|Year : 2020 | Volume
| Issue : 1 | Page : 70-75
Erectile dysfunction in prostate cancer patients treated with intensity-modulated radiation therapy
Halil Cumhur Yildirim1, Sefika Arzu Ergen1, Emine Sedef1, Merve Sahin1, Songul Cavdar Karacam1, Mustafa Sukru Senocak2, Fazilet Oner Dincbas1
1 Department of Radiation Oncology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
2 Department of Biostatistics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
|Date of Submission||18-Jul-2018|
|Date of Decision||17-Nov-2018|
|Date of Acceptance||11-Jan-2019|
|Date of Web Publication||26-Feb-2020|
Halil Cumhur Yildirim
Department of Radiation Oncology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul
Source of Support: None, Conflict of Interest: None
Background: Sexual dysfunction is an important side-effect after radiotherapy (RT) for prostate cancer (PCa). The aim of this study was to compare sexual functions of PCa patients before and after intensity-modulated RT and to analyze their correlation with penile bulb (PB) doses and patient characteristics.
Materials and Methods: Forty-two patients who underwent RT ± hormone therapy for PCa between 2010 and 2013 were analyzed. Sexual functions assessed by patient-reported questionnaire and physician reported scale before and 3 years after treatment. The effect of patients' age, prostate volume, testosterone levels, comorbidity, smoking status, tumor stage, RT technique, hormone therapy, and PB doses to sexual functions were investigated.
Results:After 3 years of RT, 64.3% of all patients had a lower erectile score; and 75% of patients who were previously potent (n = 24) had become impotent after treatment. However sexual desire still remained in 75.8% of patients who had desire before treatment (n = 33). Statistical analysis showed that two parameters were correlated with postradiotherapy impotency outcome; PB mean radiation dose (P = 0.033) and testosterone levels (P = 0.032).
Conclusions: RT, despite modern techniques, affects the sexual function of PCa patients in varying degrees. Reducing radiation doses to penile structures may play a role in preventing erectile dysfunction.
Keywords: Erectile dysfunction, intensity modulated radiotherapy, penile bulb, prostate cancer
|How to cite this article:|
Yildirim HC, Ergen SA, Sedef E, Sahin M, Karacam SC, Senocak MS, Dincbas FO. Erectile dysfunction in prostate cancer patients treated with intensity-modulated radiation therapy. Indian J Cancer 2020;57:70-5
|How to cite this URL:|
Yildirim HC, Ergen SA, Sedef E, Sahin M, Karacam SC, Senocak MS, Dincbas FO. Erectile dysfunction in prostate cancer patients treated with intensity-modulated radiation therapy. Indian J Cancer [serial online] 2020 [cited 2020 Apr 1];57:70-5. Available from: http://www.indianjcancer.com/text.asp?2020/57/1/70/279172
| » Introduction|| |
Prostate cancer (PCa) is the most common nondermatological malignancy in men all around the world. Treatment options for localized disease include active surveillance, radical prostatectomy, external-beam radiation therapy (EBRT), and brachytherapy (BT). Recently, focal therapies such as cryotherapy, high-intensity focused ultrasound, photodynamic therapy, electroporation, and laser ablation are also under investigation. External radiotherapy is usually implemented alone on patients with localized PCa without risk factors and in combination with hormone treatment (androgen deprivation therapy [ADT]) in locally advanced disease and/or presence of high-risk factors.
All treatment options could cause urinary, bowel, and sexual dysfunctions; albeit in different severity, frequency, and duration., Of these, sexual health is one of the main issues after cancer control in patients whose sexual life is ongoing. The patient's preference is accepted as an important factor for determining treatment schedule; therefore, revealing the side effects of treatments in regard to sexual function is important for PCa treatments.
Corpora cavernosa, neurovascular bundle, and penile vasculature injuries are all involved in erectile dysfunction (ED) after radiation exposure. There are at least three hypotheses about the mechanisms of ED related to radiotherapy (RT): 1) Vasculogenic: Endothelial cell damage in penile arteries and sinusoids cause stenosis and vascular insufficiency. 2) Neural: Injury of the nerve bundles may lead to diminish nitric oxide synthase. 3) Structural: Fibrosis in corporal tissue has an adverse effect on keeping blood in the penis by venous leakage. According to these hypotheses, it seems reasonable to investigate the effect of radiation dose on penile structures. Penile bulb (PB), which is just a spongiosa tissue but visible and contourable on computed tomography (CT) of RT planning, is one of the simplest surrogates of regional anatomic structures.
Studies exploring the relationship between penile structures and ED have conflicted results. Additionally, most of them were performed with three-dimensional conformal radiotherapy (3D-CRT). At present, by means of more sophisticated technics such as intensity-modulated radiotherapy (IMRT) with image-guided radiotherapy (IGRT), it is possible to give higher doses to prostate and lower doses to surrounding tissue. Our aim was to evaluate the sexual function of patients who underwent IMRT with IGRT and to investigate the effect of PB doses and patient characteristics on ED.
| » Materials and Methods|| |
The study is a retrospective analysis of prospectively collected data on PCa patients treated with RT at a single center. All patients provided written informed consent.
At our center, PCa patients treated with IMRT were evaluated retrospectively. Inclusion criteria were as follows. Patient 1) had completed both sexual function assessments before and 3 years after treatment; 2) had testosterone levels measured at last follow-up; and 3) had attended regular follow-up until the last assessment. During the study period, there were a total of 134 patients who underwent primary RT for PCa at our department and 42 of them were available for the analysis.
Patients were classified into three groups according to European Association of Urology guidelines. Over all, 16 (38.1%) low-risk patients were treated with RT alone, 4 (9.5%) intermediate risk patients with RT + short-term (6 month) hormone therapy, and 22 (52.4%) high-risk patients with RT + long-term (24 month) hormone therapy with luteinizing hormone-releasing hormone agonists. In patients who received hormone therapy, injections were given 3 months before RT or at the same time with RT.
CT simulations were performed in the supine position with a full bladder and empty rectum. Bladder volume was assessed by portable ultrasound at every session and kilo-voltage cone beam CT was used for image guidance for all patients. Prostate and the proximal seminal vesicles were delineated in all; and for six patients, the delineation included pelvic lymph nodes. Planning target volume margins of 8 mm (5 mm posterior) were used. A median radiation dose of 76 Gy (range: 74–78 Gy) for the prostate and a 56 Gy (range: 54–56 Gy) for the proximal seminal vesicles were administered. Dose calculation was done by Eclipse version 8.6 IMRT treatment planning system. Eleven treatments were done by seven field IMRT, and 31 were done by two arc volumetric modulated arc therapy.
The contouring process was done by two radiation oncologists. PB was defined as a proximal enlargement of the corpus spongiosum; landmarks were, corpora cavernosa anteriorly, paired crura laterally and levator ani posteriorly. Mean doses of PB were recorded and subgroup dosimetric doses were calculated as V30, V50, V60, V70 (volume of the PB receiving 70 Gy) and D25, D50, D75, D90 (mean dose to 90% of the PB).
Sexual function evaluation
The evaluation of ED was achieved with a four-degree method reported by physician. Impotency was defined if the scores were zero and one [Table 1].
Sexual desire was assessed by patient report with two questions selected from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Turkish Version for patients with PCa (EORTC-QLQ-PR25). Sexual desire existence was defined as a score of three or four from both questions [Table 2].
The scale and questionnaire were applied to patients before and 3 years after treatment. Sexual evaluations were done by two physicians in all patients. All second evaluations were made 1 year after the completion of hormone therapy.
Patients were required to attend follow-up examinations every 3 months for the first 2 years, then every 6 months. The age, prostate-specific antigen (PSA) value, T-stage, Gleason score, prostate volume, testosterone value, comorbidities (hypertension, diabetes mellitus, coronary artery disease), smoking status, hormone therapy, and RT field and technique information were recorded for all patients.
All analyses were performed on IBM SPSS v19. Categorical data were described with frequency (percentage). Assessments of patient sexual functions before and after treatment were made using McNemar–Bowker test. Chi-square of Fisher's test as appropriate is used for the categorical evaluations between sexually potent and impotent patients.
Shapiro–Wilk test was used for normality check in continuous variables. Continuous data were described with mean and standard deviation for normally distributed variables and with median (minimum – maximum) for non-normally distributed variables. Continuous variables were compared with Student t-test or Mann–Whitney U-test as appropriate. A P value <0.05 was considered statistically significant.
| » Results|| |
In total, 42 patients with a mean age of 67.31 ± 7.10 were enrolled in our study. All of the patients were alive and disease free at the last follow-up. Characteristics of patients are given in [Table 3].
Eighteen (42.9%) patients were already sexually impotent at presentation. After the treatment, 18 (75.0%) of the previously potent 24 patients became sexually impotent (P< 0.001). Nine (21.4%) patients already had no sexual desire before treatment. After the treatment, 8 (24.2%) of the 33 patients were found to have lost their sexual desire (P = 0.008).
When we compared erectile scores before and after treatment, there was a significant decrease in erectile scores (P< 0.001). In total, 27 (64.3%) of the 42 patients had a decrease in their erectile scores, whereas 15 (35.7%) of the 42 patients had no change [Table 4].
We classified patients into two groups in regard to sexual potency as “Still Potent” and “Became Impotent” after treatment. There was significant difference between our groups for PB median dose and testosterone levels. Patients who remained potent had been given a median of 26.11 (16.15–43.61) Gy, whereas patients who became impotent received a median dose of 46.20 (13.00–79.78) Gy. Further analysis of individual values yielded that PB D50, D75, and D90 doses were significantly associated with impotency development (P = 0.030, 0.012, and 0.010, respectively). There was no significant difference between our groups regarding age, prostate volume, and PSA levels [Table 5].
We found that smoking status, comorbidity, tumor stage, Gleason score, RT field, RT technique, and hormone therapy had no significant effect on potency. ED rates according to hormone therapy of the 24 patients who were previously potent were 8/11 (72.7%) for hormone-naive patients, 3/3 (100%) for short-term, and 7/10 (70%) for long-term users, respectively (P = 0.559). Of the 24 patients with normal erectile functions, 11 had chronic diseases. Six patients had hypertension, three had diabetes mellitus, six had coronary artery disease, and four had a combination of two. ED rates were 8/11 (72.7%) and 10/13 (76.9%) in patients with and without chronic illness, respectively (P = 0.813). Also, we evaluated the same variables between the patients who lost their sexual desire and still have sexual desire after treatment; but, we found no significant difference between our groups regarding the same variables (data not shown).
| » Discussion|| |
In our study, we had a group of 42 patients who had undergone EBRT with or without hormone therapy for PCa. Some other studies exclude patients who receive adjunct hormone treatment. The reason we included these patients was to evaluate the real-life treatment effects associated with EBRT and ADT on sexual functions and due to some studies reporting the effect of adjunct hormone therapy to be insignificant. In addition, our evaluations were made 1 year after the completion of hormone therapy to reduce the effects of ADT.
A recent prospective, population-based cohort study which assessed patient reported outcomes at 3 years after treatment reported that sexual functions are worse with surgery in comparison with RT and active surveillance. Potency preservation rates at 3 years for prostatectomy, EBRT, and active surveillance were 43%, 53%, and 75%, respectively, in patients who had sufficient erections before the treatment. Two prospective trials have found ED incidence as 30%–40% within 2 years of 3D-CRT treatment., Several studies report that IMRT may be beneficial due to the achievement of lower radiation doses to neighboring structures. In contrast, 64.3% of our patients had a decrease in their erectile scores despite using IMRT and IGRT.
There are a number of reasons why our patients may have lower sexual functions compared with other studies reporting low impotence rates. First, 52.4% of patients had long-term hormone therapy which can facilitate a long-lasting impotency. A recent study including 1,641 men treated for PCa with initial testosterone values of 358 ng/dL found that testosterone levels were 96 ng/dL after 6–12 months of ADT cessation and 273 ng/dL after 2 years. In patients >65 years, who underwent ≥6 months of ADT and who had a baseline testosterone level of <400 ng/dL, the recovery time was significantly slower. According to these findings, the 1-year waiting period may not be sufficient for testosterone recovery in our study group. Second, during erectile function and impotence scaling, none of our patients used any pharmacological agents or any potency aid. ED therapies may improve the sexual life of the patients. Third, according to the 2017 report of the Turkish Society of Andrology Male Sexual Health Study Group, the prevalence of ED in the Turkish population is 68.8% for 60–69 years and 82.9% over 70 years. They found that age was the main predictor of ED, and diabetes, hypertension, atherosclerosis, dyslipidemia, lower urinary tract symptoms, educational status, and monthly income were strongly correlated with ED as well. However, we could not detect a statistically significant effect of comorbidity and hormone therapy on sexual functions. High rates of ED and a small number of patients may have supressed the significant effect of these main factors on sexual functions. In addition, mean age of our patients were 67 and they might have some subclinic comorbid diseases. Therefore, ED rates may rise even without treatment every year.
In our study, statistical evaluation yielded that PB mean radiation dose and testosterone levels were significantly correlated with the development of impotency. Several studies that evaluate the effect of RT in regard to dose to anatomic structures have contrasting results. Two large BT studies found no significant correlation with PB mean radiation dose., The latter showed that dose to 50% of the proximal crura were significantly associated with BT-related ED. A study comprised of 28 patients that received 3D EBRT by Selek et al. found no relationship whatsoever between impotency development and the dosage of radiation on the PB, crura, or corpora cavernosa. Furthermore, a study by Brown et al. concluded that the dose and volume of RT treatment on the PB were not associated with post-treatment ED (P = 0.38 and 0.76, respectively). However, a study by Wernicke et al.; which had a median of 35-month follow-up and assessed erectile status through an EDFS (ED firmness score) found that a lower radiation dose to a smaller volume of the PB resulted in a higher rate of preserved potency. They proposed that EBRT directly or indirectly damaged the vascular and nervous structure supplying the smooth muscles of the cavernosa, resulting in impotence.
A dose–escalation study which comprised of 158 patients' studies by Roach et al. (RTOG 9406) also found that ED development to be associated with the dose received by the penile structure. They reported that patients receiving a median PB dose ≥52.5 Gy via 3D EBRT were at greater risk of developing ED when compared with patients who received a lower dose (P = 0.039). They also reported that age, dose to the prostate, or the application of adjunct hormone therapy had no effect in the development of ED. A study by Fisch et al. found that a dose <40 Gy applied on 70% of the PB was associated with greater likelihood of maintaining potency. Also, they found that patients who received a dose in excess of 70 Gy applied on 70% of the bulb were at very high risk of developing impotence post-treatment (P = 0.03). A randomized control trial on 51 patients who received 3D EBRT and neoadjuvant hormonal therapy by Mangar et al. divided patients into three groups (potent, reduced potency, and impotent) during a 3-year follow-up and found significant difference in point of mean doses on the PB (45.5, 48, and 59.2 Gy, respectively). They also found that 83.3% of impotent patients had received a PB D90 dose in excess of 50 Gy, while this ratio was only 29.4% for potent patients in a 2-year follow-up (P = 0.006).
In our findings, median PB dose and impotence development were found to be significantly associated. Moreover, when individual radiation doses were analyzed, we found PB D50, PB D75, and PB D90 doses to be significantly associated with impotence development. In our clinical practice, we are trying to keep the mean dose to PB <50 Gy if appropriate.
Other than ED, frequent sexual complaints and symptoms following RT treatment for PCa are ejaculatory problems (absence of ejaculate, lower ejaculate volume, discomfort during ejaculation, and hemospermia), dissatisfaction with sexual life, decreased libido, and sexual desire. A longitudinal study by Yoshimura et al. reported a significant decrease in sexual desire. Whereas two recent studies from northern Europe reported the loss of sexual desire in 8%–9% of patients treated with RT for PCa., We found that 78.6% of our patients had sexual desire before treatment and 59.5% had remained after treatment. In that case, identifying the probability and frequency of sexual dysfunction after EBRT is of utmost importance for the patient's quality of life (QoL).
Our study reflects a single-center experience with a limited number of patients. In addition, physician-reported assessment of impotency can cause biases. Although this four-degree method is a validated and useful evaluation, patient reported instruments such as the international index of erectile function may be more accurate.
| » Conclusion|| |
Despite modern techniques, EBRT (with or without adjunct ADT) affects sexual life of PCa patients, and PB radiation doses may be associated with erectile dysfuntion. However, the complex etiology of impotence makes it difficult to understand the causes of post-treatment ED. Detailed studies with high number of patients may provide new insights into RT management of PCa and ultimately would increase the QoL of patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]