LONG-TERM URINARY TOXICITY AFTER 3-DIMENSIONAL CONFORMAL RADIOTHERAPY FOR PROSTATE CANCER IN PATIENTS WITH PRIOR HISTORY OF TRANSURETHRAL RESECTION

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1 PII S (00) Int. J. Radiation Oncology Biol. Phys., Vol. 48, No. 3, pp , 2000 Copyright 2000 Elsevier Science Inc. Printed in the USA. All rights reserved /00/$ see front matter CLINICAL INVESTIGATION Prostate LONG-TERM URINARY TOXICITY AFTER 3-DIMENSIONAL CONFORMAL RADIOTHERAPY FOR PROSTATE CANCER IN PATIENTS WITH PRIOR HISTORY OF TRANSURETHRAL RESECTION AJAYPAL S. SANDHU, M.D., D.M.R.T., MICHAEL J. ZELEFSKY, M.D., HENRY J. LEE, M.D., PH.D., DANNA LOMBARDI, B.A., ZVI FUKS, M.D., AND STEVEN A. LEIBEL, M.D. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY Purpose: To report on the long-term urinary morbidity among prostate cancer patients with a prior history of a transurethral resection of the prostate (TURP) treated with high-dose 3-dimensional conformal radiotherapy (3D-CRT). Methods and Materials: Between 1988 and 1997, 1100 patients with clinically localized prostate cancer were treated with 3D-CRT. Of these, 120 patients (8%) were identified as having had a prior TURP and are the subjects of this analysis. The median age was 71 years (range: years). The clinical stages of the patients were T1c: 33 (28%); T2a: 38 (32%); T2b: 15 (13%); and T3: 34 (27%). Neoadjuvant androgen ablation therapy was given to 39 (33%). The median radiation dose prescribed to the planning target volume was 75.6 Gy (range: Gy). The median elapsed time from TURP to initiation of 3D-CRT was 69 months (range: months). The median follow-up time was 51 months (range: months). Results: Five patients of the 120 with a prior history of TURP (4%) developed a urethral stricture after 3D-CRT which was corrected with dilatation. The 5-year actuarial likelihood of > Grade 2 late urinary toxicities was 9%. No Grade 4 urinary toxicities were observed in this group of patients. Among 110 patients who were completely continent of urine prior to 3D-CRT, 10 (9%) developed stress incontinence requiring 1 pad daily for protection or experienced occasional leakage (not requiring pad protection). The 5-year incidence of > Grade 1 stress incontinence was 18% in patients who developed acute > Grade 2 GU symptoms during the course of 3D-CRT compared to 7% for patients who experienced Grade 1 or no acute urinary symptoms (p 0.05). The radiation dose (>75.6 Gy vs. <75.6 Gy), the number of prior TURP procedures, or the volume of resected tissue at the time of TURP had no significant impact on the long-term urinary morbidity outcome. A multivariate analysis demonstrated that the presence of Grade 2 acute urinary symptoms was the only predictor of > Grade 1 stress incontinence after 3D-CRT in this group of patients. Conclusions: Despite prior TURP, the incidence of > Grade 3 urinary toxicities is low. Nevertheless, especially among patients with a prior history of TURP who experience Grade 2 acute urinary symptoms during radiation treatment, a higher risk of stress incontinence is observed Elsevier Science Inc. Prostate cancer, Conformal radiotherapy, Transurethral resection, Toxicity. INTRODUCTION Reprint request to: Michael J. Zelefsky, M.D., Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY zelefskm@ mskcc.org Several reports have suggested a higher incidence of late urinary complications after external beam radiotherapy among patients who underwent a previous transurethral resection of prostate (TURP) (1 3). Higher rates of urinary toxicities in the setting of a prior TURP have also been reported after permanent interstitial implantation of the prostate (4, 5). Post-treatment complications have included chronic urethritis, stress incontinence, and in rare cases, fistula and necrosis. The likely mechanism of increased urinary toxicity in these patients is related to the relative devascularization of the urethra after TURP (6) and the decreased capability of the mucosa to repair sublethal damage after radiotherapy. Although a prior TURP does not constitute a contraindication to radiotherapy, treatment must be undertaken in a cautious fashion. Because of the high central prostate doses achieved with brachytherapy, in particular, the risk of increased late urinary toxicity is well recognized. Limited information, however, is available regarding the outcome of such patients after high-dose conformal 3-dimensional radiotherapy (3D-CRT). Although the delivery of higher doses with conformal radiotherapy can compound the effect of previous TURP on urinary morbidity, the improved homogeneity of the dose distribution associated with 3D-CRT compared to conventional treatment techniques may reduce the expected late sequelae. In this paper, Accepted for publication 23 May

2 644 I. J. Radiation Oncology Biology Physics Volume 48, Number 3, 2000 we report the long-term urinary morbidity among 120 prostate cancer patients with a prior history of TURP treated to high-dose 3D-CRT. METHODS AND MATERIALS Between 1988 and 1998, 1100 patients with clinically localized prostate cancer were treated with 3D-CRT. Of these, 120 patients (11%) were identified as having had a prior TURP. The median age of the patients was 71 years (range; years). The American Joint Committee on Cancer (AJCC) 1997 clinical stage was T1c in 33 patients (28%), T2a in 38 (32%), T2b in 15 (13%), and T3 in 34 patients (27%). The technique of radiotherapy has been previously described in detail (7). In brief, the planning target volume (PTV) was derived from simulation CT scans and included the entire prostate and seminal vesicles plus a 1.0-cm margin, except at the prostate rectum interface where a 0.6-cm margin was used to decrease the risk of rectal toxicity. An additional 0.5-cm margin was added circumferentially around the clinical target volume (CTV) and 1.0 cm superiorly and inferiorly to account for penumbra of the radiation beams. Patients were immobilized and treated in the prone position as previously described (8). In general, treatments were delivered with six individually shaped coplanar fields, with MV X-rays in daily fractions of 1.8 Gy. More recently a five-field intensity-modulated treatment plan was used for patients treated to 81 Gy (9). Radiation doses were prescribed to the maximum isodose surface distribution that completely encompassed the PTV. A minimum tumor dose of 64.8 Gy was given to 18 patients (15%), 70.2 Gy to 37 (31%), 75.6 Gy to 48 (40%), and 81.0 Gy to 17 patients (14%). In general, the isocenter doses (ICRU prescription point) were 4 7% higher than the aforementioned prescription doses. Dose volume histograms were used to ensure that no more than 30% of the rectal wall and/or 50% of bladder wall received a maximum dose of 75.6 Gy. Thirty-nine patients (33%) with large-volume prostate glands, in whom the best feasible plan yielded dose volume histograms that exceeded these limits, were treated with a 3-month course of neoadjuvant androgen deprivation therapy to decrease the size of the prostatic target volume (10, 11). This treatment was continued throughout the course of radiotherapy and stopped at its completion. The median elapsed time from TURP to initiation of 3D-CRT was 69 months with a range of months. Thirty-nine patients (36%) had TURP within 3 years of 3D-CRT. Based on available information, extent and volume of TURP was estimated. TURP volume was described as minimal (volume 10 grams, biopsy or chips) in 38 (32%) patients, extensive (volume 10 grams) in 43 (36%), and unknown in the remaining 39 (32%). Twentyfive patients (23%) underwent 1 prior TURP procedure, and 95 (77%) underwent only one TURP before treatment. Acute reactions included those arising either during the course of treatment or within the first 90 days after its completion. Detailed toxicity data were prospectively collected by the treating physicians during the course of therapy and in the follow-up period. Acute toxicity was graded according to the most severe reaction observed at 2 or more consecutive weekly examinations. Follow-up evaluations after treatment were performed at 3- to 6-month intervals. Late complications were defined as those developing more than 90 days after the completion of irradiation or those that started during treatment and persisted for longer than 90 days after its completion. Acute and late toxicities were graded according to the Radiation Therapy Oncology Group morbidity scoring scale (12). The degree of stress incontinence after therapy was scored according to the Late Effects Normal Tissue/Radiation Therapy Oncology Group (LENT/ RTOG) classification (13). The median follow-up time was 51 months, ranging from months. Distribution of times to develop late toxicity was calculated according to the product-limit (Kaplan-Meier) method (14). Differences between time-adjusted incidence rates were evaluated using the Mantel log-rank test for censored data (15). The relative impact of covariates that affect time-adjusted outcomes (multivariate analysis) was determined using the stepwise Cox proportional hazards regression model (16). Late complications were determined as of the time of analysis in December RESULTS Overall, 84 of the 120 patients (70%) had no or only mild (Grade 1) acute GU toxicity not requiring any therapeutic intervention. Medications were required for relief of acute GU-related symptoms (Grade 2) in 36 patients (30%). These symptoms included urinary frequency and urgency which in general improved with alpha blocker medications as previously reported (17). The 5-year actuarial likelihood of Grade 2 late urinary toxicities was 9% among patients with a prior history of TURP compared to 10% for patients with no history of TURP ( p 0.5). Five patients (4%) developed a urethral stricture after 3D-CRT, which was corrected with dilatation. As shown in Fig. 1, the 5-year actuarial likelihood of developing a urethral stricture was 4% compared to 1% for patients (n 980) who did not undergo a prior TURP ( p 0.01). No urinary toxicities occurred after 30 months from completion of 3D-CRT, and no Grade 4 urinary toxicities were observed. One hundred ten of the 120 patients (92%) were completely continent of urine prior to 3D-CRT. Of these, 2 (2%) developed stress incontinence requiring 1 pad daily for protection, and 8 (7%) experienced occasional leakage not requiring pad protection. The 5-year actuarial likelihood of Grade 1 stress incontinence development in this group was 9%. Among the 10 patients who had some form of urinary incontinence prior to 3D-CRT, one patient developed worsening of his incontinence after therapy whereas the remaining 9 patients experienced no significant changes in their

3 Conformal radiotherapy after TURP A. S. SANDHU et al. 645 Fig. 1. Actuarial incidence of urethral strictures after 3D-CRT among patients with and without a prior history of TURP. continence status. Patients who developed acute Grade 2 GU symptoms during the course of 3D-CRT were more likely to develop post-treatment urinary incontinence. As shown in Fig. 2, among patients who were continent prior to therapy but developed Grade 2 acute urinary symptoms during the course of 3D-CRT, the 5-year incidence of Grade 1 stress incontinence development was 18% compared to 7% for patients who experienced Grade 1 or no acute urinary symptoms ( p 0.05). A multivariate analysis demonstrated that the presence of Grade 2 acute urinary symptoms ( p 0.01; relative risk, 4.8) was the only predictor of Grade 1 stress incontinence in these patients. The radiation dose ( 75.6 Gy versus 75.6 Gy), volume of resected tissue at the time of TURP, and the number of prior TURP procedures had no significant impact on longterm urinary incontinence. DISCUSSION This report indicates that high-dose conformal radiotherapy is well tolerated among patients who previously underwent TURP. A small but significantly increased risk of urethral stricture development after 3D-CRT was observed for patients who underwent a prior TURP compared to those Fig. 2. Actuarial incidence of Grade 1 urinary incontinence among 110 TURP patients who were completely continent at baseline prior to 3D-CRT. A significant increase in incontinence was observed for those patients who experienced acute urinary symptoms during the course of 3D-CRT.

4 646 I. J. Radiation Oncology Biology Physics Volume 48, Number 3, 2000 who never underwent this procedure (4% versus 1%, respectively). Nevertheless, it remains unclear to what extent 3D-CRT increases the risk of stricture development among patients who previously underwent TURP compared to similar prior TURP patients who are not treated with 3D-CRT. Several reports have documented a 2 12% incidence of urethral strictures after TURP alone in patients who never underwent other therapy including surgery or radiotherapy (18 20). In our report, there was no significant increase in the incidence of urethral strictures among TURP patients who received high-dose 3D-CRT ( 75.6 Gy) compared to similar patients who received lower doses. Previous studies have reported a higher frequency of urethral toxicities for patients undergoing prior TURP after conventional radiotherapy (2, 6). Seymore et al. (6) reported statistically significant differences in the development of urethral strictures or bladder neck contractures after radiotherapy when comparing patients with prior TURP to no prior TURP (15% vs. 6% p 0.025). The higher incidence of stricture development in that study may be related to the relative close temporal relationship with the TURP procedure and the initiation of radiotherapy. In that study the majority of patients who developed complications underwent TURP within 33 days of treatment. The 4% incidence of urethral strictures in our study for patients with a prior history of TURP is similar to the rates reported by Perez et al. and Lawton et al. in similar patients (2, 12). These lower rates may be attributed to the increased elapsed time between TURP and initiation of radiation treatment. In our study, the median time elapsed between TURP and initiation of treatment was greater than 5 years. Second, the use of conformal 3D- CRT in our study with associated improved homogeneity of the dose distribution could also have contributed to a lower incidence of urethral strictures despite the higher radiation doses routinely used. This report also confirms the findings of others concerning the increased risk of urinary incontinence following radiation therapy among patients who underwent prior TURP. At least two other studies (1, 2) have reported a higher incidence of urinary incontinence for patients with a history of prior TURP following external beam radiotherapy. Lee et al. (1) observed a higher urinary incontinence (Grade 2 or 3) rate of 2% in patients undergoing prior TURP compared to 0.2% in patients without prior TURP. A history of prior TURP was the only factor associated with a higher risk of this sequela. In our report, although no patient developed Grade 3 or 4 incontinence according to the LENT scale, a 9% incidence of Grade 1 incontinence was observed among 110 patients who were completely continent before the initiation of 3D-CRT. We also noted a higher incidence of post-treatment urinary incontinence among prior TURP patients who experienced acute Grade 2 urinary symptoms during 3D-CRT. These findings are consistent with previously reported results from our institution and others demonstrating increased long-term urinary toxicities among patients who experienced acute urinary symptoms during the course of radiotherapy (21, 22). In conclusion, these data suggest that despite a previous history of TURP, the risk of severe long-term urinary toxicities is relatively minimal after 3D-CRT and may be lower than what could be observed for similar patients after brachytherapy. Several reports have suggested higher risks of Grade 3 urinary toxicities among patients with an antecedent history of TURP who are treated with brachytherapy (4, 5). Zelefsky and Whitmore (23) reported on the 10-year urinary morbidity outcome after retropubic I-125 implantation among patients who underwent a prior TURP. In that report the incidence of Grade 2 or higher late urinary toxicities among treated patients with a prior TURP was 19% compared to 11% for patients without a history of TURP ( p 0.001). Blasko et al. (4) reported a 17% rate of incontinence and observed in some patients urethral necrosis among patients treated with a prior TURP. The higher urinary toxicity rates observed in TURP patients may be attributed to the expected increased central doses with this form of therapy. On the other hand, Wallner et al. (24) reported a significantly lower risk of late urethral toxicities after brachytherapy in a select group of patient who underwent a prior TURP. These authors speculated that lower complication rates may be more likely associated with peripheral-based seed loading schemes, and the avoidance of implantation in patients with large TURP defects. Nevertheless, in the absence of long-term toxicity outcome reports, brachytherapy for patients with a prior TURP should be performed with caution as inevitably doses in excess of the prescription doses are routinely delivered to the urethra and long-term toxicity could be higher than expected compared to patients undergoing 3D-CRT. REFERENCES 1. Lee WR, Schultheiss TE, Hanlon AL, Hanks GE. Urinary incontinence following external-beam radiotherapy for clinically localized prostate cancer. Urology 1996;48: Perez CA, Lee HK, Georgiou A, Lockett MA. Technical factors affecting morbidity in definitive irradiation for localized carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1994;28: Green N, Treible D, Wallack H. Prostate cancer: Postirradiation incontinence. 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