LDR brachytherapy is an effective and safe treatment for VAIN. The major interests of our series are the long clinical and cytological follow-up, the relatively high number of patients, and the use of a homogeneous treatment procedure over time, which allow drawing conclusions about efficacy and toxicity. In our series, only one relapse was seen in 28 patients after a median follow-up of 41 months. As mentioned before, the relapse occurred in a heavily pretreated patient, with the brachytherapy procedure performed in two 30-Gy sessions using a very limited irradiated volume (18 cm3). These two factors, along with the biologically resistant nature of VAIN-3 in this patient, could explain why brachytherapy was ineffective. Seven years after the unsuccessful brachytherapy, she was alive without any sign of invasive vaginal cancer, which underlines the uncertainty of the natural history of VAIN and the controversies in choosing the optimal time for treatment and treatment technique.
The vast majority of studies on vaginal brachytherapy for high-grade VAIN report recurrence rates in the range of 0%–14% [13
]. This high cure rate is similar to that seen in our series and in the other largest series of vaginal LDR brachytherapy reported by Perez et al. [13
]. Only one recurrence in 20 patients was recorded after a median follow-up of 10 years. Graham et al. [17
] reported the results of their MDR technique with a follow-up of 77 months and noted three local relapses in 22 patients. The HDR series by Ogino et al. [14
] reported no recurrence in 14 patients after a mean follow-up of 90.5 months. Teruya et al. [16
] also reported no recurrence in 13 patients with a median follow-up of 127 months. After a median follow-up of 46 months, MacLeod et al. [15
] reported one VAIN persistence and one invasive relapse among 14 patients treated with HDR. Overall, the success rates achieved using definitive brachytherapy are high and homogeneous across published series. The remaining variability in the success rate might be explained by differences in treatment; for instance, the prescription point (vaginal mucosa or 5 mm deeper) and prescribed dose, population (only VAIN-3 or all grades of VAIN), or duration of follow-up.
The long-term toxicity profile of LDR vaginal brachytherapy for high-grade VAIN is very favorable, because no grade 3 or 4 early or late toxicity was recorded in our series. This is consistent with the report by Perez et al. [13
], who noted one grade 3 urinary complication (bladder neck stenosis requiring surgery) among 40 patients with stage 0 or 1 vaginal cancer. This compares favorably with HDR and MDR vaginal brachytherapy published series. Indeed, in the MDR series by Graham et al. [17
], five grade 3 and one grade 4 toxicities were reported. Ogino et al. [14
] reported three cases of rectal bleeding and two cases of moderate-to-severe vaginal adhesions in 20 patients treated with HDR vaginal brachytherapy for CIN-3 or VAIN-3. Vaginal toxicity was greater when the entire vagina was treated. Teruya et al. [16
] reported three cases of rectal bleeding or macroscopic hematuria in 13 patients after vaginal HDR treatment for VAIN after hysterectomy for CIN. This toxicity appeared only in the patients for whom brachytherapy was delivered to 10 mm below the vaginal mucosa (n
= 3 patients) and not for those in whom it was delivered to 5 mm (n
= 10 patients) below the vaginal mucosa [16
]. MacLeod et al. [15
] reported two cases of grade 3 late vaginal toxicity (atrophy and stenosis) in 14 patients treated with HDR for high-grade VAIN. In their series, the whole residual vagina was treated.
The favorable toxicity profile achieved in our series can be explained by different reasons. First, the upper half of the vagina, not the whole vagina, was treated in the majority of patients, because VAIN is predominantly located in the upper third of the vagina. Second, the use of LDR brachytherapy might relatively spare normal tissues. Third, the dose was prescribed to 5 mm below the vaginal surface (and not to the vaginal mucosa or 10 mm below the vaginal mucosa, which leads to either recurrence or toxicity). Last, the use of the mold technique, expanding the vagina without the use of packing, allowed lowering the dose received by the healthy parts of the vaginal walls. This toxicity profile might even be further improved by individualization of the prescription depth according to findings using vaginal ultrasound, as previously described by Onsrud et al. [20
Other treatment options for VAIN-3 include surgery, topical 5-FU, laser therapy, interferon therapy, and imiquimod. There is no comparative study testing which treatment is the best, so no treatment can be considered standard, although local excision or upper colpectomy are the most frequently used treatments in the largest published series [2
]. Topical 5-FU is considered the least active treatment. It is often poorly tolerated, because it induces a hypersensitivity reaction, vaginal burning, and vulvar irritation. Recurrence rates among patients with VAIN treated using topical 5-FU, laser therapy, and partial colpectomy were 59%, 38%, and 0%, respectively, according to Dodge et al. [4
]. In a study reported by Rome and England [6
], the respective recurrence rates after local excision, laser ablation, and topical 5-FU were 31%, 31%, and 25% in 132 patients. Altogether, relapse rates seemed lower, or at least comparable, after vaginal brachytherapy than after other treatment modalities.
No invasive cancer was found in our series. It is important that VAIN-3 patients treated with a conservative approach are followed up carefully and for a long time. This allows early detection of recurrence, either intraepithelial or invasive. Second cancers are always a concern with radiotherapy, especially for diseases with a high cure rate and long life expectancy, but none has been reported in all the retrospective series of vaginal brachytherapy. This could be related to the small irradiated volume. Major potential shortcomings of brachytherapy are that, unlike surgery, it does not allow a detailed pathological review to be performed, therefore leading to undertreatment of patients with microinvasive disease. Indeed, rates of occult invasive vaginal cancer could be as high as 12%–28% according to surgical series [21
]. Besides, surgery after radiotherapy is more complex, leading to a higher rate of perioperative complications. On the other hand, surgery can lead to overtreatment because the rate of negative pathology after upper colpectomy for VAIN is estimated at around 20% [20
To conclude, the outcome of this series of patients treated for VAIN-3 shows that vaginal LDR brachytherapy is a safe and very effective treatment. It should be offered to and discussed with patients, along with other treatment options. In the end, the choice of a treatment option for patients with VAIN-3 relies on the number of lesions, their location, the length of the vagina, whether the patient is sexually active, her menopausal status, previous radiation therapy, and physician experience and preference. And also, and very importantly, for a condition for which no standard treatment exists, the choice of treatment modality depends on patient preference.