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The Primary Local Stage at Diagnosis Predicts Regional Symptoms Caused by Local Progression in Patients With Castration-resistant Prostate Cancer
Oncology The Primary Local Stage at Diagnosis Predicts Regional Symptoms Caused by Local Progression in Patients With Castration-resistant Prostate Cancer Kohei Hashimoto, Takahiro Mizuno, Hiroshi Kitamura, Tetsuya Shindo, Satoshi Takahashi, and Naoya Masumori OBJECTIVE METHODS
RESULTS
CONCLUSION
To identify the characteristics that predict occurrence of local progression-related events (LPREs) in patients with castration-resistant prostate cancer (CRPC) to adjust its management. We retrospectively reviewed the medical records of 39 patients with CRPC. LPREs were defined as regional symptoms caused by local progression and categorized into urinary events and rectal events. Urinary events were defined as ureteral obstruction, acute urinary retention, or hematuria requiring treatment, and rectal events were rectal obstruction or rectal bleeding caused by tumor invasion. The median prostate-specific antigen level at diagnosis was 185 ng/mL. During the median follow-up period of 4.4 years, 10 patients (25.6%) had LPREs. Urinary events were observed in 8 patients (20.5%) and rectal events in 2 (5.1%). The proportion of T4 in patients with LPREs was higher than in those without LPREs (70.0% vs 10.3%; P <.001). Stage T4 at diagnosis was an independent factor to predict LPREs in multivariate analysis (hazard ratio, 8.62; P ¼ .004). The 5-year cumulative incidence of LPREs in patients with stage T4 was 70.0%, whereas in those with stage T3, they were 3.6% (P <.001). Patients with stage T4 at diagnosis are more likely to have a risk of LPREs than those with stage T3. These results indicate that patients with locally advanced prostate cancer on androgen deprivation therapy need to be closely monitored for early diagnosis of CRPC and treated with the appropriate intervention for LPREs at the appropriate time. UROLOGY 85: 430e435, 2015. 2015 Elsevier Inc.
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rostate cancer is the most common noncutaneous malignancy in men in developed countries.1 Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. However, in most cases, the disease progresses despite the castration level of serum testosterone and results in castration-resistant prostate cancer (CRPC). Some patients with CRPC experience symptoms caused by local progression, including ureteral obstruction, bladder outlet obstruction, severe hematuria, and rectal obstruction.2-4 These can lead to poor quality of life (QOL). However, local progression is commonly accompanied by life-threatening systemic progression of CRPC. We always face a dilemma as to whether aggressive
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan Address correspondence to: Naoya Masumori, M.D., Department of Urology, Sapporo Medical University School of Medicine, S1, W16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: [email protected] Submitted: April 11, 2014, accepted (with revisions): September 2, 2014
430
ª 2015 Elsevier Inc. All Rights Reserved
intervention for local progression provides a significant clinical effect for such patients. Thus, the strategy for local progression in patients with CRPC remains to be determined because its profile is unclear. The aim of this study was to identify the characteristics that predict occurrence of local progression-related events (LPREs) in patients with CRPC to adjust its management.
METHODS We reviewed patients with advanced prostate cancer who initially received androgen deprivation monotherapy (ADMT) or complete androgen blockade (CAB) with an antiandrogen as the first-line treatment in our institution between 1999 and 2009 and isolated 39 patients who progressed to CRPC during the follow-up period. All patients had serum prostate-specific antigen (PSA) determination (ECLusys PSA II assay; Roche Diagnostics, Tokyo, Japan) before prostate biopsy. Systematic prostate biopsy was performed using an 18-gauge needle under the guidance of transrectal ultrasound, and 6-14 biopsy cores were taken from each patient. The clinical stage was determined via digital rectal examination, transrectal ultrasound, abdominal http://dx.doi.org/10.1016/j.urology.2014.09.044 0090-4295/15
Table 1. Clinical characteristics of patients N ¼ 39 Median age at diagnosis (range), y 73 (51-88) Median PSA at diagnosis (range), 185 (10.7-8190) ng/mL Median prostate volume 40.2 (16.3-79.8) (range), mL Gleason score on biopsy (%) 6 2 (5.1) 7 9 (23.1) 8 28 (71.8) TNM stage (%) T2-4N0M0 7 (17.9) TanyN1M0 6 (15.4) TanyN0M1 11 (28.2) TanyN1M1 15 (38.5) Local symptoms at diagnosis (%) 5 (12.8) Primary ADT (%) Surgical castration/LHRH 11 (28.2)/22 (56.4) agonist CAB 5 (12.8) LHRH antagonist 1 (2.6) Time to progression during ADT 9.1 (0.8-79.8) (range), mo ADT, androgen deprivation therapy; CAB, complete androgen blockade; LHRH, luteinizing hormoneereleasing hormone; PSA, prostate-specific antigen; TNM, tumor-nodes-metastasis.
computed tomography, chest x-ray, and bone scanning using 99mTc-methylene-diphosphonate. The stage and histologic grade were assigned using the 2009 The Union for International Cancer Control-American Joint Committee on Cancer tumornodes-metastasis staging system and Gleason grading system based on the criteria of the 2005 International Society of Urological Pathology consensus conference.5 As the first-line treatment, 34 patients were treated with ADMT, with surgical castration for 11 patients, the administration of a luteinizing hormoneereleasing hormone agonist for 22 patients and a luteinizing hormoneereleasing hormone antagonist for 1 patient (Table 1). Five patients were treated with CAB, with bicalutamide 80 mg daily for 2 patients, chlormadinone acetate 100 mg daily for 2 patients, and flutamide 375 mg daily for 1 patient. As all patients had PSA progression during ADMT or CAB, second-line treatment was done using an additional antiandrogen for those who underwent ADMT and an alternative antiandrogen for those with CAB. If PSA elevation developed during CAB, the antiandrogen was terminated, and the patient was observed for antiandrogen withdrawal syndrome. Positive antiandrogen withdrawal syndrome was defined as a PSA decline of 50% from the PSA level at the time when the antiandrogen was discontinued. After failure of the second-line treatment for those with the second-line CAB, another alternative antiandrogen, estrogen, glucocorticoid with ADMT, or docetaxel was given as the thirdline treatment. Drugs used in the second-line or later treatment were decided based on the preferences of the physicians. Physical examination and serum PSA measurement were performed every 3 months throughout the follow-up period. Digital rectal examination, transrectal ultrasonography, abdominal computed tomography, chest x-ray, and bone scanning were performed when clinically indicated. LPREs were defined as regional symptoms caused by local progression and categorized into urinary events and rectal events. Urinary events were defined as ureteral obstruction (either unilateral or bilateral), acute urinary retention, or hematuria requiring treatment, UROLOGY 85 (2), 2015
and rectal events were rectal obstruction and rectal bleeding caused by tumor invasion. Data were extracted, including the characteristics of the patients (age, clinical stage, PSA level, prostate volume, biopsy findings, treatments, and local symptoms at diagnosis of CRPC) and local progression data (LPREs, treatments, and time to LPREs). The time of PSA progression was defined as the time of the first of 3 consecutive increases in the PSA level. Survival time from the start of the first therapy to death of prostate cancer was calculated. The Fisher exact test and the Mann-Whitney U test were carried out to compare various clinical variables between the groups with and without LPREs. The Fine-Gray regression model was used to calculate the probability of LPREs and prostate cancer mortality.6 Cumulative incidence curves were used in a competing risk setting, with death without LPREs for probability of LPREs or death due to other cause for prostate cancer mortality as a competing event. The proportional hazards regression model for the subdistribution of a competing risk was used to estimate the prognostic factors of LPREs based on the optimal cutoff value for each parameter. P <.05 was considered to be statistically significant. All statistical analyses were performed with EZR for Windows (Saitama Medical Center, Jichi Medical University, Saitama), which is a graphical user interface for R (version 2.13.0; The R Foundation for Statistical Computing, Vienna, Austria).7 More precisely, it is a modified version of R commander (version 1.6-3) that was designed to add statistical functions frequently used in biostatistics.
RESULTS The characteristics of the patients are shown in Table 1. The median PSA level at diagnosis was 185 ng/mL. Stage T2 was observed in 3 patients (7.7%), T3 in 26 (66.7%), and T4 in 10 (25.6%). Although 5 patients had local symptomatic events such as ureteral obstruction and urinary retention at diagnosis, all of them improved immediately after the primary ADT (ADMT or CAB). The profiles of all patients with LPREs are shown in Table 2. During the median follow-up period of 4.4 years, 10 patients (25.6%) had LPREs. Urinary events were observed in 8 patients (20.5%) and rectal events in 2 patients (5.1%). Of the 3 patients with ureteral obstruction, 2 patients (No. 1 and 2) underwent bilateral percutaneous nephrostomy because of suffering and renal insufficiency. Of the 4 patients with acute urinary retention, 2 patients (No. 4 and 5) were successfully treated with clean intermittent self-catheterization. One patient (No. 6) gave up self-catheterization and underwent percutaneous cystostomy because catheterization induced occasional hematuria. The other one (No. 7) with urinary retention had urinary catheter placement because of severe systemic progression of CRPC. One patient (No. 8) with severe hematuria was successfully treated with transurethral electrocoagulation (TUEC). Of the 2 patients with rectal bleeding and obstruction, 1 patient (No. 9) underwent colostomy and cystostomy, and the other (No. 10) was observed because of severe systemic progression. Median survival after LPREs was 2.4 years. We compared the characteristics of patients with LPREs and those without them. The proportion of T4 in patients with LPREs was higher than in those without 431
Table 2. Profiles of 10 patients with local progression-related events
Pt
PSA at Diagnosis, Age ng/mL
Urinary events 1 54 50.9 2 57 39.4 3 81 469.8 4 71 10.7 5 67 54.1 6 52 22.6 7 84 440.0 8 82 419.9 Rectal events 9 59 11.2 10
63
218.5
TNM
Local Symptoms at Diagnosis
LPREs
Treatment for LPREs
Survival Time to After LPREs, y LPREs, y
T3bN1M1a T4N1M0 T4N1M1b T4N0M1b T3bN0M0 T4N1M1b T3aN1M0 T4N1M1b
— — Present Present — — — —
Ureteral obstruction (bilateral) Ureteral obstruction (bilateral) Ureteral obstruction (unilateral) Urinary retention Urinary retention Urinary retention Urinary retention Hematuria
PNS (bilateral) PNS (bilateral) — CIC CIC Cystostomy Urethral catheter TUEC
T4N1M1b
—
Rectal obstruction
T4N1M1a
—
Rectal bleeding
Colostomy, Cystostomy —
1.4 0.8 1.4 0.8 5.5 2.9 12.2 2.9
3.2* 0.8* 0.5* 0.4y 4.2* 8.2* 0.3* 2.4*
2.4
0.6y
3.6
0.1*
CIC, clean intermittent self-catheterization; LPREs, local progression-related events; Pt, patient; PNS, percutaneous nephrostomy; TUEC, transurethral electrocoagulation; other abbreviations as in Table 1. * Patients who died of cancer. y Patients who are alive with cancer.
Table 3. Univariate and multivariate proportional hazards regression analysis of factors for predicting local progressionrelated events Univariate PSA at diagnosis, ng/mL Prostate volume, mL Gleason score on biopsy T stage Lymph node metastasis Distant metastasis Local symptoms at diagnosis
Multivariate
Category
HR
95% CI
P Value
HR
95% CI
P Value
<100 vs 100 <40 vs 40 7 vs 8 T3 vs T4 Absent vs present Absent vs present Absent vs present
0.32 1.15 1.09 11.44 3.74 1.33 2.26
0.10-1.09 0.33-4.04 0.33-3.64 3.12-41.34 0.81-17.24 0.37-4.71 0.41-12.30
.069 .83 .89 <.001 .091 .66 .35
0.17 0.68 1.61 8.62 1.65 2.28 1.18
0.01-2.49 0.11-4.24 0.33-7.76 1.96-37.88 0.26-10.50 0.17-30.90 0.05-26.24
.20 .68 .56 .004 .59 .54 .92
HR, hazard ratio; CI, confidence interval; other abbreviation as in Table 1.
them (70.0% vs 10.3%; P <.001). There was no significant difference in other clinical parameters between patients with LPREs and those without them. Univariate and multivariate proportional hazards regression analyses were performed to evaluate factors that could predict LPREs (Table 3). Stage T4 at diagnosis was a significant independent risk factor for LPREs in multivariate analysis (hazard ratio, 8.62; P ¼ .004). The 5-year cumulative incidence of LPREs in patients with stage T4 were 70.0%, whereas in those with stage T3 they were 3.6% (P <.001; Fig. 1A). During the follow-up period, 21 patients (53.8%) died of cancer, and no one died because of other causes. The median overall survival period was 6.5 years. There was no significant difference in the cumulative incidence of mortality between patients with LPREs and those without them (5-year mortality, 48.1% vs 42.2%; P ¼ .295; Fig. 1B).
COMMENT The present study demonstrated the characteristics of patients with CRPC who had LPREs. In all, 25.6% of the patients developed LPREs during the follow-up period of 4.4 years. Multivariate analysis revealed that stage T4 at diagnosis was a significant independent risk factor for 432
LPREs. This indicated that aggressive expansion of the tumor in the prostate at diagnosis proceeded to regional problems when progressing to CRPC. Local extension, lymphatic spread, and infiltration of the retroperitoneum by prostate cancer are responsible for urogenital morbidity. Several studies have shown that this morbidity is associated with poor prognosis.8-11 The cohorts in these studies, however, included not only patients with CRPC but also those without prior ADT (watchful waiting). Whether CRPC patients with regional problems caused by local progression are more likely to have a risk of reduced survival remains to be determined. In the present study, there was no significant difference in the overall survival between patients with LPREs and those without them. It was noteworthy that those with LPREs had a median survival of 2.4 years after the LPREs. Recently, the treatment for CRPC has evolved to include taxane-based chemotherapy12 and abiraterone,13 indicating that patients with CRPC can be expected to survive longer. Therefore, it is very important to understand the characteristics of patients who have LPREs so as to be able to adjust the management. In patients with CRPC, the most common site for spread of disease is bone, although this is less true for local progression. Actually, ureteric obstruction emerging during ADT is observed in from 3.3% to 13.9% of the UROLOGY 85 (2), 2015
Figure 1. (A) Cumulative incidence of local progression-related events (LPREs) after androgen deprivation therapy according to T stage. (B) Cumulative incidence of mortality after androgen deprivation therapy in patients with and without local progression-related events. LPREs, local progression-related events.
patients,2,10,11 and acute urinary retention in from 5.0% to 43.8%.2,11,14-17 This may be explained by the heterogenous behavior of CRPC. Arai and Yoshida18 showed the pattern of disease progression in 100 patients with CRPC. The rates of local progression alone, distant progression alone, and local progression with distant progression in 66 patients with stage Nþ or M1 were 15.2%, 54.5%, and 30.3%, respectively, whereas in 34 patients with stage T1-3N0M0, the rates were 64.7%, 20.6%, and 14.7%, respectively. In the present study, stage T4 at diagnosis was an independent factor to predict LPREs. This suggested that locally advanced prostate cancer could be biologically aggressive locally and highly likely to cause regional problems at the time of disease progression. Although ureteral stent indwelling for malignant extrinsic ureteral obstruction has been shown to fail in from 34.0% to 40.6% of patients,19-21 the rate of treatment failure could be higher in the case of local progression of prostate cancer. Ganatra and Loughlin21 showed that conversion to percutaneous nephrostomy was needed in 55.9% of patients with direct invasion to the bladder on cystoscopy. In addition, high complication rates were pointed out for initial indwelling ureteral stents and periodic exchange. Thus, percutaneous nephrostomy may be required when ureteral obstruction emerges in patients with CRPC. The present study demonstrated that acute urinary retention was successfully treated with intermittent selfcatheterization, followed by percutaneous cystostomy in 1 patient. TUEC was conducted in 1 patient with severe hematuria. Many patients with urinary retention or hematuria can be expected to respond to transurethral resection of the prostate (TURP) or TUEC.16,17,22 However, they have high rates of complication with UROLOGY 85 (2), 2015
reoperation, bleeding, and incidences of incontinence, and their effects are limited.22 In a palliative external beam radiotherapy (EBRT) series, high-dose irradiation with 60 Gy was shown to be effective for local symptoms in patients with CRPC.3,23 On the other hand, Kawakami et al24 reported that low-dose irradiation with 30 Gy in 10 fractions was able to control urinary retention with or without severe hematuria. Recently, Din et al4 showed that irradiation with 20 Gy in 5 fractions was effective in 58 CRPC patients with regional symptoms. Of these patients, 89% had complete or partial resolution of symptoms at 4 months. The response rates for urinary retention, hematuria, and rectal symptoms were 54%, 42%, and 75%, respectively. In the present study, 1 of the 2 patients with rectal events underwent colostomy. We believe that it is also important to consider colostomy for rectal obstruction if the symptoms are severe and urgent. Whether local treatment for advanced prostate cancer contributes to reduction of local progression and its related symptoms remains controversial. Won et al2 examined regional symptoms according to various primary treatment groups in patients with CRPC. The radical prostatectomy group had a lower rate of urinary retention than EBRT and ADT groups (4.4% vs 15.6% and 12.1%, respectively). However, there was no significant difference in the incidences of ureteral obstruction among the groups (13.3% vs 17.8% and 13.9%, respectively). Likewise, Oefelein11 reported that patients with CRPC who had undergone primary local treatment had the same risk of ureteral obstruction as those treated with primary ADT. On the other hand, a randomized trial showed that ADT with EBRT in patients with locally advanced disease was beneficial for local control and survival compared with ADT alone.25 Several studies reported that patients with 433
lymph node metastasis treated with ADT and radical prostatectomy had low rates of local progression and urinary retention compared with ADT alone.16,17 Thus, some patients with advanced disease might be candidates for preventative local therapy before the development of CRPC. What is important is to consider how to select and treat patients to prevent urogenital morbidity and not compromise QOL at the time of progression. In the present study, patients with stage T4 were revealed to have a high risk of LPREs. Palliative treatment for urogenital morbidity was performed in 8 of the 10 patients with LPREs. However, this does not indicate that the intervention such as TURP, an indwelling ureteral stent, and percutaneous nephrostomy before the development of LPREs have preventative benefits for patients with stage T4. It is rather difficult to perform TURP or percutaneous nephrostomy without evidence of obstruction. As mentioned previously, the effect of an indwelling ureteral stent is limited, even if it is performed before the development of obstruction or when mild obstruction is evident without renal impairment. Intervention to relieve urogenital morbidity also has its own complications compromising QOL. Therefore, such patients should be closely monitored for early diagnosis of CRPC and LPREs and treated with the proper intervention at the appropriate time. The limitations of the present study must also be addressed. This is a retrospective study, and there was potential bias in the patient selection as well as the problem of incomplete data. This might have substantially affected the results. In addition, the small number of patients might have affected the analytical outcomes. However, the present study demonstrated an independent factor to predict LPREs in patients with CRPC, which will help adjust the management for local progression. A further study with large numbers of patients is needed to validate the conclusion of this study. In the future, we need to conduct a prospective investigation to confirm whether local treatment in patients with stage T4 at diagnosis can help to prevent the emergence of LPREs.
CONCLUSION In patients with CRPC, regional symptoms caused by local progression are a serious problem. In the present study, LPREs were observed in 25.6% of the patients. In addition, patients with stage T4 at diagnosis were more likely to have a risk of LPREs than those with stage T3 regardless of distant metastasis. Those patients can be expected to survive longer with an evolving treatment strategy for CRPC. Patients with locally advanced prostate cancer on ADT need to be closely monitored for early diagnosis of CRPC and treated with the appropriate intervention for LPREs at the appropriate time. References 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;612:69-90.
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2. Won AC, Gurney H, Marx G, et al. Primary treatment of the prostate improves local palliation in men who ultimately develop castrate-resistant prostate cancer. BJU Int. 2013;112:250-255. 3. Hindson B, Turner S, Do V. Palliative radiation therapy for localized prostate symptoms in hormone refractory prostate cancer. Australas Radiol. 2007;51:584-588. 4. Din OS, Thanvi N, Ferguson CJ, et al. Palliative prostate radiotherapy for symptomatic advanced prostate cancer. Radiother Oncol. 2009;93:192-196. 5. Epstein JI, Allsbrook WC Jr, Amin MB, et al. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005;29:1228-1242. 6. Fine JP, Gray RJ. A proportional hazards model for subdistribution of a competing risk. J Am Stat Assoc. 1999;94:456-509. 7. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452-458. 8. Chiou RK, Chang WY, Horan JJ. Ureteral obstruction associated with prostate cancer: the outcome after percutaneous nephrostomy. J Urol. 1990;143:957-959. 9. Colombel M, Mallame W, Abbou CC. Influence of urological complications on the prognosis of prostate cancer. Eur Urol. 1997; 31(Suppl 3):21-24. 10. Paul AB, Love C, Chisholm GD. The management of bilateral ureteric obstruction and renal failure in advanced prostate cancer. Br J Urol. 1994;74:642-645. 11. Oefelein MG. Prognostic significance of obstructive uropathy in advanced prostate cancer. Urology. 2004;63:1117-1121. 12. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. 13. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011; 364:1995-2005. 14. Steinberg GD, Epstein JI, Piantadosi S, et al. Management of stage D1 adenocarcinoma of the prostate: the Johns Hopkins experience 1974 to 1987. J Urol. 1990;144:1425-1432. 15. Fowler JE Jr, Bigler SA, White PC, et al. Hormone therapy for locally advanced prostate cancer. J Urol. 2002;168:546-549. 16. Schmeller N, Lubos W. Early endocrine therapy versus radical prostatectomy combined with early endocrine therapy for stage D1 prostate cancer. Br J Urol. 1997;79:226-234. 17. Grimm MO, Kamphausen S, Hugenschmidt H, et al. Clinical outcome of patients with lymph node positive prostate cancer after radical prostatectomy versus androgen deprivation. Eur Urol. 2002; 41:628-634; discussion 634. 18. Arai Y, Yoshida O. A heterogeneous pattern of progression in endocrine-treated patients with prostate cancer. Eur Urol. 1996;29: 331-336. 19. Kamiyama Y, Matsuura S, Kato M, et al. Stent failure in the management of malignant extrinsic ureteral obstruction: risk factors. Int J Urol. 2011;18:379-382. 20. Chung SY, Stein RJ, Landsittel D, et al. 15-year experience with the management of extrinsic ureteral obstruction with indwelling ureteral stents. J Urol. 2004;172:592-595. 21. Ganatra AM, Loughlin KR. The management of malignant ureteral obstruction treated with ureteral stents. J Urol. 2005;174:2125-2128. 22. Crain DS, Amling CL, Kane CJ. Palliative transurethral prostate resection for bladder outlet obstruction in patients with locally advanced prostate cancer. J Urol. 2004;171:668-671. 23. Furuya Y, Akakura K, Akimoto S, et al. Radiotherapy for local progression in patients with hormone-refractory prostate cancer. Int J Urol. 1999;6:187-191. 24. Kawakami S, Kawai T, Yonese J, et al. Palliative radiotherapy for local progression of hormone refractory stage D2 prostate cancer. Nihon Hinyokika Gakkai Zasshi. 1993;84:1681-1684. 25. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011;378:2104-2111.
UROLOGY 85 (2), 2015
EDITORIAL COMMENT Despite prostate-specific antigen screening and progress in treatment of clinically localized prostate cancer, a sizable proportion of patients either develop or present with hormoneresistant locally advanced disease. Early identification of patients who will need palliation of ureteral, bladder outlet, and rectal obstruction and the decision who, when, and how should be treated is a clinical challenge. This study1 looked into predictors of developing symptomatic local progression in a subset of men diagnosed with prostate cancer and treated with primary hormonal therapy. The authors1 identified stage T4 at diagnosis as a single independent predictor of symptomatic local progression. However intuitive, the result contributes to our understanding of the natural history of the advanced prostate cancer. The small cohort size is the main limitation of this study, whereas data completeness is to its advantage. A population study by Berge et al2 have previously shown tumor grade to be a predictor for ureteral obstruction; however, their study did not include T4 cases. Knowing that a subset of patients with T4 disease is more likely to need a palliative procedure for relief of ureteral, bladder outlet, or rectal obstruction may also be helpful in early patient counseling while determining treatment goals. Furthermore, considering current trends against prostate-specific antigen screening, we are likely to see an increase in patients presenting with locally advanced prostate cancer. Sergey Shikanov, M.D., Department of Urology, Battle Creek VA Medical Center, Battle Creek, MI
References 1. Hashimoto K, Mizuno T, Kitamura H, et al. The primary local stage at diagnosis predicts regional symptoms caused by local progression in patients with castration-resistant prostate cancer. Urology. 2015;85: 430-435. 2. Berge V, Thompson T, Blackman D. Additional surgical intervention after radical prostatectomy, radiation therapy, androgen-deprivation therapy, or watchful waiting. Eur Urol. 2007;52:1036-1043.
prostate cancer at diagnosis, which has been intuitively noticed by clinicians. Some of the patients developed local progressionrelated events such as ureteral, bladder outlet, and rectal obstruction when castration-resistant prostate cancer progressed. Although we did not directly evaluate the quality of life, local events such as acute urinary retention and invasive management for local progression by placement of nephrostomy, cystostomy, and colostomy would impair the quality of life, sometimes accompanied by systemic symptoms such as bone pain. The answer to the question of whether decreasing opportunities for screening for prostate cancer increase the number and the proportion of locally advanced prostate cancers remains unknown because it may be influenced by differences in the exposure rates of such screening and medical systems among countries. However, locally advanced prostate cancer is likely to eventually lead to castration-resistant prostate cancer. On the other hand, the prognosis of the patients with castration-resistant prostate cancer has been improving owing to the introduction of novel hormonal and chemotherapeutic drugs. Thus, care to maintain the quality of life is mandatory for patients with prostate cancer throughout life. To prevent local progression-related events, in addition to systemic treatment using androgen deprivation therapy, more aggressive treatment for the prostate itself may be necessary even though the patients have distant metastases. Because the patients with clinical T4 diseases had a high probability of local progression-related events, the rate of which was 70% in this study, these patients may be candidates for application of local preventive therapy. Although the conclusive method remains unknown, external beam radiation therapy after maximum shrinkage of local tumors by androgen deprivation therapy, but before the occurrence of castration-resistant prostate cancer, may be a reasonable option. A large-scale randomized controlled study or prospective observational study should be conducted to evaluate the efficacy of local prophylactic treatment of patients with clinical T4 prostate cancer who are highly likely to develop local progression-related events during androgen deprivation therapy. Naoya Masumori, M.D., Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan
http://dx.doi.org/10.1016/j.urology.2014.09.047 UROLOGY 85: 435, 2015. 2015 Elsevier Inc.
REPLY Thank you for your editorial comment1 on our article. With regard to the comments1, although the small number of analyzed patients was the major limitation, our study could predict the end of androgen deprivation therapy for locally advanced
UROLOGY 85 (2), 2015
Reference 1. Shikanov S. The primary local stage at diagnosis predicts regional symptoms caused by local progression in patients with castrationresistant prostate cancer [Editorial Comment]. Urology. 2015;85: 430-435.
http://dx.doi.org/10.1016/j.urology.2014.09.048 UROLOGY 85: 435, 2015. 2015 Elsevier Inc.
435
RESULTS
CONCLUSION
To identify the characteristics that predict occurrence of local progression-related events (LPREs) in patients with castration-resistant prostate cancer (CRPC) to adjust its management. We retrospectively reviewed the medical records of 39 patients with CRPC. LPREs were defined as regional symptoms caused by local progression and categorized into urinary events and rectal events. Urinary events were defined as ureteral obstruction, acute urinary retention, or hematuria requiring treatment, and rectal events were rectal obstruction or rectal bleeding caused by tumor invasion. The median prostate-specific antigen level at diagnosis was 185 ng/mL. During the median follow-up period of 4.4 years, 10 patients (25.6%) had LPREs. Urinary events were observed in 8 patients (20.5%) and rectal events in 2 (5.1%). The proportion of T4 in patients with LPREs was higher than in those without LPREs (70.0% vs 10.3%; P <.001). Stage T4 at diagnosis was an independent factor to predict LPREs in multivariate analysis (hazard ratio, 8.62; P ¼ .004). The 5-year cumulative incidence of LPREs in patients with stage T4 was 70.0%, whereas in those with stage T3, they were 3.6% (P <.001). Patients with stage T4 at diagnosis are more likely to have a risk of LPREs than those with stage T3. These results indicate that patients with locally advanced prostate cancer on androgen deprivation therapy need to be closely monitored for early diagnosis of CRPC and treated with the appropriate intervention for LPREs at the appropriate time. UROLOGY 85: 430e435, 2015. 2015 Elsevier Inc.
P
rostate cancer is the most common noncutaneous malignancy in men in developed countries.1 Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. However, in most cases, the disease progresses despite the castration level of serum testosterone and results in castration-resistant prostate cancer (CRPC). Some patients with CRPC experience symptoms caused by local progression, including ureteral obstruction, bladder outlet obstruction, severe hematuria, and rectal obstruction.2-4 These can lead to poor quality of life (QOL). However, local progression is commonly accompanied by life-threatening systemic progression of CRPC. We always face a dilemma as to whether aggressive
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan Address correspondence to: Naoya Masumori, M.D., Department of Urology, Sapporo Medical University School of Medicine, S1, W16, Chuo-ku, Sapporo 060-8543, Japan. E-mail: [email protected] Submitted: April 11, 2014, accepted (with revisions): September 2, 2014
430
ª 2015 Elsevier Inc. All Rights Reserved
intervention for local progression provides a significant clinical effect for such patients. Thus, the strategy for local progression in patients with CRPC remains to be determined because its profile is unclear. The aim of this study was to identify the characteristics that predict occurrence of local progression-related events (LPREs) in patients with CRPC to adjust its management.
METHODS We reviewed patients with advanced prostate cancer who initially received androgen deprivation monotherapy (ADMT) or complete androgen blockade (CAB) with an antiandrogen as the first-line treatment in our institution between 1999 and 2009 and isolated 39 patients who progressed to CRPC during the follow-up period. All patients had serum prostate-specific antigen (PSA) determination (ECLusys PSA II assay; Roche Diagnostics, Tokyo, Japan) before prostate biopsy. Systematic prostate biopsy was performed using an 18-gauge needle under the guidance of transrectal ultrasound, and 6-14 biopsy cores were taken from each patient. The clinical stage was determined via digital rectal examination, transrectal ultrasound, abdominal http://dx.doi.org/10.1016/j.urology.2014.09.044 0090-4295/15
Table 1. Clinical characteristics of patients N ¼ 39 Median age at diagnosis (range), y 73 (51-88) Median PSA at diagnosis (range), 185 (10.7-8190) ng/mL Median prostate volume 40.2 (16.3-79.8) (range), mL Gleason score on biopsy (%) 6 2 (5.1) 7 9 (23.1) 8 28 (71.8) TNM stage (%) T2-4N0M0 7 (17.9) TanyN1M0 6 (15.4) TanyN0M1 11 (28.2) TanyN1M1 15 (38.5) Local symptoms at diagnosis (%) 5 (12.8) Primary ADT (%) Surgical castration/LHRH 11 (28.2)/22 (56.4) agonist CAB 5 (12.8) LHRH antagonist 1 (2.6) Time to progression during ADT 9.1 (0.8-79.8) (range), mo ADT, androgen deprivation therapy; CAB, complete androgen blockade; LHRH, luteinizing hormoneereleasing hormone; PSA, prostate-specific antigen; TNM, tumor-nodes-metastasis.
computed tomography, chest x-ray, and bone scanning using 99mTc-methylene-diphosphonate. The stage and histologic grade were assigned using the 2009 The Union for International Cancer Control-American Joint Committee on Cancer tumornodes-metastasis staging system and Gleason grading system based on the criteria of the 2005 International Society of Urological Pathology consensus conference.5 As the first-line treatment, 34 patients were treated with ADMT, with surgical castration for 11 patients, the administration of a luteinizing hormoneereleasing hormone agonist for 22 patients and a luteinizing hormoneereleasing hormone antagonist for 1 patient (Table 1). Five patients were treated with CAB, with bicalutamide 80 mg daily for 2 patients, chlormadinone acetate 100 mg daily for 2 patients, and flutamide 375 mg daily for 1 patient. As all patients had PSA progression during ADMT or CAB, second-line treatment was done using an additional antiandrogen for those who underwent ADMT and an alternative antiandrogen for those with CAB. If PSA elevation developed during CAB, the antiandrogen was terminated, and the patient was observed for antiandrogen withdrawal syndrome. Positive antiandrogen withdrawal syndrome was defined as a PSA decline of 50% from the PSA level at the time when the antiandrogen was discontinued. After failure of the second-line treatment for those with the second-line CAB, another alternative antiandrogen, estrogen, glucocorticoid with ADMT, or docetaxel was given as the thirdline treatment. Drugs used in the second-line or later treatment were decided based on the preferences of the physicians. Physical examination and serum PSA measurement were performed every 3 months throughout the follow-up period. Digital rectal examination, transrectal ultrasonography, abdominal computed tomography, chest x-ray, and bone scanning were performed when clinically indicated. LPREs were defined as regional symptoms caused by local progression and categorized into urinary events and rectal events. Urinary events were defined as ureteral obstruction (either unilateral or bilateral), acute urinary retention, or hematuria requiring treatment, UROLOGY 85 (2), 2015
and rectal events were rectal obstruction and rectal bleeding caused by tumor invasion. Data were extracted, including the characteristics of the patients (age, clinical stage, PSA level, prostate volume, biopsy findings, treatments, and local symptoms at diagnosis of CRPC) and local progression data (LPREs, treatments, and time to LPREs). The time of PSA progression was defined as the time of the first of 3 consecutive increases in the PSA level. Survival time from the start of the first therapy to death of prostate cancer was calculated. The Fisher exact test and the Mann-Whitney U test were carried out to compare various clinical variables between the groups with and without LPREs. The Fine-Gray regression model was used to calculate the probability of LPREs and prostate cancer mortality.6 Cumulative incidence curves were used in a competing risk setting, with death without LPREs for probability of LPREs or death due to other cause for prostate cancer mortality as a competing event. The proportional hazards regression model for the subdistribution of a competing risk was used to estimate the prognostic factors of LPREs based on the optimal cutoff value for each parameter. P <.05 was considered to be statistically significant. All statistical analyses were performed with EZR for Windows (Saitama Medical Center, Jichi Medical University, Saitama), which is a graphical user interface for R (version 2.13.0; The R Foundation for Statistical Computing, Vienna, Austria).7 More precisely, it is a modified version of R commander (version 1.6-3) that was designed to add statistical functions frequently used in biostatistics.
RESULTS The characteristics of the patients are shown in Table 1. The median PSA level at diagnosis was 185 ng/mL. Stage T2 was observed in 3 patients (7.7%), T3 in 26 (66.7%), and T4 in 10 (25.6%). Although 5 patients had local symptomatic events such as ureteral obstruction and urinary retention at diagnosis, all of them improved immediately after the primary ADT (ADMT or CAB). The profiles of all patients with LPREs are shown in Table 2. During the median follow-up period of 4.4 years, 10 patients (25.6%) had LPREs. Urinary events were observed in 8 patients (20.5%) and rectal events in 2 patients (5.1%). Of the 3 patients with ureteral obstruction, 2 patients (No. 1 and 2) underwent bilateral percutaneous nephrostomy because of suffering and renal insufficiency. Of the 4 patients with acute urinary retention, 2 patients (No. 4 and 5) were successfully treated with clean intermittent self-catheterization. One patient (No. 6) gave up self-catheterization and underwent percutaneous cystostomy because catheterization induced occasional hematuria. The other one (No. 7) with urinary retention had urinary catheter placement because of severe systemic progression of CRPC. One patient (No. 8) with severe hematuria was successfully treated with transurethral electrocoagulation (TUEC). Of the 2 patients with rectal bleeding and obstruction, 1 patient (No. 9) underwent colostomy and cystostomy, and the other (No. 10) was observed because of severe systemic progression. Median survival after LPREs was 2.4 years. We compared the characteristics of patients with LPREs and those without them. The proportion of T4 in patients with LPREs was higher than in those without 431
Table 2. Profiles of 10 patients with local progression-related events
Pt
PSA at Diagnosis, Age ng/mL
Urinary events 1 54 50.9 2 57 39.4 3 81 469.8 4 71 10.7 5 67 54.1 6 52 22.6 7 84 440.0 8 82 419.9 Rectal events 9 59 11.2 10
63
218.5
TNM
Local Symptoms at Diagnosis
LPREs
Treatment for LPREs
Survival Time to After LPREs, y LPREs, y
T3bN1M1a T4N1M0 T4N1M1b T4N0M1b T3bN0M0 T4N1M1b T3aN1M0 T4N1M1b
— — Present Present — — — —
Ureteral obstruction (bilateral) Ureteral obstruction (bilateral) Ureteral obstruction (unilateral) Urinary retention Urinary retention Urinary retention Urinary retention Hematuria
PNS (bilateral) PNS (bilateral) — CIC CIC Cystostomy Urethral catheter TUEC
T4N1M1b
—
Rectal obstruction
T4N1M1a
—
Rectal bleeding
Colostomy, Cystostomy —
1.4 0.8 1.4 0.8 5.5 2.9 12.2 2.9
3.2* 0.8* 0.5* 0.4y 4.2* 8.2* 0.3* 2.4*
2.4
0.6y
3.6
0.1*
CIC, clean intermittent self-catheterization; LPREs, local progression-related events; Pt, patient; PNS, percutaneous nephrostomy; TUEC, transurethral electrocoagulation; other abbreviations as in Table 1. * Patients who died of cancer. y Patients who are alive with cancer.
Table 3. Univariate and multivariate proportional hazards regression analysis of factors for predicting local progressionrelated events Univariate PSA at diagnosis, ng/mL Prostate volume, mL Gleason score on biopsy T stage Lymph node metastasis Distant metastasis Local symptoms at diagnosis
Multivariate
Category
HR
95% CI
P Value
HR
95% CI
P Value
<100 vs 100 <40 vs 40 7 vs 8 T3 vs T4 Absent vs present Absent vs present Absent vs present
0.32 1.15 1.09 11.44 3.74 1.33 2.26
0.10-1.09 0.33-4.04 0.33-3.64 3.12-41.34 0.81-17.24 0.37-4.71 0.41-12.30
.069 .83 .89 <.001 .091 .66 .35
0.17 0.68 1.61 8.62 1.65 2.28 1.18
0.01-2.49 0.11-4.24 0.33-7.76 1.96-37.88 0.26-10.50 0.17-30.90 0.05-26.24
.20 .68 .56 .004 .59 .54 .92
HR, hazard ratio; CI, confidence interval; other abbreviation as in Table 1.
them (70.0% vs 10.3%; P <.001). There was no significant difference in other clinical parameters between patients with LPREs and those without them. Univariate and multivariate proportional hazards regression analyses were performed to evaluate factors that could predict LPREs (Table 3). Stage T4 at diagnosis was a significant independent risk factor for LPREs in multivariate analysis (hazard ratio, 8.62; P ¼ .004). The 5-year cumulative incidence of LPREs in patients with stage T4 were 70.0%, whereas in those with stage T3 they were 3.6% (P <.001; Fig. 1A). During the follow-up period, 21 patients (53.8%) died of cancer, and no one died because of other causes. The median overall survival period was 6.5 years. There was no significant difference in the cumulative incidence of mortality between patients with LPREs and those without them (5-year mortality, 48.1% vs 42.2%; P ¼ .295; Fig. 1B).
COMMENT The present study demonstrated the characteristics of patients with CRPC who had LPREs. In all, 25.6% of the patients developed LPREs during the follow-up period of 4.4 years. Multivariate analysis revealed that stage T4 at diagnosis was a significant independent risk factor for 432
LPREs. This indicated that aggressive expansion of the tumor in the prostate at diagnosis proceeded to regional problems when progressing to CRPC. Local extension, lymphatic spread, and infiltration of the retroperitoneum by prostate cancer are responsible for urogenital morbidity. Several studies have shown that this morbidity is associated with poor prognosis.8-11 The cohorts in these studies, however, included not only patients with CRPC but also those without prior ADT (watchful waiting). Whether CRPC patients with regional problems caused by local progression are more likely to have a risk of reduced survival remains to be determined. In the present study, there was no significant difference in the overall survival between patients with LPREs and those without them. It was noteworthy that those with LPREs had a median survival of 2.4 years after the LPREs. Recently, the treatment for CRPC has evolved to include taxane-based chemotherapy12 and abiraterone,13 indicating that patients with CRPC can be expected to survive longer. Therefore, it is very important to understand the characteristics of patients who have LPREs so as to be able to adjust the management. In patients with CRPC, the most common site for spread of disease is bone, although this is less true for local progression. Actually, ureteric obstruction emerging during ADT is observed in from 3.3% to 13.9% of the UROLOGY 85 (2), 2015
Figure 1. (A) Cumulative incidence of local progression-related events (LPREs) after androgen deprivation therapy according to T stage. (B) Cumulative incidence of mortality after androgen deprivation therapy in patients with and without local progression-related events. LPREs, local progression-related events.
patients,2,10,11 and acute urinary retention in from 5.0% to 43.8%.2,11,14-17 This may be explained by the heterogenous behavior of CRPC. Arai and Yoshida18 showed the pattern of disease progression in 100 patients with CRPC. The rates of local progression alone, distant progression alone, and local progression with distant progression in 66 patients with stage Nþ or M1 were 15.2%, 54.5%, and 30.3%, respectively, whereas in 34 patients with stage T1-3N0M0, the rates were 64.7%, 20.6%, and 14.7%, respectively. In the present study, stage T4 at diagnosis was an independent factor to predict LPREs. This suggested that locally advanced prostate cancer could be biologically aggressive locally and highly likely to cause regional problems at the time of disease progression. Although ureteral stent indwelling for malignant extrinsic ureteral obstruction has been shown to fail in from 34.0% to 40.6% of patients,19-21 the rate of treatment failure could be higher in the case of local progression of prostate cancer. Ganatra and Loughlin21 showed that conversion to percutaneous nephrostomy was needed in 55.9% of patients with direct invasion to the bladder on cystoscopy. In addition, high complication rates were pointed out for initial indwelling ureteral stents and periodic exchange. Thus, percutaneous nephrostomy may be required when ureteral obstruction emerges in patients with CRPC. The present study demonstrated that acute urinary retention was successfully treated with intermittent selfcatheterization, followed by percutaneous cystostomy in 1 patient. TUEC was conducted in 1 patient with severe hematuria. Many patients with urinary retention or hematuria can be expected to respond to transurethral resection of the prostate (TURP) or TUEC.16,17,22 However, they have high rates of complication with UROLOGY 85 (2), 2015
reoperation, bleeding, and incidences of incontinence, and their effects are limited.22 In a palliative external beam radiotherapy (EBRT) series, high-dose irradiation with 60 Gy was shown to be effective for local symptoms in patients with CRPC.3,23 On the other hand, Kawakami et al24 reported that low-dose irradiation with 30 Gy in 10 fractions was able to control urinary retention with or without severe hematuria. Recently, Din et al4 showed that irradiation with 20 Gy in 5 fractions was effective in 58 CRPC patients with regional symptoms. Of these patients, 89% had complete or partial resolution of symptoms at 4 months. The response rates for urinary retention, hematuria, and rectal symptoms were 54%, 42%, and 75%, respectively. In the present study, 1 of the 2 patients with rectal events underwent colostomy. We believe that it is also important to consider colostomy for rectal obstruction if the symptoms are severe and urgent. Whether local treatment for advanced prostate cancer contributes to reduction of local progression and its related symptoms remains controversial. Won et al2 examined regional symptoms according to various primary treatment groups in patients with CRPC. The radical prostatectomy group had a lower rate of urinary retention than EBRT and ADT groups (4.4% vs 15.6% and 12.1%, respectively). However, there was no significant difference in the incidences of ureteral obstruction among the groups (13.3% vs 17.8% and 13.9%, respectively). Likewise, Oefelein11 reported that patients with CRPC who had undergone primary local treatment had the same risk of ureteral obstruction as those treated with primary ADT. On the other hand, a randomized trial showed that ADT with EBRT in patients with locally advanced disease was beneficial for local control and survival compared with ADT alone.25 Several studies reported that patients with 433
lymph node metastasis treated with ADT and radical prostatectomy had low rates of local progression and urinary retention compared with ADT alone.16,17 Thus, some patients with advanced disease might be candidates for preventative local therapy before the development of CRPC. What is important is to consider how to select and treat patients to prevent urogenital morbidity and not compromise QOL at the time of progression. In the present study, patients with stage T4 were revealed to have a high risk of LPREs. Palliative treatment for urogenital morbidity was performed in 8 of the 10 patients with LPREs. However, this does not indicate that the intervention such as TURP, an indwelling ureteral stent, and percutaneous nephrostomy before the development of LPREs have preventative benefits for patients with stage T4. It is rather difficult to perform TURP or percutaneous nephrostomy without evidence of obstruction. As mentioned previously, the effect of an indwelling ureteral stent is limited, even if it is performed before the development of obstruction or when mild obstruction is evident without renal impairment. Intervention to relieve urogenital morbidity also has its own complications compromising QOL. Therefore, such patients should be closely monitored for early diagnosis of CRPC and LPREs and treated with the proper intervention at the appropriate time. The limitations of the present study must also be addressed. This is a retrospective study, and there was potential bias in the patient selection as well as the problem of incomplete data. This might have substantially affected the results. In addition, the small number of patients might have affected the analytical outcomes. However, the present study demonstrated an independent factor to predict LPREs in patients with CRPC, which will help adjust the management for local progression. A further study with large numbers of patients is needed to validate the conclusion of this study. In the future, we need to conduct a prospective investigation to confirm whether local treatment in patients with stage T4 at diagnosis can help to prevent the emergence of LPREs.
CONCLUSION In patients with CRPC, regional symptoms caused by local progression are a serious problem. In the present study, LPREs were observed in 25.6% of the patients. In addition, patients with stage T4 at diagnosis were more likely to have a risk of LPREs than those with stage T3 regardless of distant metastasis. Those patients can be expected to survive longer with an evolving treatment strategy for CRPC. Patients with locally advanced prostate cancer on ADT need to be closely monitored for early diagnosis of CRPC and treated with the appropriate intervention for LPREs at the appropriate time. References 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;612:69-90.
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2. Won AC, Gurney H, Marx G, et al. Primary treatment of the prostate improves local palliation in men who ultimately develop castrate-resistant prostate cancer. BJU Int. 2013;112:250-255. 3. Hindson B, Turner S, Do V. Palliative radiation therapy for localized prostate symptoms in hormone refractory prostate cancer. Australas Radiol. 2007;51:584-588. 4. Din OS, Thanvi N, Ferguson CJ, et al. Palliative prostate radiotherapy for symptomatic advanced prostate cancer. Radiother Oncol. 2009;93:192-196. 5. Epstein JI, Allsbrook WC Jr, Amin MB, et al. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005;29:1228-1242. 6. Fine JP, Gray RJ. A proportional hazards model for subdistribution of a competing risk. J Am Stat Assoc. 1999;94:456-509. 7. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452-458. 8. Chiou RK, Chang WY, Horan JJ. Ureteral obstruction associated with prostate cancer: the outcome after percutaneous nephrostomy. J Urol. 1990;143:957-959. 9. Colombel M, Mallame W, Abbou CC. Influence of urological complications on the prognosis of prostate cancer. Eur Urol. 1997; 31(Suppl 3):21-24. 10. Paul AB, Love C, Chisholm GD. The management of bilateral ureteric obstruction and renal failure in advanced prostate cancer. Br J Urol. 1994;74:642-645. 11. Oefelein MG. Prognostic significance of obstructive uropathy in advanced prostate cancer. Urology. 2004;63:1117-1121. 12. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. 13. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011; 364:1995-2005. 14. Steinberg GD, Epstein JI, Piantadosi S, et al. Management of stage D1 adenocarcinoma of the prostate: the Johns Hopkins experience 1974 to 1987. J Urol. 1990;144:1425-1432. 15. Fowler JE Jr, Bigler SA, White PC, et al. Hormone therapy for locally advanced prostate cancer. J Urol. 2002;168:546-549. 16. Schmeller N, Lubos W. Early endocrine therapy versus radical prostatectomy combined with early endocrine therapy for stage D1 prostate cancer. Br J Urol. 1997;79:226-234. 17. Grimm MO, Kamphausen S, Hugenschmidt H, et al. Clinical outcome of patients with lymph node positive prostate cancer after radical prostatectomy versus androgen deprivation. Eur Urol. 2002; 41:628-634; discussion 634. 18. Arai Y, Yoshida O. A heterogeneous pattern of progression in endocrine-treated patients with prostate cancer. Eur Urol. 1996;29: 331-336. 19. Kamiyama Y, Matsuura S, Kato M, et al. Stent failure in the management of malignant extrinsic ureteral obstruction: risk factors. Int J Urol. 2011;18:379-382. 20. Chung SY, Stein RJ, Landsittel D, et al. 15-year experience with the management of extrinsic ureteral obstruction with indwelling ureteral stents. J Urol. 2004;172:592-595. 21. Ganatra AM, Loughlin KR. The management of malignant ureteral obstruction treated with ureteral stents. J Urol. 2005;174:2125-2128. 22. Crain DS, Amling CL, Kane CJ. Palliative transurethral prostate resection for bladder outlet obstruction in patients with locally advanced prostate cancer. J Urol. 2004;171:668-671. 23. Furuya Y, Akakura K, Akimoto S, et al. Radiotherapy for local progression in patients with hormone-refractory prostate cancer. Int J Urol. 1999;6:187-191. 24. Kawakami S, Kawai T, Yonese J, et al. Palliative radiotherapy for local progression of hormone refractory stage D2 prostate cancer. Nihon Hinyokika Gakkai Zasshi. 1993;84:1681-1684. 25. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011;378:2104-2111.
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EDITORIAL COMMENT Despite prostate-specific antigen screening and progress in treatment of clinically localized prostate cancer, a sizable proportion of patients either develop or present with hormoneresistant locally advanced disease. Early identification of patients who will need palliation of ureteral, bladder outlet, and rectal obstruction and the decision who, when, and how should be treated is a clinical challenge. This study1 looked into predictors of developing symptomatic local progression in a subset of men diagnosed with prostate cancer and treated with primary hormonal therapy. The authors1 identified stage T4 at diagnosis as a single independent predictor of symptomatic local progression. However intuitive, the result contributes to our understanding of the natural history of the advanced prostate cancer. The small cohort size is the main limitation of this study, whereas data completeness is to its advantage. A population study by Berge et al2 have previously shown tumor grade to be a predictor for ureteral obstruction; however, their study did not include T4 cases. Knowing that a subset of patients with T4 disease is more likely to need a palliative procedure for relief of ureteral, bladder outlet, or rectal obstruction may also be helpful in early patient counseling while determining treatment goals. Furthermore, considering current trends against prostate-specific antigen screening, we are likely to see an increase in patients presenting with locally advanced prostate cancer. Sergey Shikanov, M.D., Department of Urology, Battle Creek VA Medical Center, Battle Creek, MI
References 1. Hashimoto K, Mizuno T, Kitamura H, et al. The primary local stage at diagnosis predicts regional symptoms caused by local progression in patients with castration-resistant prostate cancer. Urology. 2015;85: 430-435. 2. Berge V, Thompson T, Blackman D. Additional surgical intervention after radical prostatectomy, radiation therapy, androgen-deprivation therapy, or watchful waiting. Eur Urol. 2007;52:1036-1043.
prostate cancer at diagnosis, which has been intuitively noticed by clinicians. Some of the patients developed local progressionrelated events such as ureteral, bladder outlet, and rectal obstruction when castration-resistant prostate cancer progressed. Although we did not directly evaluate the quality of life, local events such as acute urinary retention and invasive management for local progression by placement of nephrostomy, cystostomy, and colostomy would impair the quality of life, sometimes accompanied by systemic symptoms such as bone pain. The answer to the question of whether decreasing opportunities for screening for prostate cancer increase the number and the proportion of locally advanced prostate cancers remains unknown because it may be influenced by differences in the exposure rates of such screening and medical systems among countries. However, locally advanced prostate cancer is likely to eventually lead to castration-resistant prostate cancer. On the other hand, the prognosis of the patients with castration-resistant prostate cancer has been improving owing to the introduction of novel hormonal and chemotherapeutic drugs. Thus, care to maintain the quality of life is mandatory for patients with prostate cancer throughout life. To prevent local progression-related events, in addition to systemic treatment using androgen deprivation therapy, more aggressive treatment for the prostate itself may be necessary even though the patients have distant metastases. Because the patients with clinical T4 diseases had a high probability of local progression-related events, the rate of which was 70% in this study, these patients may be candidates for application of local preventive therapy. Although the conclusive method remains unknown, external beam radiation therapy after maximum shrinkage of local tumors by androgen deprivation therapy, but before the occurrence of castration-resistant prostate cancer, may be a reasonable option. A large-scale randomized controlled study or prospective observational study should be conducted to evaluate the efficacy of local prophylactic treatment of patients with clinical T4 prostate cancer who are highly likely to develop local progression-related events during androgen deprivation therapy. Naoya Masumori, M.D., Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan
http://dx.doi.org/10.1016/j.urology.2014.09.047 UROLOGY 85: 435, 2015. 2015 Elsevier Inc.
REPLY Thank you for your editorial comment1 on our article. With regard to the comments1, although the small number of analyzed patients was the major limitation, our study could predict the end of androgen deprivation therapy for locally advanced
UROLOGY 85 (2), 2015
Reference 1. Shikanov S. The primary local stage at diagnosis predicts regional symptoms caused by local progression in patients with castrationresistant prostate cancer [Editorial Comment]. Urology. 2015;85: 430-435.
http://dx.doi.org/10.1016/j.urology.2014.09.048 UROLOGY 85: 435, 2015. 2015 Elsevier Inc.
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