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Outcomes for prostate glands >60 cc treated with low-dose-rate brachytherapy
Brachytherapy
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(2015)
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Outcomes for prostate glands O60 cc treated with low-dose-rate brachytherapy Yvonne D. Pham1, Jeffrey A. Kittel1, Chandana A. Reddy1, Jay P. Ciezki1, Eric A. Klein2, Kevin L. Stephans1, Rahul D. Tendulkar1,* 1 Department of Radiation Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH Department of Urology, Cleveland Clinic Glickman Urological and Kidney Institute, Cleveland, OH
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ABSTRACT
PURPOSE: We sought to analyze whether outcomes of biochemical relapseefree survival (bRFS), late genitourinary (GU), and late gastrointestinal toxicity are different for prostate cancer patients with small (#60 cc) vs. large (O60 cc) prostates following low dose-rate brachytherapy. METHODS AND MATERIALS: The bRFS outcomes for 2076 low- or intermediate-risk prostate cancer patients from 1996 to 2012 were determined from a review of a prospectively maintained database. All patients were treated with 125I monotherapy without androgen deprivation therapy. Biochemical failure was defined per the Phoenix definition. Patient-related factors and dosimetric values were examined in Cox regression analyses for bRFS and late toxicity. Late toxicity was scored according to a modified Common Terminology Criteria for Adverse Events version 4.0 scale. RESULTS: The median followup for all patients was 55 months. The 5-year bRFS rates for all patients, prostates O60 cc, and prostates #60 cc were 93.4% (95% confidence interval [CI]: 92.1%, 94.7%), 96.7% (95% CI: 94.4%, 98.9%), and 92.9% (95% CI: 91.4%, 94.3%), respectively. On multivariable analysis, prostate size O60 cc was significantly associated with improved bRFS ( p 5 0.01), as were initial prostate-specific antigen and biopsy Gleason score ( p ! 0.0001 and p 5 0.0002, respectively). Patients with prostates O60 cc had significantly higher rates of Grade 3e4 late GU toxicity at 5 years than patients with smaller prostates; 7.2% (95% CI: 4.0%, 10.4%) and 3.2% (95% CI: 2.3%, 4.1%), respectively ( p 5 0.0007). The overall late gastrointestinal toxicity rate for all patients was 0.7% at 5 years with no significant difference between the two groups. CONCLUSIONS: Implantation of large prostates O60 cc results in favorable bRFS outcomes and is associated with increased but acceptable rates of Grade 3 and higher late GU toxicities. Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Prostate cancer; Large; Gland; Volume; Biochemical relapseefree survival; Low dose-rate brachytherapy
Introduction The American Brachytherapy Society (ABS) Consensus guidelines for permanent prostate brachytherapy (PPB) (1) state that prostate volume larger than 60 cc is a relative contraindication to brachytherapy due to possible pubic arch interference and technical challenges that may affect
Received 5 November 2015; received in revised form 3 December 2015; accepted 8 December 2015. * Corresponding author. Department of Radiation Oncology (T28), Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Tel.: þ1-216-445-9869; fax: þ1-216-445-1068. E-mail address: [email protected] (R.D. Tendulkar).
the overall efficacy of the intervention. As such, patients with larger prostates may be at higher risk for complications and toxicities. However, in experienced hands, there may be no differences in clinical outcomes in terms of biochemical relapseefree survival (bRFS) (2,3) based on gland size, and some have actually reported improved outcomes for larger glands (4,5). We previously reported our institutional outcomes for 390 patients (4) revealing that large gland volume and width predicted for better bRFS on multivariable analysis. This present study is an updated analysis with a larger cohort of 2076 patients who underwent low-dose-rate PPB with 125I at our high-volume tertiary care institution regarding outcomes of bRFS and late genitourinary (GU)
1538-4721/$ - see front matter Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2015.12.002
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and gastrointestinal (GI) toxicities for small (#60 cc) vs. large (O60 cc) prostate glands.
Methods and materials We identified 2076 patients with Stage T1eT2N M0 low- and intermediate-risk prostate cancer treated with PPB alone without androgen deprivation therapy from 1996 to 2012 from a prospectively maintained and institutional review boardeapproved database. We included only low- and intermediate-risk cancer patients as determined by the National Comprehensive Cancer Network guidelines (6). Low risk patients had Gleason score #6, prostatespecific antigen (PSA) !10 ng/mL, and clinical tumor classification T1eT2a. Intermediate-risk patients had Gleason score 7, or PSA 10e20 ng/mL, or clinical tumor classification T2b-T2c. All patients had a minimum of three posttreatment PSA values and at least 1 year of followup. All treatment-related and dosimetric assessments were performed according to the ABS guidelines (1) and postimplant dosimetric analysis (7). All patients underwent PPB using 125I with a planned dose of 144 Gy to the prostate planning treatment volume. Prostate gland volume was measured at the time of implant using a transrectal ultrasound in the lithotomy position under general anesthesia. Real-time intraoperative planning was done using a peripheral loading technique to limit the central prostate to !150% of the prescription dose. Postimplant computed tomographye based dosimetry was performed approximately 4 weeks after implantation. Toxicity was recorded after review of visit and procedure notes from electronic charts and via communication from patients and referring physicians. Late toxicity was defined as occurring O6 months after PPB and was scored according to a modified Common Terminology Criteria for Adverse Events 4.0 scale (8) as follows: Grade 1, asymptomatic/mild symptoms; Grade 2, managed medically or observed; Grade 3, requiring procedural intervention (e.g., transurethral resection of the prostate); Grade 4, life threatening; and Grade 5, resulting in death. We distinguished between PPB-related rectal bleeding vs. other etiologies of rectal bleeding as diagnosed by colonoscopy. The c2 test and unpaired t test were used to compare the pretreatment and treatment characteristics between the two gland volume groups. Biochemical failure was defined as a PSA value $2.0 ng/mL above the postimplant nadir, consistent with the American Society for Radiation Oncology Phoenix consensus definition (9). A PSA bounce was defined as any PSA rise O0.2 ng/mL above the posttreatment nadir PSA with a subsequent PSA value that was equal to or lower than the initial posttreatment nadir PSA. KaplaneMeier analysis was performed to calculate bRFS and rates of late toxicity. Log-rank tests were performed to determine if there were significant differences
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among the survival curves for the two gland volume groups. Univariate and multivariable analyses were performed with Cox proportional hazards regression to identify factors predicting for bRFS and late GU or GI toxicity. A backward stepwise selection method was used for constructing the multivariable model. In addition to prostate volume, these additional factors were examined to see whether they had an effect on bRFS: patient age, race, risk group, clinical stage, iPSA (initial PSA), biopsy Gleason score, and postimplant dosimetric values. The following factors were examined to see whether they had an effect on late GU or GI toxicity: prostate volume, patient age, race, risk group, and postimplant dosimetric values.
Results Of the 2076 patients analyzed, 1807 (87%) patients had prostate volume #60 cc (median, 33.5 cc; range, 9.7e 59.9 cc), whereas 269 (13%) patients had prostate volume O60 cc (median, 72.5 cc; range, 60.01e178.9 cc). Patient characteristics are summarized in Table 1. Notably, patients with glands O60 cc had comparable low- and intermediaterisk disease but more Gleason 6 disease and higher iPSA compared with patients with glands #60 cc. Median followup for all patients, prostate volume #60 cc, and prostate volume O60 cc were 55 months (range, 12e198 months), 55 months (range, 12e198 months), and 55 months (range, 13e180 months), respectively. The overall 5-year bRFS rate was 93.4% for all patients. Men with prostate volume O60 cc had a 5-year bRFS of 96.7% (95% confidence interval [CI]: 94.4%, 98.9%) which was significantly better than for men with prostate volume #60 cc who had a 5-year bRFS of 92.9% (95% CI: 91.4%, 94.3%), p 5 0.02. The 8-year bRFS rate for all patients, prostate volume O60 cc, and prostate volume #60 cc were 86.9% (95% CI: 84.5%, 89.2%), 92.4% (95% CI: 87.1%, 97.7%), and 86% (95% CI: 83.4%, 88.6%), respectively. The 10-year bRFS for all patients, prostate volume O60 cc, and prostate volume #60 cc were 83% (95% CI: 79.6%, 86.4%), 92.4% (95% CI: 87.1%, 97.7%), and 81.5% (95% CI: 77.6%, 85.3%), respectively. Figure 1 shows the bRFS rates over time by prostate size. On univariate analysis, factors that predicted for improved bRFS were larger prostate volume as a continuous variable; prostate volume O60 cc; increasing prostate length, width, and height; low risk disease; biopsy Gleason score of 6; lower iPSA; and greater V100, V150, and V200 (volume of the prostate receiving 100%, 150%, and 200% of prescribed dose, respectively) (Table 2). On multivariable analysis, the only factors that remained predictive for improved bRFS were prostate volume O60 cc, lower iPSA, and Gleason score of 6 (Table 3).
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Table 1 Patient characteristics All patients (n 5 2076) Characteristic
Median or number (range or %)
Age (y) #65 O65 Race African American NoneAfrican American iPSA Median (ng/mL) !4 ng/mL 4e10 ng/mL O10e20 ng/mL Biopsy Gleason score 6 7 Clinical T stage T1eT2a T2beT2c Risk group Low Intermediate Prostate volume (cc) Prostate length (cm) Prostate width (cm) Prostate height (cm) Needles used Seed activity (U) Seeds inserted D90 (Gy) D100 (Gy) V100 (%) V150 (%) V200 (%) R100 (cc) PSA followup (mo) PSA measurements Overall followup (mo)
66 (41e86) 942 (45) 1134 (55)
Prostate volume #60 cc (n 5 1807)
Prostate volume O60 cc (n 5 269) p-value
66 (41e85) 851 (47) 956 (53)
69 (51e86) 91 (34) 178 (66)
!0.0001
0.4447 310 (15) 1766 (85)
274 (15) 1533 (85)
36 (13) 233 (87)
5.8 282 1624 170
5.6 267 1415 125
6.6 15 209 45
!0.0001 (0.18e20) (14) (78) (8)
(0.18e20) (15) (78) (7)
(2.1e19.6) (5) (78) (17) !0.0001
1375 (66) 701 (34)
1158 (64) 649 (36)
217 (81) 52 (19)
2049 (99) 27 (1)
1783 (99) 24 (1)
266 (99) 3 (1)
1234 842 35.6 4.4 4.9 3.2 28 0.436 100 146.3 91.0 91.0 46.7 19.6 0.05 52 7 55
1061 746 33.5 4.3 4.8 3.2 28 0.435 96 146.1 91.5 91.0 46.2 19.3 0.05 51 7 55
0.7737
0.0812 (59) (41) (9.7e178.9) (2.2e8.0) (2.0e7.7) (1.6e7.5) (6e54) (0.216e0.604) (44e324) (35.9e262.3) (15.0e171.1) (16.5e100.0) (5.0e97.1) (2.3e84.6) (0e3.7) (12e198) (3e41) (12e198)
(58) (41) (9.7e59.9) (2.2e6.4) (2.0e6.6) (1.6e5.8) (6e50) (0.216e0.604) (44e166) (35.9e262.3) (15.0e171.1) (16.5e100.0) (5.0e97.1) (2.3e84.6) (0e3.7) (12e198) (3e41) (12e198)
173 96 72.5 5.8 6.0 4.2 36 0.440 150 148.4 87.7 91.6 49.3 20.5 0.09 53 8 55
(64) (36) (60.01e178.9) (4.4e8.0) (4.0e7.7) (3.1e7.5) (24e54) (0.355e0.531) (100e324) (88.7e226.6) (36.2e141.7) (39.4e100.0) (18.2e93.0) (6.5e59.9) (0e3.7) (12e180) (3e27) (13e180)
!0.0001 !0.0001 !0.0001 !0.0001 !0.0001 0.5806 !0.0001 0.0861 0.0336 0.0786 0.0004 0.0093 0.0001 0.3784 0.7148 0.3280
PSA 5 prostate-specific antigen; iPSA 5 initial prostate-specific antigen; D90, D100 5 minimal dose received by 90% and 100% of gland, respectively; V100, V150, V200 5 percentage of prostate volume receiving 100%, 150%, and 200% of prescribed dose, respectively; R100 5 volume of rectum receiving 100% of prescribed dose. Bolded values represent statistically significant p-values !0.05.
For late Grade 3e4 GU and GI toxicities, patients with prostates O60 cc had significantly higher rates of Grade 3e4 late GU toxicity at 5 years (7.2%) than patients with prostates #60 cc (3.2%) ( p 5 0.0007) (Table 4). The 8-year rate of Grade 3e4 late GU toxicity for prostates O60 cc and prostates #60 cc was 11.3% and 5.1%, respectively; at 10 years, the rates were 11.3% and 6.2%, respectively. Figure 2 shows the cumulative rates of late GU toxicities over time as a function of prostate size. Approximately 97% of our patients with late Grade 3e4 GU toxicities were scored as Grade 3 per our modified Common Terminology Criteria for Adverse Events 4.0 scale and required interventions such as transurethral resection of the prostates, prostate laser surgeries, cystoscopies with
dilation, and cauterization. There were 2 patients who were scored as Grade 4 late GU toxicity after developing biopsyproven sarcomatoid carcinomas of the bladder and prostate 8 and 10 years after PPB; these patients required cystoprostatectomies and ileal conduit diversions. There were no Grade 5 late GU toxicities. On univariate analysis, factors that predicted for late Grade 3e4 GU toxicities were prostate volume O60 cc; larger prostate volume as a continuous variable; age O65 years; increasing age; and increasing prostate length, width, and height (Table 5). On multivariable analysis, prostate volume O60 cc and age O65 years remained predictive for late Grade 3e4 GU toxicity (Table 6). We performed an additional multivariable analysis, taking into
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Table 3 Multivariable analysis: factors predicting for bRFS Variable
p-value
HR
95% CI
Volume (#60 cc vs. O60 cc) iPSA GS (7 vs. 6) V100 V150 V200
0.0114 !0.0001 0.0002 0.1565 0.5011 0.2204
2.249 1.132 1.919 0.986 1.011 0.972
1.200e4.217 1.079e1.187 1.361e2.710 0.968e1.005 0.979e1.044 0.929e1.017
bRFS 5 biochemical relapseefree survival; GS 5 Gleason score; HR 5 hazard ratio; CI 5 confidence interval; iPSA 5 initial prostatespecific antigen. Bolded values represent statistically significant p-values !0.05.
Fig. 1. Biochemical relapseefree survival by gland volume. bRFS 5 biochemical relapseefree survival.
account the three dimensions of volume, and found that greater prostate length (hazard ratio, 1.422; 95% CI, 1.063, 1.902; p 5 0.0176) and age O65 years (hazard ratio, 1.669; 95% CI, 1.065, 2.618; p 5 0.0254) were significantly associated with increased late Grade 3e4 GU toxicity, whereas width and height were not significant. There was no difference in late GI toxicity between the two groups ( p 5 0.45), and the 5-year rate of late Grade 3e4 GI toxicity for patients with prostates O60 cc was 0.4% vs. 0.7% for patients with prostates #60 cc (Table 4).
Discussion According to current ABS guidelines, prostate gland sizes O60 cc are a relative contraindication for PPB. In Table 2 Univariate analysis: factors predicting for bRFS Variable
p-value
HR
95% CI
Volume (#60 cc vs. O60 cc) Volume (continuous) Age (#65 vs. O65) Age (continuous) Race (AA vs. non-AA) Risk group (intermediate vs. low) Stage (T2BC vs. T1T2a) iPSA (continuous) BX GS (7 vs. 6) D90 (Gy) V100 V150 V200 Length (cm) Width (cm) Height (cm)
0.0202 0.0011 0.2470 0.2462 0.4529 !0.0001 0.2347 !0.0001 !0.0001 0.0610 0.0122 0.0122 0.0141 0.0046 0.0007 0.0195
2.070 0.983 1.208 0.987 1.176 2.009 2.000 1.108 1.988 0.993 0.984 0.987 0.978 0.742 0.687 0.710
1.120e3.824 0.972e0.993 0.877e1.662 0.965e1.009 0.770e1.794 1.453e2.778 0.637e6.289 1.057e1.161 1.420e2.786 0.987e1.000 0.972e0.996 0.976e0.997 0.961e0.996 0.604e0.912 0.553e0.853 0.532e0.946
AA 5 African-American; Bx GS 5 biopsy Gleason score; bRFS 5 biochemical relapseefree survival; HR 5 hazard ratio; CI 5 confidence interval; iPSA 5 initial prostate-specific antigen. Bolded values represent statistically significant p-values !0.05.
1998, Prestidge et al. (10) analyzed questionnaire responses from 35 brachytherapists and found that only 9% of the practitioners would perform PPB for gland sizes O60 cc; this article concluded that PPB should be reserved for gland sizes !60 cc. One reason to explain the preclusion of PPB for larger gland volumes is the possibility of pubic arch interference which may make PPB technically more challenging for practitioners. Numerous techniques have been described to overcome pubic arch interference including (1) prostate downsizing with androgen deprivation therapy or 5-alpha reductase inhibitors, (2) using higher activity seeds, (3) making intraoperative modifications such as placement into an extended lithotomy position, (4) manipulating the needle tip to deflect toward the area of interest, using free-hand needle placement (11), angling the probe tip anteriorly, and (5) using a ‘‘two-phase’’ technique to help place anterior peripheral needles without sacrificing dose distribution (3). As techniques have improved, attitudes toward implanting larger glands have begun to change. In 2010, Buyyounouski et al. (12) sent out an updated survey modeled after that of Prestidge et al.(10) to 65 brachytherapy practitioners and found that 25% of practitioners would implant glands O60 cc vs. only 9% in 1998, suggesting that more practitioners are becoming comfortable with implanting larger glands. The present analysis represents among the largest published experience to date with 2076 patients who underwent PPB with 125I. The main finding of this study is that patients with prostate glands O60 cc have improved bRFS compared with glands #60 cc. This is consistent with our previously published findings (4). Patients with glands O60 cc had more Gleason 6 disease compared with glands #60 cc, and our multivariable analysis shows that both larger gland size and Gleason 6 disease remained independently predictive of improved bRFS. In regard to toxicity, our current analysis reveals that 5-year grade $3 late GU toxicities were significantly increased for larger glands compared with smaller glands (7.2% vs. 3.2%; p 5 0.0007). It has been suggested that implanting larger glands may result in the possibility of suboptimal postimplant dosimetry given the need to place seeds more medially which may lead to increasing urethral
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Table 4 Late GU and GI toxicity by prostate volume Late toxicity
All patients
Volume #60 cc
Volume O60 cc
p-value
5-Year late GU toxicity 5-Year late GI toxicity
3.7% (95% CI: 2.8e4.6%) 0.7% (95% CI: 0.3e1.1%)
3.2% (95% CI: 2.3e4.1%) 0.7% (95% CI: 0.3e1.1%)
7.2% (95% CI: 4.0e10.4%) 0.4% (95% CI: 0.0e1.1%)
0.0007 0.45
GU 5 genitourinary; GI 5 gastrointestinal; CI 5 confidence interval. Bolded values represent statistically significant p-values !0.05.
doses. Stone and Stock (13) showed that prostate glands $50 cc had safe urethral postimplant dosimetric values. Despite this, several studies have reported increased acute risks of urinary retention and obstructive symptoms after PPB for larger glands (14e19). The rates of late grade $3 GU toxicities found in our analysis are similar to those published in other large series of prostate brachytherapy (20e24). It is also interesting to note how the rates of GU toxicity in our analysis compare to the rates within the general population. Jacobsen et al. (25) found the incidence of acute urinary retention to be 6.8/1000 personyears within a cohort of 2115 men ages 40e79 years who were randomly selected from a Minnesota population. The rate of procedural interventions in the general population that would have qualified as a late Grade 3 GU toxicity within our assessment is approximately 0.28% for males ages 50e79 years within the United States or approximately 277 procedures per 100,000 men (26,27). Given these baseline rates of procedural interventions for the general population, this suggests that our subset of large gland patients likely would have required an intervention whether they had received PPB. Despite hypothetical concerns of unfavorable postimplant dosimetry, we did not identify any dosimetric parameters that correlated with late GU toxicity likely because of the relatively uniform method of treatment planning for our cohort of patients. In regard to late GI toxicities, our study found no differences in the rate of late GI toxicities which suggests that implantation of large glands is safe in this regard.
The limitations of our study include the lack of an acute toxicity assessment and absence of patient-reported outcomes; however, we have previously published our acute toxicity rates and baseline urinary function scores (28,29). We also did not report on late Grade 1 or 2 toxicities due to subjectivity in this assessment compared with smaller glands. There is an increasing body of literature revealing that larger glands may achieve better bRFS outcomes compared with smaller glands (4,5). One possible explanation for why patients with larger glands may have better bRFS outcomes compared with smaller glands is that larger glands often have benign prostatic hyperplasia with an associated increase in serum PSA; thus, patients are more likely to undergo biopsies with an earlier diagnosis of a small and/or indolent prostate cancer. Patients may also have a lower disease density compared with patients with smaller glands, but this is difficult to prove because a pathologic specimen of the whole prostate cannot be acquired. Another explanation is the possible presence of paracrine signals that may regulate benign prostatic hyperplasia and coexisting malignant cells for larger glands (5,30). Finally, all patients in this series were treated by experienced prostate brachytherapists at a tertiary referral center, and so, our results may not be generalizable to a broader community practice setting. In summary, PPB is feasible for men with prostate glands larger than 60 cc, with improved biochemical control but also higher rates of grade $3 late GU toxicity. Our data suggests that prostate size alone should not be a contraindication to PPB. Table 5 Univariate analysis: factors predicting for late Grade 3e4 GU toxicity Variable
p-value
HR
Volume (O60 cc vs. #60 cc) 0.0010 2.208 Volume (continuous) 0.0001 1.015 Length (cm) !0.0001 1.522 Width (cm) 0.0152 1.403 Height (cm) 0.0039 1.534 Age (O65 vs. #65) 0.0085 1.815 Age (continuous) 0.0003 1.059 Race (AA vs. non-AA) 0.1720 0.619 Risk group (intermediate vs. low) 0.6313 1.110 D90 (Gy) 0.9235 1.000 0.7010 0.996 V100 (%) V150 (%) 0.5122 1.004 V200 (%) 0.9448 1.001 Activity (U) 0.1438 116.118 Fig. 2. Late Grade $3 GU toxicity by gland volume. GU 5 genitourinary.
95% CI 1.377e3.534 1.008e1.023 1.236e1.875 1.067e1.845 1.147e2.052 1.164e2.833 1.027e1.093 0.311e1.232 0.725e1.698 0.991e1.008 0.977e1.015 0.991e1.018 0.981e1.021 0.198e68226.805
AA 5 African-American; GU 5 genitourinary; HR 5 hazard ratio; CI 5 confidence interval. Bolded values represent statistically significant p-values !0.05.
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Table 6 Multivariable analysis: factors predicting for late Grade 3e4 GU toxicity Variable
p-value
HR
95% CI
Volume (O60 cc vs. #60 cc) Age (O65 vs. #65)
0.0029 0.0190
2.058 1.709
1.279e3.311 1.092e2.674
GU 5 genitourinary; HR 5 hazard ratio; CI 5 confidence interval. Bolded values represent statistically significant p-values !0.05.
Conclusions We have provided long-term data on biochemical disease control and GU/GI toxicity outcomes for a large series of patients treated by experienced brachytherapists at a tertiary referral center. Our data suggest that use of PPB for patients with larger prostate glands results in better bRFS compared with patients with smaller glands. This improvement in bRFS must be weighed against an increased risk of late Grade 3 or higher GU toxicity. References [1] Davis BJ, Horwitz EM, Lee WR, et al. American Brachytherapy Society consensus guidelines for transrectal ultrasound-guided permanent prostate brachytherapy. Brachytherapy 2012;11:6e19. [2] Yamoah K, Eldredge-Hindy HB, Zaorsky NG, et al. Large prostate gland size is not a contraindication to low-dose-rate brachytherapy for prostate adenocarcinoma. Brachytherapy 2014;13:456e464. [3] Stone NN, Stock RG. Prostate brachytherapy in men with gland volume of 100cc or greater: technique, cancer control, and morbidity. Brachytherapy 2013;12:217e221. [4] Quan AL, Ciezki JP, Reddy CA, et al. Improved biochemical relapsefree survival for patients with large/wide glands treated with prostate seed implantation for localized adenocarcinoma of prostate. Urology 2006;68:1237e1241. [5] Lehrer S, Stone NN, Stock RG. Prostate cancer in a large prostate is associated with a decreased prostate specific antigen failure rate after brachytherapy. J Urol 2005;173:79e81. [6] Mohler J, Bahnson RR, Boston B, et al. NCCN clinical practice guidelines in oncology: prostate cancer. J Natl Compr Canc Netw 2010;8:162e200. [7] Nag S, Bice W, DeWyngaert K, et al. The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 2000;46: 221e230. [8] National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 2010. Available at: http://evs.nci.nih. gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed May 2, 2014. [9] Roach M 3rd, Hanks G, Thames H Jr, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965e974. [10] Prestidge BR, Prete JJ, Buchholz TA, et al. A survey of current clinical practice of permanent prostate brachytherapy in the United States. Int J Radiat Oncol Biol Phys 1998;40:461e465. [11] Gibbons EP, Smith RP, Beriwal S, et al. Overcoming pubic arch interference with free-hand needle placement in men undergoing prostate brachytherapy. Brachytherapy 2009;8:74e78. [12] Buyyounouski MK, Davis BJ, Prestidge BR, et al. A survey of current clinical practice in permanent and temporary prostate brachytherapy: 2010 update. Brachytherapy 2012;11:299e305.
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[13] Stone NN, Stock RG. Prostate brachytherapy in patients with prostate volumes $50 cm(3): dosimetric analysis of implant quality. Int J Radiat Oncol Biol Phys 2000;46:1199e1204. [14] Petit JH, Gluck C, Kiger WS 3rd, et al. Androgen deprivationmediated cytoreduction before interstitial brachytherapy for prostate cancer does not abrogate the elevated risk of urinary morbidity associated with larger initial prostate volume. Brachytherapy 2007;6: 267e271. [15] Crook J, McLean M, Catton C, et al. Factors influencing risk of acute urinary retention after TRUS-guided permanent prostate seed implantation. Int J Radiat Oncol Biol Phys 2002;52:453e460. [16] Elshaikh MA, Angermeier K, Ulchaker JC, et al. Effect of anatomic, procedural, and dosimetric variables on urinary retention after permanent iodine-125 prostate brachytherapy. Urology 2003; 61:152e155. [17] Lee N, Wuu CS, Brody R, et al. Factors predicting for postimplantation urinary retention after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000;48:1457e1460. [18] Martens C, Pond G, Webster D, et al. Relationship of the International Prostate Symptom score with urinary flow studies, and catheterization rates following 125I prostate brachytherapy. Brachytherapy 2006;5:9e13. [19] Schwartz DJ, Schild SE, Wong WW, Vora SA. Factors associated with the frequency of self-intermittent catheterization after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2005;61: 60e63. [20] Zelefsky MJ, Yamada Y, Cohen GN, et al. Five-year outcome of intraoperative conformal permanent I-125 interstitial implantation for patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2007;67:65e70. [21] Keyes M, Miller S, Moravan V, et al. Predictive factors for acute and late urinary toxicity after permanent prostate brachytherapy: longterm outcome in 712 consecutive patients. Int J Radiat Oncol Biol Phys 2009;73:1023e1032. [22] Crook J, Fleshner N, Roberts C, Pond G. Long-term urinary sequelae following 125iodine prostate brachytherapy. J Urol 2008;179:141e 145. discussion 146. [23] Brown D, Colonias A, Miller R, et al. Urinary morbidity with a modified peripheral loading technique of transperineal (125)i prostate implantation. Int J Radiat Oncol Biol Phys 2000;47: 353e360. [24] Niehaus A, Merrick GS, Butler WM, et al. The influence of isotope and prostate volume on urinary morbidity after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2006;64:136e143. [25] Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997; 158:481e487. [26] Wei JT, Calhoun E, Jacobsen SJ. Urologic diseases in America project: benign prostatic hyperplasia. J Urol 2005;173:1256e 1261. [27] Howden LM, Meyer JA. Age and sex composition: 2010. Washington D.C.: 2010 Census Briefs, US Department of Commerce, Economics and Statistics Administration. US CENSUS BUREAU; 2010. [28] Elshaikh MA, Ulchaker JC, Reddy CA, et al. Prophylactic tamsulosin (Flomax) in patients undergoing prostate 125I brachytherapy for prostate carcinoma: final report of a double-blind placebocontrolled randomized study. Int J Radiat Oncol Biol Phys 2005; 62:164e169. [29] Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358:1250e1261. [30] D’Amico AV, Whittington R, Malkowicz SB, et al. A prostate gland volume of more than 75 cm3 predicts for a favorable outcome after radical prostatectomy for localized prostate cancer. Urology 1998; 52:631e636.
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Outcomes for prostate glands O60 cc treated with low-dose-rate brachytherapy Yvonne D. Pham1, Jeffrey A. Kittel1, Chandana A. Reddy1, Jay P. Ciezki1, Eric A. Klein2, Kevin L. Stephans1, Rahul D. Tendulkar1,* 1 Department of Radiation Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH Department of Urology, Cleveland Clinic Glickman Urological and Kidney Institute, Cleveland, OH
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ABSTRACT
PURPOSE: We sought to analyze whether outcomes of biochemical relapseefree survival (bRFS), late genitourinary (GU), and late gastrointestinal toxicity are different for prostate cancer patients with small (#60 cc) vs. large (O60 cc) prostates following low dose-rate brachytherapy. METHODS AND MATERIALS: The bRFS outcomes for 2076 low- or intermediate-risk prostate cancer patients from 1996 to 2012 were determined from a review of a prospectively maintained database. All patients were treated with 125I monotherapy without androgen deprivation therapy. Biochemical failure was defined per the Phoenix definition. Patient-related factors and dosimetric values were examined in Cox regression analyses for bRFS and late toxicity. Late toxicity was scored according to a modified Common Terminology Criteria for Adverse Events version 4.0 scale. RESULTS: The median followup for all patients was 55 months. The 5-year bRFS rates for all patients, prostates O60 cc, and prostates #60 cc were 93.4% (95% confidence interval [CI]: 92.1%, 94.7%), 96.7% (95% CI: 94.4%, 98.9%), and 92.9% (95% CI: 91.4%, 94.3%), respectively. On multivariable analysis, prostate size O60 cc was significantly associated with improved bRFS ( p 5 0.01), as were initial prostate-specific antigen and biopsy Gleason score ( p ! 0.0001 and p 5 0.0002, respectively). Patients with prostates O60 cc had significantly higher rates of Grade 3e4 late GU toxicity at 5 years than patients with smaller prostates; 7.2% (95% CI: 4.0%, 10.4%) and 3.2% (95% CI: 2.3%, 4.1%), respectively ( p 5 0.0007). The overall late gastrointestinal toxicity rate for all patients was 0.7% at 5 years with no significant difference between the two groups. CONCLUSIONS: Implantation of large prostates O60 cc results in favorable bRFS outcomes and is associated with increased but acceptable rates of Grade 3 and higher late GU toxicities. Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Prostate cancer; Large; Gland; Volume; Biochemical relapseefree survival; Low dose-rate brachytherapy
Introduction The American Brachytherapy Society (ABS) Consensus guidelines for permanent prostate brachytherapy (PPB) (1) state that prostate volume larger than 60 cc is a relative contraindication to brachytherapy due to possible pubic arch interference and technical challenges that may affect
Received 5 November 2015; received in revised form 3 December 2015; accepted 8 December 2015. * Corresponding author. Department of Radiation Oncology (T28), Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Tel.: þ1-216-445-9869; fax: þ1-216-445-1068. E-mail address: [email protected] (R.D. Tendulkar).
the overall efficacy of the intervention. As such, patients with larger prostates may be at higher risk for complications and toxicities. However, in experienced hands, there may be no differences in clinical outcomes in terms of biochemical relapseefree survival (bRFS) (2,3) based on gland size, and some have actually reported improved outcomes for larger glands (4,5). We previously reported our institutional outcomes for 390 patients (4) revealing that large gland volume and width predicted for better bRFS on multivariable analysis. This present study is an updated analysis with a larger cohort of 2076 patients who underwent low-dose-rate PPB with 125I at our high-volume tertiary care institution regarding outcomes of bRFS and late genitourinary (GU)
1538-4721/$ - see front matter Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2015.12.002
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and gastrointestinal (GI) toxicities for small (#60 cc) vs. large (O60 cc) prostate glands.
Methods and materials We identified 2076 patients with Stage T1eT2N M0 low- and intermediate-risk prostate cancer treated with PPB alone without androgen deprivation therapy from 1996 to 2012 from a prospectively maintained and institutional review boardeapproved database. We included only low- and intermediate-risk cancer patients as determined by the National Comprehensive Cancer Network guidelines (6). Low risk patients had Gleason score #6, prostatespecific antigen (PSA) !10 ng/mL, and clinical tumor classification T1eT2a. Intermediate-risk patients had Gleason score 7, or PSA 10e20 ng/mL, or clinical tumor classification T2b-T2c. All patients had a minimum of three posttreatment PSA values and at least 1 year of followup. All treatment-related and dosimetric assessments were performed according to the ABS guidelines (1) and postimplant dosimetric analysis (7). All patients underwent PPB using 125I with a planned dose of 144 Gy to the prostate planning treatment volume. Prostate gland volume was measured at the time of implant using a transrectal ultrasound in the lithotomy position under general anesthesia. Real-time intraoperative planning was done using a peripheral loading technique to limit the central prostate to !150% of the prescription dose. Postimplant computed tomographye based dosimetry was performed approximately 4 weeks after implantation. Toxicity was recorded after review of visit and procedure notes from electronic charts and via communication from patients and referring physicians. Late toxicity was defined as occurring O6 months after PPB and was scored according to a modified Common Terminology Criteria for Adverse Events 4.0 scale (8) as follows: Grade 1, asymptomatic/mild symptoms; Grade 2, managed medically or observed; Grade 3, requiring procedural intervention (e.g., transurethral resection of the prostate); Grade 4, life threatening; and Grade 5, resulting in death. We distinguished between PPB-related rectal bleeding vs. other etiologies of rectal bleeding as diagnosed by colonoscopy. The c2 test and unpaired t test were used to compare the pretreatment and treatment characteristics between the two gland volume groups. Biochemical failure was defined as a PSA value $2.0 ng/mL above the postimplant nadir, consistent with the American Society for Radiation Oncology Phoenix consensus definition (9). A PSA bounce was defined as any PSA rise O0.2 ng/mL above the posttreatment nadir PSA with a subsequent PSA value that was equal to or lower than the initial posttreatment nadir PSA. KaplaneMeier analysis was performed to calculate bRFS and rates of late toxicity. Log-rank tests were performed to determine if there were significant differences
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among the survival curves for the two gland volume groups. Univariate and multivariable analyses were performed with Cox proportional hazards regression to identify factors predicting for bRFS and late GU or GI toxicity. A backward stepwise selection method was used for constructing the multivariable model. In addition to prostate volume, these additional factors were examined to see whether they had an effect on bRFS: patient age, race, risk group, clinical stage, iPSA (initial PSA), biopsy Gleason score, and postimplant dosimetric values. The following factors were examined to see whether they had an effect on late GU or GI toxicity: prostate volume, patient age, race, risk group, and postimplant dosimetric values.
Results Of the 2076 patients analyzed, 1807 (87%) patients had prostate volume #60 cc (median, 33.5 cc; range, 9.7e 59.9 cc), whereas 269 (13%) patients had prostate volume O60 cc (median, 72.5 cc; range, 60.01e178.9 cc). Patient characteristics are summarized in Table 1. Notably, patients with glands O60 cc had comparable low- and intermediaterisk disease but more Gleason 6 disease and higher iPSA compared with patients with glands #60 cc. Median followup for all patients, prostate volume #60 cc, and prostate volume O60 cc were 55 months (range, 12e198 months), 55 months (range, 12e198 months), and 55 months (range, 13e180 months), respectively. The overall 5-year bRFS rate was 93.4% for all patients. Men with prostate volume O60 cc had a 5-year bRFS of 96.7% (95% confidence interval [CI]: 94.4%, 98.9%) which was significantly better than for men with prostate volume #60 cc who had a 5-year bRFS of 92.9% (95% CI: 91.4%, 94.3%), p 5 0.02. The 8-year bRFS rate for all patients, prostate volume O60 cc, and prostate volume #60 cc were 86.9% (95% CI: 84.5%, 89.2%), 92.4% (95% CI: 87.1%, 97.7%), and 86% (95% CI: 83.4%, 88.6%), respectively. The 10-year bRFS for all patients, prostate volume O60 cc, and prostate volume #60 cc were 83% (95% CI: 79.6%, 86.4%), 92.4% (95% CI: 87.1%, 97.7%), and 81.5% (95% CI: 77.6%, 85.3%), respectively. Figure 1 shows the bRFS rates over time by prostate size. On univariate analysis, factors that predicted for improved bRFS were larger prostate volume as a continuous variable; prostate volume O60 cc; increasing prostate length, width, and height; low risk disease; biopsy Gleason score of 6; lower iPSA; and greater V100, V150, and V200 (volume of the prostate receiving 100%, 150%, and 200% of prescribed dose, respectively) (Table 2). On multivariable analysis, the only factors that remained predictive for improved bRFS were prostate volume O60 cc, lower iPSA, and Gleason score of 6 (Table 3).
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Table 1 Patient characteristics All patients (n 5 2076) Characteristic
Median or number (range or %)
Age (y) #65 O65 Race African American NoneAfrican American iPSA Median (ng/mL) !4 ng/mL 4e10 ng/mL O10e20 ng/mL Biopsy Gleason score 6 7 Clinical T stage T1eT2a T2beT2c Risk group Low Intermediate Prostate volume (cc) Prostate length (cm) Prostate width (cm) Prostate height (cm) Needles used Seed activity (U) Seeds inserted D90 (Gy) D100 (Gy) V100 (%) V150 (%) V200 (%) R100 (cc) PSA followup (mo) PSA measurements Overall followup (mo)
66 (41e86) 942 (45) 1134 (55)
Prostate volume #60 cc (n 5 1807)
Prostate volume O60 cc (n 5 269) p-value
66 (41e85) 851 (47) 956 (53)
69 (51e86) 91 (34) 178 (66)
!0.0001
0.4447 310 (15) 1766 (85)
274 (15) 1533 (85)
36 (13) 233 (87)
5.8 282 1624 170
5.6 267 1415 125
6.6 15 209 45
!0.0001 (0.18e20) (14) (78) (8)
(0.18e20) (15) (78) (7)
(2.1e19.6) (5) (78) (17) !0.0001
1375 (66) 701 (34)
1158 (64) 649 (36)
217 (81) 52 (19)
2049 (99) 27 (1)
1783 (99) 24 (1)
266 (99) 3 (1)
1234 842 35.6 4.4 4.9 3.2 28 0.436 100 146.3 91.0 91.0 46.7 19.6 0.05 52 7 55
1061 746 33.5 4.3 4.8 3.2 28 0.435 96 146.1 91.5 91.0 46.2 19.3 0.05 51 7 55
0.7737
0.0812 (59) (41) (9.7e178.9) (2.2e8.0) (2.0e7.7) (1.6e7.5) (6e54) (0.216e0.604) (44e324) (35.9e262.3) (15.0e171.1) (16.5e100.0) (5.0e97.1) (2.3e84.6) (0e3.7) (12e198) (3e41) (12e198)
(58) (41) (9.7e59.9) (2.2e6.4) (2.0e6.6) (1.6e5.8) (6e50) (0.216e0.604) (44e166) (35.9e262.3) (15.0e171.1) (16.5e100.0) (5.0e97.1) (2.3e84.6) (0e3.7) (12e198) (3e41) (12e198)
173 96 72.5 5.8 6.0 4.2 36 0.440 150 148.4 87.7 91.6 49.3 20.5 0.09 53 8 55
(64) (36) (60.01e178.9) (4.4e8.0) (4.0e7.7) (3.1e7.5) (24e54) (0.355e0.531) (100e324) (88.7e226.6) (36.2e141.7) (39.4e100.0) (18.2e93.0) (6.5e59.9) (0e3.7) (12e180) (3e27) (13e180)
!0.0001 !0.0001 !0.0001 !0.0001 !0.0001 0.5806 !0.0001 0.0861 0.0336 0.0786 0.0004 0.0093 0.0001 0.3784 0.7148 0.3280
PSA 5 prostate-specific antigen; iPSA 5 initial prostate-specific antigen; D90, D100 5 minimal dose received by 90% and 100% of gland, respectively; V100, V150, V200 5 percentage of prostate volume receiving 100%, 150%, and 200% of prescribed dose, respectively; R100 5 volume of rectum receiving 100% of prescribed dose. Bolded values represent statistically significant p-values !0.05.
For late Grade 3e4 GU and GI toxicities, patients with prostates O60 cc had significantly higher rates of Grade 3e4 late GU toxicity at 5 years (7.2%) than patients with prostates #60 cc (3.2%) ( p 5 0.0007) (Table 4). The 8-year rate of Grade 3e4 late GU toxicity for prostates O60 cc and prostates #60 cc was 11.3% and 5.1%, respectively; at 10 years, the rates were 11.3% and 6.2%, respectively. Figure 2 shows the cumulative rates of late GU toxicities over time as a function of prostate size. Approximately 97% of our patients with late Grade 3e4 GU toxicities were scored as Grade 3 per our modified Common Terminology Criteria for Adverse Events 4.0 scale and required interventions such as transurethral resection of the prostates, prostate laser surgeries, cystoscopies with
dilation, and cauterization. There were 2 patients who were scored as Grade 4 late GU toxicity after developing biopsyproven sarcomatoid carcinomas of the bladder and prostate 8 and 10 years after PPB; these patients required cystoprostatectomies and ileal conduit diversions. There were no Grade 5 late GU toxicities. On univariate analysis, factors that predicted for late Grade 3e4 GU toxicities were prostate volume O60 cc; larger prostate volume as a continuous variable; age O65 years; increasing age; and increasing prostate length, width, and height (Table 5). On multivariable analysis, prostate volume O60 cc and age O65 years remained predictive for late Grade 3e4 GU toxicity (Table 6). We performed an additional multivariable analysis, taking into
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Table 3 Multivariable analysis: factors predicting for bRFS Variable
p-value
HR
95% CI
Volume (#60 cc vs. O60 cc) iPSA GS (7 vs. 6) V100 V150 V200
0.0114 !0.0001 0.0002 0.1565 0.5011 0.2204
2.249 1.132 1.919 0.986 1.011 0.972
1.200e4.217 1.079e1.187 1.361e2.710 0.968e1.005 0.979e1.044 0.929e1.017
bRFS 5 biochemical relapseefree survival; GS 5 Gleason score; HR 5 hazard ratio; CI 5 confidence interval; iPSA 5 initial prostatespecific antigen. Bolded values represent statistically significant p-values !0.05.
Fig. 1. Biochemical relapseefree survival by gland volume. bRFS 5 biochemical relapseefree survival.
account the three dimensions of volume, and found that greater prostate length (hazard ratio, 1.422; 95% CI, 1.063, 1.902; p 5 0.0176) and age O65 years (hazard ratio, 1.669; 95% CI, 1.065, 2.618; p 5 0.0254) were significantly associated with increased late Grade 3e4 GU toxicity, whereas width and height were not significant. There was no difference in late GI toxicity between the two groups ( p 5 0.45), and the 5-year rate of late Grade 3e4 GI toxicity for patients with prostates O60 cc was 0.4% vs. 0.7% for patients with prostates #60 cc (Table 4).
Discussion According to current ABS guidelines, prostate gland sizes O60 cc are a relative contraindication for PPB. In Table 2 Univariate analysis: factors predicting for bRFS Variable
p-value
HR
95% CI
Volume (#60 cc vs. O60 cc) Volume (continuous) Age (#65 vs. O65) Age (continuous) Race (AA vs. non-AA) Risk group (intermediate vs. low) Stage (T2BC vs. T1T2a) iPSA (continuous) BX GS (7 vs. 6) D90 (Gy) V100 V150 V200 Length (cm) Width (cm) Height (cm)
0.0202 0.0011 0.2470 0.2462 0.4529 !0.0001 0.2347 !0.0001 !0.0001 0.0610 0.0122 0.0122 0.0141 0.0046 0.0007 0.0195
2.070 0.983 1.208 0.987 1.176 2.009 2.000 1.108 1.988 0.993 0.984 0.987 0.978 0.742 0.687 0.710
1.120e3.824 0.972e0.993 0.877e1.662 0.965e1.009 0.770e1.794 1.453e2.778 0.637e6.289 1.057e1.161 1.420e2.786 0.987e1.000 0.972e0.996 0.976e0.997 0.961e0.996 0.604e0.912 0.553e0.853 0.532e0.946
AA 5 African-American; Bx GS 5 biopsy Gleason score; bRFS 5 biochemical relapseefree survival; HR 5 hazard ratio; CI 5 confidence interval; iPSA 5 initial prostate-specific antigen. Bolded values represent statistically significant p-values !0.05.
1998, Prestidge et al. (10) analyzed questionnaire responses from 35 brachytherapists and found that only 9% of the practitioners would perform PPB for gland sizes O60 cc; this article concluded that PPB should be reserved for gland sizes !60 cc. One reason to explain the preclusion of PPB for larger gland volumes is the possibility of pubic arch interference which may make PPB technically more challenging for practitioners. Numerous techniques have been described to overcome pubic arch interference including (1) prostate downsizing with androgen deprivation therapy or 5-alpha reductase inhibitors, (2) using higher activity seeds, (3) making intraoperative modifications such as placement into an extended lithotomy position, (4) manipulating the needle tip to deflect toward the area of interest, using free-hand needle placement (11), angling the probe tip anteriorly, and (5) using a ‘‘two-phase’’ technique to help place anterior peripheral needles without sacrificing dose distribution (3). As techniques have improved, attitudes toward implanting larger glands have begun to change. In 2010, Buyyounouski et al. (12) sent out an updated survey modeled after that of Prestidge et al.(10) to 65 brachytherapy practitioners and found that 25% of practitioners would implant glands O60 cc vs. only 9% in 1998, suggesting that more practitioners are becoming comfortable with implanting larger glands. The present analysis represents among the largest published experience to date with 2076 patients who underwent PPB with 125I. The main finding of this study is that patients with prostate glands O60 cc have improved bRFS compared with glands #60 cc. This is consistent with our previously published findings (4). Patients with glands O60 cc had more Gleason 6 disease compared with glands #60 cc, and our multivariable analysis shows that both larger gland size and Gleason 6 disease remained independently predictive of improved bRFS. In regard to toxicity, our current analysis reveals that 5-year grade $3 late GU toxicities were significantly increased for larger glands compared with smaller glands (7.2% vs. 3.2%; p 5 0.0007). It has been suggested that implanting larger glands may result in the possibility of suboptimal postimplant dosimetry given the need to place seeds more medially which may lead to increasing urethral
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Table 4 Late GU and GI toxicity by prostate volume Late toxicity
All patients
Volume #60 cc
Volume O60 cc
p-value
5-Year late GU toxicity 5-Year late GI toxicity
3.7% (95% CI: 2.8e4.6%) 0.7% (95% CI: 0.3e1.1%)
3.2% (95% CI: 2.3e4.1%) 0.7% (95% CI: 0.3e1.1%)
7.2% (95% CI: 4.0e10.4%) 0.4% (95% CI: 0.0e1.1%)
0.0007 0.45
GU 5 genitourinary; GI 5 gastrointestinal; CI 5 confidence interval. Bolded values represent statistically significant p-values !0.05.
doses. Stone and Stock (13) showed that prostate glands $50 cc had safe urethral postimplant dosimetric values. Despite this, several studies have reported increased acute risks of urinary retention and obstructive symptoms after PPB for larger glands (14e19). The rates of late grade $3 GU toxicities found in our analysis are similar to those published in other large series of prostate brachytherapy (20e24). It is also interesting to note how the rates of GU toxicity in our analysis compare to the rates within the general population. Jacobsen et al. (25) found the incidence of acute urinary retention to be 6.8/1000 personyears within a cohort of 2115 men ages 40e79 years who were randomly selected from a Minnesota population. The rate of procedural interventions in the general population that would have qualified as a late Grade 3 GU toxicity within our assessment is approximately 0.28% for males ages 50e79 years within the United States or approximately 277 procedures per 100,000 men (26,27). Given these baseline rates of procedural interventions for the general population, this suggests that our subset of large gland patients likely would have required an intervention whether they had received PPB. Despite hypothetical concerns of unfavorable postimplant dosimetry, we did not identify any dosimetric parameters that correlated with late GU toxicity likely because of the relatively uniform method of treatment planning for our cohort of patients. In regard to late GI toxicities, our study found no differences in the rate of late GI toxicities which suggests that implantation of large glands is safe in this regard.
The limitations of our study include the lack of an acute toxicity assessment and absence of patient-reported outcomes; however, we have previously published our acute toxicity rates and baseline urinary function scores (28,29). We also did not report on late Grade 1 or 2 toxicities due to subjectivity in this assessment compared with smaller glands. There is an increasing body of literature revealing that larger glands may achieve better bRFS outcomes compared with smaller glands (4,5). One possible explanation for why patients with larger glands may have better bRFS outcomes compared with smaller glands is that larger glands often have benign prostatic hyperplasia with an associated increase in serum PSA; thus, patients are more likely to undergo biopsies with an earlier diagnosis of a small and/or indolent prostate cancer. Patients may also have a lower disease density compared with patients with smaller glands, but this is difficult to prove because a pathologic specimen of the whole prostate cannot be acquired. Another explanation is the possible presence of paracrine signals that may regulate benign prostatic hyperplasia and coexisting malignant cells for larger glands (5,30). Finally, all patients in this series were treated by experienced prostate brachytherapists at a tertiary referral center, and so, our results may not be generalizable to a broader community practice setting. In summary, PPB is feasible for men with prostate glands larger than 60 cc, with improved biochemical control but also higher rates of grade $3 late GU toxicity. Our data suggests that prostate size alone should not be a contraindication to PPB. Table 5 Univariate analysis: factors predicting for late Grade 3e4 GU toxicity Variable
p-value
HR
Volume (O60 cc vs. #60 cc) 0.0010 2.208 Volume (continuous) 0.0001 1.015 Length (cm) !0.0001 1.522 Width (cm) 0.0152 1.403 Height (cm) 0.0039 1.534 Age (O65 vs. #65) 0.0085 1.815 Age (continuous) 0.0003 1.059 Race (AA vs. non-AA) 0.1720 0.619 Risk group (intermediate vs. low) 0.6313 1.110 D90 (Gy) 0.9235 1.000 0.7010 0.996 V100 (%) V150 (%) 0.5122 1.004 V200 (%) 0.9448 1.001 Activity (U) 0.1438 116.118 Fig. 2. Late Grade $3 GU toxicity by gland volume. GU 5 genitourinary.
95% CI 1.377e3.534 1.008e1.023 1.236e1.875 1.067e1.845 1.147e2.052 1.164e2.833 1.027e1.093 0.311e1.232 0.725e1.698 0.991e1.008 0.977e1.015 0.991e1.018 0.981e1.021 0.198e68226.805
AA 5 African-American; GU 5 genitourinary; HR 5 hazard ratio; CI 5 confidence interval. Bolded values represent statistically significant p-values !0.05.
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Table 6 Multivariable analysis: factors predicting for late Grade 3e4 GU toxicity Variable
p-value
HR
95% CI
Volume (O60 cc vs. #60 cc) Age (O65 vs. #65)
0.0029 0.0190
2.058 1.709
1.279e3.311 1.092e2.674
GU 5 genitourinary; HR 5 hazard ratio; CI 5 confidence interval. Bolded values represent statistically significant p-values !0.05.
Conclusions We have provided long-term data on biochemical disease control and GU/GI toxicity outcomes for a large series of patients treated by experienced brachytherapists at a tertiary referral center. Our data suggest that use of PPB for patients with larger prostate glands results in better bRFS compared with patients with smaller glands. This improvement in bRFS must be weighed against an increased risk of late Grade 3 or higher GU toxicity. References [1] Davis BJ, Horwitz EM, Lee WR, et al. American Brachytherapy Society consensus guidelines for transrectal ultrasound-guided permanent prostate brachytherapy. Brachytherapy 2012;11:6e19. [2] Yamoah K, Eldredge-Hindy HB, Zaorsky NG, et al. Large prostate gland size is not a contraindication to low-dose-rate brachytherapy for prostate adenocarcinoma. Brachytherapy 2014;13:456e464. [3] Stone NN, Stock RG. Prostate brachytherapy in men with gland volume of 100cc or greater: technique, cancer control, and morbidity. Brachytherapy 2013;12:217e221. [4] Quan AL, Ciezki JP, Reddy CA, et al. Improved biochemical relapsefree survival for patients with large/wide glands treated with prostate seed implantation for localized adenocarcinoma of prostate. Urology 2006;68:1237e1241. [5] Lehrer S, Stone NN, Stock RG. Prostate cancer in a large prostate is associated with a decreased prostate specific antigen failure rate after brachytherapy. J Urol 2005;173:79e81. [6] Mohler J, Bahnson RR, Boston B, et al. NCCN clinical practice guidelines in oncology: prostate cancer. J Natl Compr Canc Netw 2010;8:162e200. [7] Nag S, Bice W, DeWyngaert K, et al. The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 2000;46: 221e230. [8] National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 2010. Available at: http://evs.nci.nih. gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed May 2, 2014. [9] Roach M 3rd, Hanks G, Thames H Jr, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965e974. [10] Prestidge BR, Prete JJ, Buchholz TA, et al. A survey of current clinical practice of permanent prostate brachytherapy in the United States. Int J Radiat Oncol Biol Phys 1998;40:461e465. [11] Gibbons EP, Smith RP, Beriwal S, et al. Overcoming pubic arch interference with free-hand needle placement in men undergoing prostate brachytherapy. Brachytherapy 2009;8:74e78. [12] Buyyounouski MK, Davis BJ, Prestidge BR, et al. A survey of current clinical practice in permanent and temporary prostate brachytherapy: 2010 update. Brachytherapy 2012;11:299e305.
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