Long-Term Patient-Reported Dyspareunia After Definitive Chemoradiation for Anal Cancer: Using the Anterior Vaginal Wall as an Organ-at-Risk to Define an Actionable Dosimetric Goal

Abstract

Purpose

Chemoradiation therapy (CRT) is the standard treatment for squamous cell carcinoma of the anus (SCCA). This study aimed to investigate the relationship between vaginal dosimetry and long-term patient-reported dyspareunia after treatment. We further aimed to use the anterior vaginal wall (AVW) as an organ at risk to define an actionable dosimetric clinical goal to decrease the risk of patient-reported dyspareunia.

Methods and Materials

Women with SCCA treated with intensity modulated radiation therapy–based CRT were surveyed at least 2 years after successfully completing therapy. A Female Sexual Function Index (FSFI) pain subscore ≤4 was used to define dyspareunia. Dosimetric parameters were calculated for both the full vaginal canal and AVW. Multivariable linear regression models were created to identify predictors of FSFI pain subscore using backward selection to identify final variables include in the models. An actionable dosimetric predictor for dyspareunia was established using the Youden index method for cutoff optimization.

Results

Of 184 women who were contacted, 90 (49%) returned completed surveys. Of those who completed surveys, 51 (56.7%) reported being sexually active, and 47 had dosimetric data available for review. Of sexually active respondents, 32 (68%) had an FSFI pain subscore ≤4. Multiple regression models were generated using the full vaginal canal and AVW as organs at risk, and both models showed similar predictive relationships with volumetric dose parameters emerging as the best dosimetric predictors for dysparenuia. Age over 65 years was also associated with higher FSFI pain subscores (eg, less pain with intercourse) in both models. AVW V35 Gy < 60% was identified as the optimal cutoff to reduce the risk of patient-reported dyspareunia.

Conclusions

Increased dose to the vaginal canal is significantly associated with worse patient-reported dyspareunia following CRT for SCCA. Minimizing dose to the AVW to V35 Gy < 60% may reduce the risk of this quality of life-limiting toxicity. Further prospective evaluation is needed to validate these findings.

Introduction

Pelvic chemoradiation therapy (CRT) is the preferred treatment for localized squamous cell carcinoma of the anus (SCCA). This treatment achieves high rates of local control and good overall survival outcomes with an estimated 5-year freedom from local failure of 81.2% and 5-year overall survival of 85.8%.¹ However, radiation to the pelvis can lead to significant acute and permanent side effects that impair patient quality of life (QOL).2, 3, 4

In particular, there is a paucity of data pertaining to the incidence, severity, and risk factors for female sexual dysfunction after pelvic radiation for anal cancer. We have previously described long-term patient-reported outcomes (PROs) following the receipt of pelvic CRT for SCCA.⁵ Using the Female Sexual Function Index (FSFI) to quantitatively describe patient-reported sexual function, we found that the majority of women (80%) experience clinically significant sexual dysfunction after treatment. However, female sexual dysfunction is certainly multifactorial, and the precise impact of radiation dose distribution on the risk of patient-reported sexual toxicity remains unclear.

Most prior studies investigating the relationship between vaginal dosimetry and sexual toxicity have used the full vaginal canal as the relevant organ at risk (OAR), most often in the setting of gynecologic cancers.6, 7, 8, 9, 10, 11, 12 Consensus target delineation guidelines for anal cancer radiation therapy recommend geometric expansions from the gross tumor volume to define high-dose target volumes.¹³ This often leads to large portions of the posterior vaginal wall being included in the prescription volumes and, therefore, prevents meaningful avoidance of the full vaginal canal OAR. At our institution, we use a vaginal dilator during daily radiation treatments for patients without vaginal involvement. This displaces the anterior vaginal wall (AVW) from the target volumes and thus allows for sparing of at least part of the circumference of the vaginal canal.

We hypothesized that the utilization of the AVW as an OAR as opposed to the full vaginal canal could lead to more clinically actionable dosimetric constraints. In this investigation, we test this hypothesis by creating and comparing multiple dosimetric-based models using the full vaginal canal and the AVW to identify predictors of patient-reported sexual dysfunction. The FSFI includes subscores for sexual function domains such as arousal, desire, orgasm, satisfaction, lubrication, and pain. For our dosimetric analysis, we focus on the FSFI pain subscore because vaginal fibrosis postradiation contributes to vaginal stenosis and foreshortening, which often manifests as pain during sexual activity. We further aimed to determine an optimal AVW dosimetric constraint that could be used as a reasonable clinical goal to decrease risk of patient-reported dyspareunia.

Methods and Materials

Patient identification and survey distribution

Upon institutional review board approval, we reviewed electronic health records to identify women with SCCA treated definitively with intensity modulated radiation therapy–based CRT at our institution from 2010 to 2018.

Patients were eligible if they were alive and without evidence of disease. We contacted individuals by phone and email to request participation in a survey to investigate long-term QOL following pelvic CRT. For those willing to participate, we distributed a PRO survey including the Female Sexual Function Index (FSFI) questionnaire, which contains 19 questions across 6 domains of female sexual health (desire, arousal, lubrication, orgasm, satisfaction, and pain).¹⁴ Surveys were sent at only 1 timepoint and, therefore, the interval between treatment completion and survey distribution varied according to time of treatment completion. Responses are integrated using weighting factors to develop a composite score ranging from 2 to 36, with lower scores indicating worse sexual function.^15,16 A score of ≤26.55 for composite FSFI has been validated as a clinically meaningful cutoff for identifying patients with clinically significant sexual dysfunction.¹⁷ For this investigation, we focused primarily on the pain subscore, which combines responses from 3 survey questions quantifying genital pain related to vaginal penetration (Table E1). Numeric scores are summed and weighted to create a composite pain subscore, which ranges from 0 to 6, with lower scores indicating worse pain. To our knowledge, however, there are no robust data to suggest a cutoff to define clinically meaningful dyspareunia. Therefore, we used a similar proportion of the composite score (26.55/36) to define a pain subscore of ≤4 as meaningful pain score, which is similar to a cutoff proposed in a cross-sectional study of women living in urban China.¹⁸ The pain subscore was a prespecified primary endpoint of the study team. We additionally collected demographic, disease, and treatment-related information for participants.

Dosimetric evaluation and OAR delineation

For survey respondents, we reviewed the final approved radiation treatment plan and tabulated an array of dosimetrics which were used as potential predictors for the dyspareunia. Dosimetrics were calculated for 2 primary OAR volumes: the full vaginal canal and the AVW. The full vaginal canal was contoured as per the Eastern Cooperative Oncology Group De-Intensified ChemoRadiation for Early Stage Anal Squamous Cell Carcinoma (DECREASE) trial.¹³ This including contouring the vaginal dilator, expanding that volume by 5 mm and subtracting the volume of the dilator itself as well as projections of this volume outside the body. The AVW was contoured by removing the posterior 180° of the full vaginal canal volume. Representative contours are displayed in Fig. 1.

Figure 1.

Representative contour of the full vaginal wall (A, axial plane; C, sagittal plane) and anterior vaginal wall (B, axial plane; D, sagittal plane).

For the full vaginal canal and the AVW, we calculated the following volumetric and dosimetric parameters: volume of the OAR (cc), minimum dose (Gy), maximum dose (Gy), mean dose (Gy), Dxxcc (Gy), Vxx (%), Dxx (Gy), and MOHxx (Gy). Dxxcc refers to the dose in Gy received by a particular volume xx of the OAR in cc. Vxx is the percent volume of the OAR that receives a particular radiation dose xx. Dxx refers to the dose in Gy received by xx percent of the OAR. MOHxx refers to the mean dose within the hottest xx% of the structure, measured in Gy. Lxx-yyGy describes the contiguous length measured along the centerline of the structure such that, at each slice within this length, at least xx% of the structure circumference is receiving at least yy Gy, measured in cm. We calculated the Lxx-yyGy (cm) for the full vaginal canal, but because the AVW was calculated by Boolean subtraction and thus was not a native circumferential volume, we did not measure Lxx-yyGy for this volume. A full description of the included dosimetrics is provided in Table 1.

Table 1.

Description of the evaluated dosimetrics

Dosimetric abbreviation	Unit	Description
Dxxcc	Gy	Minimum dose to the hottest xx ccs of structure volume
Vxx	Unitless	Fractional volume of the structure receiving at least xx Gy
Dxx	Gy	Minimum dose to the hottest xx% of structure volume
MOHxx	Gy	Mean dose within the hottest xx% of structure volume
Lxx-yyGy	cm	Contiguous length measured along the centerline of the structure such that, at each slice within this length, at least xx% of the structure circumference is receiving at least yy Gy

Statistical analysis

We used descriptive statistics to characterize the study population including demographic, disease, and treatment factors. We created multivariable linear regression models to identify both clinical and dosimetric factors that were predictive of FSFI pain subscore. We generated 2 models that incorporated dosimetric predictors based upon the definition of the relevant OAR (eg, full vaginal canal vs AVW). For each model, we considered the following demographic and clinical variables as potential predictors: age, tumor stage, node stage, receipt of pelvic floor physical therapy after CRT, vaginal dilator use after CRT, and volume of the OAR. Dosimetrics were also included as potential predictors if there was significant univariate correlation with FSFI pain score; only 1 dosimetric with the strongest correlation of each type (eg, Dxxcc, Dxx, Vxx, etc) was considered due to collinearity. MOHxx was excluded because the greatest correlation occurred at high values, and thus the overall mean dose was the optimal predictor for inclusion. Backward stepwise selection was used to identify factors for inclusion in the final model.

We used FSFI pain subscore <4 for binary classification to estimate an optical cutoff for actionable dosimetric clinical goals via the Youden index method. Statistical significance was defined as P < .05. All statistical analyses were performed with R version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Of 184 eligible women, 114 agreed to participate in the survey; of those, 90 completed surveys for a response rate of 79% for administered surveys and 49% of the eligible population. Fifty-one respondents (57%) were sexually active, and 47 of those patients had radiation plans available for review and were included in the final analysis. Median time to survey completion was 58 months (first quartile 41 to third quartile 89.5). Demographic, disease, and treatment characteristics of the study population are summarized in Table 2. All patients were white with a median age of 64 years at survey completion. Most tumors were staged at T2 (55%) N0 (60%). Three patients (6%) had T4 disease with radiographically detected vaginal involvement; none of these patients had clinical evidence of vaginal invasion. The median dose of radiation therapy prescribed to the gross tumor volume was 54 Gy delivered in a median 27 fractions. All patients were treated with a vaginal dilator in place, and 85% reported that they continued to use the dilator after completion of therapy. Seven patients (15%) underwent pelvic floor physical therapy after CRT. The median FSFI pain subscore was 2.4 (1.2-4.2). The majority of patients (68%) reported FSFI pain subscores <4, meeting our prespecified definition of significant dyspareunia.

Table 2.

Demographic, clinical, and treatment characteristics of the study population

Characteristic	Count (%) or median (Q1-Q3)
Survey interval (mos)	58 (41-89.5)
Age at survey completion (y)	64 (57-69.5)
Race
White	47 (100)
Other	0
T stage
1	12 (26)
2	26 (55)
3	6 (13)
4	3 (6)
N stage
0	28 (60)
1	19 (40)
GTV dose	54 (54-54)
Dilator use after RT
No	6 (13)
Yes	40 (85)
Unknown	1 (2)
Vaginal dilator size (length × diameter)
Small: 3 × 0.75 in	3 (6)
Medium: 3.5 × 0.88 in	17 (36)
Large: 4.5 × 1.13 in	27 (57)
Pelvic floor PT
No	39 (83)
Yes	7 (15)
Unknown	1 (2)
Clinically documented dyspareunia
No	25 (53)
Yes	21 (45)
Unknown	1 (2)
FSFI overall	20.1 (14.24-25.7)
FSFI pain subscore	2.4 (1.2-4.2)
FSFI pain subscore <4
No	15 (32)
Yes	32 (68)

Abbreviations: FSFI = Female Sexual Function Index; GTV = gross tumor volume; N = node; PT = physical therapy; Q = quarter; RT = radiation therapy; T = tumor.

Distributions of dosimetrics for the full vaginal canal and AVW are summarized in E2. Correlations between FSFI pain subscores and all dosimetrics for the full vaginal canal and AVW are displayed in Figs. E1 and E2, respectively. Dosimetrics with significant correlation were included as potential predictors in a multivariable linear regression model. For dosimetric types (eg, Vxx, Dxx, etc) with multiple significant results by Pearson correlation, only the dosimetric with the strongest correlation was considered. For the full vaginal canal model, mean dose (P = .02), V45 Gy (P = .013), and L50%50 Gy (P = .005) were included as predictors in the multivariable model. For the AVW model, mean dose (P = .01), D2.0 cc (P = .01), and V35 Gy (P = .01) were considered as predictors in a multivariable model. The final models after backward stepwise factor selection are summarized in Table 3. Overall, similar clinical and dosimetric predictors emerged as independently predictive of FSFI pain score when considering either the full vaginal canal or the AVW as the relevant OAR. Age 65 years or older was associated with significantly higher FSFI pain subscore (signifying lower reported pain) in both models (P < .001). V35 Gy and V45 Gy were the only other significant predictors for the full vaginal canal and AVW models, respectively.

Table 3.

Multivariable models to predict Female Sexual Function Index pain subscore, with models described separately by organ-at-risk definition (full vaginal canal vs anterior vaginal wall [AVW] only)

	AVW		Full vaginal canal
Characteristic	β estimate (95% CI)	P value	β estimate (95% CI)	P value
Age >65		<.001		<.001
No	Ref		Ref
Yes	2.04 (0.9, 3.18)		2.1 (0.97, 3.23)
OAR volume (cc)	0.1 (−0.01, 0.2)	.06	0.04 (−0.01, 0.09)	.11
V35	−0.03 (−0.05, −0.01)	.02	NA	NA
V45	NA	NA	−0.03 (−0.06, -0.01)	.01

Abbreviation: NA = not applicable; OAR = organ at risk; Ref = reference

Potential clinical predictors included age, tumor stage, node stage, receipt of pelvic floor physical therapy, vaginal dilator use after radiation therapy, volume of the organs at risk, and a variety of dosimetrics. Dosimetrics were considered if there was significant univariate correlation with Female Sexual Function Index pain score; only 1 dosimetric with the strongest correlation of each type (eg, Dxxcc, Dxx, Vxx, etc) was included as a potential predictor due to collinearity (Figs. E1, E2). MOHxx was excluded because the highest correlation occurred at high values, and thus the overall mean value was the optimal predictor for inclusion. Backward stepwise factor selected was used to generate the final models.

The Youden method for cutoff optimization identified V35 Gy > 60% for the AVW as the optimal cutoff to discriminate individuals at risk of developing clinically significant dyspareunia (eg, FSFI pain subscore <4). Figure 2 shows the correlation between FSFI pain subscore and AVW V35 Gy (R = -0.39, P = .0072). Figure 3 shows the distribution of FSFI pain subscores for all patients with results stratified according to age and V35 Gy to the AVW.

Figure 2.

Correlation between anterior vaginal wall V35 and female sexual function index pain subscore. An optimal cutoff was identified at V35 < 60 (vertical line) using maximization of the Youden index based upon the dichomization at Female Sexual Function Index < 4 (horizontal line) to indicate clinically significant pain.

Figure 3.

Distribution of Female Sexual Function Index pain subscores (A) overall, (B) with stratification by age, and (C) V35 to the anterior vaginal wall.

The median composite FSFI score was 20.1 (14.24-25.7). The correlation between the FSFI pain subscore and nonpain composite FSFI score is described in Fig. 4. There was a significant positive correlation between scores (R = 0.43, P = .003).

Figure 4.

Correlation between Female Sexual Function Index pain subscore and overall score.

Discussion

In this single institutional study, we describe the relationship between vaginal dosimetry and long-term patient-reported dyspareunia following CRT for the treatment of SCCA. We investigated a variety of clinical and dosimetric factors to identify potentially actionable clinical goals using both the full vaginal canal and AVW as target OARs. In a multivariable model, V35 Gy < 60% for the AVW emerged as an optimal and clinically feasible target to decrease the risk of long-term dyspareunia. There was a strong correlation between FSFI pain subscore and the composite nonpain FSFI subscore, suggesting that although female sexual function is complex and multidimensional, pain during sexual activity is predictive of overall patient-reported sexual function. Efforts to minimize pain via personalized radiation therapy treatment planning are needed.

Prior research has demonstrated the relationship between dose to the vaginal canal and subsequent risk of vaginal and sexual toxicity (Table 4). The majority of studies in this space have included patients with gynecologic malignancies, especially cervical cancer. A vaginal dose reporting method was created in 2013 that evaluates composite dose between external beam radiation therapy and brachytherapy to reference points along the vagina. Specifically, the posterior-inferior border of symphysis was used to define points along the vaginal canal that correlate with risk of vaginal stenosis following treatment.⁶ A number of studies have demonstrated the utility of this vaginal dose reporting system for cervical cancer including validation in the image-guided intensity modulated External beam radiochemotherapy and Magnetic resonance imaging–based adaptive BRAchytherapy in locally advanced CErvical cancer (EMBRACE) studies.^7,8,11,12 To our knowledge, Son et al in 2015 is the only report to investigate vaginal dosimetry and propose an actionable clinical goal specifically for the treatment of lower gastrointestinal cancers.⁹ They identified generalized equivalent uniform dose and vaginal mean dose as significant predictors of vaginal stenosis, with a reduction of severe stenosis when generalized equivalent uniform dose <35 Gy and mean dose <43 Gy (P = .02).

Table 4.

Previously described dosimetric clinical goals and contouring guidelines for the vaginal canal

First author	Year published	Journal	Trial Name, if applicable	Primary treatment disease site	Significant dosimetric with proposed cutoff, if applicable	Toxicity outcome
Westerveld	2016	Radiation therapy and Oncology	EMBRACE	Cervical	PIBS-2 cm < 5 Gy	Decreased vaginal stenosis (P = .03)
Potter	2018	Clinical and Translational Radiation Oncology
Westerveld	2022	Radiation therapy and Oncology
Son	2015	International Journal of Radiation Oncology Biology Physics	NA	Rectal and Anal	gEUD (a = −1) <35 Gy and mean vaginal dose <43 Gy	Decreased vaginal stenosis (P = .02)
Zhang	2021	Clinical and Translational Oncology	NA	Endometrial	Vaginal 2 cc < 68 Gy EQD2	Low rates of vaginal stenosis
Ruanla	2022	Brachytherapy	NA	Cervical	Mean dose of lateral 5-mm, PIBS-2 cm	Decreased vaginal stenosis
Dankulchai	2022	Radiation Therapy and Oncology	NA	Cervical	PIBS +2≤ 55 Gy, PIBS-2≤5 Gy,D +5 ≤ 65 Gy	Grade 3 vaginal stenosis <20%
Damico	2022	Practical Radiation Oncology	DECREASE	Anal	NA	NA
Arzola	2023	Practical Radiation Oncology	NA	Anal	NA	FSFI

Abbreviations: FSFI = Female Sexual Function Index; gEUD = generalized equivalent uniform dose; NA = not applicable; PIBS = dose at posterior-inferior border of the symphysis.

Our investigation provides unique insight in this clinical space for several reasons. We are the first to describe the relationship between vaginal dosimetry and PRO measures of sexual dysfunction; all other studies in this niche have focused on physician-reported toxicity or biologic measurements (eg, vaginal stenosis). We selected the pain subscore as the optimal endpoint of interest to capture patient-reported toxicity in this population because long-term radiation therapy–related fibrotic changes within the vaginal canal contribute to narrowing and shortening of the vaginal canal that can manifest as pain with vaginal penetration during sexual activity. Other components of the FSFI such as sexual desire and interest may be less directly related to effects of radiation therapy on the vaginal canal and thus were not the focus of the investigation. There is ongoing work by Marshall et al evaluating the impact of radiation dose to the bulboclitorus on sexual function postpelvic radiation, and this mechanism may more directly contribute to issues with orgasm and sexual satisfaction during survivorship.¹⁹

Another unique contribution of this investigation is our comparison of OAR definitions. We were most interested in identifying potentially actionable dosimetric cutoff parameters that could be used to optimize radiation therapy plans for the treatment of anal cancer. Consideration of the entire vaginal canal as the OAR of interest would lead to difficulty when defining actionable cutoffs because large portions of the vaginal canal, especially the posterior canal, can be included in the target volumes. Indeed, in the Eastern Cooperative Oncology Group DECREASE atlas, dose constraints are given for the vaginal wall planned target volume so that coverage of the targets is prioritized over avoidance of the vaginal canal. By contrast, the AVW, especially when using a daily vaginal dilator, is often displaced geometrically from the target volumes such that dose avoidance is more feasible. Furthermore, we hypothesized that vaginal fibrosis and stenosis leading to dyspareunia would most likely occur with high doses to the full circumference of the vaginal canal, and, thus, sparing at least a portion of the canal might preserve vaginal flexibility and reduce pain with penetrative sexual activity.

We compared the utility of both the full vaginal canal and the AVW as predictive OARs. Encouragingly, we found that the AVW appears to be as robust of a predictive volume as the full vaginal canal and, therefore, can be used as the relevant OAR when designing radiation therapy plans. After generating a multivariable model considering both clinical demographic and dosimetric factors, we found that V35 Gy < 60% emerged as the optimal goal to decrease the risk of patient-reported dyspareunia in this cohort. This cutpoint could be used routinely in clinical practice but warrants further validation in a prospective cohort.

Another potentially counterintuitive but important finding of this investigation is the relationship between age and patient-reported sexual pain. We hypothesized that increased age would be predictive of dyspareunia due to age-related vaginal narrowing/shortening; however, age <65 years was independently associated with worse dyspareunia (lower FSFI scores) in this cohort. This may be partially due to the fact that a larger percentage of younger women were sexually active after CRT compared with older women. We speculate that differences in expectations and relationship dynamics may contribute to younger women being more likely to continue to engage in sexual activity despite it being painful. Regardless of precise etiology for this trend, it is critical that practitioners are aware of the impact of age on experienced dyspareunia so they may be able to provide proactive support and education to help patients maintain QOL.

When interpreting these results, it is also critical to consider other influences and patient-specific factors that may influence the risk of patient-reported dyspareunia following CRT. Perhaps most importantly is the use of complementary mitigation or treatment strategies as part of a survivorship plan. For example, at our institution during this study period, all women completing pelvic radiation therapy for SCCA were instructed to use a vaginal dilator starting at 6 weeks following treatment, with recommendations for use 3 times weekly for at least 2 years. Additionally, patients who experienced difficulty with bowel or bladder incontinence were referred for pelvic floor physical therapy. Use of these preventative or treatment strategies are critical for optimization of patient QOL and should not be omitted for women for whom dosimetric goals are met. Indeed, our current institutional practice is proactive pelvic floor physical therapy referral for all women regardless of treatment dosimetry or symptom burden.

Although this study draws strength from a rigorous dosimetric evaluation with consideration of multiple predictive OARs, it nonetheless is limited by several factors related to the experimental design. First, as with any retrospective study, it is not possible to make definitive statements regarding causal relationships between variables. We attempted to address confounding through the creation of a multivariable model, but it is possible that some causal factors were not collected and, thus, could not be considered. Second, it is important to consider the complexity of sexuality and sexual experience. We focused specifically on dyspareunia based on our hypothesis of how radiation dose to the vaginal canal would most directly affect sexual function, but this endpoint will only partially capture the reality of any woman's lived experience. However, we did find a strong correlation between the FSFI pain subscore and composite score, suggesting that most domains are likely interrelated. Third, our institutional practice is to use daily vaginal dilators during radiation for women without disease involving the vagina. A dilator is necessary to define the AVW and, therefore, for institutions that do not use daily vaginal dilators or for women for whom a dilator cannot be used, these data will be less clinically actionable. Furthermore, the majority of women (85%) who returned surveys reported that they continued to use a vaginal dilator after completion of therapy, which likely would influence the predicted risk of vaginal stenosis and dyspareunia. We were also unable to accurately measure the regularity or duration of dilator use. Therefore, these results should be considered with caution for women who are unable to routinely use a dilator after therapy. Last, given the retrospective single time-point survey study design, we were not able to measure individual baseline FSFI pain subscores or longitudinal changes, which may introduce unaccounted confounding or response bias that could influence the observed relationships.

Conclusion

Dose to the vaginal canal during pelvic radiation therapy for the treatment of SCCA is a strong predictor of long-term patient-reported sexual pain related to vaginal penetration. Consideration of the AVW as an OAR allows for a potentially actionable dosimetric clinical goal, V35 Gy < 60, to decrease the risk of this toxicity. These results may be used to optimize radiation therapy plans and warrant prospective evaluation.

Disclosures

Joshua S. Niedzielski receives unrelated funding from Varian Medical Systems. Albert Koong is a stockholder in Aravive, Inc. All other authors have no disclosures to report.