Treatment outcomes of bladder/prostate rhabdomyosarcoma (RMS) in multi- and single-institutional trials are reviewed. Remarkable strides have occurred in the treatment of this disease. Decreasing duration of chemotherapy, less cumulative doses of radiation therapy, and improving survival have been documented. A focus on bladder preservation has not adversely affected survival in most studies. Even if organ preservation is not possible, improvements in urinary diversion surgical technique still offer improved quality of life. The IRS III was a pivotal study in improving survival and quality of life. We recommend protocol enrollment whenever available. We also emphasize the use of magnetic resonance imaging and second look surgery.
Bladder and/or prostate (B/P) rhabdomyosarcoma (RMS) therapy before the early 1970s yielded a survival rate of 10–40%.1,2 Therapeutic approaches of that era usually involved radical or partial surgery; subsequent spread of tumor because of poor local control and/or inadequate chemotherapy occurred frequently. Since the early 1970s, large multi- and single-center prospective trials in the US, UK, Europe, and Asia began using risk-based multimodality therapy. Risk-based multimodality therapy involves the synthesis of surgery and chemotherapy, with and without radiation therapy based on the tumor site, size, nodal status, and metastasis.3,4 Such advances in medical and surgical decision making have yielded a 5-y survival rate of 83%, and a much better quality of life through organ preservation.4
Epidemiology, histology, and clinical presentation
RMS is a highly malignant mesenchymal tumor representing 15–20% of malignancies of childhood and is the most common childhood soft-tissue sarcoma. The incidence is about 250 new cases each year in the United States.5 Genitourinary (G/U) RMS makes up about 24% of all RMS.6,7 Of that number, about half involve the bladder, prostate or both.4 It presents across all ages with peak incidences between age 2 and 6?y and at adolescence with a male to female ratio of 1.9?:?1.1.5 For B/P RMS, mean age of presentation is about 5?y,8 although this varies among studies.9,10 Patients younger than 1-y old have a higher rate of G/U tumors than older children: 24 vs 10%.11 Age does not seem to be an important prognostic factor.11
Histologically, 90% of B/P RMS are of the embryonal type. This type is considered a favorable type for prognosis.9,12 About 10% are localized to the dome of the bladder; most tumors are at the trigone or neck of the bladder.13,14 Early reports suggested that involvement of the prostate carries a worse prognosis,15,16 but more recent data suggest similar prognosis from either site.17
Clinically, there is a similar presentation whether the tumor is of bladder or prostate origin:10 lesions may manifest as urinary tract obstruction, hematuria, or abdominal mass.8,18 Often it is clinically difficult to distinguish between whether the tumor is prostate or a bladder primary.8,18,19 At the time of clinical presentation, the tumor is usually larger than 5?cm,18,20,21 and is often invasive of surrounding tissue.17
The Intergroup Rhabdomyosarcoma Study Group (IRSG)
Four IRSG studies have been completed since 1972; IRS V is ongoing. The ultimate population analyzed in IRS I–IV was 3389.4,22,23,24,25 Up to 116 institutions were involved, encompassing about 85% of the new cases of RMS in the United States. Patients were age 21?y and less. In IRS I–IV, 445 children had B/P RMS. All four studies utilized the same clinical grouping system (Figure 1) for staging; however IRS IV utilized a TNM staging system for presurgical staging (Table 1) in addition to the first trial postsurgical system.25 The overwhelming goal of the IRSG studies has not only been to increase survivability but to improve quality of life of those survivors. The IRS regimens are summarized in Tables 2, 3 and 4.
The IRS I was mainly a surgical study with adjuvant chemotherapy (CTX). In IRS I, 35 of the 80 patients with B/P RMS underwent radical surgery incorporating a total cystectomy often via anterior pelvic exenteration before initiating CTX.26 Radical surgery was considered the conventional approach by most at that time.27,28 These patients were then staged in clinical groups I and II. Radical surgery, while originally thought to increase survival,29 has complications of its own: wound infection, fistula, abscess, hydronephrosis, bowel obstruction, and uretural stenosis.30 The remaining patients were deemed to have tumors considered nonresectable by radical surgery or had metastatic disease and hence fell into groups III and IV, respectively. After 2?y of the study, the focus changed towards a more conservative surgical approach to attempt bladder preservation. Bladder preservation in those alive 2 and 3?y after starting treatment were 26 and 23%, respectively.31
Some crucial points were learned in IRS I. Specifically related to B/P RMS, lymph node involvement could not be correlated with recurrence or survival rates.31 Lawrence et al32 recommended ‘routine regional lymph node dissection for all G/U primary sites that are primarily treated by surgical resection.’ The IRS specifically looked at nodal involvement in GU B/P, recommending combined CTX/radiation therapy (RT), with RT doses delivered over 4 weeks. In node-negative cases nodes, it was recommended that RT may be neglected.33
In IRS II (1979–1984), the focus was primary CTX with or without RT. A major goal of this study was organ preservation. Many tumors that ordinarily would be staged clinical groups I and II were only biopsied, and thus fell into clinical group III. Of the clinical group III B/P tumors, about 90% of patients were nonrandomly assigned to regimen 27 (Table 2). Surgery and RT were withheld based upon initial CTX response after 8 weeks. Hays34 notes that RT was not utilized in some cases until 18?months after diagnosis. In the first 2?y of the study, RT dose was 25?Gy over 3 to 4 weeks, but after 1980, the dose was increased to 40–45?Gy over 4–5 weeks.31
Initially, this approach was successful in the first year, with 97% bladder retention compared to 58% in IRS I. However, only 22% of children retained their bladder 3?y after starting treatment. The 5-y survival rate of bladder and/or prostate RMS was 72%,4 statistically equivalent to IRS I. The disease-free survival (DFS) for patients with B/P tumor at 5?y was 58%.4 The IRSG concluded that the regimen of IRS II failed to improve bladder salvage.31 Nonetheless, Wharam et al35 reported that RT provided ‘local control in most cases’ for clinical group III.
Raney and associates reviewed the 109 patients who retained their bladder from IRS I and II with 5–15?y follow-up. About half eventually went on to total cystectomy, and the other half retained their bladder, with 73% able to maintain normal urinary function. Interestingly, bladder retention compared to total cystectomy had fewer urologic side effects: bactiuria of 35% contrasted to 12%; hematuria 39% contrasted to 20%; elevated BUN/Cr 9% contrasted to 2%. Over the entire 109 patients, eight had osseous problems varying from slipped epiphyses (4) to contracted pelvis (2) and sacral sclerosis. Significant problems with growth were seen in 10%.
Some of the crucial lessons of the IRS II included the importance of frequent follow-up to evaluate response from combination therapy. In addition, it was described that delaying local therapy decreases survival.36
In the IRS III (1984–1991), therapy was randomized by group, primary tumor, and favorable vs unfavorable histology. Unfavorable histology mainly included the alveolar type. Bladder and/or prostate tumor unfavorable histology lesions were not included in IRS III.4
For B/P tumors, the IRSG made significant changes in IRS III. First RT was set at 6 weeks from diagnosis for most tumors (Table 3). Adriamycin (ADR), cis platinum (CDDP), and etoposide (VP-16) were added to the chemotherapeutic regimens for clinical group III and IV tumors. Surgically, there was a focus from the outset on using conservative measures such as primary or secondary partial cystectomy or prostatectomy without cystectomy. In this surgical approach, more patients were placed in clinical groups I and II, thereby receiving less intensive CTX. Second look surgery (SLS) was often used in cases of partial cystectomy. If at week 20 there was complete remission (CR), or if CR was achieved by SLS, then therapy without RT continued. If by week 20 there was partial response (PR), defined by greater than 50% decrease in volume of tumor, then two cycles of actinomycin-D (AMD) and VP-16 were added, followed by RT starting on week 20. For tumors in the bladder neck or trigone, the CTX was the same, but RT started at week 6. Noteworthy, of the 90 patients achieving CR, 26 were made tumor free by SLS resection.4,18 In IRS I–III, it is worth mentioning that patients who relapsed would usually undergo radical surgery.34
Hays noted that in both IRS II and III there was a trial of delayed partial cystectomy in seven patients. CTX with or without RT was used for several months, then on SLS, partial cystectomy was performed.34 This population was relapse free at 3.9–13.9?y. Hays and colleagues reviewed all of the cases of partial cystectomy for bladder RMS in IRS I–III. Of the 40 cases, 31(78.5%) were disease free from 2 to 16?y follow-up, which is comparable to the 79.5% of all bladder RMS in the same interval for those without bladder preservation. Of the 31 survivors, only one required secondary total cystectomy, and two required bladder augmentation. Of note, about 75% of this population have no bladder-related symptoms or lower urinary tract disease. The IRSG stressed, however, that bladder complications were greater in the irradiated vs the nonirradiated population.20
The novel approaches of IRS III led to dramatic improvements. In prostatic tumors, the IRSG claimed a bladder salvage of 64% contrasted to 57% in IRS II in the overall surviving population.37 In both sites, the combined bladder salvage was about 60%. Hays and colleagues stressed that those who received CDDP and ADR were all long-term survivors. The 5-y DFS was 74%, and the 5-y overall survival was (OS) 83% across all groups4 and 90% for children with nonmetastatic disease.20,38 However, the IRSG concluded that there was no benefit for metastatic disease from the intensified CTX regimen.
Heyn and colleagues, in their review of Group III bladder RMS, reported that the imaging modalities of CT scan, intravenous pyelogram and ultrasound were inadequate in evaluating tumor response. Cystoscopy was the most effective way to assess tumor status at periodic intervals. They recommended cystoscopy at 1–2 month intervals.39
Interestingly, Ortega and associates described the presence of well-differentiated RMS at the completion of therapy as a ‘common finding.’ They added that these cells can persist up to 2?y, but do not represent persistent malignant disease. Thus, they recommend not continuing therapy beyond the originally prescribed regimen based on discovery of this histology.40
The IRS IV (1991–1997) had the principal goals of testing new CTX regimens and the utility of conventional RT (C-RT) vs hyperfractionated RT (H-RT). Another change was incorporating a presurgical TNM staging system (Table 1) while keeping the clinical grouping system (Figure 1) as a postsurgical staging system. CTX regimens were implemented to test the efficacy of ifosfamide (IFOS), a cyclophosphamide analog and VP-16. The combinations were vincristine, ifosfamide, and etoposide (VIE) and vincristine, acitinomycin D,and Ifosfamide (VAI) contrasted to VAC. The B/P population was stratified as shown in Table 3. G/U tumors of B/P origin were not deemed stage 1 in the TNM system.
RT was based on IRS clinical group. Stage II group I received no RT. Patients with stage III groups I and II received C-RT of 41.4?Gy. Those with group III and pre-existing renal abnormalities were nonrandomly assigned to receive C-RT of 50.4?Gy and VAC. In February 1995, patients with group III and pre-existing renal abnormalities were randomized to receive C-RT and H-RT. C-RT dose was 50.4?Gy into 28 daily fractions (1.8?Gy/day), while H-RT dose of 59.4?Gy was divided into 54 fractions of 1.1?Gy two times daily with a 6-h interval between daily doses.25 The irradiated target size was a 2?cm margin of the presurgical, prechemotherapeutic volume and was usually started on week 9 (day 62) of therapy. RT was interrupted if the absolute neutrophil count ⩽750 or platelets <75?000, and actinomycin-D and VP-16 were temporarily halted during RT. RT was usually from megavoltage photon, or less frequently, from electron beam sources.24 Brachytherapy was used in a few cases, but was not randomized.25 The CTX regimen schedule involved frequent response checks. AMD and VCR were given in 8-week cycles of twice: once at week 12 and once at week 24. Response was checked on weeks 11–12, 23, and 35–36. G-CSF was used to limit marrow toxicity. VAC, VIE, and VAI were given through week 23. Doses were decreased 50% for patients less than 1?y old.
Despite these changes, OS was 81% for GU B/P tumors.24 The IRSG reported that H-RT was of no greater efficacy than C-RT.25 At this time, neither the brachytherapy results nor the bladder salvage rate been been reported. CTX duration was only for 1?y instead of 2 with nearly the same survival. Consequently, IRSG recommended then that VAC with or without RT remain the ‘gold standard,’ for nonmetastic disease.24
The IRS V is ongoing. One aspect of the study is the possible utility of the campthecins, a group of DNA topoisomerase inhibitors. A pilot study has already used topetecan (T). In this study, there was an alternating regimen of VAC and vincristine, topetecan and cyclophosphamide (VTC) against stage 4 or metastatic disease of which 7(15%) were B/P without renal abnormalities. It was more efficacious on alveolar histology than embryonal histology in RMS in general.41
The German Cooperative Study
There have been three completed German soft-tissue sarcoma studies, CWS 81, 86 91, and an ongoing fourth CWS 96. As of this writing, only trial reports of CWS 91 have been published. CWS 81 had an eligible population of 218, which of that number, 8% were GU B/P.42 The CWS 86 population numbered 372, of which 32 (9%) had B/P RMS.43 Patients for all tumor sites were less than 19?y old. The CWS 81 combined the data from 54 institutions, and CWS 86 used data from 57 institutions. The CWS uses a staging system identical to the IRSG Clinical grouping system (Figure 1).
Treatment regimens are shown in Table 5. It is clear that primary CTX is the focus in both, incorporating the use of RT until completion of first cycle of CTX.
In CWS 81, SLS was implemented on all patients except stage I to assess whether to use RT. If on SLS the tumor could be completely resected, RT was withheld unless there was microscopic residual. Interestingly, the 5-y DFS of stage III compares well to IRS Clinical Group III at 57%31 in spite of the shorter CTX duration of 35 weeks instead of 2?y.
In CWS, 86 the option to use RT was based on response after the first CTX cycle. Dosage was varied by stage and the amount of tumor volume reduction after CTX. Stage I–III patients who achieved CR post-first cycle, with the exclusion of those with extremity and parameningeal tumors, did not receive RT. A dosage of 32?Gy was used for stage III with good response, while 54.4?Gy was used on stage III showing poor response after the first cycle of CTX. The higher dose was divided into two periods 27.2?Gy each. All stage III tumors had SLS after two cycles of vincristine, actinomycin-D, ifosfamide and adriamycin (VAIA) and RT. For stage III tumors, RT was concomitant with the second VAIA cycle. Children less than 2?y old did not receive RT. Between ages 2 and 3?y, the use of RT varied.42
The CWS 86 reached a number of conclusions. One discovery was that a reduction in treatment time showed an improved survival for stages I and II. The efficacy of IFOS could not be clearly interpreted except in stage III disease where it appeared superior. The CWS concluded that patients with stage III disease also gained benefit from initial CTX followed by gauging subsequent therapy from initial response. Starting RT earlier than in CWS 81, and hyperfractionating it, was thought to be a contributing factor in improved outcomes. Moreover, the earlier RT and hyperfractionation protocol decreased relapse rate compared to CTX alone. Remarkably, CWS 86 reported that only 1.6% of the patients developed cardiac damage, while IRS III was 9%.43 The authors also tout that compared to the IRS, the CWS 86 had lower cumulative doses of RT, VCR, and alkylating agents.
International Society of Pediatric Oncology
This group has performed three studies: the RMS 75 (1975–1983), MMT84 (1984–1988), and MMT 89 (1989–1995).44,45,46 Populations of RMS of RMS 75 and MMT 84 were 281 and 186, respectively, and B/P populations were 39 and 14, respectively.
The RMS 75 was mainly a primary surgical study. A presurgical TNM classification was used. Stage I with complete excision received either VAC or VAC-VADR for 18 months until 1978 when therapy duration was decreased to 8 months. No RT was given for stage I. Patients with incomplete excision received either RT (45?Gy) or brachytherapy with VAC or VAC-VADR over 18 months. Some centers randomized stage II and III patients, comprising a population of 63, to receive primary CTX or primary RT. The B/P RMS 3-y OS was 51%; DFS was 43%.43
The MMT 84 was a primary CTX study. Irradiation was not used unless the child was older than 12?y. The goal was to increase survival, but also to reduce late effects of therapy by ‘restricting surgery’ and/ or RT after good initial response to CTX.
In MMT 84, 12 of the 14 B/P tumors were classified stage II (tumor involving adjacent tissue or organ, yet no nodes or mets). Stage II in this study had essen-tially two treatment options.44 In the first, conservative surgery was performed, followed by three cycles of VAI, then SLS. If the biopsy was negative, then three more cycles of VAI were given. If the biopsy was positive (hence microscopic residual), then CTX was changed to three cycles of ADR and CDDP, with or without RT. The second option was used specifically for macroscopic disease after initial surgery with SLS being performed more often to assess response. In the case of PR, then VAI was continued with intermittent SLS with or without RT; if NR, then ADR and CDDP were used for the remainder of therapy along with SLS with or without SLS. Duration of CTX did not exceed 36 weeks. The 5-y OS was 79%.
The MMT 89 population was 625 for all tumor sites. The SIOP reported a 5-y survival of 83% for nonmetastatic B/P RMS. The authors claimed for all tumor sites of RMS, a CR of 93%, most (66%) without using RT, however, OS and DFS were 73 and 57%, respectively. They elaborate that only parameningeal tumors were regularly irradiated and described a better response of stage III tumors to using VAI or VAI+carboplatin, epirubicon, and VP-16.45
The results of several single-institution retrospective studies invoking bladder salvage are summarized in Table 6. Many studies included stage IV patients. All used some sort of combination CTX, usually VAC, and surgery with or without RT on most of their populations.15,19,47,48,49,50,51,52,53,54,55,56,57 Two of the studies49,55 were primary surgery studies, while the remainder were primary CTX studies. Some of the primary CTX studies would base subsequent use of either surgery and/or RT on the initial CTX response.15,47,54 Most of the studies with better OS and bladder salvage have less than 5?y follow-up.19,49,52,54 Some of the studies showing poor long-term organ salvage had irregular use of RT.53,56,57 Others with poor long-term salvage would employ radical surgery if initial response was poor or progressive disease on SLS.15,19,50
Many interesting conclusions were made from these studies. Flamant and Hill58 in a large study population of 345 (24% were GU), described an impressive improvement in survival from 30 to 50% when combination CTX was used over single-agent CTX in addition to surgery with or without RT.58 Verga and Parigi55,57 and Ortega59 began conservative surgical technique against the trend of radical surgery in 1968 and 1969. Mugerian et al48, Duel et al49 and Hicks et al52 emphasized the importance of nerve sparing techniques to maintain potency and bladder reconstruction and augmentation for long-term continance. Heij et al53 foreshadowed that decreased CTX therapy would likely give improved survival. Atra et al54 Lerner et al50 espoused the need for SLS for long-term survival.
The role of low-dose RT (about 40?Gy: 1.5–1.8?Gy fractions) for local control was looked at in a population of 103 with RMS of which 28 had GU tumors by Regine et al. Local control was achieved in almost 90% with IRS group II tumors with <40?Gy and 64% for group III tumors with the same dose. The authors ultimately conclude that for IRS group III patients with only microscopic disease postinduction CTX with or without delayed surgery will ‘likely’ have local control with low dose RT.60
The concern of the side effects of EBRT has prompted some to look at brachytherapy.24,43,61,62 These side effects are well documented and particularly troublesome in infants. Generally, the side effects include severe growth retardation and organ deformity. With respect to B/P RMS, side effects include bladder contracture, urethral stricture, cystitis, pelvic bone deformity, and avascular necrosis of the femoral head. Such side effects of EBRT underscore the reasons that the larger multi-institutional studies avoid RT in infants less than 1 to 2?y old. Nag et al61 explain that brachytherapy should be reserved for those with microscopic or small volume residual disease. If there is extensive disease, EBRT should also be used along with brachytherapy in older children.61 At this time, most studies invoking brachytherapy have a very small number of patients.
Rodary et al63 in their review of 951 children with nonmetastatic RMS looked at prognostic factors. They looked at the data of four large cooperative studies: RMS-75, IRS II, CWS-81, and RMS-79, an Italian study. They found that survival was most negatively impacted in nonmetastatic patients by tumor invasiveness, size >5cm, +locoregional lymph nodes, and site, with bladder/prostate tumors being an unfavorable site.
Metastatic RMS was thoroughly reviewed by Koscielnak et al.64 Their retrospective analysis of European multicenter studies showed that DFS is about 20% after 2?y. The majority of survivors had embryologic-type histology, and the majority of metastatic tumors were of the alveolar type. Whether these data were significant to B/P RMS was hard to tell since only eight of the population of 164 had B/P tumors.
Shapiro and Strother65 in their review of GU RMS make some insightful observations. They cite the improved staging of B/P RMS using magnetic resonance imaging (MRI). They explain that MRI has better contrast resolution, plus the utility of coronal and sagittal imaging are particularly advantageous for imaging the bladder neck and trigone as well as the extension of tumor into the prostate.
Brenneman and Wiener address methods of local control of RMS. They argue that patients with presumptively positive lymph nodes seen on physical exam, pretreatment imaging and/or at time of initial surgery should be considered truly positive, and recommend irradiation of these lymph nodes. They recommend that RT not to be concurrently given with an anthracycline or actinomycin-D. Doses of RT should be 41.4?Gy for microscopic residual and 50.4 for macroscopic residual. They observe that RT gives better local control contrasting this experience to the European studies of the 1980s where DFS was worse than in the IRSG. They specifically address that primary surgery is very difficult on GU RMS since the tumors are large. They cite literature regarding the use of primary CTX for large bladder tumors and that ‘radical or exenterative procedures should be delayed’ when there is response. When early failure or disease progression occurs, then more aggressive surgical procedures are warranted. Those in whom the bladder cannot be salvaged would likely benefit from anterior exenteration, hence sparing the rectum. They specify that reconstructive surgery should incorporate a nonrefluxing colon or ileal conduit. They explore future directions such as the increased utility of SLS to monitor disease progression; the possible use of 3D conformal RT and/or intensity modulated therapy offering fewer side effects and better control; and the use of biodegradable mesh which could be placed internally to hold the small bowel away from the pelvic field during RT.14
Ruyman and Grovas make several points about improved therapy for RMS. They press that there are problems of variability with IRSG clinical grouping system. This variability stems from the inherent variable interpretations of surgeons and pathologist, while a pretreatment TNM staging would offer improved standardization in agreement with others.66,67 The authors emphasize that much of the improved survival in RMS is attributable to improved imaging technology, particularly MRI. They cite the future utility of PET in assessing post-therapeutic disease. The importance of SLS is noted and its possible use instead of RT at week 12 as an ‘elective local control strategy.’ They describe several examples where relapse increased in studies where RT was delayed or not used and vice versa where regular use of RT decreased relapse rate. They conclude that RT given ‘before or at week 15 but after initial chemotherapy appears to have the best chance of preventing any local relapse.’
Filipas, in a very limited review (14 references), points to the value of the older surgical approaches with respect to B/P RMS. He claims that in trying to preserve the bladder risks leaving positive margins, thus leading to increase in relapse. One crucial aspect he does not mention is the use of SLS to watch for relapse. He does mention the improvement in reconstructive techniques that allow for continent urinary diversion providing improved quality of life.27
It is clear that the use of multimodality therapy has improved survival. Remarkably, therapy has not only increased survival, but the necessary duration of therapy has decreased by nearly 50%. It is equally remarkable that the largest study group, the IRSG, after looking at various regimens, still recommend the original CTX combination of VAC as the ‘gold standard.’24 It is also notable that some of the European studies are likewise showing increased OS with decreased therapy duration.
The most salient aspect of multimodality therapy is the intricate and organized blending of surgery, CTX and RT. It is evident that stage dictates how these modalities will be used and in what order. The IRS III appears to be the pivotal and breakthrough study for this tumor site. By having the largest population of the cooperative studies, it has the most statistical power.68 One aspect of improvement in the IRS IV over IRS III was the decrease in duration of therapy for about the same survival; however, results of IRS IV pertaining to metastatic disease and bladder preservation have not been released at the time of this writing. The MMT 89 data appear impressive in their ability to restrict RT, yet there are no data regarding relapse rates for that study at this time. We recommend protocol entry whenever possible. MRI with T2-weighted images seems to be the best imaging modality for presurgical staging and for follow-up during therapy to watch for relapse. Age should be a consideration in the use of RT, with likely restrictions on children less than 2?y old. The use of SLS has proven its utility and should be used at regular intervals. If there is relapse or continued disease progression, then more radical surgical techniques should be invoked with the hope of using bladder reconstructive techniques later on. Bladder reconstructive techniques or continent urinary diversion should be considered in patients who have very poor bladder function. Bladder preservation should be an overall goal with little controversy over this approach if confined to the dome of the bladder. Finally, metastatic RMS has shown little improvement in 5-y survival, despite new therapeutic strategies. Perhaps the IRS V will provide new insight into therapy.
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Ashlock, R., Johnstone, P. Treatment modalities of bladder/prostate rhabdomyosarcoma: a review. Prostate Cancer Prostatic Dis 6, 112–120 (2003). https://doi.org/10.1038/sj.pcan.4500652
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