Similarly, Onal et al77 described air pockets in 43% of patients treated with cylinders, but only 6.3% of the total patients received less than the prescribed dose (average 93.9% of the prescribed dose, range 79%–99.2%). Monte Carlo calculations show a maximum dose deviation due to air pockets of 2.4% compared with the TG-43 formalism.78 This study observed that the most common radial size was between 2 and 3 mm, and the average dose reduction was 14.8%.
Only one study has analyzed the influence of patient position on dose to organs at risk.30 Planning with legs extended produced significantly lower rectum D1cc and D2cc values compared with planning in the gynecology position (4.69 vs 5.66 Gy and 4.24 vs 5.14 Gy, respectively). The angle of the applicator influences the location of dose deposition. The “natural” angle position of the cylinder,31 which tips the cylinder points posteriorly, has been linked to an increase in the rectal dose, while cylinders placed horizontally reduced rectal doses and increased the bladder values.32 Nevertheless, one study failed to demonstrate a correlation between the cylinder angle and the bladder dose although a posterior angle increased rectal D2cc.79
The majority of the patients have irradiation of the upper 2.5–3 cm or the upper third of the vagina. Nevertheless, an interesting study limiting the vaginal coverage to the upper 1 cm length has been reported, but only in the abstract form.80 Increasing the length of the vagina irradiation has been linked to an increase in toxicity,81 but no relationship has been described between the length of the vagina irradiation and vaginal relapses or survival.82