Acta Oncologica, 2015; Early Online: 1–7
ORIGINAL ARTICLE
Late urinary toxicity modeling after stereotactic body radiotherapy (SBRT) in the definitive treatment of localized prostate cancer
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Thomas P. Kole1, Michael Tong1, Binbin Wu1, Siyuan Lei1, Olusola Obayomi-Davies1, Leonard N. Chen1, Simeng Suy1, Anatoly Dritschilo1, Ellen Yorke2 & Sean P. Collins1 1Department 2Department
of Radiation Medicine, Georgetown University Hospital, Washington, DC, USA and of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Abstract Background. Late urinary symptom flare has been shown to occur in a small subset of men treated with ultrahypofractionated stereotactic body radiotherapy (SBRT) for prostate cancer. The purpose of this study was to use normal tissue complication probability modeling in an effort to derive SBRT specific dosimetric predictor’s of late urinary flare. Material and methods. Two hundred and sixteen men were treated for localized prostate cancer using ultrahypofractionated SBRT. A dose of 35–36.25 Gy in 5 fractions was delivered to the prostate and proximal seminal vesicles. Functional surveys were conducted before and after treatment to assess late toxicity. Phenomenologic NTCP models were fit to bladder DVHs and late urinary flare outcomes using maximum likelihood estimation. Results. Twenty-nine patients experienced late urinary flare within two years of completion of treatment. Fitting of bladder DVH data to a Lyman NTCP model resulted in parameter estimates of m, TD50, and n of 0.19 (0–0.47), 38.7 Gy (31.1–46.4), and 0.13 (-0.14–0.41), respectively. Subsequent fit to a hottest volume probit model revealed a significant association of late urinary flare with dose to the hottest 12.7% of bladder volume. Multivariate analysis resulted in a final model that included patient age and hottest volume probit model predictions. Kaplan-Meier analysis demonstrated a two-year urinary flare free survival of 95.7% in patients 65 years or older with a bladder D12.7% of 33.5 Gy or less, compared to 74.5% in patients meeting none of these criteria. Conclusion. NTCP modeling of late urinary flare after ultra-hypofractionated prostate SBRT demonstrates a relatively small volume effect for dose to the bladder, suggesting that reduction of volume receiving elevated dose will result in decreased incidence of late urinary toxicity. Future studies will be needed to examine the impact of dose to other potential sources of late genitourinary toxicity. Over the last decade, significant advances in image guidance and robotic radiation therapy along with the low estimated a/b ratio of prostate cancer cells (∼1.5 Gy) [1–3] has led to the development of new ultra-hypofractionated treatment options for selected patients with localized prostate cancer [4]. Using these typically five fraction stereotactic body radiotherapy (SBRT) techniques, excellent rates of disease control have been reported in several institutional clinical trials and a multi-institutional pooled analysis [5]. Overall, these studies have shown similar rates of late genitourinary (GU) and gastrointestinal (GI)
toxicity as compared to conventionally fractionated dose-escalated intensity-modulated radiation therapy (IMRT) series [5–10]. Recently, Woo et al. reported a transient late urinary flare in 13.4% of patients who received ultrahypofractionated SBRT for localized prostate cancer [11]. This was clinically similar to that described in patients treated with low dose rate (LDR) interstitial brachytherapy [12–15] and consisted of an abrupt increase in urinary symptoms following a posttreatment nadir, which subsequently returned to previous nadir with conservative management. Consistent
Correspondence: S. P. Collins, Georgetown University Hospital, Department of Radiation Medicine, 3800 Reservoir Rd, NW, LL Bles, Washington, DC 20007, USA. Tel: 1 202 444-3320. Fax: 1 202 444-9323. E-mail: [email protected] (Received 22 January 2015; accepted 29 March 2015) ISSN 0284-186X print/ISSN 1651-226X online © 2015 Informa Healthcare DOI: 10.3109/0284186X.2015.1037011
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with previous studies, young patient age was the only clinically related factor that was predictive of developing late urinary flare. Due to the lack of sufficient evidence, there is very little specific data regarding normal tissue GU dose constraints in ultra-hypofractionated SBRT. Available normal tissue dose constraints have largely been extrapolated from HDR brachytherapy series and are based on biologically equivalent dose comparisons to conventionally fractionated limits [16,17]. Recent attempts have also been made to determine objective prostate SBRT plan evaluation criteria based upon databases of achievable dose distributions in relation to anatomic geometry [18,19], however, no specific toxicity related dose-volume criteria were determined. In a limited series of patients treated at a single institution, Elias et al. recently reported correlates of quality of life (QOL) in patients treated with prostate SBRT, however, no associated dosimetric predictors of long-term urinary toxicity were found [20]. Therefore, in the present study we performed a retrospective dosimetric analysis of patients treated for localized prostate cancer using robotic ultra-hypofractionated SBRT in conjunction with long-term urinary functional outcomes to develop a normal tissue complication probability (NTCP) model for the development of late urinary flare after ultra-hypofractionated prostate SBRT. Material and methods We retrospectively reviewed the records of 216 consecutive patients treated definitively for localized prostate cancer using robotic ultra-hypofractionated SBRT at Georgetown University Hospital from 2008 to 2011. The median patient age was 69 years old (range 48–90) and the majority of patients had low to intermediate risk disease by the D’Amico risk stratification (Table I). Twenty-nine patients received androgen deprivation therapy (ADT) consisting of four weeks of bicalutimide and 3–6 months of leuprolide that started three months prior to SBRT. The Charlson Comorbidity Index (CCI) was used as a classifier of medical comorbidity as previously described [21]. Pre-SBRT PSA values were collected on the first day of radiotherapy. All patients were treated using the CyberKnife Radiosurgical System (CK, Accuray Inc., Sunnyvale, CA, USA), and had gold prostate fiducials implanted one week prior to simulation. Patients were instructed to empty their bladder prior to simulation and treatment, and the entire bladder and its contents were contoured as a single structure. The planning target volume (PTV) consisted of the prostate and proximal seminal vesicles as defined on non-contrast computed tomography (CT) and fused T2 magnetic
Table I. Patient characteristics (n 216). Age Median Range Pre-SBRT PSA (ng/ml) Median Range Clinical stage T1c T2a T2b T2c Gleason score 6 7 8 D’Amico risk group Low Intermediate High Prostate volume (cm3) Median Range Bladder volume (cm3) Median Range Charlson Comorbidity Index (CCI) 0 1 2 Pre-SBRT AUA score median range a1A antagonist use Yes No Previous TURP Yes No Pre-SBRT androgen deprivation therapy Yes No
69 48–90 5.8 0.2–32.5 160 29 20 7 97 109 10 83 111 22 38 11.6–138.7 82.3 42.5–687.4 146 51 19 7.5 0–33 62 154 19 197 29 187
resonance imaging (MRI) with a 3 mm posterior margin and a 5 mm margin in all other directions. In order to prevent anatomic distortion, a foley catheter was not inserted during simulation and therefore the prostatic urethra was not routinely visualized or used as a dose limiting structure. Inverse plans were generated with a prescription dose (PD) of 35–36.25 Gy in 5 fractions to the PTV using 6 MV photons. All plans were evaluated by a single physician and verified to meet our institutional planning objectives (Table II). All fractions were delivered within two weeks and real-time kV imaging based fiducial tracking was used to account for intra-fraction prostate translational and rotational motion. As part of our institutional policy, all patients were given patient reported QOL surveys including the Expanded Prostate Index Composite 26 (EPIC26) and underwent urinary functional assessment using the International Prostate Symptom Score
Late genitourinary toxicity modeling after prostate SBRT
Table II. 36.25 Gy plan dose-volume criteria. Global max dose
48.33 Gy
PTV GTV Rectum
V (36.25 Gy) 95% V (40 Gy) 95% V (36 Gy) 1 cm3 V (100%) 5% V (90%) 10% V (80%) 20% V (75%) 25% V (50%) 50% V (37 Gy) 10 cm3 V (50%) 40% V (29.5 Gy) 50% V (37 Gy) 50% V (30 Gy) 1 cm3 D (20%) 2 Gy
Bladder
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Penile bulb Membranous urethra Sigmoid colon Testicles
(IPSS) before treatment and at each follow-up visit which occurred every three months for the first year and then every six months thereafter. Late urinary flare was defined using the Princess Margaret criteria [15]: increase in IPSS score 5 above post-treatment baseline, with an absolute IPSS score 15, followed by a return to baseline within 2 years. NTCP modeling Cumulative absolute volume bladder dose-volume histograms (DVHs) were extracted from the treatment planning system and converted into relative volume
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differential DVHs using custom software written in Matlab (MathWorks, Inc., MA, USA). Phenomenologic NTCP models including the generalized Lyman, hottest volume, and threshold model were fit to the physical bladder DVH and late urinary toxicity data using maximum likelihood estimation (MLE) as previously described (see Appendix, available online at http://informahealthcare.com/doi/abs/10.3109/0284 186X.2015.1037011). The profile likelihood and Wald methods were used to generate estimates of the parameter 95% confidence intervals. Statistics Patient- and disease-related covariates along with NTCP model predictions were independently tested for significant association with the development of late urinary flare using univariate logistic regression. A multivariate model was then constructed using forward selection with a cut-off p-value of 0.05. Significant parameter cut-off values were obtained with Fischer’s exact test and then used to group patients by risk of developing late urinary flare. Late urinary flare free survival was evaluated for each group using the KaplanMeier method and statistically compared using the log-rank test. Results
Figure 1. Mean cumulative (A) and differential (B) whole bladder DVHs for patients with and without late urinary flare after ultrahypofractionated prostate SBRT.
At a median follow-up of four years, 216 patients were evaluated and 29 (13.4%) met the criteria of late urinary flare after receiving definitive ultrahypofractionated prostate SBRT at a median time to flare of nine months. At the time of last follow-up, all patients had returned to their baseline urinary status according to IPSS symptom index. Bladder DVH data was available for all but one patient in the no toxicity group. Figure 1 shows group-averaged cumulative (A) and differential (B) DVH data for the entire cohort with clear separation of the two curves in the 18–37Gy range. Fitting of bladder differential DVH data and incidence of late urinary flare to a generalized Lyman NTCP model (Equations 1–3, to be found online at http://informahealthcare.com/doi/abs/10.3109/0284 186X.2015.1037011) using MLE resulted in estimated Lyman parameters of m 0.19 (95% CI 0–0.47), n 0.13 (95% CI -0.14–0.41), and TD50 38.7 Gy (95% CI 31.1–46.4 Gy). Comparison of the model estimate to the actual incidence of late urinary flare in five equally sized EUD bins demonstrates that the generalized Lyman model describes the data well (Figure 2), suggesting a relatively low volume dependence of dose to the bladder in development of late urinary flare after ultra-hypofractionated prostate SBRT.
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Figure 2. Results of LKB model fit to differential whole bladder DVH data versus EUD (solid line) together with two-year incidence of urinary flare among five equally sized EUD bins (triangles). Vertical error bars indicate the standard deviation of the binomial distribution and horizontal error bars represent the standard deviation of the EUD in each bin. Inset shows the EUD range covered in our cohort.
A similar approach was used to examine the association of volume of bladder receiving more than a threshold dose Dc or dose to the hottest volume of bladder Vc in threshold or hottest volume NTCP models (Equations 1 and 4, to be found online at http://informahealthcare.com/doi/abs/10.3109 / 0284186X.2015.1037011), respectively. Using MLE, we estimated an optimal bladder threshold dose of 36.6 Gy, however, the model did not describe the data well as suggested by infinite estimates of the 95% confidence intervals for each of the model parameters. Alternatively, the hottest volume NTCP model fit our data well (Figure 3) with an estimated hottest volume threshold Vc 12.7% (95% CI 0–39.2%) with slope m 0.19 (95% CI 0–0.49), and dose to the hottest volume of bladder predicted to result in a 50% complication rate, DVc 44.6 Gy (95% CI 35.2–54 Gy). Univariate logistic regression was used to assess specific patient- and disease-related covariates, along
Figure 3. Results of hottest volume model fit to differential whole bladder DVH data versus dose to the hottest 12.7% of bladder (D12.7%, solid line) together with two-year incidence of urinary flare among five equally sized D12.7% bins (triangles). Vertical error bars indicate the standard deviation of the binomial distribution and horizontal error bars represent the standard deviation of the dose in each bin. Inset shows the dose range covered in our cohort.
with NTCP model predictions for statistically significant associations with the development of late urinary flare after prostate SBRT (Table III). Only younger patient age (OR 0.93, 95% CI 0.88–0.98), Lyman model prediction (OR 1.49, 95% CI 1.01–2.18), and hottest volume model prediction (OR 1.59, 95% CI 1.06–2.39) were statistically predictive of developing late urinary flare. A final model was generated using multivariate logistic regression and a forward selection method which only included younger patient age and hottest volume model estimates as independent predictors (Table III). Candidates for cut-off values of patient age and hottest volume model prediction were determined using Fischer’s exact test and a maximum threshold p-value of 0.05. Several significant age cut-offs were found, however, an age of 65 years or greater was selected based upon its association with late urinary flare in previous LDR brachytherapy studies. A hottest volume model cut-off of 10% complications was chosen as an acceptable clinical risk and corresponds to a bladder D12.7% 33.5 Gy. Patients were then grouped based upon the presence of these criteria, and late urinary flare free survival was estimated Table III. Predictors of late urinary flare. Parameter Univariate logistic regression Age (years) Pre-treatment PSA (ng/ml) Clinical stage T1c T2a T2b T2c Gleason score 6 7 D’Amico risk group Low Intermediate High Prostate volume (ml) Bladder volume (ml) CCI 0 1 2 Pre-treatment AUA score a1A antagonist use Previous TURP Pre-SBRT ADT LKB modela Hottest volume modela Threshold modela Multivariate logistic regression Age (years) Hottest volume modela
OR
95% CI
p-value
0.93 0.94
(0.88–0.98) (0.85–1.05)
0.01 0.28
1.00 1.08 1.15 1.07
(0.35–3.37) (0.31–4.19) (0.12–9.24)
0.89 0.84 0.95
1.00 0.90
(0.41–1.97)
0.80
1.00 0.97 0.44 1.00 0.99
(0.44–2.13) (0.06–3.47) (0.98–1.02) (0.98–1.01)
0.94 0.43 0.83 0.14
1.00 1.03 1.23 0.93 0.80 0.28 0.71 1.49 1.59 1.27
(0.41–2.56) (0.33–4.50) (0.86–1.01) (0.32–1.98) (0.04–2.17) (0.20–2.52) (1.01–2.18) (1.06–2.39) (0.99–1.62)
0.95 0.76 0.09 0.63 0.22 0.60 0.04 0.03 0.06
0.93 1.53
(0.88–0.99) (1.01–2.31)
0.01 0.04
a odds ratios expressed as odds per 5% increase in complication probability.
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Late genitourinary toxicity modeling after prostate SBRT
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Figure 4. Kaplan-Meier analysis of urinary flare free survival. Patients are grouped according age and hottest volume model prediction. (p-value 0.05).
using Kaplan-Meier analysis (Figure 4). Patients age 65 or greater with a bladder D12.7% 33.5 Gy had a two-year late urinary flare free survival of 95.7% compared to 83.9% for patients meeting only one of these criteria, or 74.5% for patients meeting none of these criteria (p 0.05). Discussion Early reports of post-treatment biochemical relapsefree survival and QOL following ultra-hypofractionated SBRT for selected patients with localized prostate cancer have been encouraging [5–10]. However, a recent Surveillance, Epidemiology, and End Results Program (SEER) based analysis has called into question the safety of these treatments in terms of longterm urinary toxicity as compared to conventionally fractionated IMRT [22]. Recently, we reported QOL outcomes for patients treated according to our institutional protocol and noted a small subset of patients who developed a late increase in urinary symptoms following a post-treatment nadir that subsequently returned to previous nadir, termed late urinary flare [11]. These patients experienced higher rates of CTCAE-graded dysuria, urinary frequency, urgency, and retention in the first two years of follow-up after prostate SBRT, and demonstrated significant declines in QOL in the EPIC urinary domain. This was similar to that described previously in the prostate LDR interstitial brachytherapy literature by several institutions [12–15]. In our previous analysis, only young patient age correlated with the development of late urinary flare after prostate SBRT, and that the majority of these patients experienced complete resolution of
their symptoms with medical management consisting of a short course of anti-inflammatory medications. While there is a significant amount of data in regards to specific planning objectives and risks of late urinary toxicity in the conventionally fractionated literature, very little information exists regarding dosimetric predictors of late toxicity using ultrahypofractionated treatment regimens. Therefore, we sought to identify potential dose-related risk factors for the development of late urinary flare by applying well established NTCP models to dose-volume data extracted from the treatment plans of our previously treated patients. Though our study has a limited number of events, the well defined and robust nature of our late urinary toxicity endpoint suggested that a rigorous analysis of this type was possible. Fits of our cohort bladder dose-volume data to a generalized Lyman model demonstrates a relatively low volume effect for dose to the bladder in the development of late urinary flare after ultra-hypofractionated prostate SBRT. This is similar to that observed in previous studies examining dosimetric predictors of late grade 2 or greater urinary toxicity in patients treated with dose-escalated IMRT [23]. Together, these results suggest that the bladder contribution to urinary function following prostate radiotherapy behaves in a serial fashion and is sensitive to small volumes of elevated dose. This is further supported by the observation in the Cheung et al. study [23] and in our cohort that the best fit of the data was achieved using the hottest volume model for dose to the bladder although, our hottest volume threshold was considerably larger than that obtained in the conventionally fractionated study (12.7% vs. 2.9%).
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Several potential explanations exist for this discrepancy including difference in GU toxicity endpoint, fraction size, as well as simulation and treatment technique. Due to the relatively long treatment times ( 30 min) associated with our robotic ultra-hypofractionated SBRT treatment regimen, we simulate and treat our patients with an empty bladder to facilitate patient comfort. When considering relative volumes, this decreases the value of the denominator (whole bladder volume), thus increasing the value of the relative volume of bladder tissue most at risk for elevated dose, including the bladder trigone, which has recently been shown to correlate with late urinary toxicity in a singleinstitution dose-escalated series [24]. In that study, Ghadjar et al. noted a significant correlation between long-term GU toxicity and volume of bladder trigone receiving more than 90 Gy, as well as increasing maximum point dose to the trigone. In addition to bladder D12.7%, our multivariate analysis confirmed patient age as an independent predictor of late urinary flare in our cohort. A trend for development of late urinary flare in younger patients receiving definitive interstitial prostate LDR brachytherapy has been previously described [12], however, to the best of our knowledge no statistically significant correlation has ever been found. It is unclear whether the etiology of this association is biological versus psychological in nature. Conventional thought would incorrectly predict that benign enlargement of prostate glandular tissue associated with aging would predispose older patients to worse long-term treatment-related GU toxicity. However, no correlation with prostate volume was seen in our analysis. Perhaps younger patients are more aware of their urinary function whereas older patients have grown accustomed to a lower baseline GU QOL so that any detrimental changes in urinary function are more apparent in younger patient populations. In stark opposition to this theory is the fact that pre-treatment IPSS symptom index had no statistically significant association with development of late urinary flare in our cohort, although a trend for lower initial IPSS symptom index in patients with late urinary flare was observed (OR 0.93, p 0.09). Furthermore, there was no association with any other pre-treatment GU QOL indexes including a1a antagonist use or ADT (Table 3). Our study highlights the importance of combined application of patient- and dose-related criteria in the prediction of potential treatment-related toxicity after prostate SBRT. The combination of our ultrahypofractionated prostate 5 fraction SBRT dosevolume cut-off of D12.7% 33.5 Gy and age 65 years predicts for a low two-year incidence of late urinary flare in our cohort. Validation with prospec-
tive data sets will determine the future clinical applicability of these criteria as well as their applicability to other non-robotic methods of ultra-hypofractionated prostate SBRT. Declaration of interest: Sean P. Collins is a clinical consultant for Accuray Inc. and receives an educational grant to fund a research coordinator in the Department of Radiation Medicine at Georgetown University Hospital. Leonard N. Chen is a research coordinator and is partially funded through the educational grant provided by Accuray Inc. References [1] Dasu A, Toma-Dasu I. Prostate alpha/beta revisited – an analysis of clinical results from 14 168 patients. Acta Oncol 2012;51:963–74. [2] Miralbell R, Roberts SA, Zubizarreta E, Hendry JH. Dosefractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5,969 patients in seven international institutional datasets: Alpha/beta 1.4 (0.9–2.2) Gy. Int J Radiat Oncol Biol Phys 2012;82:e17–24. [3] Proust-Lima C, Taylor JM, Secher S, Sandler H, Kestin L, Pickles T, et al. Confirmation of a low alpha/beta ratio for prostate cancer treated by external beam radiation therapy alone using a post-treatment repeated-measures model for PSA dynamics. Int J Radiat Oncol Biol Phys. 2011;79:195–201. [4] American Society for Radiation Oncology (ASTRO) Model Policy on Steretoactic Body Radiotherapy 2013. Available from: https://www.astro.org/uploadedFiles/Main_Site/Practice_Management/Reimbursement/2013HPcoding%20 guidelines_SBRT_Final.pdf. Accessed 17th, April 2013. [5] King CR, Freeman D, Kaplan I, Fuller D, Bolzicco G, Collins S, et al. Stereotactic body radiotherapy for localized prostate cancer: Pooled analysis from a multi-institutional consortium of prospective phase II trials. Radiother Oncol 2013;109:217–21. [6] Chen LN, Suy S, Uhm S, Oermann EK, Ju AW, Chen V, et al. Stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer: The Georgetown University experience. Radiat Oncol 2013;8:58. [7] Freeman DE, King CR. Stereotactic body radiotherapy for low-risk prostate cancer: Five-year outcomes. Radiat Oncol 2011;6:3. [8] Katz AJ, Santoro M, Diblasio F, Ashley R. Stereotactic body radiotherapy for localized prostate cancer: Disease control and quality of life at 6 years. Radiat Oncol 2013;8:118. [9] King CR, Brooks JD, Gill H, Presti JC, Jr. Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. Int J Radiat Oncol Biol Phys Feb 2012;82:877–82. [10] McBride SM, Wong DS, Dombrowski JJ, Harkins B, Tapella P, Hanscom HN, et al. Hypofractionated stereotactic body radiotherapy in low-risk prostate adenocarcinoma: Preliminary results of a multi-institutional phase 1 feasibility trial. Cancer 2012;118(15):3681–90. [11] Woo JA, Chen LN, Bhagat A, Oermann EK, Kim JS, Moures R, et al. Clinical characteristics and management of late urinary symptom flare following stereotactic body radiation therapy for prostate cancer. Front Oncol 2014;4:122. [12] Cesaretti JA, Stone NN, Stock RG. Urinary symptom flare following I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003;56:1085–92.
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Late genitourinary toxicity modeling after prostate SBRT
[13] Keyes M, Miller S, Moravan V, Pickles T, Liu M, Spadinger I, et al. Urinary symptom flare in 712 125I prostate brachytherapy patients: Long-term follow-up. Int J Radiat Oncol Biol Phys. 2009;75:649–55. [14] Lehrer S, Cesaretti J, Stone NN, Stock RG. Urinary symptom flare after brachytherapy for prostate cancer is associated with erectile dysfunction and more urinary symptoms before implantation. Br J Urol Int 2006;98:979–81. [15] Crook J, Fleshner N, Roberts C, Pond G. Long-term urinary sequelae following 125iodine prostate brachytherapy. J Urol 2008;179:141–5; discussion 6. [16] Martinez AA, Pataki I, Edmundson G, Sebastian E, Brabbins D, Gustafson G. Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: A feasibility report. Int J Radiat Oncol Biol Phys 2001;49:61–9. [17] Michalski JM, Gay H, Jackson A, Tucker SL, Deasy JO. Radiation dose-volume effects in radiation-induced rectal injury. Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S123–9. [18] Descovich M, Carrara M, Morlino S, Pinnaduwage DS, Saltiel D, Pouliot J, et al. Improving plan quality and consistency by standardization of dose constraints in prostate cancer patients treated with CyberKnife. J Appl Clin Med Phys 2013;14:162–72. [19] Wu B, Pang D, Lei S, Gatti J, Tong M, McNutt T, et al. Improved robotic stereotactic body radiation therapy plan
Supplementary material available online Appendix: NTCP Modeling, to be found online at http://informahealthcare.com/doi/abs/10.3109/ 0284186X.2015.1037011.
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quality and planning efficacy for organ-confined prostate cancer utilizing overlap-volume histogram-driven planning methodology. Radiother Oncol 2014;112:221–6. [20] Elias E, Helou J, Zhang L, Cheung P, Deabreu A, D’Alimonte L, et al. Dosimetric and patient correlates of quality of life after prostate stereotactic ablative radiotherapy. Radiother Oncol 2014;112:83–8. [21] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987;40:373–83. [22] Yu JB, Cramer LD, Herrin J, Soulos PR, Potosky AL, Gross CP. Stereotactic body radiation therapy versus intensity-modulated radiation therapy for prostate cancer: Comparison of toxicity. J Clin Oncol 2014;32: 1195–201. [23] Cheung MR, Tucker SL, Dong L, de Crevoisier R, Lee AK, Frank S, et al. Investigation of bladder dose and volume factors influencing late urinary toxicity after external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2007;67:1059–65. [24] Ghadjar P, Zelefsky MJ, Spratt DE, Munck af Rosenschold P, Oh JH, Hunt M, et al. Impact of dose to the bladder trigone on long-term urinary function after high-dose intensity modulated radiation therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2014;88:339–44.
ORIGINAL ARTICLE
Late urinary toxicity modeling after stereotactic body radiotherapy (SBRT) in the definitive treatment of localized prostate cancer
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Thomas P. Kole1, Michael Tong1, Binbin Wu1, Siyuan Lei1, Olusola Obayomi-Davies1, Leonard N. Chen1, Simeng Suy1, Anatoly Dritschilo1, Ellen Yorke2 & Sean P. Collins1 1Department 2Department
of Radiation Medicine, Georgetown University Hospital, Washington, DC, USA and of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Abstract Background. Late urinary symptom flare has been shown to occur in a small subset of men treated with ultrahypofractionated stereotactic body radiotherapy (SBRT) for prostate cancer. The purpose of this study was to use normal tissue complication probability modeling in an effort to derive SBRT specific dosimetric predictor’s of late urinary flare. Material and methods. Two hundred and sixteen men were treated for localized prostate cancer using ultrahypofractionated SBRT. A dose of 35–36.25 Gy in 5 fractions was delivered to the prostate and proximal seminal vesicles. Functional surveys were conducted before and after treatment to assess late toxicity. Phenomenologic NTCP models were fit to bladder DVHs and late urinary flare outcomes using maximum likelihood estimation. Results. Twenty-nine patients experienced late urinary flare within two years of completion of treatment. Fitting of bladder DVH data to a Lyman NTCP model resulted in parameter estimates of m, TD50, and n of 0.19 (0–0.47), 38.7 Gy (31.1–46.4), and 0.13 (-0.14–0.41), respectively. Subsequent fit to a hottest volume probit model revealed a significant association of late urinary flare with dose to the hottest 12.7% of bladder volume. Multivariate analysis resulted in a final model that included patient age and hottest volume probit model predictions. Kaplan-Meier analysis demonstrated a two-year urinary flare free survival of 95.7% in patients 65 years or older with a bladder D12.7% of 33.5 Gy or less, compared to 74.5% in patients meeting none of these criteria. Conclusion. NTCP modeling of late urinary flare after ultra-hypofractionated prostate SBRT demonstrates a relatively small volume effect for dose to the bladder, suggesting that reduction of volume receiving elevated dose will result in decreased incidence of late urinary toxicity. Future studies will be needed to examine the impact of dose to other potential sources of late genitourinary toxicity. Over the last decade, significant advances in image guidance and robotic radiation therapy along with the low estimated a/b ratio of prostate cancer cells (∼1.5 Gy) [1–3] has led to the development of new ultra-hypofractionated treatment options for selected patients with localized prostate cancer [4]. Using these typically five fraction stereotactic body radiotherapy (SBRT) techniques, excellent rates of disease control have been reported in several institutional clinical trials and a multi-institutional pooled analysis [5]. Overall, these studies have shown similar rates of late genitourinary (GU) and gastrointestinal (GI)
toxicity as compared to conventionally fractionated dose-escalated intensity-modulated radiation therapy (IMRT) series [5–10]. Recently, Woo et al. reported a transient late urinary flare in 13.4% of patients who received ultrahypofractionated SBRT for localized prostate cancer [11]. This was clinically similar to that described in patients treated with low dose rate (LDR) interstitial brachytherapy [12–15] and consisted of an abrupt increase in urinary symptoms following a posttreatment nadir, which subsequently returned to previous nadir with conservative management. Consistent
Correspondence: S. P. Collins, Georgetown University Hospital, Department of Radiation Medicine, 3800 Reservoir Rd, NW, LL Bles, Washington, DC 20007, USA. Tel: 1 202 444-3320. Fax: 1 202 444-9323. E-mail: [email protected] (Received 22 January 2015; accepted 29 March 2015) ISSN 0284-186X print/ISSN 1651-226X online © 2015 Informa Healthcare DOI: 10.3109/0284186X.2015.1037011
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with previous studies, young patient age was the only clinically related factor that was predictive of developing late urinary flare. Due to the lack of sufficient evidence, there is very little specific data regarding normal tissue GU dose constraints in ultra-hypofractionated SBRT. Available normal tissue dose constraints have largely been extrapolated from HDR brachytherapy series and are based on biologically equivalent dose comparisons to conventionally fractionated limits [16,17]. Recent attempts have also been made to determine objective prostate SBRT plan evaluation criteria based upon databases of achievable dose distributions in relation to anatomic geometry [18,19], however, no specific toxicity related dose-volume criteria were determined. In a limited series of patients treated at a single institution, Elias et al. recently reported correlates of quality of life (QOL) in patients treated with prostate SBRT, however, no associated dosimetric predictors of long-term urinary toxicity were found [20]. Therefore, in the present study we performed a retrospective dosimetric analysis of patients treated for localized prostate cancer using robotic ultra-hypofractionated SBRT in conjunction with long-term urinary functional outcomes to develop a normal tissue complication probability (NTCP) model for the development of late urinary flare after ultra-hypofractionated prostate SBRT. Material and methods We retrospectively reviewed the records of 216 consecutive patients treated definitively for localized prostate cancer using robotic ultra-hypofractionated SBRT at Georgetown University Hospital from 2008 to 2011. The median patient age was 69 years old (range 48–90) and the majority of patients had low to intermediate risk disease by the D’Amico risk stratification (Table I). Twenty-nine patients received androgen deprivation therapy (ADT) consisting of four weeks of bicalutimide and 3–6 months of leuprolide that started three months prior to SBRT. The Charlson Comorbidity Index (CCI) was used as a classifier of medical comorbidity as previously described [21]. Pre-SBRT PSA values were collected on the first day of radiotherapy. All patients were treated using the CyberKnife Radiosurgical System (CK, Accuray Inc., Sunnyvale, CA, USA), and had gold prostate fiducials implanted one week prior to simulation. Patients were instructed to empty their bladder prior to simulation and treatment, and the entire bladder and its contents were contoured as a single structure. The planning target volume (PTV) consisted of the prostate and proximal seminal vesicles as defined on non-contrast computed tomography (CT) and fused T2 magnetic
Table I. Patient characteristics (n 216). Age Median Range Pre-SBRT PSA (ng/ml) Median Range Clinical stage T1c T2a T2b T2c Gleason score 6 7 8 D’Amico risk group Low Intermediate High Prostate volume (cm3) Median Range Bladder volume (cm3) Median Range Charlson Comorbidity Index (CCI) 0 1 2 Pre-SBRT AUA score median range a1A antagonist use Yes No Previous TURP Yes No Pre-SBRT androgen deprivation therapy Yes No
69 48–90 5.8 0.2–32.5 160 29 20 7 97 109 10 83 111 22 38 11.6–138.7 82.3 42.5–687.4 146 51 19 7.5 0–33 62 154 19 197 29 187
resonance imaging (MRI) with a 3 mm posterior margin and a 5 mm margin in all other directions. In order to prevent anatomic distortion, a foley catheter was not inserted during simulation and therefore the prostatic urethra was not routinely visualized or used as a dose limiting structure. Inverse plans were generated with a prescription dose (PD) of 35–36.25 Gy in 5 fractions to the PTV using 6 MV photons. All plans were evaluated by a single physician and verified to meet our institutional planning objectives (Table II). All fractions were delivered within two weeks and real-time kV imaging based fiducial tracking was used to account for intra-fraction prostate translational and rotational motion. As part of our institutional policy, all patients were given patient reported QOL surveys including the Expanded Prostate Index Composite 26 (EPIC26) and underwent urinary functional assessment using the International Prostate Symptom Score
Late genitourinary toxicity modeling after prostate SBRT
Table II. 36.25 Gy plan dose-volume criteria. Global max dose
48.33 Gy
PTV GTV Rectum
V (36.25 Gy) 95% V (40 Gy) 95% V (36 Gy) 1 cm3 V (100%) 5% V (90%) 10% V (80%) 20% V (75%) 25% V (50%) 50% V (37 Gy) 10 cm3 V (50%) 40% V (29.5 Gy) 50% V (37 Gy) 50% V (30 Gy) 1 cm3 D (20%) 2 Gy
Bladder
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Penile bulb Membranous urethra Sigmoid colon Testicles
(IPSS) before treatment and at each follow-up visit which occurred every three months for the first year and then every six months thereafter. Late urinary flare was defined using the Princess Margaret criteria [15]: increase in IPSS score 5 above post-treatment baseline, with an absolute IPSS score 15, followed by a return to baseline within 2 years. NTCP modeling Cumulative absolute volume bladder dose-volume histograms (DVHs) were extracted from the treatment planning system and converted into relative volume
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differential DVHs using custom software written in Matlab (MathWorks, Inc., MA, USA). Phenomenologic NTCP models including the generalized Lyman, hottest volume, and threshold model were fit to the physical bladder DVH and late urinary toxicity data using maximum likelihood estimation (MLE) as previously described (see Appendix, available online at http://informahealthcare.com/doi/abs/10.3109/0284 186X.2015.1037011). The profile likelihood and Wald methods were used to generate estimates of the parameter 95% confidence intervals. Statistics Patient- and disease-related covariates along with NTCP model predictions were independently tested for significant association with the development of late urinary flare using univariate logistic regression. A multivariate model was then constructed using forward selection with a cut-off p-value of 0.05. Significant parameter cut-off values were obtained with Fischer’s exact test and then used to group patients by risk of developing late urinary flare. Late urinary flare free survival was evaluated for each group using the KaplanMeier method and statistically compared using the log-rank test. Results
Figure 1. Mean cumulative (A) and differential (B) whole bladder DVHs for patients with and without late urinary flare after ultrahypofractionated prostate SBRT.
At a median follow-up of four years, 216 patients were evaluated and 29 (13.4%) met the criteria of late urinary flare after receiving definitive ultrahypofractionated prostate SBRT at a median time to flare of nine months. At the time of last follow-up, all patients had returned to their baseline urinary status according to IPSS symptom index. Bladder DVH data was available for all but one patient in the no toxicity group. Figure 1 shows group-averaged cumulative (A) and differential (B) DVH data for the entire cohort with clear separation of the two curves in the 18–37Gy range. Fitting of bladder differential DVH data and incidence of late urinary flare to a generalized Lyman NTCP model (Equations 1–3, to be found online at http://informahealthcare.com/doi/abs/10.3109/0284 186X.2015.1037011) using MLE resulted in estimated Lyman parameters of m 0.19 (95% CI 0–0.47), n 0.13 (95% CI -0.14–0.41), and TD50 38.7 Gy (95% CI 31.1–46.4 Gy). Comparison of the model estimate to the actual incidence of late urinary flare in five equally sized EUD bins demonstrates that the generalized Lyman model describes the data well (Figure 2), suggesting a relatively low volume dependence of dose to the bladder in development of late urinary flare after ultra-hypofractionated prostate SBRT.
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Figure 2. Results of LKB model fit to differential whole bladder DVH data versus EUD (solid line) together with two-year incidence of urinary flare among five equally sized EUD bins (triangles). Vertical error bars indicate the standard deviation of the binomial distribution and horizontal error bars represent the standard deviation of the EUD in each bin. Inset shows the EUD range covered in our cohort.
A similar approach was used to examine the association of volume of bladder receiving more than a threshold dose Dc or dose to the hottest volume of bladder Vc in threshold or hottest volume NTCP models (Equations 1 and 4, to be found online at http://informahealthcare.com/doi/abs/10.3109 / 0284186X.2015.1037011), respectively. Using MLE, we estimated an optimal bladder threshold dose of 36.6 Gy, however, the model did not describe the data well as suggested by infinite estimates of the 95% confidence intervals for each of the model parameters. Alternatively, the hottest volume NTCP model fit our data well (Figure 3) with an estimated hottest volume threshold Vc 12.7% (95% CI 0–39.2%) with slope m 0.19 (95% CI 0–0.49), and dose to the hottest volume of bladder predicted to result in a 50% complication rate, DVc 44.6 Gy (95% CI 35.2–54 Gy). Univariate logistic regression was used to assess specific patient- and disease-related covariates, along
Figure 3. Results of hottest volume model fit to differential whole bladder DVH data versus dose to the hottest 12.7% of bladder (D12.7%, solid line) together with two-year incidence of urinary flare among five equally sized D12.7% bins (triangles). Vertical error bars indicate the standard deviation of the binomial distribution and horizontal error bars represent the standard deviation of the dose in each bin. Inset shows the dose range covered in our cohort.
with NTCP model predictions for statistically significant associations with the development of late urinary flare after prostate SBRT (Table III). Only younger patient age (OR 0.93, 95% CI 0.88–0.98), Lyman model prediction (OR 1.49, 95% CI 1.01–2.18), and hottest volume model prediction (OR 1.59, 95% CI 1.06–2.39) were statistically predictive of developing late urinary flare. A final model was generated using multivariate logistic regression and a forward selection method which only included younger patient age and hottest volume model estimates as independent predictors (Table III). Candidates for cut-off values of patient age and hottest volume model prediction were determined using Fischer’s exact test and a maximum threshold p-value of 0.05. Several significant age cut-offs were found, however, an age of 65 years or greater was selected based upon its association with late urinary flare in previous LDR brachytherapy studies. A hottest volume model cut-off of 10% complications was chosen as an acceptable clinical risk and corresponds to a bladder D12.7% 33.5 Gy. Patients were then grouped based upon the presence of these criteria, and late urinary flare free survival was estimated Table III. Predictors of late urinary flare. Parameter Univariate logistic regression Age (years) Pre-treatment PSA (ng/ml) Clinical stage T1c T2a T2b T2c Gleason score 6 7 D’Amico risk group Low Intermediate High Prostate volume (ml) Bladder volume (ml) CCI 0 1 2 Pre-treatment AUA score a1A antagonist use Previous TURP Pre-SBRT ADT LKB modela Hottest volume modela Threshold modela Multivariate logistic regression Age (years) Hottest volume modela
OR
95% CI
p-value
0.93 0.94
(0.88–0.98) (0.85–1.05)
0.01 0.28
1.00 1.08 1.15 1.07
(0.35–3.37) (0.31–4.19) (0.12–9.24)
0.89 0.84 0.95
1.00 0.90
(0.41–1.97)
0.80
1.00 0.97 0.44 1.00 0.99
(0.44–2.13) (0.06–3.47) (0.98–1.02) (0.98–1.01)
0.94 0.43 0.83 0.14
1.00 1.03 1.23 0.93 0.80 0.28 0.71 1.49 1.59 1.27
(0.41–2.56) (0.33–4.50) (0.86–1.01) (0.32–1.98) (0.04–2.17) (0.20–2.52) (1.01–2.18) (1.06–2.39) (0.99–1.62)
0.95 0.76 0.09 0.63 0.22 0.60 0.04 0.03 0.06
0.93 1.53
(0.88–0.99) (1.01–2.31)
0.01 0.04
a odds ratios expressed as odds per 5% increase in complication probability.
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Figure 4. Kaplan-Meier analysis of urinary flare free survival. Patients are grouped according age and hottest volume model prediction. (p-value 0.05).
using Kaplan-Meier analysis (Figure 4). Patients age 65 or greater with a bladder D12.7% 33.5 Gy had a two-year late urinary flare free survival of 95.7% compared to 83.9% for patients meeting only one of these criteria, or 74.5% for patients meeting none of these criteria (p 0.05). Discussion Early reports of post-treatment biochemical relapsefree survival and QOL following ultra-hypofractionated SBRT for selected patients with localized prostate cancer have been encouraging [5–10]. However, a recent Surveillance, Epidemiology, and End Results Program (SEER) based analysis has called into question the safety of these treatments in terms of longterm urinary toxicity as compared to conventionally fractionated IMRT [22]. Recently, we reported QOL outcomes for patients treated according to our institutional protocol and noted a small subset of patients who developed a late increase in urinary symptoms following a post-treatment nadir that subsequently returned to previous nadir, termed late urinary flare [11]. These patients experienced higher rates of CTCAE-graded dysuria, urinary frequency, urgency, and retention in the first two years of follow-up after prostate SBRT, and demonstrated significant declines in QOL in the EPIC urinary domain. This was similar to that described previously in the prostate LDR interstitial brachytherapy literature by several institutions [12–15]. In our previous analysis, only young patient age correlated with the development of late urinary flare after prostate SBRT, and that the majority of these patients experienced complete resolution of
their symptoms with medical management consisting of a short course of anti-inflammatory medications. While there is a significant amount of data in regards to specific planning objectives and risks of late urinary toxicity in the conventionally fractionated literature, very little information exists regarding dosimetric predictors of late toxicity using ultrahypofractionated treatment regimens. Therefore, we sought to identify potential dose-related risk factors for the development of late urinary flare by applying well established NTCP models to dose-volume data extracted from the treatment plans of our previously treated patients. Though our study has a limited number of events, the well defined and robust nature of our late urinary toxicity endpoint suggested that a rigorous analysis of this type was possible. Fits of our cohort bladder dose-volume data to a generalized Lyman model demonstrates a relatively low volume effect for dose to the bladder in the development of late urinary flare after ultra-hypofractionated prostate SBRT. This is similar to that observed in previous studies examining dosimetric predictors of late grade 2 or greater urinary toxicity in patients treated with dose-escalated IMRT [23]. Together, these results suggest that the bladder contribution to urinary function following prostate radiotherapy behaves in a serial fashion and is sensitive to small volumes of elevated dose. This is further supported by the observation in the Cheung et al. study [23] and in our cohort that the best fit of the data was achieved using the hottest volume model for dose to the bladder although, our hottest volume threshold was considerably larger than that obtained in the conventionally fractionated study (12.7% vs. 2.9%).
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Several potential explanations exist for this discrepancy including difference in GU toxicity endpoint, fraction size, as well as simulation and treatment technique. Due to the relatively long treatment times ( 30 min) associated with our robotic ultra-hypofractionated SBRT treatment regimen, we simulate and treat our patients with an empty bladder to facilitate patient comfort. When considering relative volumes, this decreases the value of the denominator (whole bladder volume), thus increasing the value of the relative volume of bladder tissue most at risk for elevated dose, including the bladder trigone, which has recently been shown to correlate with late urinary toxicity in a singleinstitution dose-escalated series [24]. In that study, Ghadjar et al. noted a significant correlation between long-term GU toxicity and volume of bladder trigone receiving more than 90 Gy, as well as increasing maximum point dose to the trigone. In addition to bladder D12.7%, our multivariate analysis confirmed patient age as an independent predictor of late urinary flare in our cohort. A trend for development of late urinary flare in younger patients receiving definitive interstitial prostate LDR brachytherapy has been previously described [12], however, to the best of our knowledge no statistically significant correlation has ever been found. It is unclear whether the etiology of this association is biological versus psychological in nature. Conventional thought would incorrectly predict that benign enlargement of prostate glandular tissue associated with aging would predispose older patients to worse long-term treatment-related GU toxicity. However, no correlation with prostate volume was seen in our analysis. Perhaps younger patients are more aware of their urinary function whereas older patients have grown accustomed to a lower baseline GU QOL so that any detrimental changes in urinary function are more apparent in younger patient populations. In stark opposition to this theory is the fact that pre-treatment IPSS symptom index had no statistically significant association with development of late urinary flare in our cohort, although a trend for lower initial IPSS symptom index in patients with late urinary flare was observed (OR 0.93, p 0.09). Furthermore, there was no association with any other pre-treatment GU QOL indexes including a1a antagonist use or ADT (Table 3). Our study highlights the importance of combined application of patient- and dose-related criteria in the prediction of potential treatment-related toxicity after prostate SBRT. The combination of our ultrahypofractionated prostate 5 fraction SBRT dosevolume cut-off of D12.7% 33.5 Gy and age 65 years predicts for a low two-year incidence of late urinary flare in our cohort. Validation with prospec-
tive data sets will determine the future clinical applicability of these criteria as well as their applicability to other non-robotic methods of ultra-hypofractionated prostate SBRT. Declaration of interest: Sean P. Collins is a clinical consultant for Accuray Inc. and receives an educational grant to fund a research coordinator in the Department of Radiation Medicine at Georgetown University Hospital. Leonard N. Chen is a research coordinator and is partially funded through the educational grant provided by Accuray Inc. References [1] Dasu A, Toma-Dasu I. Prostate alpha/beta revisited – an analysis of clinical results from 14 168 patients. Acta Oncol 2012;51:963–74. [2] Miralbell R, Roberts SA, Zubizarreta E, Hendry JH. Dosefractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5,969 patients in seven international institutional datasets: Alpha/beta 1.4 (0.9–2.2) Gy. Int J Radiat Oncol Biol Phys 2012;82:e17–24. [3] Proust-Lima C, Taylor JM, Secher S, Sandler H, Kestin L, Pickles T, et al. Confirmation of a low alpha/beta ratio for prostate cancer treated by external beam radiation therapy alone using a post-treatment repeated-measures model for PSA dynamics. Int J Radiat Oncol Biol Phys. 2011;79:195–201. [4] American Society for Radiation Oncology (ASTRO) Model Policy on Steretoactic Body Radiotherapy 2013. Available from: https://www.astro.org/uploadedFiles/Main_Site/Practice_Management/Reimbursement/2013HPcoding%20 guidelines_SBRT_Final.pdf. Accessed 17th, April 2013. [5] King CR, Freeman D, Kaplan I, Fuller D, Bolzicco G, Collins S, et al. Stereotactic body radiotherapy for localized prostate cancer: Pooled analysis from a multi-institutional consortium of prospective phase II trials. Radiother Oncol 2013;109:217–21. [6] Chen LN, Suy S, Uhm S, Oermann EK, Ju AW, Chen V, et al. Stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer: The Georgetown University experience. Radiat Oncol 2013;8:58. [7] Freeman DE, King CR. Stereotactic body radiotherapy for low-risk prostate cancer: Five-year outcomes. Radiat Oncol 2011;6:3. [8] Katz AJ, Santoro M, Diblasio F, Ashley R. Stereotactic body radiotherapy for localized prostate cancer: Disease control and quality of life at 6 years. Radiat Oncol 2013;8:118. [9] King CR, Brooks JD, Gill H, Presti JC, Jr. Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. Int J Radiat Oncol Biol Phys Feb 2012;82:877–82. [10] McBride SM, Wong DS, Dombrowski JJ, Harkins B, Tapella P, Hanscom HN, et al. Hypofractionated stereotactic body radiotherapy in low-risk prostate adenocarcinoma: Preliminary results of a multi-institutional phase 1 feasibility trial. Cancer 2012;118(15):3681–90. [11] Woo JA, Chen LN, Bhagat A, Oermann EK, Kim JS, Moures R, et al. Clinical characteristics and management of late urinary symptom flare following stereotactic body radiation therapy for prostate cancer. Front Oncol 2014;4:122. [12] Cesaretti JA, Stone NN, Stock RG. Urinary symptom flare following I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003;56:1085–92.
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[13] Keyes M, Miller S, Moravan V, Pickles T, Liu M, Spadinger I, et al. Urinary symptom flare in 712 125I prostate brachytherapy patients: Long-term follow-up. Int J Radiat Oncol Biol Phys. 2009;75:649–55. [14] Lehrer S, Cesaretti J, Stone NN, Stock RG. Urinary symptom flare after brachytherapy for prostate cancer is associated with erectile dysfunction and more urinary symptoms before implantation. Br J Urol Int 2006;98:979–81. [15] Crook J, Fleshner N, Roberts C, Pond G. Long-term urinary sequelae following 125iodine prostate brachytherapy. J Urol 2008;179:141–5; discussion 6. [16] Martinez AA, Pataki I, Edmundson G, Sebastian E, Brabbins D, Gustafson G. Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: A feasibility report. Int J Radiat Oncol Biol Phys 2001;49:61–9. [17] Michalski JM, Gay H, Jackson A, Tucker SL, Deasy JO. Radiation dose-volume effects in radiation-induced rectal injury. Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S123–9. [18] Descovich M, Carrara M, Morlino S, Pinnaduwage DS, Saltiel D, Pouliot J, et al. Improving plan quality and consistency by standardization of dose constraints in prostate cancer patients treated with CyberKnife. J Appl Clin Med Phys 2013;14:162–72. [19] Wu B, Pang D, Lei S, Gatti J, Tong M, McNutt T, et al. Improved robotic stereotactic body radiation therapy plan
Supplementary material available online Appendix: NTCP Modeling, to be found online at http://informahealthcare.com/doi/abs/10.3109/ 0284186X.2015.1037011.
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quality and planning efficacy for organ-confined prostate cancer utilizing overlap-volume histogram-driven planning methodology. Radiother Oncol 2014;112:221–6. [20] Elias E, Helou J, Zhang L, Cheung P, Deabreu A, D’Alimonte L, et al. Dosimetric and patient correlates of quality of life after prostate stereotactic ablative radiotherapy. Radiother Oncol 2014;112:83–8. [21] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987;40:373–83. [22] Yu JB, Cramer LD, Herrin J, Soulos PR, Potosky AL, Gross CP. Stereotactic body radiation therapy versus intensity-modulated radiation therapy for prostate cancer: Comparison of toxicity. J Clin Oncol 2014;32: 1195–201. [23] Cheung MR, Tucker SL, Dong L, de Crevoisier R, Lee AK, Frank S, et al. Investigation of bladder dose and volume factors influencing late urinary toxicity after external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2007;67:1059–65. [24] Ghadjar P, Zelefsky MJ, Spratt DE, Munck af Rosenschold P, Oh JH, Hunt M, et al. Impact of dose to the bladder trigone on long-term urinary function after high-dose intensity modulated radiation therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2014;88:339–44.
