18. Primary vaginal cancer and vaginal recurrences - The GEC-ESTRO Handbook of Brachytherapy

SECOND EDITION

The GEC ESTRO Handbook of Brachytherapy

PART II: CLINICAL PRACTICE 18 Primary vaginal cancer and vaginal recurrences Henrike Westerveld, Nicole Eder-Nesvacil, Maximilian Schmid

Editors Bradley Pieters Erik Van Limbergen Richard Pötter

Peter Hoskin Dimos Baltas

Primary vaginal cancer and vaginal recurrences

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

18 Primary vaginal cancer and vaginal recurrences Henrike Westerveld, Nicole Eder-Nesvacil, Maximilian Schmid

1. Summary 2. Introduction 3. Anatomy 4. Pathology

3 3 3 4 4 6 7 8

9. Treatment planning

10 11 12 12 13 14 15

10. Dose, dose rate and fractionation

11. Monitoring

12. Results

5. Work up

13. Adverse Events 14. Key messages 15. References

6. Indications and contra-indications

7. Clinical Target Volume

8. Technique

1. SUMMARY

Definitive radiotherapy including brachytherapy plays a central role in the management of primary vaginal cancer and previously non-irradiated vaginal recurrences from cervical or endometrial cancer. Non-mutilating surgery is typically restricted to small tumours in the upper part of the vagina or close to the vulva. In the majority of patients, a combination of external beam radiotherapy (EBRT) with or without concomitant chemotherapy and brachytherapy is recommended, whereas selected small superficial tumours (T0/T1) may be treated with brachytherapy alone. MRI together with gynaecological examination are the preferred modalities for target volume definition and image-guidance. The brachytherapy application depends on the local tumour spread and the response to external beam radiotherapy +/- chemotherapy. Superficial tumours at brachytherapy can be treated with intra-vaginal applicators alone, whereas in larger tumours with residual paravaginal disease combined intracavitary and interstitial applicators should be used. Local tumour control rates >80% at 5 years can be reached with radiochemotherapy and image-guided brachytherapy in locally advanced disease. Although prospective data are limited, major treatment related toxicity seems to occur more frequently than when treating primary cervical cancer, mainly due to the higher frequency of painful vaginal ulcerations, complete vaginal stenosis, and fistulae.

2. INTRODUCTION

3. ANATOMY

This chapter describes the management of vaginal malignancies in adults referring to the treatment of primary vaginal cancer and vaginal recurrences from cervical or endometrial cancer. Due to the rarity of vaginal malignancies (primary vaginal cancer accounts for only 2% of all gynaecological malignancies) there is only limited literature and specific evidence available, especially in light of the nowadays standard of image-guided brachytherapy. Therefore, many treatment recommendations are derived from cervical cancer, with which they share anatomical and some aetiological and pathological similarities. Also, symptoms are comparable to those from cervical cancers including vaginal discharge, bleeding and pain during sexual intercourse. Radiotherapy including brachytherapy plays a central role in the management of vaginal malignancies as non-mutilating surgery is typically restricted to small superficial tumours in the upper part of the vagina or close to the vulva. Recent evidence from a SEER analysis in 2,517 patients with vaginal cancer suggests improved survival when brachytherapy is part of the treatment [1].

The vagina is a fibromuscular, tubular and expandable cavity, between the bladder, urethra and rectum. It is limited by the cervix superiorly and by the urethral meatus externus and the vulva/ introitus inferiorly. The vagina extends laterally to the paravaginal and parametrial tissues including the Bartholin glands, anteriorly to the bladder, urethra and crux of the clitoris, and posteriorly to the rectum and anorectal sphincter complex (Figure 1)[2]. The vaginal wall consists of different layers, namely the vaginal mucosa, the lamina propria including blood vessels and lymphatic tissue, a smooth muscle layer, and the adventitia, consisting of a dense layer of connective tissue with blood vessels, lymphatic tissue, and nerves [3]. Dependent on the location and expansion of the vagina, the vaginal wall has a thickness of approximately 3-5 mm. The vagina is anatomically divided in three parts: the lower, middle and upper third. The introitus is located approximately at PIBS-2cm level. The transitional zone from lower to middle part of the vagina is indicated by the PIBS. The transitional zone from middle to upper part of the vagina is in general located at the level of the caudal border of the bladder neck [4].

Primary vaginal cancer and vaginal recurrences

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Figure 1. Schematic diagram with corresponding T2WI MRI of the anatomy of the vagina and adjacent tissues in the axial (mid and lower vagina) and sagittal planes. Adopted and re-used with permission from Albuquerque et. al. [2].

4. PATHOLOGY

The lymphatic drainage of vaginal tumours is correlated to the double embryologic origin of the vagina from the Müllerian canal and urogenital sinus. Its drainage is via the lymphatic vessels in the vaginal submucosa to the iliac and obturator nodes for the upper two thirds of the vagina, and to the hypogastric and inguinal nodes for the lower third; the drainage of the posterior wall and rectovaginal septum is to the sacral nodes, and in some cases the mesorectum [5]. Due to its superior soft-tissue contrast, magnetic resonance imaging (MRI) is the best imaging modality to display the anatomy of the vagina, especially in comparison to computed tomography (CT)[6]. In addition, ultrasound/sonography (US) also has a good soft-tissue contrast and could be helpful in the operating room (OR) to localize the vaginal tumour and guide the implantation of the applicator and interstitial needles [7]. Minimal requirements to visualize the vaginal tumour are the acquisition of three orthogonal (axial, sagittal and coronal) T2 weighted series, preferably supplemented with functional series such as diffusion-weighted images (DWI). On T2-weighted images a vaginal tumour is usually demarked as an intermediate to hyper-intense lesion [2, 6]. The application of intravaginal gel could be considered for better visualisation of the tumour.

Primary vaginal cancer resembles the aetiology of cervical cancer as the majority of cases are HPV-positive squamous cell carcinomas (80 - 85%)[8]. The other known histological subtypes are adeno- or adenosquamous carcinoma (10 - 15%), sarcoma and melanoma (2 - 3%), and others like clear cell carcinomas from diethylstilbestrol (DES) application (1 - 2%)( https://www. uptodate.com/contents/vaginal-cancer). In case of a vaginal recurrence of a different origin like cervical, endometrial, rectal or ovarian cancer, the histology resembles the primary tumour.

5. WORK UP

Staging for primary vaginal cancer is defined using the TNM (Union for International Cancer Control) and FIGO (The International Federation of Gynaecology and Obstetrics) classification (Table 1)[9, 10]. The diagnostic work up consists of a combination of careful gynaecological examination with biopsies and imaging. It is important to exclude a tumour arising elsewhere and involving the vagina, or vaginal metastases from gynaecological tumours

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TABLE 1 FIGO AND TNM STAGE FOR PRIMARY VAGINAL CANCER. FIGO stage TNM stage

Primary tumour definition

Primary tumour

Regional lymph nodes Distant metastasis

I

T1

N0

M0

Tumour confined to the vagina

II

T2

N0

M0

Tumour invades paravaginal tissue

III

T3

N0

M0

Tumour extends to pelvic wall

IVA

T4

N0

M0

Tumour invades bladder or rectum or extends beyond true pelvis

IVB

Any T

Any N

M1

90%

FIGO=International Federation of Gynaecology and Obstetrics; TNM=Tumour, Node, and Metastasis; N0=no regional lymph node metastasis; N1=regional lymph node metastasis; M0=no distant metastasis; M1=distant metastasis.

Figure 2a.

Figure 2b.

Figure 2. Clinical drawing cartoons (a) with and (b) without uterus in situ that can be used for precise and reproducible description of the local extend of the vaginal tumour at the time of diagnosis and brachytherapy. Re-used with permission from Schmid et. al. [12].

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Figure 3. Transverse MRI and corresponding transverse TRUS imaging before, during and after applicator implantation in a patient with primary vaginal cancer with urinary bladder invasion. Upper row: plain images, lower row: same images with contours and marks indicating the inserted needles. From left to right: Panel 1: pre-brachytherapy MRI with cylinder in situ; Panel 2-6: TRUS during implantation showing stepwise needle insertion; Panel 7: Treatment planning MRI with final implant; yellow contour: urinary bladder; red contour: CTV-T HR , white circles indicate interstitial needles.

brachytherapy. Finally, a vaginal mould with the impression of the tumour could be useful for documentation and even used for treatment of superficial tumours [13]. Nowadays the standard imaging modality for evaluation of the primary vaginal tumour, and for contouring and planning at the time of brachytherapy, is an abdominal-pelvic MRI including the whole vagino-vulvar region. Trans-vaginal and trans-rectal ultrasound is helpful to precisely evaluate the morphology and topography of the tumour in the vagina and guide the implantation (Figure 3). In addition, for assessment of lymph node and distant metastases CT or PET CT is advised. In selected cases, cystoscopy or proctoscopy is performed, in particular when involvement of bladder or rectum is suspected [7, 12]. Careful pre-brachy treatment planning is of great value to achieve the best possible implant and therefore the best treatment plan at time of brachytherapy (BT). A pre-brachytherapy MRI in the fourth or fifth week of external beam radiotherapy (EBRT) with an intracavitary applicator (e.g., cylinder) or vaginal gel could be helpful (Figure 4). This pre-BT MRI in combination with the diagnostic MRI allows for contouring of the target, and helps to decide which applicator should be used and where, and how many, interstitial needles should be inserted. At the time of implantation or in the week before, gynaecological examination and vaginal ultrasound further help to fine-tune the implantation. Locally advanced primary vaginal cancer (T2-T4) and early stage disease (T1) not amenable for non-mutilating surgery should be treated with definitive external beam radiotherapy (EBRT) and platinum-based concurrent chemotherapy [14], followed by a brachytherapy (BT) boost to the primary tumour [7, 15]. Patients unfit for concurrent chemotherapy may be considered for regional hyperthermia [16]. Selected primary or recurrent vaginal tumours up to 2cm diameter and 7mm thickness without any evidence of nodal disease may be considered for treatment with brachytherapy alone [15]. Locally advanced vaginal recurrences from cervical or endometrial cancer without a previous history of radiotherapy should be treated the same as primary vaginal tumours, with a combination of EBRT 6. INDICATIONS AND CONTRA-INDICATIONS

Figure 4. Examples of (a, b, c) MRI at diagnosis with vaginal gel in situ and, (d, e, f) pre brachytherapy MRI in the fourth week of EBRT with a cylinder dummy in situ, in transversal, sagittal and coronal view, respectively (from left to right). The green line indicates the location in the corresponding orthogonal views. The red star indicates the vaginal gel (white); the tau indicates the vaginal cylinder.

(endometrium, ovarian cancer) and other malignancies. When a vaginal tumour extends to less than 1 cm of the ostium of the cervix or to the vulva, it should be classified as a cervical or vulvar cancer, respectively [11]. The local extent of a vaginal tumour is in general easily evaluated by gynaecological examination, preferably by two examiners, which should not be abandoned as it gives valuable and additional information to imaging, especially in the case of superficial tumours. Recently, the Groupe Européen de Curiethérapie – European Society for Radiotherapy and Oncology (GEC-ESTRO) GYN (gynaecology) taskforce for vaginal tumours adapted the clinical drawings used for cervical cancer for a precise and reproducible description of the local extent of the vaginal tumour [12] (Figure 2a and b). This clinical drawing diagram allows for a full three-dimensional description which implies a clockwise definition of the tumour spread at upper, middle and lower third, the length of the tumour along the vaginal axis, the thickness perpendicular to the vaginal axis, and the width of the tumour including any paravaginal extension. In addition, the tumour-free distance from the vaginal top at the cervix to the proximal part of the tumour, and from the distal part towards the introitus should be documented. The implantation of markers at the borders of the tumour at time of diagnosis is helpful for target volume definition at time of

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Figure 5a.

Figure 5b.

Figure 5. Example of the GEC-ESTRO target concept applied in a locally advanced primary vaginal cancer case. Re-used with permission from Schmid et al [12]. (a) T2-weighted MRI and clinical drawings at the time of diagnosis (upper row) and at the time of brachytherapy (lower row) in a woman with primary vaginal cancer in the upper third posteriorly, FIGO stage II. The patient was primarily treated with 46 Gy in 2 Gy fractions IMRT without concomitant chemotherapy, but with concomitant regional hyperthermia. The tumour showed good response, but significant residual disease was detected at the time of brachytherapy. A combined intracavitary and interstitial approach was used. The white arrow indicates the tumour on the MR images. The tumour is outlined in red on the clinical drawings. (b) Target delineation and OAR based on the recommended structures: GTV-Tres (white), CTV-T HR (red), CTV-T IR (blue), vagina outside CTV-T HR (light blue), bladder (yellow), rectum (light brown), sigmoid (green), bowel (olive), anal canal (dark brown), urethra (grey, partly depicted).

7. TUMOUR AND TARGET VOLUME

and brachytherapy. Concurrent chemotherapy may be considered depending on the origin and pathology of the primary tumour. Tumour infiltration and fistulation of urethra, bladder or rectum (T4) at initial presentation is not a contraindication for definitive radiotherapy including brachytherapy, however bladder, bowel or rectal diversion may be considered before the start of treatment, particularly for symptomatic patients. Alternatively, pelvic exenteration can be an alternative approach for definitive radiotherapy in selected cases. Selected patients with a previous history of vaginal or pelvic radiotherapy and non-metastatic disease may be offered re irradiation including EBRT and brachytherapy depending on their general condition, tumour extent and location, prognostic factors, previous radiotherapy dose, technique and dose distribution, and time-to-recurrence and re-irradiation.

Recommendations for target volume definition for EBRT and image-guided adaptive brachytherapy (IGABT) have been recently published by the Gynaecological GEC-ESTRO Working Group for primary vaginal cancer [12] and a collaboration between GEC ESTRO, American Brachytherapy Society (ABS) and Canadian Brachytherapy Group (CBG) for vaginal recurrences [17]. Target volume definition is based on imaging (primarily T2-weighted MRI) and gynaecological examination and is similar for both entities with only minor differences (see definitions below). The principle of response-adaptive target definition based on previous experiences with IGABT in primary cervical cancer described in the ICRU-89 report [18] was adopted as both primary and recurrent vaginal malignancies typically show substantial early response to chemoradiation. Therefore, availability of imaging and proper documentation of gynaecological examination at the

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extensive lymphovascular space invasion (LVSI) or multifocality larger margins along the vaginal wall may be applied [12, 17]. An example of the above-mentioned target concept in the treatment of a locally advanced primary vaginal tumour is shown in figure 5. There is currently no specific recommendation for target volume definition in image-guided brachytherapy as a single modality. Traditionally, this was the gross tumour volume with a safety margin of 10 – 20 mm along the vaginal wall.

time of diagnosis prior to the start of EBRT and at the time of brachytherapy is mandatory. The tumour shrinkage observed during chemoradiation is taken into account for target volume definition, which consists of three target volumes. The following section refers to a brachytherapy boost after conventionally fractionated EBRT of 45 to 50 Gy in 1.8-2.0 Gy per fraction: GTV-T res : The GTV-T res is the remaining visible and palpable residual macroscopic tumour during gynaecological examination at the time of brachytherapy. On T2-weighted MRI this is visualized as a remaining mass with hyper-intense to isointense signal intensity, within the initial tumour extension at diagnosis [12]. CTV-T HR : The high-risk clinical target volume includes the GTV T res and any abnormal thickened or irregular vaginal wall within the initial tumour extension before EBRT. On T2-weighted MRI the thickened or deformed wall typically has a more hypo-intense appearance. In case of tumours infiltrating the paravaginal or parametrial space at diagnosis, so called “grey zones“ can be observed, and are included in the CTV-T HR . “Grey zones” are considered as signs of tumour regression in terms of conversion of tumour cells into fibrotic tissue and are defined as areas with hypo-isointense signal intensity on T2-weighted MRI occurring within the initial tumour extension in the paravaginal or parametrial space [12]. CTV-T IR : The intermediate risk clinical target volume should include all significant microscopic disease adjacent to the CTV THR. Practically, the CTV-T IR should minimally encompass the initial tumour extension at diagnosis adapted to the anatomical situation at brachytherapy including a safety margin of at least 0.5 cm in tissue around the CTV-T HR , limited by previously unaffected anatomical borders (primary vaginal cancer). In patients with vaginal recurrences with high risk histologies (e.g., serous cancer),

8. TECHNIQUE

8.1 Application techniques Intracavitary (IC) as well as interstitial (IS) implants are used, often in combination. In both, intracavitary and interstitial implantation, different dose rates can be used. High-dose rate (HDR) and pulsed-dose rate (PDR) schedules are nowadays the most frequent choices, while low-dose-rate brachytherapy (LDR) is on the decline. Iridium-192 sources are mainly used for HDR and PDR afterloaders [19]. Cobalt-60 sources are also used as an alternative. 8.1.1 Intracavitary brachytherapy Different vaginal applicators are commercially available: metallic or plastic colpostats, cylinders of different diameters with or without peripheral needles, ring applicators, split rings with or without vaginal caps (serving as a multichannel cylinder) or a vaginal mould, to be adapted to the anatomy of the patient, the volume and the topography of the tumour (Figure 6). In tumours of the upper third

Figure 6. Examples for applicator types for vaginal brachytherapy*: 1a, b: intracavitary multichannel cylinders in different diameters; 2a, b: intracavitary/interstitial multichannel cylinder with a perineal template (four peripheral needles in cylinder and tissue, two needles in paravaginal tissue); 3a, b: ovoid-type intracavitary and interstitial applicator (one needle shown) tandem; 4a, b: ring-type applicator with three needles inserted through vaginal caps and ring. Many applicators include optional intrauterine tandem, as shown in panel 4. *Disclaimer: Example products were selected solely to represent different applicators types.

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Figure 7. Comparison of loading patterns for intracavitary multichannel cylinder implants, all with dose prescribed at a dose point to 5mm tissue depth. (a) Central channel loading only, (b) equal loading of central and peripheral channels, (c) peripheral needle loading only. Note variations in distribution of surface doses for different loading, as well as the variation of the shape of the 100% isodose.

Figure 8. Differences and challenges in brachytherapy planning of a locally advanced vaginal tumour by an intracavitary or intracavitary and interstitial approach. Re-used with permission from Westerveld et. al. [7]. A transversal and coronal T2-weighted MRI of the anatomy and target volume is shown. (a) Target volume is delineated in red. (b) The use of intracavitary brachytherapy alone in a standard intracavitary plan with dose prescription to 5 mm tissue depth results in underdosage of the target. Target volume [red] is not covered by 100% of the prescribed dose [blue]. (c) The use of intracavitary brachytherapy alone in a suboptimal intracavitary plan has an improved, yet still not optimal, coverage of the target and the dose to the vaginal mucosa is too high (200–400% of prescribed dose). (d) The use of an optimal combined intracavitary and interstitial plan has good coverage of the target and good sparing of the organs at risk.

of uninvolved vaginal mucosa is achieved by selection of the largest cylinder the patient can accommodate. Shielding inside cylinders has been used to protect part of the vaginal wall, rectum, bladder or urethra. However, with the rise of MRI as a primary imaging modality for treatment planning, MRI-compatible multichannel applicators have become more popular. In addition to the central catheter, these multichannel IC applicators have peripheral source channels close to the cylinder surface, which are equally spaced, about every 5 mm, and cover the whole circumference of the cylinder. This allows an increased number of degrees of freedom for dwell point activation. The whole vagina can be treated with these cylinders. Multichannel versions allow for an increased dose in the region of the CTV-T HR , while keeping the dose on the uninvolved side of the applicator as low as needed.

of the vagina, the technique is analogous to that in cervix cancer with a uterus in situ (see techniques in cervical cancer, chapter 16) and similar applicators can be used including an intra-uterine tandem. 3D printing of patient-anatomy adapted applicators instead of the mould technique is an upcoming technique. For all applicator types, metallic components have gradually been replaced by plastic, as MRI has become the gold standard imaging modality for gynaecological IGABT treatment planning. There are different applicators dedicated to vaginal tumours. In vaginal cylinders the sources are located within a central linear catheter. These cylinders are typically available with diameters of 2 to 4 cm (Figure 6, panel 1 and 2). Following the inverse square law, the dose is higher when closer to the central source. Therefore, sparing

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of IS needles is done via the perineum or intravaginally. Perineal needles are inserted in a parallel configuration, with preferably equal spacing (10-15 mm depending on the target and anatomy), covering at least the residual tumour or CTV-T HR . In the case of upper tumours this can be challenging because of possible divergence or convergence of the needles. However, with 3D imaging, deviations from an ideal implant geometry can be partly compensated by dwell time optimisation during treatment planning. Nowadays, plastic needles are predominantly used, either with round or sharp tips. The advantage of sharp tips is a better steering during insertion, however there is an increased risk of puncturing organ walls. To aid precision during needle placement, it is recommended to use real-time ultrasound guidance in the operating theatre, via a trans-rectal or an endovaginal probe. In-room-CT or –MR suite solutions are also possible for fast implant quality verification in the operating room. Intracavitary BT alone is performed for target lesions less than 5-7 mm CTV-T HR thickness at the time of brachytherapy. In this case, the reference isodose follows the round curvature of the cylinder surface. It is prescribed to the vaginal wall for a certain length and thickness (in general 3-5 mm), either to cover the whole vagina or part of the vaginal length and circumference, respectively. Target delineation recommendations should be followed. The dose is reported to the CTV-T HR , as well as to a reference point at 5 mm radial into the tissue from the IC applicator surface, on the involved side (independent of dose prescription at a certain tissue depth). Using a multichannel cylinder, it is possible to spare OAR dose and the vagina wall on the opposite side of the CTV. To do so, either only the dwell positions in the peripheral needles near the CTV are activated, or the loading is distributed over the central catheter and the peripheral needles (Figure 7). The latter loading pattern will result in higher doses to the uninvolved vaginal tissue, but it may result in lower surface dose on the CTV side. The magnitude of the difference between these loading strategies, assuming the same target coverage, depends on the weighting of central vs. peripheral needles, and the cylinder diameter. There are currently no evidence-based recommendations for one or the other loading strategy. In interstitial implants, Paris system rules are applied for the implantation geometry, aiming for parallel and equidistant needle placement. If combined intracavitary and interstitial brachytherapy is performed ICRU 89 recommendations can be applied for reporting. In case of target volumes thicker than 5-7 mm at time of BT, the application of interstitial needles is advised, in addition to a multichannel intracavitary applicator. The reason for this is that with thicker tumours the vaginal mucosa will receive an excessive dose, or the CTV-T HR will not be adequately covered (Figure 8). The dose is prescribed to the GTV-T res , the CTV-T HR and CTV T IR . Depending on the complexity of the application, initial dose prescription can be based on dose points placed along the cylinder axis (e.g., at a tissue depth of 3 or 5 mm), followed by subsequent adjustment of the loading to cover the delineated target volumes. Depending on the anatomical configuration, a combination of loading of the peripheral catheters in the IC applicator +/- central catheter, and interstitial needles is performed (Figure 9). The choice of the IC loading is made as in an IC only implant, taking 9. TREATMENT PLANNING

In tumours limited to the upper third of the vagina and with an intact cervix, tandem-ovoids, tandem-ring applicators or tandem split rings with or without vaginal caps can be used (Figure 6, panel 3 and 4). In difficult cases, these plastic applicators are used as they allow the use of a central source (e.g., through a short tandem) and specific holes near to the applicator surface for introducing tubes or needles according to the geometry and extension of the specific tumour. Like vaginal cylinders, these applicators could be combined with a perineal template for placement of paravaginal needles or combined with free needles. 8.1.2 Interstitial implants The technique and the principles of interstitial (IS) brachytherapy, including the Paris system, are described in chapter 7. Although an IS only technique could be considered for treatment of extended vaginal disease, a combination of IC/IS is generally used. Implantation Figure 9. Example of a complex implant with intracavitary multichannel cylinder plus interstitial needles. Different loading patterns are shown. Top panel: loading only in peripheral IC and IS needles; middle panel: equal loading of central IC catheter, peripheral and interstitial needles; bottom panel: main IC loading in central catheter, low loading of peripheral needles, plus IS needles. All dose distributions were normalized to equal D90 of CTV-T HR . Green isodose line corresponds to 100% of planning aim for D90 CTV-THR. Other isodoses relate to this planning aim dose as follows: dark blue: 30%, light blue: 50%, cyan: 70%, yellow: 150%, red: 200%. Contours for rectum, CTV-T HR , CTV-T IR , and vagina outside of CTV-T HR are shown. This figure illustrates the effect of the loading pattern on contralateral dose to vagina, dose to rectum, and high dose volumes around needles, inside CTV. The planner‘s choice of the loading pattern will depend strongly on the given planning aims for all CTVs, including dose to contralateral vagina

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(HIPO) algorithm [20) would be the preferred choice, comparable to cervical cancer BT [21]. It allows locking of the loading of the intracavitary implant after initial optimization, and inverse optimisation of the loading of interstitial needles, based on total dose objectives for targets and OARs. For interstitial loading only, the inverse planning simulated annealing (IPSA) algorithm could be applied [22, 23).

TABLE 2 HDR PLANNING AIM DOSES DESCRIBED IN LITERATURE FOR THE TREATMENT FOR PRIMARY AND RECURRENT VAGINAL TUMOURS (27, 28, 30-32) Number of fractions Physical dose per fraction (Gy)

2

5.5 – 8.5

3

6.0 – 7.0

10. DOSE, DOSE RATE AND FRACTIONATION

4

6.0 – 7.0

Traditionally, vaginal tumours were treated with continuous low dose rate (LDR) brachytherapy [24]. However, due to, among others, protection issues this technique has been abandoned and replaced by PDR and HDR. Among the large European centres there is a tendency to treat these tumours with PDR [24]; it resembles the former LDR technique and is thought to better spare the organs at risk and vaginal mucosa leading to less toxicity. In the treatment of large tumours especially, when an intracavitary and interstitial (IC/IS) approach is applied, the preference is to treat with PDR. However, the availability of PDR is declining and an increasing number of centres are using HDR. In general, for superficial tumours treated with intracavitary only techniques HDR can be safely used with brachytherapy planning based on volumetric imaging with CT or MRI, and preferably with the use of a multichannel vaginal cylinder (MCVC) to spare the parts of the uninvolved vaginal wall [25, 26]. In recent years, some small studies have been published about the use of HDR in large tumours treated with an intracavitary and interstitial approach with encouraging results [27-29]. Typically, brachytherapy is given as a boost at the end or after EBRT (typical schedule: 45-50 Gy in 1.8-2.0 Gy fraction). Depending on the logistics in the centre one to three applications are used, and one to five fractions are given per application in the case of HDR. In the case of PDR, in general one or two applications are performed with an hourly pulse dose schedule with total of 30-60 pulses of 0.5-1.0 Gy per pulse. HDR schedules are listed in Table 2 [27, 28, 30-32]. An overall treatment time of less than 50 days should be aimed for, especially in case of primary vaginal cancer or recurrent cervical cancer. According to the GEC-ESTRO/ACROP recommendations for image-guided adaptive brachytherapy (IGABT) in primary vaginal cancer, the dose should be prescribed to a clinical target volume instead of to a dose point [12]. In general, dose is prescribed as the D90 (the minimum dose received by 90% of the volume) of the high-risk CTV (CTV-T HR ), and to the D98 of the residual gross tumour volume (GTV-T res ) and the intermediate risk target volume (CTV-T IR ) which are important parameters to be taken into consideration. Moreover, the D0.1 cm 3 and the D2cm 3 doses for the adjacent organs (rectum, bladder, sigmoid, bowel, urethra and anal canal) should be documented [12]. In case of a complete response, and no visible abnormalities on the MRI that can be contoured as high-risk CTV, alternatively the dose could be prescribed to 3-5 mm tissue depth (depending on the thickness of the vaginal wall) perpendicular to the vaginal wall at the location where the tumour at diagnosis was originated (corresponding with the CTV-T IR ) Due to the rarity of vaginal cancer, no strong recommendations can be given regarding the prescription dose. In principle, dose prescription follows that for cervical cancer and is prescribed to

5

4.0 – 5.0

into account the planning aim dose for the overall vagina, and sparing of nearby organs at risk. Multichannel cylinders again have an advantage to shape the dose distribution at the edge of challenging OARs. Loading of the interstitial implant component should follow the principles of the Paris system (ICRU report 58), in order to keep control of the size of hyper dose sleeves around the active needles. According to a survey among MR-IGABT treating centres in the GEC-ESTRO GYN network, typically up to 150-200% of the CTV-T HR planning aim dose (see paragraph 10) are considered. The volumes of these isodoses should not be confluent with hyperdose sleeves of neighbouring needles. The same survey showed that special attention is given to the surface dose at the IC applicator, taking into account the additional contribution arising from the active needles. Typically, a surface dose planning aim to stay below 150-200% of the planning aim dose for CTV T HR , can be achieved. However, there is no clear clinical evidence to recommend a maximum surface dose yet. The planner should consider that a constraint for the surface dose and high dose islands around the interstitial needles which are based on a percentage of the planning aim dose will be highly dependent on the choice of planning aim and fractionation. Individual assessment of this constraint is therefore essential. For OAR dose reporting, recommendations from ICRU89 can be analogously applied. These include the reporting of volumes, D0.1cm³ and D2cm³ doses for bladder, rectum, sigmoid, bowel and anal canal; and D0.1cm³ and D10% for urethra. In addition, the ICRU-bladder point, and the PIBS and PIBS-2cm points in case of a vaginal tumour located in the proximal part of the vagina, might have additional value to report. D98% should be reported for all target volumes and represents a near minimum dose. D90% is additionally reported for larger target volumes, such as CTV-T HR and CTV-T IR . Total reference air kerma (TRAK) should be reported. All dose metrics should be reported for individually planned fractions and for the total treatment, taking into account an EBRT treatment component. For calculating the equi-effective dose in 2 Gy fractions (EQD2), using the linear quadratic model, the use of α/β =10Gy is recommended for target, and 3 Gy for organs at risk. Inverse planning may be applied, taking into account differences in available algorithms. In order to allow for unequal loading of interstitial and intracavitary applicators for hybrid intracavitary and-interstitial implants, the hybrid inverse planning optimization

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and duration of the planned treatment. In addition, use of an intra uterine tandem where there is an intact uterus can help to prevent displacements. In parallel, strategies to detect applicator shifts are necessary which should include at least visual inspection of the outer parts of the applicator before dose delivery related to the situation at treatment planning. Documentation with skin marks and photos can be very helpful. In addition, repeated imaging preferably with the same imaging modality as for treatment planning should be performed in the case of longer lasting treatments (e.g. more than one day) to evaluate the need for re-planning or re-positioning of the applicator [36].

the D90 of the CTV-T HR . However, doses prescribed for vaginal tumours are in general lower, especially in those tumours that are located in the distal part of the vagina. This is because this part of the vagina appears to be more prone to severe toxicity due to the close proximity of the anorectum, urethra and vulva, and the increased risk of mucosal ulceration and obliteration. Consequently, in vaginal tumours, the dose prescribed to the target is dependent on the location. A total D90 dose in the CTV-T HR of 75-85 Gy in EQD2 αβ10 is aimed for. It mirrors the interquartile range (IQR) from the RetroEMBRAVE study (73-85 Gy), reflecting current practice in five European centres [24]. This corresponds well with the guidelines of the ABS from 2012, recommending 70-85 Gy to a CTV, which is dependent on tumour location, extent of disease and response to EBRT [27]. According to the retroEMBRAVE data, a D90 for the CTV-T HR > 80Gy should be considered for large (T2-4) tumours [24]. The ABS recommends limiting the total dose in the lower third of the vagina to 75 Gy [27]. Evidence-based planning aims for GTV-T res and CTV-T IR are not available yet, however based on the concept of cancer cell densities a higher dose could be considered for the GTV-T res and a lower dose for the CTV-T IR with the aim of at least 60 Gy to the D98 according to the target planning aims for CTV-T IR in cervical cancer[33]. In some centres it is common practice to prescribe with brachytherapy additional dose to the adjacent vaginal wall not included in the CTV-T IR for possible multifocal spread. However, it is under debate if this is needed on top of the prescribed EBRT dose, and will be a topic of future prospective studies in which patients are treated according to the GEC-ESTRO and GEC-ESTRO-ABS-CBG recommendations for contouring of vaginal tumours [12, 17]. For the organs at risk the currently used dose constraints for cervical cancer (D2cm 3 rectum < 65-75 Gy, D2cm 3 bladder < 80 90 Gy, and D2cm 3 sigmoid/bowel < 70-75 Gy) are also applied to the treatment of vaginal tumours [33]. Hopefully, upcoming prospective multicentre trials in vaginal cancer will help us to adapt our planning aims and constraints more precisely and comprehensively. Finally, in some specific conditions brachytherapy only can be considered, especially in the case of a very small, superficial tumour or in a re-irradiation setting [31, 34]. Although limited literature is available about the prescribed dose in BT-only setting, an HDR planning aim of 6 x 6-7 Gy prescribed to 3-5 mm tissue depth has been used in the past [31].

12. RESULTS

Data published in the 26th annual FIGO report regarding the outcome of patients with primary vaginal cancer showed a 5-year overall survival of 77%, 52%, 42%, 20% and 13% for FIGO stages I, II, III, IVA and IVB, respectively [37]. These data have not been recently updated. Due to the rarity of the disease, the published results include mainly monocentric, retrospective studies in the era before the use of 3D image-guided adaptive brachytherapy (IGABT). In addition, the ranges of published outcome data are very large and centre dependent. Larger (> 50 patients) 2D-image guided brachytherapy studies report a five-year pelvic control of 74-81% [7]. In comparison, results from the 3D IGABT studies showed a two-year local control of 82-93% [7]. The results from the 3D IGABT studies compares especially favourable in larger (≥T2) tumours. In the international multicentre RetroEMBRAVE study actuarial five-year local control was 75% versus 0-70% in the 2D brachytherapy era [7, 24]. The concept of image-guided adaptive brachytherapy has been gradually adopted for primary vaginal cancer. In the last decade, an increasing number of publications on image-guided brachytherapy were published indicating improved local and pelvic control and improved survival in comparison to 2D-radiograph based brachytherapy. Two year local control rates are in the range of 82-93% and two year overall survival is 62-91% (Table 3)[7].The benefit of IGABT, with the use of an intracavitary/interstitial approach if necessary, seems especially pronounced in the advanced tumours (T3/4), with an increased pelvic control of approximately 15% compared to earlier published results [7, 24]. The most advanced data on image-guided brachytherapy was reported in the RetroEMBRAVE study comprising 148 patients treated between 2001-2016 with relatively homogeneous treatment schedules. At a median follow-up of 29 months, two- and five-year local control was 86% and 83%; disease-free survival (DFS) was 73% and 66%, and overall survival (OS) was 79% and 68%, respectively. Differences in local tumour stage (5 year local control: T1/2 vs T3/4: 85% vs 75%) and in nodal status (5 year disease free survival: N0 vs N1: 74% vs 46%) had impact on clinical outcome [24]. Known prognostic factors for oncological outcome in primary vaginal cancer are age, lymph node metastases, stage, tumour size, and histological type [7]. In addition, the use of concurrent chemotherapy and the use of brachytherapy seems to result in better outcome [1, 14]. Results regarding oncological outcomes in the treatment of vaginal recurrences before and after the introduction of image-guided

11. MONITORING

Movements and displacement of cylinder-type applicators with or without additional use of interstitial needles are generally larger and more frequent than with tandem-ring applicators in cervical cancer [35]. Displacements typically imply caudal shifts or rotations and can cause major changes in the dose distribution. Therefore, optimal fixation of the applicator to avoid any shifts are of utmost importance. Recommendations for fixation are difficult as they depend on the local infrastructure and individual work flows. However, in general, perineal sutures or sutures through the labia majora and taping or bandages can substantially reduce movements and should be applied according to the applicator type

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

TABLE 3 SUMMARY OF ONCOLOGICAL OUTCOMES OF IMAGE-GUIDED BRACHYTHERAPY IN PRIMARY VAGINAL CANCER STUDIES. Author (year of publication) (ref n o ) Years of inclusion Number of patients Median FU (months) Median D90 CTV (Gy) LC at 2 years (%) DFS at 2 years (%) OS at 2 years (%) Severe toxicity (%)

Dimopoulos (2012) [46] 1999-2006 13

43

86

92*

NA

85*

23

Fokdal (2011) [39]

2005-2010 9

18

82

92†

59†

74†

4

Huertas(2018) [47]

2004-2016 27

40

73

82

75

91

15

Gebhardt (2018) [40]

2011-2016 16

39

77

93‡

64‡

67‡

3

Manuel (2016) [28]

2002-2014 47

24

81

93

86

82

2

Lee (2013) [41]

2005-2011 10

17

74

86

60

62

13

Westerveld (2021) [24]

2001-2016 148

29

80

86

73

79

17

Goodman (2021) [32]

2002-2017 67

32

74

87

74

86

10

FU=follow-up; D90=minimal dose to 90% of the volume; CTV=clinical target volume; LC=local control; DFS=disease free survival; OS=overall survival; NA=not available. *Outcome at 3 years. †Outcome at 4 years. ‡Outcome for the entire group, including recurrences. Updated table with permission adopted from Westerveld et al [7].

Differentiation between necrosis and local tumour recurrence can be difficult. Limited use of biopsies is recommended as necrosis usually worsens after invasive procedures. In the recent retrospective multicentre study on IGABT in primary vaginal cancer “RetroEMBRAVE” the crude incidence of severe (grade 3 and higher) adverse effects was 17%. Vesico-vaginal fistula and complete vaginal obliteration were the most frequent severe events [24]. However, as prospective data is lacking, under reporting of adverse effects, in particular with regard to vaginal morbidity, has to be assumed. Necrosis and chronic ulceration often require intensive treatment such as anti-inflammatory treatment, wound management including regular local washings with suitable solutions (e.g., benzydaminhydrochlorid), antibiotics for superinfection and hyperbaric oxygen therapy, and even may necessitate reconstructive surgery. Sexual and vaginal rehabilitation (e.g., psycho-oncological support, regular dilation, lubrication, hormonal replacement therapy) should be considered as patients may be able to regain satisfactory sexual life. Means to minimize or prevent vaginal side effects impacting on function in a similar way as reported after brachytherapy for cervical cancer [44, 45] are essential such as careful target selection and dose prescription balancing tumour and vaginal dose and volume.

adaptive brachytherapy are very limited. Older reports from the 2D brachytherapy era with patients treated with an IC/IS approach and in most cases LDR, showed a wide range of 5-years local control rates, namely from 29-100% [38]. In contrast, the results from the IGBT era including patient treated with IC-only and IC/ IS approach with PDR or HDR, showed more consistent results with local control rates ranging from 75-93% which appears to be comparable to the local control rates in primary vaginal cancer patients [39-42]. Although studies are small, some prognostic factors for oncological outcome are suggested, namely tumour volume at diagnosis and brachytherapy, time to first relapse, prescribed dose, and primary prognostic factors (e.g., FIGO stage)[38, 42]. Results from the prospective EMBRAVE study will provide evidence to confirm these results. Reported acute and late side effects after definitive chemoradiation are similar to those reported for cervical cancer. Brachytherapy specific severe adverse effects concern mainly the vagina, urinary bladder, rectum and depending on the location of the tumour also the urethra, clitoris, bowel and anal canal [24]. The vagina has a special role as it is both the target volume and organ at risk at the same time and the optimal balance between target dose and avoidance of side effects is challenging. Typical vaginal side effects range from mucosal atrophy and dryness to more severe conditions such as progressive fibrosis with stenosis and shortening, chronic ulceration and necrosis, which substantially impact quality of life. Low seated tumours combined with high dose radiation to the lower vagina carry an increased risk for complete obliteration, necrosis and painful ulceration [43], also for the adjacent vulvar region. 13. ADVERSE EVENTS

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14. KEY MESSAGES

• Brachytherapy plays a key role in the treatment of vaginal tumours; • State of the art brachytherapy treatment for vaginal tumours is according to the GEC-ESTRO/ACROP and GEC-ESTRO (ACROP)–ABS–CBG guidelines based on 3D volumetric image-guided adaptive brachytherapy (IGABT) preferably with the use of MRI imaging; • It is recommended to treat vaginal tumours with a residual thickness perpendicular to the vaginal wall of more than 5-7 mm at brachytherapy with an intracavitary and interstitial approach; • Treatment with 3D-based image-guided brachytherapy in vaginal tumours including combined IC/IS techniques leads to better local control compared to radiograph-based brachytherapy, especially in larger tumours; • A total D90 dose in the CTV-T HR of 75-85 Gy in EQD2 αβ10 is aimed for dependent on location, histological type and volume of the tumour; • There is a trend of a dose-effect relationship, with better local control with doses higher than 80 Gy D90 prescribed to the CTV-T HR in patients treated for large (≥ T2) primary vaginal cancer. • A substantial number of patients treated for vaginal tumours suffer from severe late effects, and in particular from vaginal and urinary symptoms.

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15. REFERENCES

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