Erectile Dysfunction and Penile Bulb Dose Following Definitive Prostate Radiation Therapy

Prostate cancer is the most frequently diagnosed cancer and the second most prevalent cause of cancer death in men (1). With the increased implementation of screening programs, more patients are being diagnosed at earlier stages, significantly improving their survival (2). Therefore, efforts should be made to reduce the side effects of treatment (3). Currently, treatment options for patients with early-stage prostate cancer include active surveillance, radical prostatectomy, and definitive radiotherapy (RT) (4, 5). In many cases of early-stage prostate cancer, definitive RT is chosen due to the patient's inability to tolerate surgery or their preference for a non-surgical procedure without compromising the outcome (6). However, acute and late toxicities related to unintentional doses to organs at risk are expected following RT administration (7).

Erectile dysfunction (ED), defined as the inability to obtain or maintain a penile erection during sexual activities, is a common problem associated with prostate RT, with an estimated rate of up to 50% in some reports (8). The underlying mechanisms may include direct radiation-induced damage to the penile bulb (PB) or the neurovascular bundles, although the exact mechanisms remain unclear (9-11). The rates of ED following definitive RT have decreased in recent years with the advancement of treatment techniques (12). Conformal treatment technologies, such as intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), and stereotactic body radiotherapy (SBRT), have improved the technical delivery and dose administered by radiation therapy, thereby reducing acute and late side effects (13-15).

These advanced techniques have made it possible to increase the doses to targeted areas while reducing the dose to at-risk organs (14, 16, 17). The PB is located near the prostate and the radiation field. The dose received by the PB is a crucial factor in the development of ED, with a dose of approximately 50 Gray (Gy) to the entire PB identified as a threshold for an increased risk of ED (13, 18). In many oncological centers in Iran and similar developing countries, 3-dimensional conformal radiotherapy (3D-CRT) is the most commonly available method. However, there is limited data on the dose to the PB and its association with sexual disorders related to prostate radiation therapy in Iran.

This study aims to investigate the relationship between the PB dose in 3D-CRT and the incidence of ED related to RT at the Mahdieh and Besat Radiation Therapy Center in Hamadan, Iran.

The study involved patients with low-risk prostate cancer (PSA < 10, Gleason Score < 7, T stage < T2) who had an expected life expectancy of more than 10 years and were referred for definitive external beam radiation therapy (EBRT) at the Mahdieh and Besat Radiation Therapy Center in Hamadan, Iran, between June 2021 and August 2023. Patients who were candidates for concurrent or adjuvant androgen deprivation therapy (ADT) were excluded from the study.

Individuals with underlying health conditions known to increase the risk of ED, such as atherosclerosis, hypertension, diabetes, and cardiovascular disease, were also excluded. Additionally, smokers or those who had smoked in the past 6 months were not included. Pelvic multiparametric MRIs were performed on all patients to ensure appropriate staging before entering the study. All patients were initially examined for proper erection by a trained urologist, and they completed the International Index of Erectile Function (IIEF-15) Questionnaire. The IIEF-15 consists of 15 questions that assess male sexual function across five main domains: Erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. Each question is scored from 0 to 5. Patients were categorized based on their total score as follows: 1 - 10: severe ED; 11 - 16: Moderate dysfunction; 17 - 21: Mild to moderate dysfunction; 22 - 25: Mild dysfunction; 26 - 30: No dysfunction. Those scoring 25 or below were classified as having ED before radiation therapy and were excluded from the study.

According to Rezaee et al., the Persian version of the IIEF-15 is a valid and reliable tool for assessing male sexual function. They reported Cronbach's alpha and intra-cluster correlation coefficients for the questionnaire at 0.893 each (with a confidence interval between 0.811 and 0.950), indicating strong internal consistency of the questionnaire items and domains (19). The Cronbach's alpha for our sample was 0.97. CT scans were performed with an empty rectum and a comfortably full bladder in the supine position. Axial CT scans with 5 mm slice thickness were used for contouring and were fused with multiplanar MRI. Clinical tumor volume (CTV), planned tumor volume (PTV), PB, rectal, and prostate anatomy were delineated on each slice. Radiotherapy was administered exclusively to the prostate, as pelvic lymph node irradiation was deemed unnecessary due to the patients' low risk. The prostate gland and seminal vesicles were included as CTV. A 5 mm margin was applied in all directions for PTV, except for a 3 mm margin posteriorly to spare the rectum. The PB was defined as the proximal part of the penis, located just caudal to the prostate gland (the proximal expansion of the corpus spongiosum attached to the urogenital diaphragm and covered by the bulbospongiosus muscle).

External beam radiation therapy was planned and delivered with the patient in the supine position. All patients underwent 3D-CRT with a total dose of 76 Gy, administered as 2 Gy per fraction. The energy used for all patients was 18 MeV, delivered by an Elekta Synergy linear accelerator. The dose received by the PB was measured using dose-volume histograms (DVH). For each DVH, the average dose received by the PB was calculated. Three months after completing radiation therapy, patients were asked about their sexual function during follow-up visits, and they completed the IIEF questionnaire again. Data collected included age, disease stage, mean dose to the PB, ED score, and Body Mass Index (BMI). The data were analyzed using SPSS version 26 software (SPSS Inc., Chicago, IL, USA). The Pearson correlation coefficient was used to investigate the relationship between ED score and dose received. A linear regression test was used to examine the adjusted association between the mean dose and ED. The normality of the ED response variable (measured as a continuous variable) was assessed using the Kolmogorov-Smirnov test. The linearity assumption for the regression model was checked using residual plots. Residuals (the differences between observed and predicted values) were plotted against the independent variables. The residuals were randomly scattered around zero with no clear pattern, suggesting that the linearity assumption holds for the three variables in the model. To determine if the two ED groups (mild versus moderate) were homogeneous with respect to age, BMI, and received dose, we used two independent sample t-tests. All tests were considered statistically significant when the P value was <0.05.

Forty patients who underwent definitive external beam radiotherapy (EBRT) for low-risk prostate cancer were enrolled in this study. The mean ± SD age of the patients was 75.5 ±5.70 years, with an age range of 68 to 85. Disease stage was I in 60% of the patients, while the remaining 40% were at stage IIA. The mean ± SD dose to the PB was 56.98 ± 9.05 Gy (95% CI = 50.50 - 63.46). The average ED score based on the questionnaire was 15 ± 10.55. The correlation between the ED score and the dose was not significant (r = -0.199; P = 0.589).

A multivariate regression analysis was conducted to investigate the association between ED and the received dose, adjusted for the effects of BMI and age. Table 1 presents the coefficients of the multivariate linear regression for the associations between the average received dose and ED. According to the results, there was no significant association between the average received PB dose and the ED score. Additionally, based on the categorization of ED, 20% of the patients had moderate ED, and 80% had mild ED. Table 2 shows the doses received by the two groups. As shown, there were no significant differences in the doses received between the two groups.

Prostate cancer is a common cancer type among men, accounting for 14.1% of all new cancer cases and 6.8% of all male cancer deaths worldwide in 2020 (20). Radiotherapy is a critical component of curative treatment for early-stage prostate cancer, with outcomes comparable to radical prostatectomy (21). Compared to surgery, RT offers several advantages, including avoiding complications associated with general anesthesia and surgery, such as bleeding, and a lower risk of urinary incontinence and stricture (22). Recent clinical trials have shown that increasing radiation doses to the prostate can improve cancer-related outcomes, though it may also increase side effects, such as sexual disorders (23).

The incidence of ED following RT varies widely, affecting 20% to 90% of patients (24). While early-stage prostate cancer patients generally have high survival rates, approximately half may develop ED within 3 to 5 years after completing treatment (25). Since sexual function is a crucial aspect of human health and cancer survivorship, understanding the potential effects of different treatment modalities on sexual health is essential (26). Key predictors of ED following treatment include the patient’s age at the time of radiation, their erectile function before treatment, the type of RT used, and the health of their erectile tissues (27). Younger men and those with better erectile function before treatment tend to have better erectile outcomes (24). Many studies have identified patient-related factors such as diabetes, smoking, a history of hypertension, and cardiovascular disease as risk factors for ED (28). A study by Cahlon et al. involving 487 patients who underwent prostate RT found that age over 70 years and diabetes were significant contributors to the development of ED (29). In this study, patients with diabetes, smokers, and those with a history of hypertension or cardiovascular disease were excluded. We also excluded patients receiving ADT, as ADT has been shown to predict ED following EBRT. Additionally, patients who had undergone brachytherapy were excluded, as the additional dosage from brachytherapy complicates the determination of the contributions of each therapy (30).

Studies on erectile function following RT have mainly focused on the dose to critical erectile structures, particularly the PB (31). Many studies suggest that the maximum dose to the PB area to prevent ED should be less than 50 Gy (18). In a study by Fisch et al., which also used 3D-CRT, 33% of patients reported ED, with a dose of D70 ≥70 Gy significantly associated with ED (32). Mangar et al. investigated the rate of ED based on patient-reported questionnaires and found that a D90 ≥50 Gy is associated with a significant risk of ED (33). In the current study, the average dose to the PB was 56.98 Gy, exceeding the recommended maximum dose.

There is inconsistency regarding the relationship between PB dose and ED occurrence in prostate cancer (34, 35). Although the PB is a primary focus in many research studies, several investigations have shown that the dose delivered to the PB is not the most significant factor for ED (36). A recent systematic review revealed that out of 23 studies on radiation-induced ED, only 15 showed a significant correlation between the PB dose and the incidence of ED (36). For instance, Roach et al. found that patients with a median penile dose of 52.5 Gy or more had a greater risk of radiation-induced impotence compared with those receiving a dose of less than 52.5 Gy (P = 0.039, odds ratio = 1.98, 95% CI = 1.03 - 3.78) (18). However, Van der Wielen et al. found no significant differences in mean dose, maximum dose, or volume of various structures between patients with and without ED 2 years after EBRT (37). Similarly, Selek et al. studied 28 patients and found that 68% developed post-treatment ED, but there was no dose-volume effect between PB dose and ED, which aligns with our research findings (38).

To explain this controversy, it is important to recognize that the development of ED in prostate cancer patients is a multifaceted phenomenon influenced by various physical and psychological factors. Some studies have focused on other anatomical structures, such as the proximal centimeter of the crura, internal pudendal arteries, neurovascular bundles, and ejaculatory ducts (37). However, there was insufficient evidence to establish a relationship between ED and the dose to the neurovascular bundles based on eight studies. One study investigated the relationship between ED and the dose received by the internal pudendal arteries but found no significant correlation (36). Nevertheless, studies that spared blood vessels reported positive outcomes in maintaining erectile function without compromising the intended treatment volume. Thus, controversy exists regarding the importance of doses to different irradiated structures in the development of ED (36).

It has been suggested that the effects of RT on penile structures may extend beyond anatomical damage and contribute to an inflammatory process (39). Radiation therapy induces a proinflammatory cytokine cascade that creates an inflammatory microenvironment, leading to neurovascular toxicity (40). The degree of inflammation is directly proportional to the amount of irradiated prostatic tissue, fraction delivery time, patient setup errors, and rectal sparing protocols (40). Endothelial damage and accelerated atherosclerosis of various vessels in the prostate area can also occur, leading to arterial occlusive disease and abnormal blood flow, which can affect a significant percentage of patients (40).

To achieve penile erection, psychogenic stimulation triggered by sexual thoughts and stimuli is required in addition to pathophysiological factors. For patients with prostate cancer, ED may result from various psychological factors such as depression, anxiety, frustration, shame, and lack of confidence in sexual performance (41). Several studies have indicated that prostate cancer treatment can lead to changes in emotional state, self-esteem, and body image, which may contribute to ED (42, 43). Therefore, to arrive at a more accurate conclusion, it is essential to assess the psychological aspects of prostate cancer treatment using appropriate questionnaires such as the Self-Esteem Scale (SES), Personal Attributes Questionnaire (PAQ), Body Image Scale (BIS), and the functional assessment of cancer therapy-prostate (FACT-P). It is worth noting that in this study, only the IIEF-15 Questionnaire was used, and this should be considered when interpreting our conclusions.

Several limitations should be considered when interpreting our findings. Firstly, our sample size was relatively small, which may impact the generalizability of our results. Additionally, while our primary focus was on exploring the relationship between ED and PB dose, we did not examine potential correlations with other anatomical structures, presenting an opportunity for future research in this area. Lastly, our data collection was restricted to patient visits over a 3-month period, which may provide only a partial understanding of long-term trends and effects. Therefore, further research with a larger sample size and extended follow-up is needed to provide a more comprehensive understanding of the topic.

Despite advancements in radiation techniques designed to minimize nerve and vascular damage to the prostate and reduce the exposure of surrounding tissues to radiation, a recent study found that 100% of patients reported experiencing post-treatment ED. This issue may be attributed to the routine use of 3D-CRT, particularly in developing countries like Iran, which can result in damage to normal tissue, including the PB, despite efforts to contour the organ at risk. As many medical centers in developing countries utilize 3D-CRT to treat prostate cancer, a multidisciplinary discussion may be necessary to select the most appropriate treatment modality. Considering advanced techniques such as IMRT, IGRT, volumetric modulated arc therapy (VMAT), and stereotactic body radiation therapy (SBRT) could be steps towards improving patient outcomes.