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 . 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 . 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.
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 .
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].
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 . 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% .
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 . Hallemeier et al. 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 .
In patients whose primary bladder cancer was treated with bladder preservation strategies, recurrent disease is evaluated and managed as a new cancer diagnosis . 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. 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 . 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].
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 . In the setting of radical cystectomy with a cutaneous diversion, urethrectomy is the gold standard even for low-grade, noninvasive disease . 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].
Usually occurring between 2 and 16 years postoperatively, adenocarcinoma is the most common neoplastic disease of urinary conduits and neobladders . 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 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 . Therefore, in the absence of chemotherapy, there is currently no role for surgical treatment with curative intent alone in the setting of metastatic disease.
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 . 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% . 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% .
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 ; in contrast, radiation salvage therapy may have a future role . Jang et al. describe four patients with isolated locoregional recurrence, all successfully treated with salvage chemoradiotherapy.
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 .
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. 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% .
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▪▪].
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. 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.
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.
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.
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