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PERSONALIZED MEDICINE IN THE MANAGEMENT OF INVASIVE BLADDER CANCER: Edited by Maximilian Burger and Andrea B. Apolo

Managing noninvasive recurrences after definitive treatment for muscle-invasive bladder cancer or high-grade upper tract urothelial carcinoma

DiBianco, John Michael; George, Arvin K.; Su, Daniel; Agarwal, Piyush K.

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doi: 10.1097/MOU.0000000000000201
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Abstract

INTRODUCTION

Urothelial carcinoma, affecting the urethra, bladder, ureter, and renal pelvis, is the most common urinary tract malignancy and the fourth most common cancer in men [1,2]. In 2015, bladder cancer, estimated to have an incidence of 74 000 and mortality of 16 000, is the fourth leading cause of cancer mortality [1,3▪▪]; whereas, upper tract urothelial carcinoma (UTUC) has an estimated incidence of 3000 and a mortality of 910 [1]. Following a diagnosis, most often identified during the investigation of hematuria, the treatment of urothelial carcinoma depends primarily on stage, which is largely determined by tumor depth of invasion [3▪▪]. Surveillance is an essential component after definitive therapy for invasive urothelial carcinoma as recurrence may occur in up to 50% of patients. Timely and appropriate management of recurrence is imperative in order to prevent progression and preserve oncologic outcomes. The currently accepted treatment for focal, low grade, non-muscle-invasive bladder cancer (NMIBC) is resection followed by surveillance [4]. There is, however, no consensus when presented with the same clinical findings in patients previously treated with definitive therapy for high grade or muscle invasive urothelial cancer. The objective of this review is to critically appraise and summarize the data regarding the management of patients with recurrence following definitive treatment for urothelial carcinoma.

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PRIMARY BLADDER CANCER

Definitive treatments for muscle invasive bladder cancer (MIBC) include: radical cystectomy with pelvic lymph node dissection and urinary diversion, with or without adjuvant/neoadjuvant chemotherapy, combination chemotherapy and radiation, and trimodal therapy, that is, combination chemotherapy and radiation, with the addition of radical trans-urethral resection of bladder tumor (TURBT) and/or partial cystectomy (Fig. 1) [3▪▪,4,5,6▪▪,7]. Multimodal therapy, partial cystectomy, and other bladder preserving techniques may be used in select patients and are becoming more widely accepted due to mounting evidence regarding equivalent oncologic outcomes [3▪▪,8]. Despite recent advances in diagnosis, chemotherapeutics, surgical techniques, and surveillance strategies, MIBC continues to have high rates of recurrence [3▪▪,8–10]. Each definitive treatment approach carries a different profile of recurrence risk and the risk factors for recurrence correlate directly with the stage of disease, and presence of positive surgical margins [9].

FIGURE 1
FIGURE 1:
Bladder cancer treatment algorithm describes the currently accepted treatment algorithm for bladder urothelial carcinoma according to the guidelines. In the context of the manuscript, we use this figure to provide a brief educational reference as to how bladder cancer, primary or recurrent, is treated. Reproduced with permission from[7].

Currently, there is no alteration of treatment strategy between patients with new bladder cancer diagnoses or recurrent disease. Each disease entity must be evaluated and treated according to the stage at presentation, the patient's ability to tolerate therapy given his/her comorbidities, and the patient's wishes [6▪▪,11–13].

Local recurrence

After radical cystectomy, the risk of local pelvic recurrence ranges from 5 to 30% and imparts a poor prognosis with a median survival of 4–7 months during which patients experience significant morbidity [6▪▪,11,14]. Patients treated with radical cystectomy for locoregionally advanced (pT3–4) disease have a higher rate of locoregional recurrence [14]. Local recurrence following multimodality therapy (MMT) is approximately 3.9–31% at 5 years and up to 36% at 10 years [3▪▪,8–10]. Recurrence rates for patients treated with radiochemotherapy alone can reach almost 60% [15].

Treatment for pelvic recurrence after radical cystectomy historically has been palliative, involving combination chemoradiotherapy [6▪▪,11]. Locoregional or node positive bladder cancer recurrence is treated as primary stage IV disease [11]. Hallemeier et al.[14] described treating patients diagnosed with locoregional recurrence after radical cystectomy for bladder cancer, with a multimodality approach (combination pre/postoperative external beam radiation and/or surgical resection with or without concurrent chemotherapy). They found lower rates of subsequent recurrence, although distant recurrence was still common and survival benefit was not significantly increased [14].

In patients whose primary bladder cancer was treated with bladder preservation strategies, recurrent disease is evaluated and managed as a new cancer diagnosis [11]. An initial staging TURBT and exam under anesthesia should be completed as an initial evaluation before commencing other treatment options [6▪▪,11]. Treatment options for low-grade NMIBC include complete TURBT and intravesical therapy; however, strong consideration for cystectomy should be entertained especially if recurrence occurs after salvage therapy for high-grade disease [6▪▪,11]. Even if bladder recurrence is diagnosed as low grade, salvage cystectomy after previous bladder preserving management (intravesical therapy, TURBT, radiation therapy, chemotherapy) for high-grade disease is a reasonable option as the procedure has complication rates comparable to those treated with primary cystectomy [16,17]. It is of the utmost importance, however, that patients with a recurrence, even low grade, undergo accurate staging. The oncologic outcomes of salvage cystectomy are comparable to those treated with cystectomy as definitive treatment for bladder localized disease, however, many patients may have unrecognized regional or metastatic progression that may make salvage cystectomy an inappropriate treatment option [16,17].

Upper tract recurrence

There is a relative risk of UTUC recurrence exceeding 40% over 10 years with an absolute risk of ∼5% (2–7%) following primary therapy for bladder cancer [4,18,19▪]. Picozzi et al.[20] reported an absolute risk range of 0.75–6.4% in their meta-analysis.

Treatment for UTUC recurrence depends on the stage at initial presentation [6▪▪]. Currently, there is no distinction made in the treatment of primary UTUC and recurrent UTUC [11]. Traditionally, for low-grade primary UTUC, endoscopic resection/ablation and/or topical Bacillus Calmette-Guerin (BCG)/chemotherapy and other nephron sparing techniques may be used, whereas radical nephroureterectomy (RNU) with bladder cuff excision is indicated for high-grade tumors (Fig. 2) [6▪▪,11]. RNU, therefore, is indicated for any upper tract recurrence, following definitive treatment for bladder cancer; however, low-volume, low-grade, noninvasive recurrences may be treated with nephron sparing techniques, although, the risk of overall recurrence is significantly higher [6▪▪,11,21].

FIGURE 2
FIGURE 2:
Treatment of metastatic urothelial carcinoma algorithm, describes the currently accepted treatment algorithm for metastatic urothelial carcinoma according to the guidelines. In the context of the manuscript, we use this figure to provide a brief educational reference as to how metastatic urothelial carcinoma is treated. Reproduced with permission from[2].

Urethral recurrence

Urethral recurrence is rare, ranging from 0 to 6%; however, prognosis is extremely poor in these patients as one study found that median survival after urethral recurrence is 6 months [6▪▪,22]. The rate of urethral recurrence increases with disease exhibiting poor pathologic features (higher grade, multifocality) up to approximately 25% in patients with prostatic urethral involvement found on the final cystectomy specimen [6▪▪,22–24]. Urethrectomy remains the gold standard treatment for primary urothelial carcinoma involving the urethra [6▪▪,11]. In the setting of patients previously treated with bladder preserving therapy, local treatment with transurethral resection and intraurethral chemotherapy/immunotherapy may be indicated [11]. In the setting of radical cystectomy with a cutaneous diversion, urethrectomy is the gold standard even for low-grade, noninvasive disease [11]. For patients with a neobladder after radical cystectomy diagnosed with subsequent urethral carcinoma in situ, ∼80% of patients may successfully be treated with intraurethral BCG. However, in the setting of papillary or invasive urethral recurrence, urethrectomy is recommended with conversion to a cutaneous urinary diversion [22,25,26].

Conduit/neobladder recurrence

Usually occurring between 2 and 16 years postoperatively, adenocarcinoma is the most common neoplastic disease of urinary conduits and neobladders [27]. Still, there are reports of urothelial carcinoma recurrence within created urinary diversions, the majority of which will occur at the urethral or uretero-enteric anastomosis [28▪]. The optimal treatment of diversion/neobladder recurrence is currently unknown and most surgeons will elect complete resection and diversion removal [28▪]. There are, however, reports of patients treated with diversion sparing techniques. Yamashita et al.[28▪] describe a case of biopsy confirmed high-grade pTa urothelial carcinoma recurrence within a neobladder 6 years after radical cystectomy. The patient was treated with multiple TURBT procedures and BCG administration. After completion of BCG, the patient experienced 8-month recurrence-free survival (RFS) [28▪]. Although intriguing, until larger trials are performed, we do not advocate diversion-sparing techniques, and any patient with urinary diversion presenting with hematuria must be investigated fully.

Distant/metastatic recurrence

Distant nodal and/or metastatic recurrence after radical cystectomy is more common than locoregional recurrence, ranging from 22 to 38% [11,29]. This phenomenon is also seen following MMT, with distant recurrence rates approaching 13 to 32% [3▪▪,9,10].

Distant and metastatic bladder cancer presenting as recurrent disease is treated with systemic chemotherapy (Fig. 3) [6▪▪,11]. Although not an accepted standard of care, recent reports have indicated the possible role of metastasectomy [30▪▪]. With a 5-year overall survival of 31%, Abe et al.[30▪▪] argue that metastasectomy should be considered, in addition to standard care, particularly in patients who recur with lymph node metastasis, or a solitary lung metastasis in which the patient may be rendered disease-free. Although metastasectomy may benefit selected patients, it may only provide improved outcomes in combination with neoadjuvant chemotherapy [31]. Therefore, in the absence of chemotherapy, there is currently no role for surgical treatment with curative intent alone in the setting of metastatic disease.

FIGURE 3
FIGURE 3:
Treatment of UTUC algorithm describes the currently accepted treatment algorithm for upper tract urothelial carcinoma according to the guidelines. In the context of the manuscript, we use this figure to provide a brief educational reference as to how upper tract urothelial carcinoma, primary or recurrent, is treated. Reproduced with permission from[6▪▪].

PRIMARY UPPER TRACT UROTHELIAL CARCINOMA

UTUC, also staged by the depth of invasion, has a higher frequency of invasive disease at the time of diagnosis compared to bladder cancer [2]. In addition, 8–13% of patients diagnosed with UTUC will have bladder cancer at the time of diagnosis [32▪]. Recurrence rates following definitive therapy vary widely, reflecting differences in location and extent of disease at presentation, including higher stages/grades of disease, smoking, positive surgical margins, and success of the primary treatment modality [9,33]. Specifically, risk factors for UTUC recurrence include: tumor characteristics (size, location, multifocality, lymphovascular invasion, higher disease stage, positive surgical margins) and patient characteristics (male gender, Glasgow prognostic score, performance status, diabetes, prior positive urine cytology) [34–37]. An accepted standard of care for recurrent disease of the UTUC remains elusive to date.

Upper tract recurrence

Locoregional recurrence after RNU can reach 28% [38]. Segmental ureterectomy and endoscopically treated UTUC is associated with an increased incidence of local ureteral tumor recurrence in the same ureter ranging from 20 to 90% [21,39]. Contralateral upper tract disease after previous RNU has an incidence of ∼1–7% and most commonly presents with gross hematuria [40▪]. Fang et al.[40▪] reported that renal insufficiency and a history of renal transplant are independent risk factors for contralateral ureteral recurrence after RNU. The retrospective analysis of 509 patients discovered a contralateral recurrence rate of 6.9% [40▪] Patients treated with percutaneous techniques report UTUC recurrence rates from 13 to 65% [21].

It has been proposed that patients with contralateral ureteral recurrence after previous RNU who are uremic and already receiving renal replacement therapy may benefit from a prophylactic RNU [40▪]. This may be particularly beneficial for patients perceived to be high risk for recurrence and who will most likely need dialysis even if the kidney is spared [40▪].

Segmental ureterectomy, endoscopic resection, and other nephron-sparing techniques may be indicated for low-grade, small (<1 cm), and unifocal ureteral recurrence [39,40▪]. Distal tumors can be removed with a distal ureterectomy with bladder cuff and ureteral reimplant with or without psoas hitch, and in some cases advanced reconstruction using a Boari flap or an ileal ureter must be performed [2,35]. Large studies examining this technique as a treatment modality for recurrent disease have not been completed.

Historically, chemotherapy has been part of salvage treatment for recurrent UTUC with only minimal efficacy [2]; in contrast, radiation salvage therapy may have a future role [38]. Jang et al.[38] describe four patients with isolated locoregional recurrence, all successfully treated with salvage chemoradiotherapy.

Bladder recurrence

Approximately 50% of patients previously treated with RNU will develop bladder recurrence [32▪] Anywhere from 15 to 53% of patients treated endoscopically for primary UTUC will develop bladder recurrence [21,39]. Bladder recurrence rates of 15–42% occur in patients treated with percutaneous techniques [21].

Treatment of bladder recurrence, following UTUC treated with RNU, is identical to the current treatment strategy for any primary bladder cancer [6▪▪,11]. Tanaka et al.[41▪] reviewed the records of 241 patients diagnosed with bladder recurrence after previous UTUC treated with RNU. Of these 241 patients, all were treated with TURBT, additionally 41.9% were given BCG, and 20.3% were given intravesical chemotherapy, based on the stage of the patient's disease [41▪]. They found no difference in recurrence rates based on the treatment strategy; however, the lack of BCG treatment was an independent predictor of progression [41▪].

Perhaps the most effective way to treat bladder recurrence is to prevent it altogether. O’Brien et al.[42] reported the outcomes of the One Dose Mitomycin trial. They showed that a single postoperative bladder instillation of mitomycin-C after RNU decreased the absolute risk of bladder recurrence by 11% (16 vs. 27%), which amounts to a relative reduction in risk of 40% [42].

Distant/metastatic recurrence

Metastatic disease following RNU has been reported in 12.5–23.3% of patients [35,43▪]. Tanaka et al.[43▪] reported that a primary UTUC tumor location of the upper ureter imparts a greater risk of metastatic recurrence, than disease of the middle or lower ureter. Distant and metastatic urothelial carcinoma presenting as recurrent disease is treated with chemotherapy according to the most updated guidelines [2,6▪▪,11]. Any surgical procedures are strictly palliative, although the possibility of the previously described metastasectomy for the treatment of recurrent urothelial carcinoma seems intriguing [30▪▪].

Future directions

As a result of the lack of any current urothelial carcinoma recurrence treatment strategies that significantly improve survival outcomes, there is growing focus on identifying patients at risk of recurrence and poor outcomes and early diagnosis of recurrence [44,45]. Study of disease biology, specifically genomic profiling represents a new frontier in this challenging patient population. Shariat et al.[45] described cellular expression of p53 as an independent predictor of disease recurrence and cancer-specific mortality. Recent studies using patient and tumor-specific genomic profiling are attempting to identify other specific genetic alterations that may aid in identifying disease that will impart improved or worse prognosis for patients [44,46▪]. Mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit A have been associated with improved RFS and cancer-specific survival whereas mutations in cyclin-dependent kinase inhibitor 2A demonstrated the opposite. Though mutations in chromatin-remodeling genes were highly prevalent in this cohort, there was no association with oncologic outcomes. Although investigators concede that there is currently insufficient evidence to support using these results to guide management, future staging for urothelial carcinoma may incorporate genetic alterations into clinical staging. Ideally, initial staging biopsies may be used to identify not only tumor grade but also genetic variations that will provide insight into disease biology and ultimately patient prognosis.

CONCLUSION

When compared to other types of cancer, the commonly encountered urothelial carcinoma continues to have high rates of recurrence and subsequently low rates of survival. As a result, the treatment of recurrent disease after prior definitive treatment for bladder cancer or UTUC remains a challenging clinical question. Currently accepted treatments for recurrence are not substantially different than for primary disease, with most approaches utilizing techniques appropriate for tumor location and extent of disease. Recent reports that describe urinary diversion-sparing alternatives and metastasectomy for distant relapse are intriguing but must be validated with future study. An emphasis on discovering the predictors of recurrence, reasons for its poor prognosis with standard treatment, and identifying early presence are needed until further research directs us to better modalities of care for recurrent disease. Perhaps, a targeted, risk-stratified approach using clinical and genetic predictors will ultimately be the future in the management of recurrences [3▪▪,5,44,47▪,48]. If we can accurately identify patients who are high risk for recurrence and manage them in a timely fashion, significant progress may be made in improving survival for our patients with urothelial carcinoma.

Acknowledgements

The authors thank our colleagues in the Urologic Oncology Branch.

Financial support and sponsorship

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

REFERENCES

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for clinicians 2014; 64:9–29.
2. Roupret M, Zigeuner R, Palou J, et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol 2011; 59:584–594.
3▪▪. Park JC, Citrin DE, Agarwal PK, Apolo AB. Multimodal management of muscle-invasive bladder cancer. Curr Problems Cancer 2014; 38:80–108.

This study provide a thorough review of muscle invasibe bladder cancer, including treatment, as well as multimodal treatment. Multimodal treatment is becoming a very intruiging treament option for patients with MIBC due to the morbidity associated with cystectomy, and all urologists may benefit from great understanding of the modality.

4. Sagalowsky AI, Jarrett TW, Flanigan RD. Wein AJ, Kavoussi LR, Novick AC. Urothelial tumors of the upper urinary tract and ureter. Campbell-Walsh urology 10 ed.Philadelphia: Elsevier Saunders; 2012. 1516–1553.
5. Apolo AB, Kim JW, Bochner BH, et al. Examining the management of muscle-invasive bladder cancer by medical oncologists in the United States. Urol Oncol 2014; 32:637–644.
6▪▪. Witjes JA, Comperat E, Cowan NC, et al. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol 2014; 65:778–792.

The current EAU guidelines provide a detailed review of the current evidnece regarding MIBC and its treatment that may aid in the treatment and counceling of patients with bladder cancer.

7. Apolo AB, Dahut W. Allegra C. Bladder Cancer. The Bethesda handbook of clinical oncology. Philadelphia: Lippincott Williams & Wilkins; 2014. 208–218.
8. Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of radiation therapy oncology group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 2014; 32:3801–3809.
9. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001; 19:666–675.
10. Cagiannos I, Morash C. Surveillance strategies after definitive therapy of invasive bladder cancer. Can Urol Assc 2009; 3 (6 Suppl 4):S237–S242.
11. Clark PE, Agarwal N, Biagioli MC, et al. Bladder cancer. J Natl Comprehens Cancer Netw 2013; 11:446–475.
12. Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol 2007; 178:2314–2330.
13. Brausi M, Witjes JA, Lamm D, et al. A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group. J Urol 2011; 186:2158–2167.
14. Hallemeier CL, Karnes RJ, Pisansky TM, et al. Multimodality therapy including surgical resection and intraoperative electron radiotherapy for recurrent or advanced primary carcinoma of the urinary bladder or ureter. Am J Clin Oncol 2013; 36:596–600.
15. Atasoy BM, Dane F, Alsan Cetin I, et al. Concurrent chemoradiotherapy with low dose weekly gemcitabine in medically inoperable muscle-invasive bladder cancer patients. Clin transl Oncol 2014; 16:91–95.
16. Chen RC, Shipley WU, Efstathiou JA, Zietman AL. Trimodality bladder preservation therapy for muscle-invasive bladder cancer. J Natl Comprehens Cancer Netw 2013; 11:952–960.
17. Eswara JR, Efstathiou JA, Heney NM, et al. Complications and long-term results of salvage cystectomy after failed bladder sparing therapy for muscle invasive bladder cancer. J Urol 2012; 187:463–468.
18. Wright JL, Hotaling J, Porter MP. Predictors of upper tract urothelial cell carcinoma after primary bladder cancer: a population based analysis. J Urol 2009; 181:1035–1039.discussion 9.
19▪. Kim SH, Yang HK, Lee JH, Lee ES. A retrospective analysis of incidence and its associated risk factors of upper urinary tract recurrence following radical cystectomy for bladder cancer with transitional cell carcinoma: the significance of local pelvic recurrence and positive lymph node. PLoS One 2014; 9:e96467.

This study report that positive lymph nodes and presence of local recurrence at the pelvis as important risk factors for recurrence after radical cystectomy. This finding may benefit urologist when considering risk of recurrence. Stratifying patients in order to more accurately identify patients early when recurrence occurs may help to improve long-term patient outcomes.

20. Picozzi S, Ricci C, Gaeta M, et al. Upper urinary tract recurrence following radical cystectomy for bladder cancer: a meta-analysis on 13,185 patients. J Urol 2012; 188:2046–2054.
21. Park BH, Jeon SS. Endoscopic management of upper urinary tract urothelial carcinoma. Kor J Urol 2013; 54:426–432.
22. Hrbacek J, Macek P, Ali-El-Dein B, et al. Treatment and outcomes of urethral recurrence of urinary bladder cancer in women after radical cystectomy and orthotopic neobladder: a series of 12 cases. Urol Int 2014; 94:45–49.
23. Wu Y, Dong Q, Liu L, et al. The impact of tumor location and multifocality on prognosis for patients with upper tract urothelial carcinoma: a meta-analysis. Sci Rep 2014; 4:6361.
24. Demirtas A, Yildirim YE, Ferahbas A, et al. The treatment of recurrent urothelial tumors of the upper urinary system and at urostomy site following radical cystectomy with intraureteral bacillus calmette-guerin and cryotherapy. Case Rep Urol 2013; 2013:490373.
25. Soukup V, Babjuk M, Bellmunt J, et al. Follow-up after surgical treatment of bladder cancer: a critical analysis of the literature. Eur Urol 2012; 62:290–302.
26. Sherwood JB, Sagalowsky AI. The diagnosis and treatment of urethral recurrence after radical cystectomy. Urol Oncol 2006; 24:356–361.
27. Jian PY, Godoy G, Coburn M, et al. Adenocarcinoma following urinary diversion. Can Urol Assoc J 2012; 6:E77–80.
28▪. Yamashita R, Matsuzaki M, Niwakawa M, Ito I. Bacillus Calmette-Guerin treatment of urothelial carcinoma arising in the ileal neobladder after radical cystectomy. Int J Urol 2014; 21:333–334.

After a large operation and the effort put forth in creating urinary diversions, it may be difficult for the patient and urologist to remove it when recurrence may occur. This study describes a case of biopsy confirmed high grade pTa urothelial carcinoma recurrence within a neobladder 6 years after radical cystectomy, subsequently treated with multiple TURBT procedures and BCG. This may be an important finding that may lead to larger trials investigating the safety and feasibility of such treatment.

29. Mitra AP, Quinn DI, Dorff TB, et al. Factors influencing postrecurrence survival in bladder cancer following radical cystectomy. BJU Int 2012; 109:846–854.
30▪▪. Abe T, Kitamura H, Obara W, et al. Outcome of metastasectomy for urothelial carcinoma: a multiinstitutional retrospective study in Japan. J Urol 2014; 191:932–936.

Because distant recurrence imparts such poor prognosis on patients, the prospect of metastasectomy in a treatment option that has begun to be investigated for recurrence urothelial carcinoma. With a 5-year overall survival of 31%, Abe et al. argue that metastasectomy should be considered, in addition to standard care, particularly in patients who recur with lymph node metastasis, or a solitary lung metastasis where the patient may be rendered disease free. Although metastasectomy may benefit selected patients, it may only provide improved outcomes in combination with neoadjuvant chemotherapy.

31. Sweeney P, Millikan R, Donat M, et al. Is there a therapeutic role for postchemotherapy retroperitoneal lymph node dissection in metastatic transitional cell carcinoma of the bladder? J Urol 2003; 169:2113–2117.
32▪. Ouzzane A, Colin P. Bladder cancer: tumour recurrence after radical nephroureterectomy for UTUC. Nat Rev Urol 2014; 11:15–16.

This study provide a detailed review of the current evidnece regarding recurrence after definitive treatement for UTUC. The information may benefit urologist when considering risk of recurrence. Stratifying patients in order to more accurately identify patients early when recurrence occurs may help to improve long-term patient outcomes.

33. Lughezzani G, Burger M, Margulis V, et al. Prognostic factors in upper urinary tract urothelial carcinomas: a comprehensive review of the current literature. Eur Urol 2012; 62:100–114.
34. Cho YH, Seo YH, Chung SJ, et al. Predictors of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma: an inflammation-based prognostic score. Kor J Urol 2014; 55:453–459.
35. Espiritu PN, Sverrisson EF, Sexton WJ, et al. Effect of tumor size on recurrence-free survival of upper tract urothelial carcinoma following surgical resection. Urol Oncol 2014; 32:619–624.
36. Colin P, Ghoneim TP, Nison L, et al. Risk stratification of metastatic recurrence in invasive upper urinary tract carcinoma after radical nephroureterectomy without lymphadenectomy. World J Urol 2014; 32:507–512.
37. Seisen T, Granger B, Colin P, et al. A systematic review and meta-analysis of clinicopathologic factors linked to intravesical recurrence after radical nephroureterectomy to treat upper tract urothelial carcinoma. Eur Urol 2014; 67:1122–1133.
38. Jang NY, Kim IA, Byun SS, et al. Patterns of failure and prognostic factors for locoregional recurrence after radical surgery in upper urinary tract transitional cell carcinoma: implications for adjuvant radiotherapy. Urol Int 2013; 90:202–206.
39. Hoffman A, Yossepowitch O, Erlich Y, et al. Oncologic results of nephron sparing endoscopic approach for upper tract low grade transitional cell carcinoma in comparison to nephroureterectomy—a case control study. BMC Urol 2014; 14:97.
40▪. Fang D, Zhang L, Li X, et al. Risk factors and treatment outcomes of new contralateral upper urinary urothelial carcinoma after nephroureterectomy: the experiences of a large Chinese center. J Cancer Res Clin Oncol 2014; 140:477–485.

This study reported that renal insufficiency and a history of renal transplant are independent risk factors for contralateral ureteral recurrence after RNU. This finding may benefit urologist when considering risk of recurrence. Stratifying patients in order to more accurately identify patients early when recurrence occurs may help to improve long-term patient outcomes.

41▪. Tanaka N, Kikuchi E, Kanao K, et al. Independent predictors for bladder outcomes after treatment of intravesical recurrence following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma. Ann Surg Oncol 2014; 21:3151–3158.

This study reviewed the records of 241 patients diagnosed with bladder recurrence after previous UTUC treated with RNU and found that a lack of BCG treatment was an independent predictor of progression. This study stresses the important role that BCG may play in the progression of urothelial carcinoma.

42. O’Brien T, Ray E, Singh R, et al. British Association of Urological Surgeons Section of O. Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a prospective, multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial). Eur Urol 2011; 60:703–710.
43▪. Tanaka N, Kikuchi E, Kanao K, et al. Metastatic behavior of upper tract urothelial carcinoma after radical nephroureterectomy: association with primary tumor location. Ann Surg Oncol 2014; 21:1038–1045.

This study reported that a primary UTUC tumor location of the upper ureter imparts a greater risk of metastatic recurrence, than disease of the middle or lower ureter. Stratifying patients in order to more accurately identify UTUC recurrence early when, may help to improve long term patient outcomes.

44. Kim PH, Cha EK, Sfakianos JP, et al. Genomic predictors of survival in patients with high-grade urothelial carcinoma of the bladder. Eur Urol 2015; 67:198–201.
45. Shariat SF, Lotan Y, Karakiewicz PI, et al. p53 predictive value for pT1-2 N0 disease at radical cystectomy. J Urol 2009; 182:907–913.
46▪. Patschan O, Sjodahl G, Chebil G, et al. A molecular pathologic framework for risk stratification of stage T1 urothelial carcinoma. Eur Urol 2015; [Epub ahead of print].

This study describe how genetic variations may be used in clinical practice in the future to risk stratify patients in predicting recurrence and prognosis. Urologist may indeed change their surveillence practices based upon geneitc factors, not simply clinical factors.

47▪. Ghosh M, Brancato SJ, Agarwal PK, Apolo AB. Targeted therapies in urothelial carcinoma. Curr Opin Oncol 2014; 26:305–320.

This study provide a great review of the ever changing future of personalized medicine, focusing on targeted therapies for urothelial carcinoma. Urologists will need to keep up to date as intense research is being done in this realm of Urology.

48. Burgess EF. Individualized management of advanced bladder cancer: where do we stand? Urol Oncol 2013; 33:187–195.
Keywords:

bladder cancer; cancer recurrence; upper tract urothelial carcinoma; urothelial carcinoma

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