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Dosimetric analysis of patients receiving radiotherapy with VMAT technique in localized prostate cancer and its correlation with side effects

1 Marmara University Radiation Oncology Department, Marmara University, İstanbul, Turkey
2 Marmara University Biostatistics Department, Marmara University, İstanbul, Turkey

Date of Submission15-Sep-2021
Date of Decision11-Feb-2022
Date of Acceptance12-Feb-2022
Date of Web Publication02-Nov-2022

Correspondence Address:
Sitki U Akay,
Fevzi Çakmak District, Muhsin Yazıcıoğlu Street, No: 10, Pendik, İstanbul
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_1621_21

 > Abstract 

Aim: The aim was to study the relationship between dosimetric data of localized prostate cancer patients who have been treated with curative radiotherapy (RT) and gastrointestinal (GIS), genitourinary (GUS), anal and sexual side effects, and whether there was a difference between dosimetric data and clinical findings between risk groups.
Methods: Eighty-seven patients who received curative radiotherapy for localized prostate cancer between 2014 and 2019 were included in the study. Dosimetrically; whether there was a relationship between V30, V40, V50, V60, V65, V70, V75 for rectum and bladder; D90 for the penile bulb, V72, V74, V76 for the bulbomembranous urethra, V30, V45, V53, Dmax for the anus, and V45 (cc) for the intestine data and the side effects were analyzed. It was evaluated whether there was a relationship between testosterone values and sexual side effects. The Kolmogorov–Smirnov test, one-way analysis of variance (ANOVA) (F-test), and paired-sample t-test were used as statistical methods. For statistical significance, P < 0.05 was accepted.
Results: The mean age of the patients was 69 (50–86), the mean Prostat specific antigen (PSA) (ng/dL) before RT was 25.1 (0.9–339), the median RT dose was 76 Gy (74–78 Gy), and the mean follow-up period was 38.2 months. PTVmax, PTVmean, PTVmin, bladder V40, bladder V50, rectum V30, rectum V40, rectum V50, and intestinal V45 (cc) were determined as dosimetric data showing differences between risk groups. A statistically significant relationship was found between rectum V30 (P = 0.017), V60 (P = 0.019), V65 (P = 0.008), V70 (P = 0.007), and V75 (P = 0.034) and chronic GIS side effects. G2 GIS side effects were observed in four patients (4.6%) in the entire patient group during the acute period. A statistically significant relationship was found between the patients receiving hormonotherapy (P = 0.021) and testosterone values at the last control (P ≤ 0.001) and chronic sexual side effects.
Conclusion: Attention should be paid to the rectum V30, V60, V65, V70, and V75 values to minimize the long-term GIS side effects in patients who have undergone RT. Testosterone level and ADT status affect chronic sexual toxicity.

Keywords: External radiotherapy, normal tissue toxicity, prostate cancer

How to cite this URL:
Akay SU, Çetin &A, Bekiroğlu GN. Dosimetric analysis of patients receiving radiotherapy with VMAT technique in localized prostate cancer and its correlation with side effects. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 9]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=360431

 > Introduction and Aim Top

Prostate cancer is one of the two most common cancers in men, and its incidence increases with advancing age.[1],[2] Surgery, external radiotherapy (RT), hormonotherapy, or brachytherapy can be applied alone or in combination according to the stage of the disease and the patient's preference. Surgery and external radiotherapy (RT) are the most preferred treatment modalities for definitive treatment of localized prostate cancer.[2],[3] Urinary incontinence and erectile dysfunction (ED) are more common in patients who have undergone radical prostatectomy than RT, and intestinal side effects are more common in patients receiving RT; these side effects should be considered when deciding on the curative treatment modality.[4],[5],[6] Treatment success and survival rates are high with curative RT for localized prostate cancer; therefore, monitoring long-term gastrointestinal (GIS), genitourinary (GUS), and sexual side effects are essential when determining the patients' quality of life.[7],[8],[9] Although biochemical recurrence-free survival and progression-free survival rates increase with dose escalation in patients undergoing prostate cancer RT, the side effects related to RT can also increase.[9],[10],[11] It is now possible to protect normal tissues and organs better while escalating the dose to the prostate.[12],[13] Studies that evaluated the side effects after external RT for localized prostate cancer that the dose received by the rectum and bladder was related to GIS and GUS symptoms and anal sphincter and fecal incontinence.[14],[15],[16],[17],[18],[19],[20] The relationship between the urethral dose and urinary symptoms has been determined for brachytherapy, but that for external RT is not well understood.[21],[22] A relationship between the penile bulb dose and ED was reported by studies evaluating ED after RT.[23],[24],[25],[26] This study aimed to determine the potential relationships between dosimetric data and acute and chronic side effects in localized prostate cancer patients treated with image-guided radiotherapy (IGRT) and volumetric arc therapy (VMAT). We also determined whether there is a difference between the dosimetric data and clinical findings according to risk groups.

 > Materials and Methods Top

This was a single-center retrospective study. Patients who received curative RT for localized prostate cancer at the Marmara University Radiation Oncology Clinic between 2014 and 2019 and were followed up for at least 6 months after treatment were included in the study. Patients with positive lymph nodes, distant metastasis, previous RT applications, or a surgical history due to prostate cancer were not included in the study. Ethics committee approval was obtained with the protocol number 09.2018.584. It was obtained on 7th September 2018.

Patients undergoing RT for localized prostate cancer in 2014 were later divided into low-, intermediate-, and high-risk classes according to the National Comprehensive Cancer Network risk classification. The GIS and GUS side effects of the patients noted in the outpatient clinical follow-ups were graded according to the Radiation Therapy Oncology Group morbidity scale, and sexual side effects were graded according to the Common Terminology Criteria for Adverse Events v5.0 side effects scale. The side effects seen from the beginning of the treatment until 3 months after the end of treatment were called acute, and the side effects seen at 6 months and the end of the treatment were defined as chronic side effects. Differences in the dosimetric data and acute and chronic side effects among the risk groups were analyzed.


Patients were situated in the supine position, with an empty rectum and a full bladder. An intravenous contrast medium was administered to the high-risk patient group. A slice thickness of 3 mm was used to simulate the computed tomography (CT) scan. The CT scan included the entire pelvis.

The organs affected by prostate cancer are the bladder, rectum, penile bulb, intestines, and femoral heads. In addition, the bulbomembranous urethra and anus were contoured. All contours drawn were checked in sagittal and coronal sections, and necessary corrections were made. The dosimetric data of PTVmax, PTVmean, PTVmin, V30, V40, V50, V60, V65, V70, and V75 for the rectum; V40, V50, V65, and V75 for the bladder; D90 for the penile bulb, V72, V74, and V76 for the bulbomembranous urethra; V30, V45, V53; Dmax for the anal sphincter; and V45 (cc) for the intestines were obtained. Significant differences in the dosimetric parameters among the risk groups were evaluated. The relationships of the bladder and urethra dosimetric data with GUS side effects, the rectal and intestinal dosimetric data with GIS side effects, the anal dosimetric data with anal side effects, penile bulb dosimetric data with the testosterone levels before and after RT and with sexual side effects were evaluated.

Urethral contours were made by fusion with pelvic magnetic resonance images (MRIs). The urethral contour was obtained in patients without MRI images by drawing the urethra in the prostatic and penile parts where the urethra was detectable, and then continuing this drawing toward the upper and lower sections, considering the urethral anatomy and studies on the urethra. Then, dosimetric data of the contoured bulbomembranous urethra were obtained.

The prostate was contoured as the gross tumor volume (GTV) in the low-risk patient group. The prostate was contoured as the GTV and the seminal vesicle as the clinical target volume (CTV) tumor in the intermediate-risk patient group. In the high-risk patient group, the prostate was contoured as the GTV and the seminal vesicle as the CTV tumor. The lymph node regions of patients with a >15% risk of lymph node involvement according to the Roach formula were also included in the treatment area. The obturator, external iliac, internal iliac, and presacral and distal main iliac lymph node areas were contoured as CTV lymph nodes in patients receiving treatment for lymph nodes. The planning target volume (PTV) was created by applying a 0.5 cm margin to the area adjacent to the rectum posterior to the GTV and CTV tumor structures and 1 cm in all other directions. A PTV lymph node was created in the high-risk patient group by applying a margin of 0.7 cm in all directions to the CTV lymph node.

The dose schemes of 74 Gy/37 fractions and 76 Gy/38 fractions were administered to the low-risk patients as the RT dose. Intermediate-risk patients were administered either a 76 Gy/38 fraction or 78 Gy/39 fraction dose scheme. A dose scheme of 54 Gy/27 fractions was applied to the seminal vesicle. High-risk patients received 78 Gy/37 fractions. Doses of 54 Gy/28 fractions to the seminal vesicle and 46 Gy/28 fractions to the lymph node area were used.

The double arc Volumetric arc therapy (VMAT) technique was used for planning in all patients. The simultaneous integrated boost technique was applied in the high-risk patient group. In the planning evaluation, attention was paid to the dose–volume data received by the normal organs and the dose limits published by The Quantitative Analysis of Normal Tissue Effects in the Clinic group, which indicates the estimated risk of toxicity due to RT. All patients were treated with IGRT. Daily cone-beam CT (CBCT) was used for IGRT.


All patients were followed up weekly during RT. Side effects were noted during these visits, and the necessary treatments were applied. The total prostate-specific antigen and total testosterone levels were determined before and after treatment in all patients. The patients were invited to follow-up visits every 3 months for 2 years, every 6 months for 2–5 years, and annually after 5 years. The side effects of the patients were noted at the follow-up visits after RT and graded according to the RTOG and CTCAE v2.0 scales, and the total prostate-specific antigen and total testosterone levels were determined.

Statistical analysis

The normality of the distribution of the dosimetric data, which are continuous random variables, was evaluated using the Kolmogorov–Smirnov test. One-way analysis of variance (F-test) was used to compare the dosimetric means of the risk groups and determine the potential relationships between the dosimetric data and side effects. If a difference was detected by the F-test, Tukey's HSD multiple comparison test was used when the variances of the risk groups were equal and Tamhane's T2 multiple comparison tests when the variances were unequal. The paired-sample t-test was used to determine the potential relationships of the chronic sexual side effects with hormonotherapy, testosterone level, and comorbidities. The Chi-square test was used to compare acute and chronic side effects between the groups. A P value < 0.05 was considered significant. Analyses were performed using the SPSS 22.0 software (SPSS Inc., Chicago, IL, USA).

 > Results Top

A total of 87 patients with prostate cancer, comprising 27 low-risk, 30 intermediate-risk, and 30 high-risk patients, were analyzed. The mean age was 69 (50–86) years in all patients, 67 years in the low-risk group, 70 years in the intermediate-risk group, and 71 years in the high-risk group. Androgen deprivation therapy (ADT) was applied to five patients (18.5%) in the low-risk group, for a duration of 3 months. In these patients, ADT was applied as neoadjuvant therapy to reduce the prostate volume before RT. ADT was applied to all patients in the intermediate risk patients for 6 months and in the high-risk patients with a median of 43 (15–72) months, respectively. None of the patients received chemotherapy for prostate cancer. The median RT dose was 76 (74–78) Gy in all patients, 76 Gy in the low- and intermediate-risk groups, and 78 Gy in the high-risk group. The mean follow-up period was 38.2 (6–66) months. The patient and treatment characteristics are shown in [Table 1]. The means of the dosimetric data in all patients and the low-, intermediate-, and high-risk groups are shown in [Table 2]. The dosimetric data were normally distributed. The dosimetric data with significant differences among the risk groups are shown in [Table 3]. The relationships of the dosimetric data with acute and chronic side effects were assessed. As a result, we detected significant relationships of the rectal V30 (P = 0.017), V60 (P = 0.019), V65 (P = 0.008), V70 (P = 0.007), and V75 (P = 0.034) with chronic GIS side effects [Table 4].
Table 1: Patient and treatment characteristics

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Table 2: Mean and standard deviation values of dosimetric data

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Table 3: Dosimetric data showing significant difference between risk groups

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Table 4: P values of rectum V30, 60, 65, 70, and 75 and chronic GIS side effect relationship

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GUS side effects were the most common acute and chronic side effects. While no G3 acute side effects were observed, chronic G3 side effects were observed in one patient. The rates of acute GIS, GUS, and anal side effects according to severity in all patients and in each risk group are shown in [Figure 1], and the respective chronic side effects are shown in [Figure 2].
Figure 1: Percentages in all patient groups and risk groups according to the degrees of acute GIS, GUS, anal side effects

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Figure 2: Percentages in all patient groups and risk groups according to the degrees of chronic GIS, GUS, anal side effects

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Of the 87 patients evaluated, 28 (32.2%) had ED before RT. These patients were excluded from the evaluation of chronic side effects. Of the remaining 59 patients, 36 (61%) had no sexual side effects, whereas eight (13.5%) had grade (G) 1 and 15 (25.4%) G2 sexual side effects. No G3 sexual side effects were observed. A significant relationship was detected between chronic sexual side effects and the testosterone level (P < 0.001) at the last control and whether patients took ADT or not (P = 0.021). No relationship was detected between comorbidities and chronic sexual side effects.

No significant difference in side effects was observed between the low- and intermediate-risk groups. Significant differences were found in acute GUS (P = 0.016) and chronic anal (P = 0.002) side effects between the low- and high-risk groups. A significant difference in chronic anal (P = 0.01) side effects was found between the intermediate- and high-risk groups [Table 5].
Table 5: Side effects showing significant differences between risk groups

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A second primary cancer was detected in five patients (6%). The median time until the development of the second cancer was 18 (12–27) months. Four patients developed non-pelvic cancer (non-small cell lung cancer, small cell lung cancer, uveal melanoma, or gastric cancer), and one developed pelvic cancer (sigmoid colon cancer).

 > Discussion Top

In the meta-analysis conducted by Ohri et al., which included 11,835 patients who received definitive RT for prostate cancer, the incidence rates of G2 GIS side effects, G2 GUS side effects, G3 GIS side effects, and G3 GUS side effects were 15%, 17%, 2%, and 3%, respectively.[9] In a meta-analysis of studies using different RT techniques conducted by Viani et al.,[10] it was concluded that morbidities due to RT could be reduced using intensity-modulated RT (IMRT) and IGRT. G3 GIS side effects were detected in 9% and GUS side effects in 12% of 1,084 patients at a PTV dose of 78 Gy in the long-term results of the RTOG 9406 study investigating dose escalation in RT for prostate cancer.[27] A reduction in acute and chronic ≥ G2 GIS and GUS side effects was detected with the use of IGRT in the study of et al. of 127 patients with localized prostate cancer treated with IMRT. Daily CBCT was used as the IGRT technique in that study.[28] In our study, chronic GIS and GUS side effects were detected in 8% of cases. As planning techniques, daily CBCT and IGRT have been influential in reducing side effects.

Rectal bleeding (≥ G2) was associated with V71 in the PTV 70.2 Gy group and with V77 in the PTV 75.6 Gy group in a study conducted by Jackson et al.[15] that included 586 patients. In a study by Fiorino et al.,[16] PTV was applied in the range of 70–78 Gy, and chronic ≥ G2 rectal bleeding was associated with rectal V50, V60, and V70. A dose of 74–78 Gy to the PTV was applied by Huang et al.[17] in 163 patients, and late ≥ G2 GIS side effects were associated with rectal V60, V70, V75.6, and V78 values at the median 5-year follow-up. Vargas et al.[18] analyzed 331 patients receiving doses of 70.2–79.2 Gy to the PTV, and chronic ≥ G2 rectal side effects were associated with the rectal V50, V66, V66.6, V70, and V72 values. Kuban et al.[19] investigated the RT dose escalation results in 301 prostate cancer patients, and the ≥ G2 rectal side effects were associated with the dosimetric values in the rectal V40–V78 range. As in the study of Vargas et al., it was suggested to maintain the rectal V70 below 25% to avoid ≥ G2 rectal side effects. Suzuki et al.[20] used IMRT planning in 82 patients and found that ≥ G1 rectal bleeding was associated with the rectal V30, V40, V50, and V60 values. In our study, there were significant relationships of rectal V30 (P = 0.017), V60 (P = 0.019), V65 (P = 0.008), V70 (P = 0.007), and V75 (P = 0.034) with chronic GIS side effects. Close relationships were detected between rectal dosimetry and side effects.

ED is a significant side effect that can develop after curative treatment for localized prostate cancer. Macdonald et al.[23] found no relationship between penile bulb dosimetry and ED among patients who underwent brachytherapy. Roach et al.[24] reported that a penile bulb Dmedian ≥52.5 was associated with ED. In a meta-analysis, Wielen et al.[25] reported that the penile bulb had a negligible effect on achieving an erection. It has been reported that the structures involved in the erection process, such as the neurovascular bundle, corpus cavernosum, and internal pudendal artery, should be considered to preserve erectile function. In a study by Yıldırım et al.,[29] the penile bulb dose and testosterone levels were associated with sexual side effects, whereas ADT was not. We found no relationship between the penile bulb D90 and ED, but a relationship was observed between the testosterone level at the last control and whether the patients took ADT or not, and sexual side effects.

According to the studies of Buwenge and Jahreiß,[30],[31] VMAT and IMRT may increase the risk of secondary malignant neoplasms after RT for prostate cancer. In our study, secondary malignant neoplasms were detected in 6% of patients, but the number of patients and the follow-up period were insufficient to derive any conclusion. Bell et al.,[32]) showed that kv-CBCT had negligible effects on plan quality. In our study, kv-CBCT was used for IGRT.

 > Conclusion Top

We found a low rate of acute and chronic side effects during definitive RT for localized prostate cancer. The applied planning technique and the use of daily IGRT affected the results. The V30, V60, V65, V70, and V75 values of the rectum were associated with chronic GIS side effects. Attention should be paid to the rectal V65 and V70 values to avoid ≥ G2 chronic rectal side effects. The testosterone levels and ADT status affected chronic sexual side effects.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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