Long-Term Efficacy and Toxicity of Low-Dose-Rate 125I Prostate Brachytherapy as Monotherapy in Low-, Intermediate-, and High-Risk Prostate Cancer

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation

Long-Term Efficacy and Toxicity of Low-Dose-Rate 125 I Prostate Brachytherapy as Monotherapy in Low-, Intermediate-, and High-Risk Prostate Cancer Jeffrey A. Kittel, MD,* Chandana A. Reddy, MS,* Kristin L. Smith, BS,* Kevin L. Stephans, MD,* Rahul D. Tendulkar, MD,* James Ulchaker, MD,y Kenneth Angermeier, MD,y Steven Campbell, MD, PhD,y Andrew Stephenson, MD,y Eric A. Klein, MD,y D. Allan Wilkinson, PhD,* and Jay P. Ciezki, MD* *Department of Radiation Oncology, Cleveland Clinic Taussig Cancer Institute, and yDepartment of Urology, Cleveland Clinic Glickman Urological and Kidney Institute, Cleveland, Ohio Received Nov 18, 2014, and in revised form Feb 19, 2015. Accepted for publication Feb 25, 2015.

Summary This study analyzed a large cohort of prostate brachytherapy patients followed up prospectively since the beginning of brachytherapy treatment at our institution. Brachytherapy was performed without external beam radiation. Our cohort included low-risk, intermediate-risk, highintermediate-risk, and highrisk patients. Toxicity is reported. Overall, the results show that prostate brachytherapy is effective and has low rates of late toxicity when performed as monotherapy.

Purpose/Objectives: To report long-term efficacy and toxicity for a single-institution cohort of patients treated with low-dose-rate prostate brachytherapy permanent implant (PI) monotherapy. Methods and Materials: From 1996 to 2007, 1989 patients with low-risk (61.3%), intermediate-risk (29.8%), high-intermediate-risk (4.5%), and high-risk prostate cancer (4.4%) were treated with PI and followed up prospectively in a registry. All patients were treated with 125I monotherapy to 144 Gy. Late toxicity was coded retrospectively according to a modified Common Terminology Criteria for Adverse Events 4.0 scale. The rates of biochemical relapse-free survival (bRFS), distant metastasis-free survival (DMFS), overall survival (OS), and prostate cancerespecific mortality (PCSM) were calculated. We identified factors associated with late grade 3 genitourinary (GU) and gastrointestinal (GI) toxicity, bRFS, DMFS, OS, PCSM, and incontinence. Results: The median age of the patients was 67 years, and the median overall and prostate-specific antigen follow-up times were 6.8 years and 5.8 years, respectively. The overall 5-year rates for bRFS, DMFS, OS, and PCSM were 91.9%, 97.8%, 93.7%, and 0.71%, respectively. The 10-year rates were 81.5%, 91.5%, 76.1%, and 2.5%, respectively. The overall rates of late grade 3 GU and GI toxicity were 7.6% and 0.8%, respectively. On multivariable analysis, age and prostate length were significantly associated with increased risk of late grade 3 GU toxicity. The risk of

Reprint requests to: Jay P. Ciezki, MD, Desk T-28, 9500 Euclid Ave, Cleveland, OH 44195. Tel: (216) 445-9465; E-mail: [email protected] Conflict of interest: none. Int J Radiation Oncol Biol Phys, Vol. -, No. -, pp. 1e10, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2015.02.047

Supplementary material for this article can be found at www. redjournal.org.

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incontinence was highly correlated with both pre-PI and post-PI transurethral resection of the prostate. Conclusions: Prostate brachytherapy as monotherapy is an effective treatment for low-risk and low-intermediate-risk prostate cancer and appears promising as a treatment for high-intermediate-risk and high-risk prostate cancer. Significant long-term toxicities are rare when brachytherapy is performed as monotherapy. Ó 2015 Elsevier Inc. All rights reserved.

Introduction Prostate cancer continues to be a significant public health problem. It remains the most commonly diagnosed non-skin malignancy in American men and, despite earlier detection and advances in treatment, is still the second leading cancer-related cause of death (1). Approximately 80% of patients with new diagnoses present with clinically localized disease (2); however, no clear consensus exists on an optimal treatment strategy. Published data on the long-term efficacy and toxicity of low-dose-rate prostate brachytherapy permanent implant (PI) used as monotherapy in contemporary patients is sparse. Prior large series, which included both single-institution and multi-institution experiences (3-10), included large numbers of low-risk patients who were treated with androgen deprivation therapy (ADT) (3), large numbers of intermediate-risk patients who were treated with bimodality therapy including external beam radiation therapy (EBRT) or ADT (3, 5-8, 10), and either excluded high-risk patients altogether (3, 4) or treated them in combination with EBRT, ADT, or both (5-8, 10). Additionally, only 1 of these series reported toxicity outcomes, and it included significant proportions of patients treated with combination therapy (55% of patients treated with ADT and 38% treated with supplemental EBRT) (8). Herein we report a large, single-institution series of patients treated with PI without supplemental EBRT.

Methods and Materials Patient selection and treatment From 1996 to 2007, 1989 patients with low-risk, intermediate-risk, and high-risk prostate cancer by National Comprehensive Cancer Network (NCCN) criteria (11) were treated with PI and enrolled in an Institutional Review Boardeapproved, inception cohort study. Five physicians performed implantations during this time period, but approximately 85% of implantations were performed by a single physician. All patients treated with PI during this time interval were included. No patient received external beam radiation. No patient was excluded from receiving PI based on preoperative urinary function or prostate volume. ADT was not mandatory for gland size reduction.

Administration of ADT based on risk category was at the physician’s discretion. Pretreatment prostate-specific antigen (iPSA), clinical T stage, biopsy Gleason score (bGS), ADT use and duration, dosimetric parameters, age, body mass index, smoking history (ever smoker and number of pack-years), Charlson comorbidity index score (12), and presence of coronary artery disease, hypertension, and dyslipidemia were recorded. Patients were treated with low-dose-rate brachytherapy using 125I. Patients were planned intraoperatively with a modified peripheral loading technique prescribed to 144 Gy using the VariSeedÔ (Varian Brachytherapy) treatment planning system, with the goal of covering the regions most likely to harbor cancer (the peripheral zone in the posterior and lateral directions) and sparing the periurethral region to <150% of the prescribed dose (216 Gy). Hard constraints for V100 or V150 were not used. Cold spots in the anterior/ superior region (which has a low risk of harboring cancer) on the postplan were considered acceptable (13). Typically, margins of 3 to 5 mm were given in the lateral, anterior, posterioresuperior, and apical directions. The margin was increased for high-risk patients to 5 mm in the anterior and lateral dimensions and 1 cm in the posterioresuperior and apical directions, where extraprostatic extension is most likely. Stranded sources were preferentially used on the periphery of the prostate and loose seeds toward the center and near the rectum. Particular attention was taken to avoid seed placement within 3 to 5 mm of the anterior rectal wall. All patients were placed in an exaggerated dorsal lithotomy position and implanted through a transperineal approach with real-time transrectal ultrasonographic guidance. Patients were typically prescribed prophylactic postoperative oral ciprofloxacin (500 mg twice daily for 10 days) and oral tamsulosin (0.8 mg daily at night until urinary symptoms returned to baseline) unless contraindicated (14). Within 4 weeks of PI, patients underwent a postimplantation CT scan. Doseevolume histograms for prostate, bladder, and rectum were calculated. Brachytherapy cases were audited in regular peer review sessions. Patients were followed up every 6 months by the referring urologist and radiation oncologist of record for approximately 3 years and then annually thereafter. Determinations of PSA were obtained every 6 months for at least the first 5 years. Patients who were treated at our institution but were followed up elsewhere were asked to send their PSA values and notes pertaining to possible

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treatment-related toxicities or treatment failure. This information was reviewed by the treating physicians and entered into the medical record and registry.

Outcome analysis Patients were analyzed according to NCCN risk group. Patients with 1 intermediate risk factor (“low-intermediate”) and patients with multiple intermediate risk factors (“high-intermediate”) were analyzed separately. Biochemical failure was defined according to the Phoenix definition (nadir þ 2 ng/mL), and distant metastasis was defined as image-defined evidence of recurrence correlated with a rising PSA, symptoms, or both. A benign PSA rise (also called PSA bounce) was defined as a rise in PSA of at least 0.2 ng/mL with a subsequent PSA decline below the previous nadir in the absence of additional therapeutic intervention. Cause-specific mortality data were obtained from the National Death Index and verified by a review of the patient’s chart.

Toxicity analysis Toxicity was recorded after a review of visit and procedure notes from all patients’ electronic charts and by communications from patients and their referring physicians. Late toxicity was defined as occurring >6 months after PI and was scored according to a modified Common Terminology Criteria for Adverse Events (CTCAE) 4.0 scale (15) as follows: grade 1, asymptomatic/mild symptoms; grade 2, managed medically or observed; grade 3, requiring procedural intervention (eg, transurethral resection of the prostate [TURP] or photocoagulation); grade 4, life-threatening; grade 5, resulting in death. We distinguished between any rectal bleeding and PI-related rectal bleeding as diagnosed by colonoscopy demonstrating sources of bleeding (eg, bleeding vessels, telangiectasias, or ulceration) in the anterior rectum adjacent to the prostate. Incontinence was defined as ever having an episode of any degree of urge or stress incontinence across the acute or late period. We did not assess severity, duration, or resolution of incontinence. Patients were excluded from the analysis of post-TURP incontinence if they had incontinence before undergoing TURP or a pre-PI TURP.

Statistical analysis The rates for biochemical relapse-free survival (bRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were calculated using actuarial analysis. Prostate cancerespecific mortality (PCSM) rates were calculated using cumulative incidence analysis. Cox proportional hazards regression was used to identify factors associated with late grade 3 toxicity, bRFS, DMFS, and OS; Fine and Gray regression was used for PCSM; and logistic regression was used to identify factors associated with incontinence. Patients with <3 follow-up PSAs were

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excluded from analysis of bRFS and DMFS (229 patients, 11.5%). All patients were included in the analysis for OS, PCSM, and toxicity. For the endpoints bRFS and DMFS, the date of the patient’s last PSA was used as the date of the last follow-up visit. For OS, PCSM, and late toxicity, the date of the last clinical assessment was taken as the date of the last follow-up visit. PSA frequency (number of PSAs per year) was calculated for all patients and was used as a variable of interest for bRFS and DMFS. To control for variation of PSAs per year over time, a time interaction variable (denoted “biochemical failure time  PSA frequency” in Table 2) was added to the models (16). SAS (version 9.3) (SAS Institute, Cary, NC) and R (version 3.0) (R Foundation for Statistical Computing, Vienna, Austria) were used for statistical analysis.

Results The median follow-up time was 6.8 years (range, 0.1-16.5 years). The median PSA follow-up time was 5.8 years (range, 0.1-16.5 years). One thousand seven hundred sixty patients (88.5%) had at least 3 follow-up PSA values. The median PSA frequency was 1.6 PSAs per year. The pretreatment characteristics are given in Table 1. The median D90 was 146 Gy (standard deviation [SD]: 24.48 Gy), and the median rectal V100 was 0.09 cc (SD: 0.62) (Table E1; available online at www.redjournal.org). ADT was given to 18.2% of patients, with a median duration of 6 months (range, 1-48 months), most commonly as neoadjuvant and adjuvant therapy. ADT use was more common in patients with high-intermediate-risk or high-risk disease (64.4% and 80.7% of patients, respectively) compared with low-risk and low-intermediate-risk disease (9.5% and 19.6% of patients, respectively). ADT use became less common over time, declining from a high of 56.3% of patients in 1997 to a low of 8.8% of patients in 2004. A PSA bounce occurred in 429 patients (21.6%). Factors associated with PSA bounce were similar to those in our previously published experience (data not shown) (17).

Efficacy Figure 1 shows bRFS, DMFS, OS, and PCSM by risk group. Owing to the small number of high-intermediaterisk and high-risk patients still at risk at 10 years, the 10-year rates for bRFS and DMFS are reported only for patients in the low-risk and low-intermediate-risk groups. Univariate and multivariable analyses for all outcomes are shown in Table 2. Of note, the high-intermediate-risk group had worse outcomes than the low-intermediate-risk group only when bRFS was considered.

Biochemical relapse-free survival Overall, 206 of 1760 patients (11.5%) experienced biochemical failure (Fig. 1). On multivariable analysis,

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Kittel et al. Table 1

Distant metastasis-free survival

Pretreatment characteristics

Characteristic Age (y) BMI* (kg/m2) Smoking (pack-years) Prostate volume (cc) Race AA Non-AA Charlson score 0 1 >2 NA CADy N Y HTNz N Y T stage T1-T2a T2b-c Initial PSA <10 10-20 >20 Biopsy Gleason score 6 7 8-10 Risk group Low Intermediate High-intermediate High ADT Y N Duration (mo) Adjuvant alone Neoadjuvant alone Neoadjuvant and adjuvant Neoadjuvant and unknown adjuvant

Median or n (%)

Standard deviation

Range

67 28.1 8 35.19

7 4.7 22.4 20.08

41-87 11.1-65.8 0-150 9.67-178.93

266 (13.4) 1723 (86.6)

-

-

1072 620 87 210

(53.9) (31.2) (4.4) (10.6)

-

-

1344 (75.5) 435 (24.5)

-

-

882 (49.6) 897 (50.4)

-

-

1952 (98.1) 37 (1.9)

-

-

1711 (86.0) 237 (11.9) 41 (2.1)

-

-

1419 (71.3) 517 (26.0) 53 (2.7)

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-

1219 592 90 88

-

-

4.5

1-48

Overall, 80 of 1760 patients (4.5%) experienced distant metastases (Fig. 1). On multivariable analysis, bGS (7 vs 6) and PSA frequency remained significant; bGS 8-10 versus 6 showed a trend toward significance (HRZ2.45, 95% CI Z 0.98-6.12, PZ.0545).

Overall survival Overall, 338 of 1989 patients (17.0%) died during follow-up (Fig. 1). On multivariable analysis, bGS 8-10, age, Charlson score, hypertension, and smoking status were predictive.

Prostate cancerespecific mortality Overall, 33 of 1989 patients (1.7%) died of prostate cancer (Fig. 1). On univariate analysis, only bGS 8-10 was significantly associated with PCSM. Notably, there was no significant difference between bGS 7 versus 6 and that no other clinical or treatment factors were predictive of PCSM.

Toxicity

(61.3) (29.8) (4.5) (4.4)

361 (18.2) 1628 (81.9) 6 16 (4.4%) 16 (4.4%) 327 (90.6%) 2 (0.6%)

Abbreviations: AA Z African American; ADT Z androgen deprivation therapy; BMI Z body mass index; CAD Z coronary artery disease; HTN Z hypertension; PSA Z prostate-specific antigen. * BMI not available for 211 patients. y CAD status not available for 210 patients. z HTN status not available for 210 patients.

iPSA, bGS (7 vs 6 and 8-10 vs 6), and PSA frequency were associated with increased risk of failure. Increased prostate volume was mildly protective (hazard ratio [HR] Z 0.99, 95% confidence interval [CI] Z 0.98-1.00, PZ.0044).

The rates of late GU and GI toxicity are given in Table 3.

GU toxicity Approximately half of the patients with grade 3 GU toxicity had undergone a TURP after PI (81 patients, 4.1% of all patients), and the remainder had predominately undergone urethral dilation. Two patients experienced rectourethral fistulas after PI, which were scored as grade 4 toxicities. Both patients underwent post-PI TURP and multiple additional procedures before development of fistula: 1 required repeated resections of recurrent urethral strictures and the other a repeat TURP. Univariate and multivariable analyses of late GU grade 3 toxicity are shown in Table 4. On multivariable analysis, age 70 years and prostate length 5 cm were significantly associated with increased risk of toxicity. Overall, the cumulative incidence of incontinence was 8.9% (176 patients). Of the patients who underwent a post-PI TURP, 28 (39.4%) experienced incontinence. The risk of incontinence was highly correlated with TURP: odds ratio (OR) Z 3.28 (95% CI Z 1.80-5.98) for pre-PI TURP; and OR Z 7.94 (95% CI Z 4.79-13.17) for post-PI TURP. Patients who underwent pre-PI TURP were at higher risk of requiring a post-PI TURP: OR Z 3.56 (95% CI Z 1.64-7.73).

GI toxicity A fistula developed in 1 patient after severe radiation proctitis and resulted in a rectal ulcer that required a

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Univariate and multivariable analyses of efficacy Univariate Factor

Biochemical relapse-free survival Prefailure PSA frequency Biochemical failure time  PSA frequency Initial PSA Prostate volume (cc) Biopsy Gleason score 7 vs 6 8-10 vs 6 8-10 vs 7 T2B&C vs T1&T2A Androgen deprivation duration (mo) Androgen deprivation (yes vs no) D90 V100 Age Distant metastases-free survival Prefailure PSA frequency Biochemical failure time  PSA frequency Initial PSA Prostate volume (cc) Biopsy Gleason score 7 vs 6 8-10 vs 6 8-10 vs 7 T2B&C vs T1&T2A Androgen deprivation duration (mo) Androgen deprivation (yes vs no) D90 V100 Age Overall survival Initial PSA Prostate volume (cc) Biopsy Gleason score 7 vs 6 8-10 vs 6 8-10 vs 7 T2B&C vs T1&T2A Androgen deprivation duration (mo) Androgen deprivation (yes vs no) D90 V100 Age Charlson score Coronary artery disease (yes vs no) Hypertension (yes vs no) Ever smoked (yes vs no) Body mass index (kg/m2) Cause-specific survival Initial PSA Biopsy Gleason score 7 vs 6 8-10 vs 6 8-10 vs 7 T2B&C vs T1&T2A Androgen deprivation duration (mo)

P value

Multivariable

HR (95% CI)

P value

HR (95% CI)

<.0001 <.0001 <.0001 <.0001

2.88 1.01 1.05 0.98

(2.41-3.45) (1.01-1.02) (1.04-1.06) (0.97-0.99)

<.0001 <.0001 .0002 .0044

2.64 1.01 1.03 0.99

<.0001 <.0001 .0051 .0052 .0037 <.0001 .0004 .0009 .69

2.32 5.24 2.26 2.74 1.04 2.06 0.99 0.98 1.00

(1.73-3.11) (3.00-9.16) (1.28-4.00) (1.35-5.56) (1.01-1.07) (1.53-2.78) (0.98-1.00) (0.97-0.99) (0.98-1.02)

.0087 .049 .44 .21 .60 .61 .17 -

1.55 2.02 1.30 1.77 0.99

<.0001 .26 .0482 .0049

3.65 1.00 1.03 0.98

(2.89-4.61) (1.00-1.01) (1.00-1.05) (0.96-0.99)

<.0001 .40 .19 .78

3.59 1.00 0.98 1.00

(2.79-4.62) (1.00-1.01) (0.96-1.01) (0.98-1.01)

.0045 <.0001 <.0001 .0043 .57 .13 .20 .54 .0554

3.06 3.69 11.29 4.37 1.01 1.47 0.99 0.99 1.03

(1.41-6.62) (2.30-5.93) (5.17-24.61) (1.59-12.05) (0.97-1.06) (0.89-2.42) (0.99-1.00) (0.98-1.01) (1.00-1.07)

.0214 .0545 .54 .20 -

1.86 2.45 1.32 2.50

(1.10-3.16) (0.98-6.12) (0.55-3.16) (0.62-10.13) -

.26 -

1.01 (0.99-1.03) -

.0277 .35 .17 <.0001 .0005 .0087 .35 .0023 .17 .16 <.0001 <.0001 <.0001 .0024 .0065 .0084 .74 .10 <.0001 .0028 .064 .097

1.02 (1.00-1.04) 1.00 (1.00-1.01) 1.20 3.13 2.61 2.33 1.01 1.45 1.00 1.01 1.08 1.41 1.58 1.41 1.39 0.97

(0.93-1.56) (1.88-5.21) (1.52-4.46) (1.24-4.37) (0.99-1.03) (1.14-1.84) (1.00-1.01) (1.00-1.02) (1.06-1.10) (1.31-1.52) (1.26-1.99) (1.13-1.75) (1.10-1.76) (0.94-0.99)

1.01 (0.96-1.06) 1.93 10.23 5.31 3.99 1.03

(0.87-4.25) (3.73-28.07) (1.78-15.90) (0.92-17.20) (0.99-1.07)

.17 .0053 .0314 .85 .46 <.0001 <.0001 .80 .0048 .0087 .13

(2.16-3.22) (1.01-1.02) (1.01-1.04) (0.98-1.00)

(1.12-2.15) (1.00-4.05) (0.66-2.55) (0.73-4.26) (0.93-1.04) 1.00 (0.99-1.01) 0.99 (0.98-1.00) -

1.21 2.38 1.96 1.07 1.11

1.07 1.42 1.03 1.38 1.38 0.98

(0.92-1.59) (1.29-4.38) (1.06-3.63) (0.52-2.22) (0.84-1.46) (1.05-1.09) (1.30-1.54) (0.81-1.31) (1.10-1.74) (1.08-1.75) (0.95-1.01)

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Kittel et al. Table 2 (continued )

Univariate Factor Androgen deprivation use (yes vs no) D90 V100 Prostate volume Age Charlson score Coronary artery disease (yes vs no) Hypertension (yes vs no) Ever smoked (yes vs no) Body mass index (kg/m2)

P value .084 .83 .15 .28 .12 .31 .78 .18 .86 .71

Multivariable

HR (95% CI) 1.91 1.00 1.02 0.99 1.05 0.80 0.89 1.66 0.93 0.98

(0.92-3.99) (0.99-1.01) (0.99-1.05) (0.97-1.01) (0.99-1.12) (0.53-1.23) (0.38-2.06) (0.79-3.53) (0.44-1.98) (0.90-1.08)

P value

HR (95% CI)

-

-

Abbreviations: CI Z confidence interval; D90 Z dose to 90% of the prostate; HR Z hazard ratio; PSA Z prostate-specific antigen; V100 Z percentage volume of prostate receiving 100% of prescription dose.

proctosigmoidectomy with Turnbull-Cutait coloanal pull-through and delayed anastomosis, which was scored as grade 4 toxicity. This patient also required several procedures for recurrent mucosal bleeding after reconstruction before the development of his colourethral fistula. This patient had a rectal V100 of 2.4 cc. One patient died of a squamous cell carcinoma that developed in the rectum 6 years after PI within the treatment field, which was thought to represent a radiation-induced malignancy and was scored as grade 5 toxicity. There were too few events to enable identification of factors associated with late grade 3 GI toxicity. Rectal bleeding developed in 325 patients (16.3%) after PI. However, on colonoscopy, only 10.8% of these patients (1.8% of total) were found to have PI-related bleeding. The remaining patients were found to have hemorrhoids, colon or rectal cancer, or other causes of bleeding. The median rectal V100 for patients with rectal bleeding from brachytherapy was 0.39 cc (range, 0.00-8.68 cc). For all other patients, the median rectal V100 was 0.11 cc (range, 0.00-3.47 cc).

Discussion There is currently no consensus on the best method of treating localized prostate cancer that maximizes the chance for cure while minimizing toxicity. This is in large part because randomized controlled trials that compare different modalities are difficult to conduct in this disease owing to its long natural history, the well-established referral patterns, and strong patient preferences about treatment options. Herein, we present a large, single-institution series of patients treated with brachytherapy as monotherapy with a uniform planning strategy that maximized dose to the peripheral zone and allowed for a variable margin outside the prostate based on risk group. Patients were followed up closely, with data from a modern electronic medical records system (Epic, Epic Systems Corporation) available for the

majority of patients since the early 2000s, allowing us to closely track treatment failure and high-grade toxicity. Low-grade toxicity from our institution was previously reported in the PROST-QA study (18).

Outcomes analysis Our disease control outcomes are consistent with the long-term results in other large published series, many of which included supplemental EBRT for a substantial proportion of patients, mandated ADT use for intermediaterisk and high-risk patients, or both (3-9). Higher Gleason score was the only factor that was negatively associated with all disease outcomes on multivariable analysis (Table 2). Our series includes a large proportion of patients with low-intermediate-risk disease: 520 patients (29.8%). This is one of the largest published single-institution experiences with PI monotherapy for low-intermediaterisk disease (19-21). In a smaller cohort of patients, we previously reported that such patients treated with PI alone had outcomes similar to those in patients treated with EBRT or radical prostatectomy, which argues against the need for dose escalation with PI combined with supplemental EBRT (22). In the current cohort, lowintermediate-risk patients treated with PI alone had outcomes similar to those in other large series that treated such patients with supplemental EBRT (5-8). Previous series have shown that supplemental EBRT is not beneficial when treating low-intermediate risk disease (6, 23). Radiation Therapy Oncology Group (RTOG) 0232, which randomized low-intermediate-risk patients to PI monotherapy versus combination therapy with supplemental EBRT, may answer this question, but in the meantime our results suggest that treatment of patients with lowintermediate-risk prostate cancer with PI alone may be sufficient. Our series is remarkable in that a relatively low percentage of patients received ADT (18.2%) despite being

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Fig. 1. (A) Biochemical relapse-free survival (bRFS). (B) Distant metastasis-free survival (DMFS). (C) Overall survival (OS). (D) Prostate cancerespecific mortality. treated without EBRT. It was not mandated that either intermediate-risk patients or high-risk patients be routinely treated with ADT; however, the majority of such patients received hormone therapy. Importantly, the use of ADT was not a significant factor in predicting any outcome in any NCCN risk category, in contrast to the external beam literature. These data suggest that ADT is not necessary in the treatment of low-risk and low-intermediate-risk prostate cancer with brachytherapy alone. Although our data also suggest that patients with highintermediate-risk and high-risk disease can be effectively treated with brachytherapy alone without ADT, this conclusion is limited by sample size, limited follow-up, relatively few patients with high-risk disease who were treated without ADT, and possible selection bias regarding ADT use. However, another recently published series of patients treated with brachytherapy also found no role for ADT in intermediate-risk or high-risk patients (10). The

role of ADT with brachytherapy for high-intermediate-risk and high-risk patients remains controversial and will be the subject of a future publication.

GU toxicity analysis Our study reports grade 3 late toxicity according to a modified CTCAE 4.0 scale. Our acute toxicity rates and baseline urinary function scores have been previously published (14). Our rate of overall grade 3 late GU toxicity is similar to the rate published in other large series (8, 24-28). Other series that include patients treated with supplemental EBRT report a higher rate of late toxicity (29). Methods of reporting toxicity differ between series, limiting the ability to draw definitive conclusions. The CTCAE scale was chosen to facilitate comparisons with surgical series and

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Kittel et al. Table 3 Location GU GI

Late genitourinary and gastrointestinal toxicity Grade 3

Grade 4

Grade 5

Overall 3

5 year % (95% CI)

10 year % (95% CI)

139 (7.0%) 14 (0.7%)

13 (0.7%) 1 (0.1%)

0 (0%) 1 (0.1%)

152 (7.6%) 16 (0.8%)

6.0 (4.9%-7.1%) 0.8 (0.4%-1.2%)

11.0 (8.9%-13.1%) 1.1 (0.5%-1.7%)

Abbreviations: CI Z confidence interval; GI Z gastrointestinal; GU Z genitourinary.

because the differences between toxicity levels were thought to be relevant to patients. By RTOG criteria, our toxicity would be under-reported (Fig. 2). Notably, the RTOG schema does not incorporate TURP or urethral dilation, which were the 2 predominant grade 3 GU toxicities observed (30). On multivariable analysis, age 70 years and prostate length 5 cm were predictive of grade 3 toxicity. Increased prostate length has previously been shown to be an important predictor of the need for acute intermittent self-catheterization after prostate brachytherapy (31). We did not identify any dosimetric parameters that correlated with late toxicity, likely because of the relatively uniform method of treatment planning used throughout this series. Approximately half of the patients who experienced grade 3 GU toxicity underwent TURP (81 patients, 4.1%). The frequency of post-PI TURP compares favorably with that in other published series (32-34). Post-PI TURP significantly increased the risk of incontinence, so patients with poor baseline urinary function or longer prostates should be counseled on the increased risk of incontinence if they require TURP after PI. Patients with a prior TURP should be counseled that they may have a higher risk of requiring a TURP after implantation. To minimize the risk of delayed healing, we typically attempt to delay TURP until at least 12 months after PI. Our crude overall rate of incontinence was 8.9% (176 patients). We used a broad definition of incontinence (any degree of stress or urge incontinence across the acute or late

Table 4

period), so we believe this rate is reasonable. This rate is inflated by patients who experienced urge incontinence in the acute period after implantation but whose incontinence resolved. Therefore, the true prevalence of incontinence is likely to be lower. Rates of incontinence should be considered in comparison with the baseline prevalence of incontinence in the general population, which is approximately 10% when daily incontinence in men older than 60 is considered (35).

GI toxicity analysis Our rate of late GI toxicity is lower than what we have previously reported for EBRT (36) and is lower than that reported in series with combination therapy (8, 29). The majority of our grade 3 toxicities were due to cauterization of PI-related rectal bleeding. Our study discriminated between any rectal bleeding (16.3% of patients) and PI-related rectal bleeding (1.8% of patients) as defined by colonoscopy. Although there is some selection bias as to which patients received colonoscopy, our institutional practice is for any patient experiencing rectal bleeding after PI to undergo colonoscopy. The majority of nonePI-related rectal bleeding was due to hemorrhoids, with the rest due to colorectal cancer or other causes. This suggests that the incidence of rectal bleeding reported in other series (7%-20%) (8, 9, 29, 37-40), which is consistent with our rate of any rectal bleeding, may have been inflated by nonePI-related causes. Patients can be

Univariate and multivariable analysis of late grade 3 genitourinary toxicity Univariate Factor

P value

Prostate volume Prostate length (5 cm vs <5 cm) Prostate width Prostate height BMI Age (70 vs <70) Duration of ADT D90 V100 Hypertension (no vs yes) Ever smoked (no vs yes) Diabetes (no vs yes)

<.0001 <.0001 .0015 .0076 .0090 .001 .6061 .2632 .5942 .8720 .5663 .5013

Multivariable

HR (95% CI) 1.015 2.40 1.391 1.355 0.948 1.71 0.986 1.004 1.004 0.972 1.108 0.831

(1.01-1.02) (1.74-3.31) (1.14-1.71) (1.08-1.69) (0.91-0.99) (1.24-2.34) (0.93-1.04) (0.9-1.02) (0.99-1.02) (0.6-1.37) (0.78-1.57) (0.49-1.42)

P value <.0001 .81 .94 .028 .0069 -

HR (95% CI) 2.30 1.03 0.99 0.95 1.62

(1.52-3.50) (0.79-1.36) (0.70-1.38) (0.91-0.99) (1.14-2.29) -

Abbreviations: ADT Z androgen deprivation therapy; BMI Z body mass index; CI Z confidence interval; D90 Z dose to 90% of the prostate; HR Z hazard ratio; V100 Z percentage volume of prostate receiving 100% of prescription dose.

Volume -  Number -  2015

Low-dose-rate

125

I prostate brachytherapy in prostate cancer

9

Fig. 2. Late grade 3 gastrointestinal (A) and genitourinary (B) toxicity by Common Terminology Criteria for Adverse Events and Radiation Therapy Oncology Group criteria. counseled that the rate of PI-related rectal bleeding with modern techniques is extremely low (<2%). Only approximately half of patients with PI-related bleeding required cauterization. These data support other studies that have found that the majority of rectal bleeding after brachytherapy will resolve without intervention (39).

Strengths and limitations This was a large series of brachytherapy delivered as monotherapy with minimal use of ADT. Our series includes high-intermediate-risk and high-risk patients treated with brachytherapy without supplemental EBRT or mandatory use of ADT, which is unique in a large institutional series. Patients were closely followed up, as indicated by the long PSA follow-up time and average of 1.6 PSA values determined per year (16). Our series reports toxicity in addition to clinical outcomes. We are a large institution, with an electronic medical records system spanning all inpatient and outpatient specialties across all facilities for nearly a decade, so toxicity was able to be comprehensively reviewed. The limitations of our series include the fact that we were unable to draw correlations between acute toxicity and the incidence of grade 3 late toxicity. Although our toxicity data were recorded prospectively, they were graded retrospectively and do not include patient-reported data. We did not assess severity, duration, or resolution of incontinence. Last, our data do not include an assessment of long-term potency.

Conclusion Prostate brachytherapy as a single radiation modality for the treatment of localized prostate cancer is highly effective for low-risk and intermediate-risk disease. ADT does not appear

to provide additional benefit compared with PI alone in these patients. The rate of late toxicity after PI is acceptable when dose is preferentially delivered to the peripheral zone with a risk-adapted margin outside the prostate and is generally lower than that seen with supplemental EBRT. The treatment of high-intermediate-risk and high-risk prostate cancer with PI as the sole method of radiation therapy appears promising and deserves further investigation.

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