A first radiotherapy application of functional bulboclitoris anatomy, a novel female sexual organ-at-risk, and organ-sparing feasibility study

Abstract

Objective:

The bulboclitoris (clitoris and vestibular bulbs) is the primary organ responsible for female sexual arousal and orgasm. Effects of radiotherapy on the bulboclitoris are unknown, as its structure/function has yet to be described in radiotherapy, and it overlaps only partially with the external genitalia structure. Our aim was to: describe bulboclitoris structure, function and delineation; compare volume of and dose delivered to the bulboclitoris vs external genitalia; and, compare bulboclitoris-sparing IMRT (BCS-IMRT) to standard IMRT (S-IMRT) to determine reoptimization feasibility.

Methods:

Our expert team (anatomist, pelvic radiologist, radiation oncologist) reviewed bulboclitoris anatomy and developed contouring guidance for radiotherapy. 20 female patients with anal cancer treated with chemoradiation were analyzed. Sexual organs at risk (OARs) included the external genitalia and the bulboclitoris. Volumes, dice similarity coefficients (DSCs) and dose received using S-IMRT were compared. Plans were reoptimized using BCS-IMRT. Dose–volume histograms (DVHs) for PTVs and all OARs were compared for BCS-IMRT vs S-IMRT.

Results:

Bulboclitoris structure, function and delineation are described herein. The bulboclitoris occupies 20cc (IQR:12–24), largely distinct from the external genitalia (DSC <0.05). BCS-IMRT was superior to S-IMRT in reducing the dose to the bulboclitoris, with the greatest reductions in V30 and V40, with no significant changes in dose to other OARs or PTV 1/V95.

Conclusion:

The bulboclitoris can be contoured on planning imaging, largely distinct from the external genitalia. Compared with S-IMRT, BCS-IMRT dramatically reduced dose to the bulboclitoris in anal cancer planning. BCS-IMRT might safely reduce sexual toxicity compared with standard approaches.

Advances in knowledge:

The structure and function of the bulboclitoris, the critical primary organ responsible for female sexual arousal and orgasm, has yet to be described in the radiotherapy literature. Structure, function and delineation of the bulboclitoris are detailed, delineation and bulboclitoris-sparing IMRT were feasible, and sparing reduces the dose to the bulboclitoris nearly in half in female patients receiving IMRT for anal cancer, warranting further clinical study.

Introduction

Concurrent chemoradiotherapy is standard treatment for anal cancer.^1,2 Pelvic radiotherapy commonly results in sexual side-effects significantly impacting quality of life after treatment.^3,4 Radiotherapy toxicity related to erectile function and ejaculation is well-studied in male patients.^5,6 However, female sexual toxicity after radiation is less well studied^7–9 despite being highly prevalent.^3,8,10,11 For example, the current RTOG/NRG normal female pelvic atlas does not include any sexual organs,¹² limiting standardization of radiation dosing relative to female sexual organs and as a result, the study of dose-related radiation effects. Functional erectile anatomy critical to arousal and orgasm during sexual activity has largely not been included in assessing radiotherapy-related female sexual toxicity.^12–14 The bulboclitoris, comprised of the clitoris and vestibular bulbs, is the primary functional erectile organ responsible for female sexual arousal and orgasm,^15,16 and the impacts of radiation on the bulboclitoris are unknown.

Other important sexual anatomy in anal cancer radiotherapy toxicity includes vulvar and vaginal tissues.^13,17–19 The vulva or external genitalia (“EG”) is an atlas-defined organ at risk (OAR) and includes skin, fat, and a small portion of the bulboclitoris (clitoral glans/body).^19,20 EG dose constraints are intended to decrease dermatologic toxicity which interferes with both non-sexual and sexual functioning. Another important OAR in pelvic radiotherapy includes the vagina or vaginal wall, and a dose-dependent relationship to vaginal toxicity has been established.^17,18 Vaginal shortening or fibrosis in addition to mucosal effects on vaginal dryness commonly cause dyspareunia. Bulboclitoris dose may also impact vaginal dryness given its primary role in arousal.^15,21,22 Additionally, while bulboclitoral stimulation can occur indirectly through vaginal or anal penetration, the bulboclitoris also functions independently and most healthy females require bulboclitoral stimulation for arousal and orgasm.^23–25 When only accounting for the dermatologic or mucosal tissues of the vulva/vagina, the functional anatomic basis of arousal and orgasm critical to pleasurable sexual activity is excluded.

In the radiotherapy literature, accurate information on bulboclitoris anatomy is limited. The clitoris and vestibular bulbs function as a singular organ (the bulboclitoris) primarily responsible for orgasm and arousal,^{15,21,22,24–26} yet depictions of the bulboclitoris in major radiotherapy texts^27,28 include only the externally visible glans clitoris (excluding >95% of bulboclitoral tissue). The bulboclitoris appears to be largely anatomically distinct from the EG structure, is in closer proximity to the pelvis,^15,19 and likely receives a higher dose of radiation during standard treatment of anal cancer. The bulboclitoris, comprised of innervated erectile tissue, is also histologically distinct from the EG (primarily fat and skin) and vaginal mucosa. These anatomic and histologic features suggest that the bulboclitoris may have its own unique normal tissue tolerance of radiation, warranting exploration as a separate OAR.

Our study aims to describe the bulboclitoris structure, function and delineation on planning imaging, to compare the volume of and dose delivered to the bulboclitoris vs the EG; and, to compare bulboclitoris-sparing IMRT (BCS-IMRT) to standard IMRT (S-IMRT) to determine feasibility of safely avoiding the bulboclitoris in patients receiving radiotherapy for anal cancer.

Methods and materials

Patients

20 consecutive female¹ anal cancer patients treated between 2013 and 2019 with concurrent chemoradiotherapy and S-IMRT were included, treated with either 5000-5040 cGy (grouped as reference category: “5000 cGy”, N = 10) with T2N0 disease or 5400 cGy with T3-4N0 or N + disease (N = 10). The Icahn School of Medicine at Mount Sinai institutional review board approved this study and waived consent, and all procedures were carried out per patient safety and best practice guidelines in the United States.

Simulation

A planning CT scan without contrast spanning from L1 to mid-thigh was acquired for each patient (3 mm slices, Phillips Big Bore CT) and an immobilization device, in the prone or supine position per the physician’s preference.

Target definition

The critical OARs and clinical target volume (CTV) were contoured on axial CT slices, per standard contouring guidelines.^2,12,19 The CTV_5400 or CTV_5000 consisted of gross primary tumor volume, the anal canal and a 2.5 cm expansion, excluding bone and air including involved nodes >3 cm or <= 3 cm, respectively. The CTV_4500 included uninvolved nodal regions and a 0.7 mm expansion, excluding bowel and bone. The planning target volumes (PTVs) were generated using a 0.5 cm uniform expansion of each CTV. Prescribed PTV doses were 5400cGy, 5000/5040cGy and 4500cGy in 1.8–2.0 Gy daily fractions, per the physician’s discretion.

Standard OAR definition

Standard OARs as contoured by the treating physician as per the original plan included bowel (small/large), bladder, femoral heads/necks, EG, and iliac crests per physician preference for the original clinical plan. Bowel included either loops of small/large bowel, or the peritoneal cavity excluding bladder and rectum extending 2 cm above the PTV. Bony contours were delineated using the external bone contour. EG were contoured per standard guidelines published by Brooks et al¹⁹ to include labial skin, fat to the pubic bone, and the external-most portion of the glans/body clitoris, excluding the vagina.

Bulboclitoris anatomy

The functional bulboclitoris anatomy included erectile tissues of the clitoris (glans and corpora cavernosa) and vestibular bulbs (corpora spongiosa). See Figure 1.

Figure 1.

Graphical representation of the bulboclitoris female erectile tissues, including the clitoris and vestibular bulbs, in relation to the pelvic bones and vaginal and urethral openings. Clitoris components include the Glans, Body (corpus), and crus (corpus cavernosum). Vestibular bulb components include the Glans, Pars intermedia, Commissure, and Vestibular bulbs (corpus spongiosum). Illustration by Jill K. Gregory, CMI, FAMI.

Clitoris anatomy: The clitoris, an upside-down “Y-shaped” structure broadly attached superoanteriorly to the pubic arch (paired ischiopubic rami and midline pubic symphysis), is comprised of a tip (glans) and body (corpus) forming the stem of the “Y”, and paired legs (crura) forming two long branches of the “Y.” The clitoris body and crus include paired cavernous erectile tissues (corpus cavernosum) extending via a broad extension of connective tissue into the glans, densely innervated for sensation. The glans, comprised proximally of non-keratinized squamous epithelium and spongy erectile tissue (of fetal corpora spongiosa origin), and distally of connective tissue attachments and the dorsal most aspect of the corpora cavernosum of the clitoral body,²² is located at the anterior fusion of the labia minora, positioned immediately anterior to the urethral opening. It is a small, rounded mass covered anteriorly by a thin hood of tissue called the prepuce (homolog of the male foreskin). The glans attaches at its superior and posterior aspect to a cylindrical corpus/body comprised of closely apposed paired erectile tissues. The corpus is positioned midline immediately inferior to the pubic arch stabilized by a suspensory ligament attaching superiorly to the pubic symphysis. Paired erectile tissues of the corpus diverge and extend laterally, forming cylindrical crura that each taper posteriorly into a cone shape. Each crus attaches under the ischiopubic ramus surrounded by connective tissue (tunica albuginea) and thin skeletal muscle (ischiocavernosus).

Vestibular bulbs (“bulbs”) anatomy: The vestibular bulbs are comprised of spongy erectile tissue (corpus spongiosum). The paired bulbs narrow anteriorly and join via a commissure (pars intermedia) apposed against the inferior surface of the clitoral corpus (near the point of divergence into the crura) and continue anteriorly as involuted appearing tissue apposed to the inferior aspect of the corpus to the glans. As they extend and separate posteriorly, each bulb expands into a large tear-drop shaped mass, flanking the urethra and distal vagina laterally. The bulbs are covered by thin skeletal muscle (bulbospongiosus). On imaging, the posterior swelling of the bulbs may be indistinguishable from the paired greater vestibular glands lying immediately posteriorly, adjacent to the lateral vaginal walls.

Bulboclitoris OAR terminology: The vestibular bulbs and clitoris are traditionally defined as separate erectile organs. However, both historical and recent work shows the pars intermedia of the vestibular bulbs becomes closely apposed against the inferior aspect of the clitoral body and both organs contribute to the structure of the glans.^22,29,30 The vascular sinuses of the glans are of two erectile tissue types: corpora cavernosa (clitoris) supporting the superoposterior region, and corpora spongiosa (bulbs) forming the anteroinferior region, suggesting that the clitoris and bulbs function as one anatomical organ.^15,22,29,30 Moreover, the clitoris and bulbs function together as an erectile apparatus or organ (similar in concept to the penis for male erectile function) that serves to establish a “platform for orgasm” as described by Masters and Johnson and others.^24–26 In areas where these organs are apposed, they are indistinguishable from each other on standard imaging. Terminology for the organ that includes both erectile tissues with a unified function is subject of ongoing debate, including: clitoris,¹⁵ bulboclitoral organ,²² erectile organs of the vulva,³¹ genital senses apparatus,³⁰ and female penis.²¹ Given that the unified function of these tissues is generally accepted but the terminology is not, we adopted a simplified name for the OAR in radiotherapy planning. Therefore, we refer to the clitoris and vestibular bulbs together as a functional organ termed ‘bulboclitoris’, similar to Di Marino,²² to represent the OAR related to the sexual function of arousal and orgasm.

Bulboclitoris OAR delineation

With detailed guidance from an expert anatomist, pelvic radiologist, and radiation oncologist, the bulboclitoris was delineated on the original planning CT and the following delineation guidelines were developed. Additional information from a fused pelvic MRI (T2 and/or T1 post-contrast) was incorporated when clinically available in 90% of patients. For dosimetric evaluation, an optimization structure was created by subtracting the PTV from the bulboclitoris (bulboclitoris-PTV). Additionally, the distal vagina was contoured to ensure definition between the vaginal tissue and laterally positioned bulbs.

Cranial: The suspensory ligament attaching to the pubic arch is superior to the corpus. The superior borders of the bifurcating crura are the inferior aspects of the ischio-pubic rami bones. The superior border of the bulbs (posterior to becoming apposed to the corpus) is the perineal membrane, separating the erectile tissues from the muscles of the urogenital diaphragm.

Caudal: The crura are covered inferiorly and laterally by the ischiocavernosus muscles, and the bulbs are covered inferiorly and laterally by the bulbospongiosus muscles, each bounded by surrounding fat. The most inferior bulboclitoral component projecting anteriorly from the distal end of the corpus is the glans.

Anterior/Ventral: The anterior or ventral boundaries of the bulbs become apposed to the corpus becoming indistinguishable in imaging, and together project anteriorly as the glans, covered anteriorly by the prepuce. Anterior and lateral to the corpus is surrounding fat. Anterior to the bulbs as they project inferiorly and posteriorly from the corpus is surrounding fat.

Posterior/Dorsal: Each cylindrical crus tapers posteriorly to a point running inferiorly along the ischio-pubic rami, bounded posteriorly by fat. The most posterior aspect is demarcated where the perineal neurovascular bundle meets the bulboclitoral tissue, identifiable by decreased signal intensity on CT. The posterior extensions of the crura diverge laterally from the more medial paired bulbs. The posterior border of the bulbs are typically in line (in the coronal plane) with the posterior boundary of the vaginal opening in the bottom 1/3 of the vagina, bounded posteriorly by surrounding fat (extending to the ischioanal/ischiorectal fossa) and vestibular glands (difficult to distinguish on CT alone).

Lateral: The crura is bounded laterally by fat. The lateral edge of the bulbs are bounded by the medial edge of the crura, that have the same signal intensity. More posteriorly, they are more clearly demarcated from the laterally diverging crura and intervening fat.

Medial: The medial borders of the crura are usually indistinguishable from the adjacent bulbs anteriorly. This edge can be distinguished if there is intervening fat, which becomes more prominent posteriorly where the two erectile bodies diverge. The medial borders of the bulbs surround the urethral and vaginal openings.

Treatment planning

6 MV VMAT plans were generated using the Eclipse commercial treatment planning system (Varian Medical Systems, Palo Alto, CA). For the bulboclitoris-sparing approach (BCS-IMRT), the original treatment plans were reoptimized from the last two resolution levels to keep the dose distribution as similar as possible to the original plans. The same priorities and objectives were used for dose optimization, adding new objectives incorporating the bulboclitoris. The maximum dose objective was kept <105% of the prescription dose where overlapping with the PTV, and high and intermediate dose was pushed out of the structures as much as possible without compromising PTV coverage, in non-overlapping regions (bulboclitoris-PTV). All plans were normalized to match previous PTV coverage. Each plan was reviewed and approved by a board-certified radiation oncologist.

Statistical analysis

Dose–volume histograms of PTVs and OARs were generated for S-IMRT and reoptimized BCS-IMRT plans. Analyses were stratified by prescribed dose (5000 cGy/5400 cGy). EG and bulboclitoris volumes, dice similarity coefficients (DSCs), and dose using S-IMRT were determined and compared using Wilcoxon signed-rank tests. DVHs for PTVs and OARs were compared for BCS-IMRT vs S-IMRT using Wilcoxon signed-rank tests. Two-sided p values with an α level <0.05 were applied to all statistical tests, performed using R v 3.3 (R Core Team, Vienna, Austria).

Results

Study population

Our study population included 20 female anal cancer patients treated with concurrent chemoradiation. Mean age was 74 years (standard deviation (SD):7).

Bulboclitoris volume and overlap with EG

The bulboclitoris occupies 20.4 cc (median; interquartile range (IQR):12.3–23.7). The bulboclitoris occupies a distinct volume from the EG [median DSC of 0 (IQR:0–0.05), indicating <5% overlap], Figures 2 and 3.

Figure 2.

Multislice axial representations of bulboclitoris contours with fused T2 magnetic resonance imaging Note: External genitalia was contoured by the treating physician as per the original plan; bulboclitoris was contoured per the instructions outlined herein.

Figure 3.

Sagittal (a), coronal (b), and volumetric (c) representations of external genitalia and bulboclitoris contours a) Sagittal representation of external genitalia (thin, white) and bulboclitoris (thick, gray) contours b) Coronal representation of external genitalia (thin, white) and bulboclitoris (thick, gray) contours. (c) Volumetric representation of external genitalia (white) and bulboclitoris (gray) contours. External genitalia was contoured by the treating physician per the original plan; bulboclitoris was contoured per the instructions outlined herein.

S-IMRT bulboclitoris vs EG dose

When not avoided, the bulboclitoris received higher doses versus the EG, Table 1. Significant differences were also seen for maximum dose and all other dose levels.

Table 1.

External Genitalia and bulboclitoris dose-volume comparison with standard intensity modulated radiotherapy

	Prescription Dose: 5000 cGy (N = 10)			Prescription Dose: 5400 cGy (N = 10)
	External Genitalia	Bulboclitoris		External Genitalia	Bulboclitoris
	Median (IQR)		sig.	Median (IQR)		sig.
Maximum Dose, cGy	5092 (3985, 5602)	5595 (5407, 5823)	0.01	5602 (5017, 5712)	5825 (5640, 5748)	0.01
Mean Dose, cGy	1979 (1427, 2635)	4541 (4350, 5063)	0.002	2299 (1928, 2791)	5075 (4309, 5188)	0.002
Dose Level, % volume
20 Gy	43.7 (18.9, 53.3)	100 (100, 100)	0.009	45.9 (43.3, 70.9)	100 (98.7, 100)	0.006
30 Gy	14.2 (2, 27.1)	97.8 (79.8, 100)	0.009	20.0 (15.7, 38.1)	99.9 (86.1, 100)	0.006
40 Gy	1.1 (0, 13.3)	73.7 (67.9, 89.2)	0.002	6.5 (0.6, 15.3)	88.2 (63.6, 94.8)	0.002
50 Gy	0.2 (0, 12.1)	52.2 (39.0, 64.7)	0.01	2.1 (0.1, 9.4)	63.9 (45.1, 71.6)	0.002

Gy, gray; IQR, interquartile range; cGy, centigray; sig, significance.

wilcoxon signed-rank tests,two-sided p<0.05 is significant

BCS-IMRT bulboclitoris and bulboclitoris-PTV dose

BCS-IMRT was superior to S-IMRT in reducing bulboclitoris and bulboclitoris-PTV dose (Tables 2 and 3). The greatest bulboclitoris-PTV DVH reductions were for V30 and V40 (Table 3). Using BCS-IMRT, V30 decreased from 90 to 50% and V40 decreased from 60 to 35%. No significant increases in dose to other OARs or changes in PTV 1/V95s were observed.

Table 2.

Dose-volume comparison of standard and bulboclitoris-sparing IMRT approaches for the entire bulboclitoris and bulboclitoris-PTV

	Prescription Dose: 5000cGy (N = 10)				Prescription Dose: 5400cGy (N = 10)
	Mean Dose, Median (IQR), cGy		Difference, Median (IQR), cGy	sig.	Mean Dose, Median (IQR), cGy		Difference, Median (IQR), cGy	sig.
Structure	S-IMRT	BCS-IMRT			S-IMRT	BCS-IMRT
Bulboclitoris	4541 (4350, 5063)	4160 (3990, 4567)	−344 (-502,–172)	<0.001	5075 (4309, 5188)	4486 (4143, 4915)	−375 (-494,–181)	0.002
Bulboclitoris-PTV	4039 (3872, 4190)	3266 (3003, 4912)	−615 (-861,–371)	<0.001	4126 (3936, 4633)	3429 (3144, 3761)	−580 (-943,–193)	0.01

BCS-IMRT, bulboclitoris sparing intensity modulated radiotherapy; IQR, interquartile range; PTV, planning target volume; S-IMRT, standard intensity modulated radiotherapy; cGy, centigray; sig, significance.

wilcoxon signed-rank tests,two-sided p<0.05 is significant

Table 3.

Dose-volume comparison of standard and bulboclitoris-sparing IMRT approaches for the entire bulboclitoris and bulboclitoris-PTV

	Prescription Dose: 50 Gy (N = 10)				Prescription Dose: 54 Gy (N = 10)
Structure	Percent Volume, Median (IQR), %		Difference, Median (IQR), %	sig.	Median Volume (IQR), %		Difference, Median (IQR), %	sig.
Dose Level	S-IMRT	BCS-IMRT			S-IMRT	BCS-IMRT
Bulboclitoris
20 Gy	100 (100, 100)	97.3 (90.4, 100)	−0.4 (-7.4, 0.0)	0.004	100 (98.7, 100)	94.9 (91.6, 100)	−2.0 (-6.0,–4.3)	0.06
30 Gy	97.8 (79.8, 100)	73.0 (66.7, 83.9)	−14.8 (-24.1,–5.6)	<0.001	99.9 (86.1, 100)	77.1 (68.2, 87.0)	−15.8 (-18.4,–3.0)	0.02
40 Gy	73.7 (67.9, 89.2)	65.6 (59.2, 75.2)	−9.0 (-11.7,–8.5)	<0.001	88.2 (63.6, 94.8)	70.6 (56.2, 82.4)	−8.4 (-17.2,–1.2)	0.02
50 Gy	52.2 (39.0, 64.7)	46.9 (36.7, 60.1)	−4.2 (-8.6,–0.4)	0.003	63.9 (45.1, 71.6)	52.4 (43.5, 69.3)	−5.1 (-8.2,–0.3)	0.02
Bulboclitoris-PTV
20 Gy	100 (99.9, 100)	94.9 (73.9, 100)	−2.7 (-21.1, 0)	0.003	100 (97.7, 100)	89.7 (75.8, 100)	−7.2 (-23.4,–16.9)	0.04
30 Gy	96.3 (76.4, 100)	50.9 (41.0, 60.9)	−35.6 (-47.8,–19.0)	<0.001	99.9 (82.8, 100)	56.9 (44.2, 61.4)	−35.6 (-42.6,–21.3)	0.01
40 Gy	52.5 (45.6, 70.9)	32.7 (25.9, 40.6)	−19.6 (-32.6,–10.1)	<0.001	64.2 (48.8, 82.7)	33.6 (28.5, 50.2)	−21.4 (-33.7,–7.6)	0.03
50 Gy	4.7 (2.5, 15.7)	3.4 (0.2, 8.7)	−2.8 (-8.8,–0.3)	0.005	15.9 (97.4, 38.3)	7.1 (5.0, 25.8)	−9.3 (-12.0,–1.2)	0.02

BCS-IMRT, bulboclitoris sparing IMRT; Gy, gray; IQR, interquartile range; PTV, planning target volume; PTV, planning target volume; S-IMRT, standard IMRT; sig, significance.

wilcoxon signed-rank tests,two-sided p<0.05 is significant.

Discussion

This study reveals the function and structure of the bulboclitoris for applications in radiotherapy. Further, we demonstrate that the bulboclitoris can be contoured on planning imaging, occupies a distinct volume and receives a higher dose when not purposefully avoided vs the EG OAR. These findings are important because the bulboclitoris is the primary organ responsible for female sexual arousal and orgasm and detailed description of the anatomy, volume and bulboclitoris dose have not been previously described in the radiotherapy literature.³²

Doses to the EG are similar to other studies evaluating IMRT. Early descriptions of IMRT in anal cancer documented dose reductions for the genitalia structures for IMRT, achieving mean dose levels V30 and V40 similar to EG doses in this study,^14,33–35 without reports of significant sexual toxicity. For the bulboclitoris, separate structures of the clitoris and bulbs have been presented only once in abstract form for patients treated with 45 Gy to the pelvis for gynecologic cancers,³⁶ although these structures included only 1–2 ccs of tissue each for both the clitoris and singular “bulb”, suggesting that the entire structures were not included. Mean doses were 26–30 Gy to the perineum and 24 Gy to the clitoris. Our study showed higher mean doses to the bulboclitoris (45–50 Gy) without avoidance, likely due to both greater amounts of tissue contoured and higher prescribed doses in closer proximity to the structures.

When evaluating feasibility of BCS-IMRT, we achieved significant sparing of the bulboclitoris and the bulboclitoris-PTV. Potentially clinically meaningful findings included reducing the V30 and V40 nearly in half while not introducing significant changes to PTV coverage or dose to other OARs. Therefore, further clinical investigation into whether this novel BCS-IMRT approach safely reduces female sexual toxicity is needed, and this will necessitate collection of patient reported outcomes. In addition, further exploration of BCS-IMRT in different age groups and menopausal status is needed. Changes in volume of certain components of the urogenital and reproductive organs, including the vestibular bulbs, occur with decreasing circulating estrogen due to aging and menopause,^25,37 therefore validation of our ability to spare the bulboclitoris in younger and pre- or perimenopausal females will be imperative. However, these changes are known to not impact clitoral function and orgasmic capacity does not change over the lifespan,^21,25,38,39 therefore, investigation of the relationship of bulboclitoral damage by radiotherapy and functional outcomes is warranted irrespective of hormone-related atrophy of these organs.

While detailed studies of radiation dose–volume effects on the bulboclitoris have not, to this point, existed, extrapolation from the effect on male erectile tissues, which have been extensively studied, is informative. Translational studies showed that increasing radiation dose to male erectile tissues was associated with decreased nerve function and nitric oxide synthase release combined with increased cavernous smooth muscle fibers, associated with diminished erectile response in male rats.⁴⁰ Additionally, ultrasound studies demonstrated radiation-related arteriogenic and cavernosal etiologies of erectile function in males receiving EBRT.⁴¹ Early studies prostate IMRT demonstrated high rates of erectile function maintenance⁴² with reduced doses to the proximal penile tissues by ~40%,⁴³ similar to the reduction observed with BCS-IMRT herein. Radiation dose–volume effects on the penile bulb were perhaps more consistent in the 3D era^44,45 vs conflicting results in the era of IMRT,⁵ possibly due to a larger proportion of the tissues receiving a higher dose with 3D vs IMRT. This is relevant given that a majority of the bulboclitoris is in close proximity to the pelvis, even with IMRT, compared to the penis for which most erectile tissues sit far from the pelvis.⁴⁶ Current penile bulb constraints include a mean of <50 Gy⁵ and a median <52.5 Gy⁴⁵, though bulboclitoris constraints are likely to be lower given the proximity of the whole bulboclitoris to the pelvis. BCS-IMRT reduced bulboclitoris mean dose from 45 to 42 Gy and 51 to 45 Gy, and bulboclitoris-PTV V30 and V40 reduced by 40–50%. In patients prescribed 54 Gy, V50 was reduced from 16 to 7%.

This study represents the first study to our knowledge accurately describing the functional bulboclitoral structures in the context of pelvic radiotherapy. Only one notable prior study specifically addresses post-radiation clitoris function and the utility of a device to help with arousal and orgasm.⁴⁷ Accurately delineating the functional anatomy for female sexual arousal and orgasm and quantifying expected dosimetric benefits of BCS-IMRT are important precursos to prospective clinical evaluation of this novel proactive approach to reducing sexual side-effects. Additionally, vaginal toxicity can be difficult to avoid due to close proximity to or inclusion in the treated volume,²⁰ therefore sparing orgasm and arousal functions may be even more important for pelvic radiotherapy patients. IMRT planning objectives for EG can be difficult to meet and are sometimes discarded to meet other goals.²⁰ Separating bulboclitoris tissues (except perhaps the cutaneous portion of the glans) from the EG contour, given their different functions, may improve feasibility of meeting dose planning objectives in IMRT for each structure respectively.⁴⁸

Our study has limitations, notably the absence of clinical and patient-reported outcomes validating our hypothesis of a clinically meaningful relationship between radiation dose–volume effects on the bulboclitoris and female sexual outcomes, representing next steps. Moreover, our data are limited by the lack of generalizability of our single institution study and limited sample size. Our sample was also largely post-menopausal females, therefore further study in pre- or perimenopausal females is warranted to ensure that sparing can similarly be achieved. Nevertheless, our results showed a considerable difference between doses received using BCS-IMRT and S-IMRT, which alleviates some impact brought by small sample size. Formal verification of the accuracy of structure delineation, interoperator variability, and the impact of incorporating MRI or contrast is needed, and will be performed in future studies.

Conclusion

The bulboclitoris is an important functional female sexual organ responsible for arousal and orgasm described herein that can be contoured on radiotherapy planning imaging. The bulboclitoris occupies a largely distinct volume from the EG and receives a higher dose when not avoided in anal cancer radiotherapy planning. BCS-IMRT is feasible and substantially reduces bulboclitoris dose. The long-term impact of BCS-IMRT on sexual function requires clinical investigation.