|Year : 2022 | Volume
| Issue : 4 | Page : 161-169
The cancer behavior and current treatment strategy for upper urinary tract cancer
Hao-Lun Luo1, Tzu-Shuang Chen1, Wen-Jeng Wu2
1 Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
2 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University; Department of Urology, Kaohsiung Medical University Hospital; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University; Department of Urology, Kaohsiung Municipal Ta-Tung Hospital; Center for Infectious Disease and Cancer Research, Kaohsiung Medical University; Center for Stem Cell Research, Kaohsiung Medical University; Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan
|Date of Submission||02-May-2022|
|Date of Decision||03-Aug-2022|
|Date of Acceptance||29-Aug-2022|
|Date of Web Publication||30-Nov-2022|
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung; Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung; Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung; Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung; Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung
Source of Support: None, Conflict of Interest: None
Upper urinary tract urothelial carcinomas (UTUCs) are rare diseases, accounting for only 5%–10% of all urothelial cancers. Radical nephroureterectomy (RNU) with bladder cuff excision remains the standard care modality of UTUCs. However, the prognosis is poor and the recurrence is high in patients with advanced UTUC treated with RNU currently. Therefore, identifying cancer behavior for UTUC is an important guide for clinical practice. Herein, we provide an overview of cancer behavior of UTUCs, including prognostic factors and clinical cancer courses. We also discuss the appropriate management of patients with UTUC, such as diagnosis, surgical management, and systemic therapies. Due to the rarity of UTUC, strong evidence of management is often lacking. Therefore, further prospective trials are needed, and regular follow-up after interventions is mandatory.
Keywords: Epidemiology, prognostic factors, review, risk factors, treatment strategy, upper urinary tract urothelial carcinoma
|How to cite this article:|
Luo HL, Chen TS, Wu WJ. The cancer behavior and current treatment strategy for upper urinary tract cancer. Urol Sci 2022;33:161-9
| Epidemiology, Risk Factors, and Histology|| |
Urothelial carcinoma (UC), which encompasses diseases of the bladder and upper (renal pelvis and ureter) urinary tract, is the sixth-most common cancer in the United States. Bladder tumors represent the majority of UCs (90% – 95%), whereas upper urinary tract UCs (UTUCs) are significantly less common, accounting for only 5%–10% of all UCs.,, UTUC is a relatively rare cancer, and the estimated annual incidence of UTUC is 2/100,000 persons in Western countries. Urothelial pyelocaliceal tumors are approximately twice as common as the UC of the ureter.
Conversely, in Taiwan, UTUC prevalence can be as high as 30% of all UCs. The age-standardized incidence rate of UTUC per 100,000 population was 3.82 in men and 4.26 in women, according to the Taiwan Cancer Registry Annual Report in 2019. Furthermore, the male-to-female ratio is between 2:1 and 4:1 for the normal UTUC prevalence in the west, such as North America and Europe, while the male-to-female ratio is 1:1.3 in Taiwan.,
Luo et al. presented a comparison between Taiwan (endemic area) and Japan UTUC (nonendemic area). The sex distribution and baseline characteristics, including preoperative and pathological features, are significantly different between these two populations, although there is no obvious difference in the stage-specific outcome. In addition, patients with UTUC in Taiwan present with unique clinical characteristics such as female predominance and prevalence of chronic kidney disease (CKD).
With similar histologic characteristics, both bladder tumors and UTUCs are neoplasms arising from the urothelium. However, the cancer behavior between UTUCs and bladder tumors differ because of different anatomical involvement and distinct genomic alterations, hence considered two clinical entities. Moreover, 60% of UTUCs are invasive at diagnosis compared with only 15% of bladder tumors.
Several potential environmental factors have been demonstrated in previous reports that lead to UTUC development. Particular environmental factors, such as smoking and aristolochic acid (AA), are specifically associated with UTUC with a strong evidence.
AA, a compound produced by Aristolochia plants, is a powerful nephrotoxin that causes serious renal function impairment through chronic tubulointerstitial fibrosis and may progress to end-stage renal disease. Moreover, AA is a carcinogen associated with a high risk of urothelial malignancy, and AA exposure is well-known to be related to a history of traditional Chinese herb intake. Chen et al. reported in a clinical study that patients with AA-induced UTUC tended to be younger, has a female predominance, and has a poorer renal function compared to other patients with UTUC in Taiwan. In addition, consumption of AA was associated with a higher risk of developing synchronous bilateral and metachronous contralateral UTUC.
Smoking is a well-established risk factor for UTUC. Cumulative tobacco exposure (the number of cigarettes smoked per day and the lifetime duration of smoking) increases the relative risk of developing UTUC from 2.5 to 7. Smoking is also significantly associated with advanced stages and high-grade upper tract tumors, suggesting that smoking promotes tumor progression. Smoking cessation may decrease the risk of disease development.
The majority of upper urinary tract tumors are pure urothelial tumors. The appearance of urothelial tumors varies from purely papillary to nodular or flat. In approximately 25% of cases, different histological variants are reported. Accounting for 15% of UC, squamous differentiation is the most common variant. Upper urinary tract tumors with variant histology are often high-grade and associated with more aggressive biological features such as sessile tumor architecture, presence of concomitant carcinoma in situ (CIS), advanced tumor stage and grade, and lymph node (LN) involvement, leading to inferior survival outcomes compared with pure UC.
| Prognosis|| |
A delayed diagnosis is common in UTUCs. Localized UTUCs are usually silent, leading to difficulty in early diagnosis. At presentation, the rate of invasive disease is around two-thirds. UTUCs with muscular invasion are usually associated with a poor prognosis and a high risk of recurrence. The 5-year disease-specific survival is <50% for pT2/T3 tumors and <10% for pT4 tumors.
Age and sex
Older age is independently associated with cancer-specific mortality. In Western countries, UTUC is more prevalent in men and sex did not play a role in CSS. Conversely, in Taiwan, patients with UTUC are predominantly female, and male patients are associated with a higher incidence of bladder recurrence, systemic recurrence, and worse cancer-specific mortality than female patients.
Cigarette smoking significantly increases the risk for UTUC recurrence and cancer-specific mortality after radical nephroureterectomy (RNU). Current smokers and heavy-long-term tobacco consumption have the highest risk of IVR. Smoking cessation is beneficial for cancer control, and counseling these patients regarding cessation is necessary.
In some study cohorts, initial tumor locations have been demonstrated as prognostic factors of UTUC., Ureteral tumors are associated with higher disease recurrence and mortality than renal pelvic tumors after controlling the effects of the tumor stage.,,, Perinephric fat was considered a barrier against the metastatic spread, and a thinner ureteral adventitia, which is rich in blood plexus and lymphatic ducts, may facilitate tumor invasion.
Multifocal tumors involving both the ureter and renal pelvis show a worse prognosis than patients diagnosed with renal pelvic tumors. Tumor multifocality may be a more aggressive feature in patients with UTUC and is associated with the panurothelial nature of UTUC. Patients with multifocal UTUCs should be considered for more aggressive management.
Tumors of >3 cm constitute important risk factors for poor recurrence-free survival, CSS, and overall survival following RNU. In patients treated with RNU, a large tumor size strongly predicts a higher rate of muscle-invasive or nonorgan-confined renal pelvis UC.
Prognostic factors of UTUC include the presence of preoperative hydronephrosis which is independently associated with advanced pathological disease and worse oncological outcomes.
Diagnostic ureteroscopy before radical nephroureterectomy
Patients who underwent preoperative diagnostic ureteroscopy (URS) are at a higher risk of IVR after RNU. To explain this URS sequela, several theories, such as intraluminal tumor seeding, intraepithelial cancer migration, and urinary tract cancerization, have been suggested.
In patients treated with RNU, obesity has been known to have a negative impact on CSS. Furthermore, preoperative pyuria is associated with an advanced tumor stage, worse survival, and a higher risk of IVR. A high American Society of Anesthesiologists score, high pretreatment-derived neutrophil-to-lymphocyte ratio, and reduced serum albumin independently predict worse CSS.
Tumor stage and grade
Currently, the most important prognostic factors are tumor stage and tumor grade.,,
Lymph node involvement
Approximately 20% to 40% of patients with locally advanced UTUC have regional LN metastasis at the time of diagnosis, which represents a well-established prognostic factor of unfavorable outcomes, with 5-year survival rates of approximately 10%–30%. A survival benefit for patients with UTUC may be provided through LN dissection (LND); however, the role of LND along with RNU remains controversial.
Lymphovascular invasion (LVI) is defined as the presence of tumor cells within the lymphatic ducts or vascular channels of the RNU specimens and has been detected in approximately 20% of UTUCs. Associated with aggressive clinicopathological features, LVI serves as a strong predictor of poor oncological outcomes for UTUC., The LVI status should be mentioned in the pathological reports of all carcinoma specimens of the upper urinary tract.
Surgical margin positivity is associated with higher disease recurrence and metastasis after RNU. Margin status should be routinely recorded on RNU specimen reports.
Other pathological factors
Extensive tumor necrosis (>10% of the tumor area) is associated with features of aggressive UTUC. Whether tumor necrosis is a prognostic factor remains to be validated. Macroscopic sessile architecture also strongly predicts poor oncological outcomes of UTUC. The presence of concomitant CIS is associated with a higher risk of disease recurrence and cancer-specific survival after RNU.
Several molecular markers as prognostic factors in UTUC, such as E-cadherin, human epidermal growth factor receptor type 2, vimentin, and Ki-67, have been evaluated in previous studies. Programmed death-ligand 1 (PD-1/PDL-1) expression and tumor microsatellite instability were also investigated as useful independent prognosticators. However, due to the small sample sizes and their retrospective nature, these studies were limited. Currently, none of the molecular markers have sufficient evidence to be used in clinical decision-making.
| Clinical Cancer Course|| |
The disease recurrence of UTUC can occur in the urinary tract (intravesical and contralateral) and outside of the urinary tract (local recurrence and distant metastasis).
Currently, the two main concepts explaining urinary tract recurrence include intraluminal seeding and field cancerization theories. Patients suffer from disease recurrence, with the majority of relapses occurring within the first 3 years after RNU.
Recurrence in the urinary tract
Intravesical recurrence occurred in 22%–47% of patients with UTUC after RNU. A number of predictors of intravesical recurrence after RNU which were patient -specific (i.e., male sex, previous BCa, and preoperative CKD), tumor-specific (i.e., positive preoperative urinary cytology, ureteral location, multifocality, invasive pT stage, and necrosis), and treatment specific (i.e., laparoscopic RNU, extravesical bladder cuff removal, and positive surgical margins) were identified by a systematic review and meta-analysis conducted by the European Association of Urology (EAU) guideline panel. These predictors may guide postoperative decision making to perform adjuvant intravesical chemotherapy instillation or cystoscopy surveillance.
The development of metachronous contralateral recurrence after removal of the primary lesion is comparatively rare. The estimated incidence ranges from 0.6%–6.9% and is related to the region, which seems to be relatively high in Taiwan (4.6%–5.8%) and China (4.5%–6.9%). To avoid a second RNU and inevitable life-long maintenance dialysis, well-identified risk factors for contralateral recurrence can help clinicians in early detection. Bladder cancer history or concurrent bladder cancer has been reported to increase contralateral recurrence. In a Taiwanese study, renal insufficiency patients, especially patients on dialysis, have a higher incidence of developing contralateral UTUC.
Disease recurrence outside the urinary tract system
The rate of local failure is as high as 30%–50% in locally advanced patients with UTUC following RNU, which is associated with mortality. Tumor stage, grade, and location were investigated to be associated with local recurrence., Adjuvant radiotherapy can reduce local recurrence and may improve survival. Template-based and complete lymphadenectomy also seems to reduce the risk of local recurrence and improve CSS in patients with muscle-invasive UTUC.
At the time of diagnosis, most UTUC tumors are invasive, and metastatic recurrence occurs in more than 25% of patients treated with RNU., The survival of patients experiencing metastatic recurrence is poor, with survival time rarely exceeding 2 years. The lungs, liver, and bone are the predominant sites of distant metastasis following RNU, and the number of recurrence sites may be related to poor survival after systemic chemotherapy.
| Surgical Management|| |
Localized nonmetastatic disease
Management of low-risk nonmetastatic urinary tract urothelial carcinomas
Recently, the role of kidney-sparing surgery (KSS) has been markedly enhanced and advocated in the latest EAU guidelines. However, KSS was originally strongly indicated in patients with solitary kidneys or significant renal insufficiency. For low-risk UTUC, KSS has similar survival outcomes and reduced morbidities, such as impaired renal function, compared with radical surgery. Therefore, KSS should be considered in all low-risk patients regardless of the status of the contralateral kidney.
For patients with low-risk tumors, endoscopic ablation of UTUC should be considered a treatment option. Flexible URS represents a valid treatment option for pelvicalyceal tumors. Early repeated URS and strict surveillance are necessary for tumor recurrence detection and disease aggressiveness characterization. Of note, due to the limitations of endoscopic surveillance and biopsy, the risk of progression remains after endoscopic management.
For low-risk or superficial UTUC located in the renal pelvis, percutaneous management can be recommended. Percutaneous access may also be applied for tumors in the lower calyx that are difficult to access or manage by flexible URS. However, this procedure is being used less due to advances in flexible ureteroscopes with better distal-tip deflection and access. Furthermore, risks of tumor seeding along the percutaneous nephrostomy tract and complications such as bleeding and perirenal hematoma that may require blood transfusion or arterial embolization remain with percutaneous access.
For tumor staging and grading, segmental ureteral resection with wide surgical margins provides an adequate histological specimen. A concurrent regional lymphadenectomy can also be performed if the cancer is at high risk., For noninvasive low-grade tumors in the distal ureter which cannot be completely removed by endoscopic surgery, segmental ureterectomy with ureteroneocystostomy is indicated. It can also be an option for selected cases with high-grade and invasive UTUC while preserving postoperative renal function., Total ureterectomy with ileal ureteral substitution is a feasible choice, especially for CKD patients with multifocal or long-segment ureteral UC.
Upper urinary tract instillation of topical agents
For UTCIS patients unable or unwilling to undergo RNU, topical therapy utilizing immunomodulator agents can be considered. Topical agents such as BCG or mitomycin C can be instilled by antegrade administration via percutaneous nephrostomy tube following completion of tumor eradication or instilled via retrograde administration through a ureteric catheter after endoscopic management. The reflux through a double-J stent with agents instilled intravesically has also been used. However, it is a suboptimal treatment because the drug often cannot be delivered to the renal pelvis. In a recent meta-analysis assessing the oncologic outcomes of patients with noninvasive UTUC treated with KSS and adjuvant endocavitary instillations, no statistically significant differences were found between the medication administration (BCG and mitomycin C) and instillation approaches (antegrade and retrograde).
Management of high-risk nonmetastatic urinary tract urothelial carcinomas
| Open radical nephroureterectomy|| |
Open RNU with excision of the ipsilateral bladder cuff is the standard treatment modality of high-risk UTUC, which provides durable local control and cancer-specific survival in organ-confined UTUC. RNU performed according to oncological principles may lower the risk of tumor seeding.
| Minimally invasive radical nephroureterectomy|| |
With the advantages of minimal blood loss, faster recovery, and shorter hospital stays, minimally invasive RNU is performed increasingly. However, concerns regarding the oncological safety of minimally invasive techniques continue to exist with regard to retroperitoneal metastatic dissemination and port-site metastases following tumor manipulation and specimen extraction in a high-pressure environment of pneumoperitoneum. Several precautions during operation for tumor spillage prevention have been included in the latest EAU guidelines, which include performing the procedure in a closed system, avoiding entry to the urinary tract and direct contact between instruments and the specimens, and removing en bloc the kidney and ureter with the bladder cuff. Minimally invasive RNU may not be recommended for locally advanced (T3/T4) or high-grade UTUC due to poorer oncological outcomes compared with the open approach.
In an experienced hand, the laparoscopic approach offers reliable perioperative safety while following strict oncological principles. A recent study showed a tendency toward comparable oncological outcomes between laparoscopic and open RNU. Despite staging, surgical refinements, and availability of active systemic treatment strategies, patient survival after RNU has not changed significantly over the past three decades., In recent data, the robotic-assisted laparoscopic approach for UTUC seems to have equivalent oncological outcomes to open and laparoscopic approaches.
Bladder cuff excision
Due to considerable risks of local and bladder recurrence, the resection of the distal ureter and its orifice is an oncological principle of RNU. Several techniques have been described to modify the excision of the bladder cuff, such as extravesical laparoscopic stapling, transvesical laparoscopic detachment and ligation, pluck, stripping, and intussusception. None of these techniques are convincingly comparable to complete bladder cuff excision in terms of oncological safety.
Lymph node dissection
LND, according to the template, shows a greater impact on patient survival than the number of LNs removed. Anatomical template-based and complete LND improves CSS in muscle-invasive disease of the renal pelvis and reduces the risk of local recurrence. To ensure accurate nodal staging, all patients should be offered a template-based LND during RNU.
| Perioperative Treatment|| |
Neoadjuvant chemotherapy for localized urinary tract urothelial carcinomas
The role of neoadjuvant chemotherapy (NAC) for UTUC was found to have favorable outcomes in tumor downstaging and pathologic complete response rates. NAC is also associated with improved survival and lower disease recurrence than RNU alone. However, a prospective randomized study for NAC in UTUC is still lacking. Furthermore, there are multiple concerns regarding the use of NAC for patients with UTUC. First, particularly in chemo-resistant patients, administration of NAC delays definite RNU, which leads to disease progression. Second, patients undergoing NAC may suffer from potential peri-operative morbidities. Third, patients without pathologically proven muscle-invasive disease may result in overtreatment.
Adjuvant chemotherapy for localized urinary tract urothelial carcinomas
The role of adjuvant chemotherapy (ACT) for UTUC has been published, revealing conflicting results. Administration of ACT after RNU is based on an accurate pathological staging from surgical specimens, which avoids overtreatment. In addition, patients do not incur delays in receiving definitive surgical treatment, including no chemo-refractory risk. However, delivering full-dose cisplatin-based regimen is mainly limited due to the decline in renal function after RNU. A recently published phase 3 prospective randomized trial (the POUT trial) demonstrated a significant improvement in disease-free survival in patients with locally advanced UTUC treated with gemcitabine–platinum combination chemotherapy initiated within 90 days after RNU.
Adjuvant radiation for localized urinary tract urothelial carcinomas
For a reduction in loco-regional recurrence in patients with locally advanced UTUC after RNU, adjuvant radiation therapy (ART) has been suggested. In addition, in a recent systematic review, ART combined with chemotherapy has a beneficial effect on oncologic outcomes in patients with UTUC. However, data regarding the role of ART remain controversial and insufficient for conclusion, and prospective randomized controlled studies are required.
Postoperative bladder instillation
For patients with UTUC, the incidence of bladder recurrence after RNU is 22%–47%. A meta-analysis evaluated the use of a single postoperative intravesical chemotherapy instillation following RNU, and it reduced the risk of bladder tumor recurrence. The risk of extravasation, which is painful and potentially lethal, is the major concern of postoperative bladder instillation. Although there is no direct evidence supporting the setting, the latest EAU guideline supposed that the administration of chemotherapy into the bladder after KSS might be effective.
| Metastatic Disease|| |
The role of RNU in metastatic patients has been evaluated recently. It is noteworthy that surgery may have survival benefits in patients with single-site metastatic UTUC. RNU may be considered in patients who have a partial or complete response to induction chemotherapy.
Metastasectomy may be advantageous in selected patients with advanced UTUC. However, metastasectomy is rarely performed, and the supporting data are scarce.
Data on metastatic UTUC management is sparse, and treatment recommendations are mainly based on extrapolating from metastatic bladder cancer and small UTUC studies. Currently, the standard first-line treatment of metastatic UTUC for eligible patients is cisplatin-based combination therapy. The efficacy of immunotherapy with PD-1 and PDL-1 inhibitors has been investigated for patients with metastatic UC in the first-line setting, including those with UTUC.
In a single-arm phase II trial (KEYNOTE-052), the objective response rate was 22% with the use of pembrolizumab in 69 (19%) cisplatin-unfit patients with metastatic UTUC. In this study, a PDL-1 expression of 10% was associated with a higher response rate to pembrolizumab, which had acceptable toxic effects.
The JAVELIN Bladder 100 study showed that first-line avelumab maintenance therapy significantly prolonged OS in patients with advanced or metastatic UC who did not progress after four to six cycles of platinum-based chemotherapy as compared with best supportive care alone. This randomized controlled trial (RCT) included approximately 30% of patients with UTUC, while there was no specific analysis based on this subgroup.
First-line combination therapy
IMvigor130 phase III RCT, which evaluated atezolizumab in a similar setting, included 1213 patients with metastatic UC, where 26% (312 patients) harbored an UTUC. The trial showed that the combination of atezolizumab with platinum-based chemotherapy was associated with a statistically significant improvement in progression-free survival (PFS) as compared to platinum-based chemotherapy alone. However, data in the subgroup of UTUC have not been analyzed.
The KEYNOTE-361 phase III trial evaluated pembrolizumab either as in combination with platinum-based chemotherapy or chemotherapy alone in the first-line setting of metastatic UC, including 64 patients (18% of patients) with UTUC. However, the results did not reach statistically significant benefits for PFS and OS, including 64 (18%) of patients with UTUC. DANBUE, another negative phase III RCT, showed that durvalumab alone or in combination with tremelimumab did not improve OS versus platinum-based chemotherapy for metastatic UC.
Second-line treatment for metastatic UTUC is variable and remains challenging. Vinflunine was reported in a phase III RCT which showed a marginal survival benefit over best supportive care in metastatic UC patients progressing after first-line treatment with platinum-based chemotherapy. Vinflunine was also demonstrated as effective in UTUC as for bladder cancer in a post-hoc subgroup analysis after a platinum-based chemotherapy in metastatic/locally advanced UC patients.
Five immune-checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab, avelumab, and durvalumab) were approved by the US Food and Drug Administration as a second-line treatment for metastatic UC, of which three (pembrolizumab, atezolizumab, and nivolumab) were approved by the European Medical Agency. In a phase III trial, pembrolizumab was significantly associated with a longer OS in the second-line, postplatinum setting for advanced UC. However, the results were borderline significant in a subgroup of UTUC. Despite no subgroup analysis available for patients with UTUC, a large single-arm phase II study showed that atezolizumab has durable antitumor responses which were associated with PDL-1 expression on immune cells in patients with metastatic UC. However, atezolizumab failed to prolong OS compared to second-line chemotherapy for patients with high PDL-1 expression in the phase III trial IMvigor211.
Other immune-checkpoint inhibitors such as nivolumab, avelumab, and durvalumab have demonstrated similar efficacy and safety in patients with platinum-resistant metastatic UC based on single-arm phase I or II trials. However, the number of patients with UTUC was only specified for avelumab (n = 7/15.9%) among these studies. The combination of nivolumab and ipilimumab provided promising antitumor benefits in phase I/II multicenter study (CheckMate 032), including 78 patients with platinum-pretreated metastatic UC. This study included patients with UTUC, while no specific data on this subgroup were reported. Combinations of immunotherapeutic agents may be safe and effective in the second-line setting. However, currently, very limited data in metastatic UTUC are available.
A recent phase II trial evaluating the use of erdafitinib, the tyrosine kinase inhibitor of FGFR 1-4, has been published; 99 patients whose tumor harbored FGFR alternations experienced disease progression after previous chemotherapy, which resulted in an overall response rate of 40%.
Financial support and sponsorship
Conflicts of interest
Dr. Wen-Jeng Wu, an editorial board member at Urological Science, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.
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