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 Table of Contents  
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 1018-1024

Predicting genitourinary toxicity in three-dimensional conformal radiotherapy for localized prostate cancer: A dose-volume parameters analysis of the bladder

1 Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy
2 Computer Science and Bioinformatics Laboratory, Integrated Research Centre, Campus Bio-Medico University, Via Alvaro del Portillo 21, 00128, Rome, Italy
3 Laboratory of Medical Physics and Expert Systems, National Cancer Institute Regina Elena, V. E. Chianesi 53, 00144 Rome, Italy

Date of Web Publication25-Jul-2016

Correspondence Address:
Paolo BagalÓ
Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.165871

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 > Abstract 

Purpose: In prostate cancer radiotherapy, the relationship between genitourinary (GU) toxicity and clinical-dosimetric parameters is debated. We report our analysis of the parameters associated with GU toxicity.
Materials and Methods: Eighty-six consecutive patients treated with conformal radiotherapy for localized prostate cancer were retrospectively analyzed; the bladder was delineated both as “whole bladder” (WB: Defined in its entirety as a solid organ) and “inferior bladder” (IB: Corresponding to the distal part of the bladder). GU toxicity and dose-volume parameters were correlated using the point biserial correlation coefficient. The normal tissue complication probability (NTCP) cut-off volume model was fitted to toxicity data; univariate analysis between GU toxicity and clinical parameters was done.
Results: Acute GU toxicity was correlated to doses higher than 80 Gy (P < 0.05) while late GU was correlated to doses higher than 77 Gy for WB and from 77.5 Gy for IB. The NTCP cut-off volume model identified for both WB and IB a bladder volume of 6 cc receiving a dose ≥77 Gy corresponding to a 50% probability of GU toxicity. At univariate analysis, acute GU toxicity was correlated with smoke (P < 0.001).
Conclusion: Bladder maximal doses quantified as hotspots show a correlation to GU toxicity.

Keywords: Bladder toxicity, dose-volume histogram analysis, normal tissue complication probability

How to cite this article:
BagalÓ P, Ingrosso G, Falco MD, Petrichella S, D'Andrea M, Rago M, Lancia A, Bruni C, Ponti E, Santoni R. Predicting genitourinary toxicity in three-dimensional conformal radiotherapy for localized prostate cancer: A dose-volume parameters analysis of the bladder. J Can Res Ther 2016;12:1018-24

How to cite this URL:
BagalÓ P, Ingrosso G, Falco MD, Petrichella S, D'Andrea M, Rago M, Lancia A, Bruni C, Ponti E, Santoni R. Predicting genitourinary toxicity in three-dimensional conformal radiotherapy for localized prostate cancer: A dose-volume parameters analysis of the bladder. J Can Res Ther [serial online] 2016 [cited 2021 Jan 27];12:1018-24. Available from: https://www.cancerjournal.net/text.asp?2016/12/2/1018/165871

 > Introduction Top

Three-dimensional conformal radiotherapy (3DCRT) is one of the standard therapies for localized prostate cancer.[1],[2],[3],[4],[5],[6],[7] Dose-volume histogram (DVH) parameters have been widely examined in order to establish dose constraints to limit toxicity; in particular, rectal dose-volume parameters have been intensively investigated.[8],[9],[10] Regarding genitourinary (GU) toxicity, there is a wide range of side effects across different reports that may be mainly due to different target margins, bladder filling and volume definition, plan development, and toxicity assessment tools. In particular, the planning DVH may not be representative of the treatment itself due to the variation of bladder filling and position between planning computed tomography (CT) and each treatment session. From the anatomo-physiological point of view, the bladder filling may lead to a huge change of its volume with an increase of its diameter, particularly in the cranial and anterior directions, while the structures of the pelvis (pubic symphysis and soft-tissues) hamper the expansion of the bladder in the caudal direction;[11] therefore the inferior bladder (IB) (inferior wall and distal part of the posterior wall) is only minimally influenced in its position by the organ filling. During the radiotherapy treatment course for localized prostate cancer the IB is exposed to high doses; hence urinary toxicity, caused by damage of the bladder wall (urothelium, smooth muscle, and vasculature) could be attributed in particular to the irradiation of the trigone and bladder neck, corresponding to the posterior and inferior surfaces of the bladder. Urinary toxicity also depends on the irradiation of the urethra, that is, within the clinical target volume (CTV) and cannot be spared during prostate cancer radiotherapy.

In the present study, we retrospectively evaluated bladder DVHs of patients treated with high dose conformal image guided radiation therapy for localized prostate cancer. Dose-volume parameters of the “whole bladder (WB)” (defined in its entirety as a solid organ) and of the “IB” (corresponding to the inferior surface and the distal part of the posterior surface of the bladder) were analyzed and correlated to acute and late urinary toxicity in order to carry out a dose-volume response analysis. In particular, the cut-off normal tissue complication probability (NTCP) model was used to estimate the optimal cut-off volume that better represent our GU toxicity data.

 > Materials and Methods Top

A retrospective analysis on 86 consecutive patients affected by localized prostate cancer referred to our Radiation Oncology Unit between 2009 and 2010 was performed. Patient characteristics are summarized in [Table 1]. Planning CT (2.5 mm slice thickness) was obtained with a GE LightSpeed ® Scanner (GE Healthcare Diagnostic Imaging, Slough, UK). For bowel preparation, we suggested a diet in combination with a daily mild laxative to obtain a reproducible bowel volume during CT acquisition and treatment sessions; patients were invited to have a comfortably full bladder during CT scan and treatment sessions: They were instructed to void their bladder 60 min prior to the treatment and then to drink 250 ml of water.[10] CTV consisted of the prostate and seminal vesicles; planning target volume (PTV) was generated by an asymmetric expansion of CTV (7 mm in all directions except at the posterior margin, where a 5 mm expansion was used); all organs at risk were defined (rectum, bladder, penile bulb, and femurs).[11] Conformal treatment plans were obtained on Pinnacle3 version 8.0m (Philips Medical System, Andover, MA); 76 Gy were prescribed to 95% of the PTV in daily fractions of 2 Gy delivered with six conformal shaped treatment fields (10–18 MV) using the Elekta Synergy Beam Modulator linear accelerator (Elekta, Crawley, UK) equipped with a kilovolt (kV) imaging system;[12] bladder dose-constraints were as follows: V65 <50%, V70 <35%, V75 <15%, and V80 <15%. Cone-beam CT (CBCT) scans were acquired for every patient before each treatment session.[10] Set-up evaluation was based on bony landmarks registration; a visual comparison of daily bladder and rectal filling to the planning CT baseline conditions was performed and treatment was postponed if relevant differences were found. Stable rectal and bladder volumes diminish uncertainties in the CTV position and, in empty rectum condition, the bladder shape and position are not influenced by the rectum itself.[13]
Table 1: Patient characteristics (86 patients)

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For the purpose of this study, we retrospectively defined two bladder volumes: The bladder in its entirety as a “WB,” and as an “IB” contoured from the upper limit of the PTV to the caudal limit of the bladder itself [Figure 1]. In particular, we evaluated the IB because it is the portion of the bladder closest to the CTV, hence during 3DCRT it receives the highest dose; in addition it has the smallest position variability during the radiotherapy treatment course.
Figure 1: Sagittal projection of the computed tomography plan with target volume and organ at risk contours: Whole bladder (blue), inferior bladder (light blue), rectum (yellow), clinical target volume (red), and planning target volume (purple)

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Acute (within 90 days from the start of radiotherapy) and late GU toxicity was scored by the radiation oncologist, according to the RTOG/EORTC toxicity scale. Patients were examined weekly during the course of treatment, 8 weeks after treatment, every 4 months for the first 2 years, and every 6 months afterward.

Statistical analysis and normal tissue complication probability model

Differential absolute DVHs of 86 planned were extracted from the treatment plans stored in the institutional archive. The paired Student's t-test was used to establish if the volumes of WB and IB were significantly different from each other.

We used the point Biserial correlation coefficient (rpb) to estimate the associations between the dose-volume parameters, that is, the volume of bladder receiving at least a defined x Gy dose level (Vx [cc]) and the GU toxicity grade, both for acute and late toxicity. GU toxicity grade was considered as the dichotomous variable while VX as the continuous one. The values 0 and 1 of the dichotomous variable were taken to correspond to G0/G1 toxicity and Grade ≥2 toxicity, respectively. The dose levels were sampled in 5 Gy intervals from 5 to 75 Gy and in 0.5 Gy intervals from 75 to 80 Gy. The reported correlation coefficients rpb were calculated as the median rpb values obtained from bootstrap resampling (1000 samples). Bootstrap was also applied to determine the 95% confidence interval (CI) and the corresponding P value; the two-sided tests were considered statistically significant at a 5% significance level (P ≤ 0.05). The point Biserial correlation coefficient was finally used to estimate the correlations between the volumes of IB and WB with acute and late toxicity.

To select the threshold volume above which we can expect toxicity, we adopted the cut-off volume model of NTCP to fit bladder late toxicity data both for the whole and IB.[14],[15],[16] The complication probability was calculated by the following general probit equation:

Where µ is a measure extracted by DVH, while m and µ50 are two unknown parameters; m determines the slope of the NTCP curve and µ50 represents the value of µ for which NTCP (µ) = 50%. In our case, µ stands for the minimal dose (DVc [Gy]) delivered to a threshold volume of whole or IB (Vc[cc]), and µ50 = DVc (50), that is, the value of Vc, corresponding to 50% complication probability. By fitting the values of DVc to the late toxicity data, the three unknown parameters can be evaluated: The threshold volume (Vc), the DVc (50) and m.

The maximum likelihood estimation method was used to fit the NTCP model with WB and IB toxicity data, respectively.[17],[18] The range of three parameters that should be determined in the fitting procedure are displayed in [Table 2] with the corresponding steps chosen for the fitting. Profile likelihood method (χ21 [5%] ≈ 1.92) was used to calculate the CIs within 95% for each estimated parameter.
Table 2: Ranges of the NTCP parameters used in the MLE for cutoff-volume model

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Finally, we performed univariate analysis using the binary logistic regression to independently predict the risk of acute and late GU toxicity ≥2. In particular, we investigated the following clinical parameters: Age, mean WB volume, mean IB volume, hormone therapy, smoking status, pretreatment urinary symptoms, and acute versus late toxicity. Multivariate analysis was performed using the Wilcoxon rank test.

Statistical calculations for the correlation coefficients and the Student's t-test were performed using R version 2.15.1 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). All data analyses for the fittings of the NTCP models and the log-likelihood tests were performed using MATLAB 2008b version 7.7 (MathWorks, Natick, Mass.).

 > Results Top

Mean and median follow-ups were 51.9 and 50.2 months, respectively, (range: 41.9–75.4 months). Acute GU toxicity ≥2 was registered in 69.7% (60/86) of patients, late GU toxicity ≥2 in 7% (6/86) of patients [Table 3].
Table 3: RTOG GU toxicity in 86 patients

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The mean WB volume was 145.8 ± 87.8 (1 standard deviation [SD]) cc (33.3–414.6) and the mean IB volume was 94.5 ± 49.9 (1 SD) cc (24.8–278.4). The paired t-test showed that the difference between the mean values of WB and IB volumes was statistically significant (P < 0.0001).

Among all the investigated correlations, no statistically significant association was found between GU toxicity and any VX up to 77 Gy, both for the WB and IB. For acute toxicity, the only statistically significant correlation was found at 80 Gy (P = 0.03 for WB, P = 0.002 for IB). Regarding late toxicity, statistically significant correlations (P < 0.05) were found starting from 77 Gy for WB and 77.5 Gy for IB. The strongest association was found at 79 Gy, both for WB and IB (rpb = 0.09 and 0.08, respectively). [Table 4] collects all the dose level values at which significant correlations were found, along with the corresponding rpb coefficients. No statistically significant correlations were found between mean WB and IB volumes with toxicity data.
Table 4: The rpb coefficients (95% CI) and P values for the dose levels at which significant associations (P≤0.05) were obtained using both the whole and the inferior bladder

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[Table 5] shows parameters estimation, CIs and log-likelihood values of the cut-off volume NTCP model fitted to late GU toxicity data for both WB and IB. As can be seen from [Table 5], the parameters estimated by the fitting procedure are quite identical for both WB and IB. In particular, the best estimates obtained were: Vc = 6 cc, DVc (50) =80 Gy and m = 0.07 (all within the 95% CI). In particular, in the patients with manifested bladder late toxicity the minimum dose at the hottest 6 cc volume of bladder was found to be 75 Gy or higher.
Table 5: Parameter estimates, CIs and log-likelihood values of the hottest volume model fitted to late toxicity data for whole bladder and inferior bladder

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Univariate analysis for acute GU toxicity shows that smoke is significantly correlated with toxicity grade ≥2 (odds ratio of 14.1, P < 0.001); for late GU toxicity we found a correlation between acute; and late GU ≥2 toxicity (odd ratio of 4.8, with a P = 0.006, tending to significance). All the odd ratios calculated are shown in [Table 6]. Multivariate analysis showed no significance for any clinical parameter.
Table 6: Univariate analysis for grade ≥2 acute and late GU toxicity (86 patients)

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 > Discussion Top

We analyzed the correlation between grade ≥2 GU toxicity with DVH and clinical parameters of the bladder, contoured in its entirety or in its caudal part (corresponding to the inferior surface and the distal part of the posterior surface). Although patients received drinking instructions, a wide intra-patient variation in the bladder volume during the treatment course was observed from CBCT scans (data not shown), and this might affect the actual dose distribution to this OAR. It is to say, however, that what dramatically changes with bladder filling is the dome position while the caudal region of the bladder is quite a little influenced in its position by the organ filling;[13],[19],[20] in particular the IB is very close to the prostate CTV and is encompassed by PTV, hence it is exposed to high doses. Even though there is not a confirmed relationship between DVH parameters and late GU toxicity, it seems that the incidence of late GU toxicity increases when higher target doses are prescribed.[21],[22],[23] Therefore, it could be important evaluating the spatial distribution of the dose, particularly in the posterior and inferior surface of the bladder because they are exposed to high doses, and they are not subjected to wide position variations during the radiation treatment course.

In our study, we obtained a strong association between high doses (>77 Gy) and late GU toxicity for both WB and IB (rpb = 0.09 and 0.08, respectively). This suggests that bladder filling at the time of planning CT was well reproduced in all patients. Indeed for every patient the likely constant ratio between prostate length and bladder length was preserved by the associated volumes, therefore, the bladder filling was approximately the same in all patients; the second result means that both WB and IB exposition to high doses is correlated with late GU toxicity. Along this way, we can, therefore, deduce that the dose to IB may be related to late GU toxicity with little influence from the degree of bladder filling. Recently, Ghadjar et al.[23] analyzed the association between bladder DVHs (i.e., WB, bladder wall, urethra, and bladder trigone) and GU toxicity. They showed that hot spots to the bladder trigone are significantly associated with late GU toxicity; in particular, the univariate analysis for late ≥2 GU toxicity-free survival comparing clinical and dosimetric variables showed that only grade ≥2 acute GU toxicity (P = 0.01) and increased trigone V90 (P = 0.047) were associated with grade ≥2 late GU toxicity. Heemsbergen et al.[24] studied the relationship between late urinary obstruction and dose parameters in 557 patients from the Dutch trial (68 Gy vs. 78 Gy); they analyzed the absolute dose surface and the dose maps representing the dose in the total “bladder region” around the prostate. In the absolute dose surface analysis, they found that high dose regions (≥80 Gy) were associated with the development of urinary obstruction; in the dose maps analysis there was a strong relationship between late GU toxicity and the dose received in the trigonal area.

The impact of high doses to the IB in the development of late GU toxicity, suggests for this organ a trend in serial rather than parallel architecture, as also reported by other authors.[14],[24] Cheung et al. showed that the Lyman Kutcher Burman model fitted the toxicity data better than the mean dose model, obtaining a volume factor n close to 0. A serial-parallel behavior, instead, was reported for chronic moderate/severe urinary toxicity;[25] in any case, the authors agree with the fact that the fraction of bladder receiving doses higher than 78–80 Gy was the most predictive of late GU toxicity (i.e., the regions of the bladder with “high dose” spots seem to be more sensitive than others and increase the risk of late GU toxicity). However, the small amount of data in literature about the dose-volume analysis and NTCP modeling of the bladder toxicity, makes difficult to identify the true radiobiological behavior of the bladder, and more information from other authors are therefore needed.

In our univariate analysis, we obtained a correlation between acute and late GU toxicity (odd ratio of 4.8, with a P = 0.06 tending to significance). We reported an acute grade ≥2 GU toxicity in about 70% of patients that was correlated with smoking status at univariate analysis (odd ratio of 14.1, P < 0.001), as reported in literature;[26] the point biserial correlation coefficient for acute grade ≥2 GU toxicity showed a statistical significance only for 80 Gy. Many authors in literature reported an acute grade ≥2 GU toxicity ranging between 30% and 60%,[27],[28],[29],[30] without a clear link between bladder DHV parameters and acute GU toxicity.[31],[32],[33],[34],[35],[36],[37],[38],[39],[40]

The cut-off volume NTCP modeling, gave a value of 6 cc (3.2–20.5) of volume bladder as the significant cut-point (95% CI) determinant of late 4-year GU toxicity, for both whole and IB. From our data, we found that late GU toxicity occurred in all patients receiving a dose ≥75 Gy to 6 cc of bladder. In addition, more than half of the GU toxicity came about in patients who had 77 Gy to 6 cc of bladder. This result confirms the previous DVH analysis for late toxicity, in which we found a strong association between high doses (>77 Gy) and late GU toxicity. Moreover, the dose value of 77 Gy that corresponds to a GU toxicity of 50% is within the 95% CI of the DVc (50) value (75.5 Gy-∞ for the IB). These results well agree with those reported by Cheung et al.[14] They found that the absolute hottest volume was 5.3 cc (95% CI: <0.1–15.3 cc), for the solid bladder, and identified, for the 2.9% of bladder, a 25% risk of grade 1 or above late urinary toxicity for patients receiving <78 Gy and a 50% for doses ≥of 78 Gy. In our study, however, we investigated the associations between DVHs and late toxicity ≥G2 without considering the G1 toxicity, as reference 14 did. Harsolia et al.[25] in his work tried to identify factors that were predictive for chronic urinary toxicity from DVH analysis, considering both the bladder wall and WB. He concluded that of all parameters under investigation, only V82 was the most strongly associated with chronic urinary toxicity, both for the wall and the WB, suggesting to limit, for the WB, the V82 to a cut-off volume of 2.5 cc. This result agrees with our results; in fact, we found that the strongest correlations between DVH data and GU toxicity were obtained at high doses for both WB and IB, even if our dose prescription to PTV was lower than Harsolia and the dose hotspots were also lower. Therefore, the cutoff volume found, was larger than reported by Harsolia et al.[25]

 > Conclusions Top

Our correlation analysis between clinical and dosimetric parameters and GU toxicity demonstrated that the IB is accountable of bladder toxicity. In any case, confirming data are needed to better understand the relationship between bladder filling and GU toxicity. Bladder maximal doses, quantified as hotspots, seem to be correlated with GU toxicity. Finally, from the NTCP cut-off volume model we identified a bladder volume of 6 cc as the cut-off volume corresponding to a GU toxicity of 50% at doses ≥77 Gy.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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