The cancer behavior and current treatment strategy for upper urinary tract cancer



    Table of Contents REVIEW ARTICLE Year : 2022  |  Volume : 33  |  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 Submission02-May-2022Date of Decision03-Aug-2022Date of Acceptance29-Aug-2022Date of Web Publication30-Nov-2022

Correspondence Address:
Wen-Jeng Wu
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
Taiwan
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/UROS.UROS_58_22

Rights and Permissions


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 Top

Epidemiology

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.[1] 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.[1],[2],[3] UTUC is a relatively rare cancer, and the estimated annual incidence of UTUC is 2/100,000 persons in Western countries.[1] 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.[4] 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.[4],[5]

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.[6] In addition, patients with UTUC in Taiwan present with unique clinical characteristics such as female predominance and prevalence of chronic kidney disease (CKD).[4]

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.[7] Moreover, 60% of UTUCs are invasive at diagnosis compared with only 15% of bladder tumors.[3]

Risk factors

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.[8]

Arsenic exposure

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.[9] 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.[10] 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.[11]

Tobacco exposure

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.[8] Smoking is also significantly associated with advanced stages and high-grade upper tract tumors, suggesting that smoking promotes tumor progression.[12] Smoking cessation may decrease the risk of disease development.[13]

Histology

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.[14] Accounting for 15% of UC, squamous differentiation is the most common variant.[15] 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.[16]

  Prognosis Top

Prognostic factors

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.[17] 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.[2]

Preoperative factors

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.[18] 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.[19]

Smoking

Cigarette smoking significantly increases the risk for UTUC recurrence and cancer-specific mortality after radical nephroureterectomy (RNU).[12] Current smokers and heavy-long-term tobacco consumption have the highest risk of IVR.[20] Smoking cessation is beneficial for cancer control, and counseling these patients regarding cessation is necessary.

Tumor location

In some study cohorts, initial tumor locations have been demonstrated as prognostic factors of UTUC.[21],[22] Ureteral tumors are associated with higher disease recurrence and mortality than renal pelvic tumors after controlling the effects of the tumor stage.[18],[21],[22],[23] Perinephric fat was considered a barrier against the metastatic spread,[24] and a thinner ureteral adventitia, which is rich in blood plexus and lymphatic ducts, may facilitate tumor invasion.[21]

Multifocality

Multifocal tumors involving both the ureter and renal pelvis show a worse prognosis than patients diagnosed with renal pelvic tumors.[22] Tumor multifocality may be a more aggressive feature in patients with UTUC and is associated with the panurothelial nature of UTUC.[22] Patients with multifocal UTUCs should be considered for more aggressive management.

Size

Tumors of >3 cm constitute important risk factors for poor recurrence-free survival, CSS, and overall survival following RNU.[25] In patients treated with RNU, a large tumor size strongly predicts a higher rate of muscle-invasive or nonorgan-confined renal pelvis UC.[26]

Hydronephrosis

Prognostic factors of UTUC include the presence of preoperative hydronephrosis which is independently associated with advanced pathological disease and worse oncological outcomes.[27]

Diagnostic ureteroscopy before radical nephroureterectomy

Patients who underwent preoperative diagnostic ureteroscopy (URS) are at a higher risk of IVR after RNU.[28] To explain this URS sequela, several theories, such as intraluminal tumor seeding, intraepithelial cancer migration, and urinary tract cancerization, have been suggested.[29]

Others

In patients treated with RNU, obesity has been known to have a negative impact on CSS.[30] Furthermore, preoperative pyuria is associated with an advanced tumor stage, worse survival, and a higher risk of IVR.[31] A high American Society of Anesthesiologists score,[32] high pretreatment-derived neutrophil-to-lymphocyte ratio,[33] and reduced serum albumin[34] independently predict worse CSS.

Pathological factors

Tumor stage and grade

Currently, the most important prognostic factors are tumor stage and tumor grade.[17],[18],[35]

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,[35] with 5-year survival rates of approximately 10%–30%.[36] A survival benefit for patients with UTUC may be provided through LN dissection (LND); however, the role of LND along with RNU remains controversial.[37]

Lymphovascular invasion

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.[38] Associated with aggressive clinicopathological features, LVI serves as a strong predictor of poor oncological outcomes for UTUC.[35],[38] The LVI status should be mentioned in the pathological reports of all carcinoma specimens of the upper urinary tract.[39]

Surgical margin

Surgical margin positivity is associated with higher disease recurrence and metastasis after RNU.[35] Margin status should be routinely recorded on RNU specimen reports.[39]

Other pathological factors

Extensive tumor necrosis (>10% of the tumor area) is associated with features of aggressive UTUC.[40] Whether tumor necrosis is a prognostic factor remains to be validated. Macroscopic sessile architecture also strongly predicts poor oncological outcomes of UTUC.[41] The presence of concomitant CIS is associated with a higher risk of disease recurrence and cancer-specific survival after RNU.[42]

Molecular markers

Several molecular markers as prognostic factors in UTUC, such as E-cadherin,[43] human epidermal growth factor receptor type 2,[44] vimentin, and Ki-67, have been evaluated in previous studies.[45] Programmed death-ligand 1 (PD-1/PDL-1) expression[46] and tumor microsatellite instability[47] 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 Top

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[48] and field cancerization[49] theories. Patients suffer from disease recurrence, with the majority of relapses occurring within the first 3 years after RNU.[50]

Recurrence in the urinary tract

Intravesical recurrence

Intravesical recurrence occurred in 22%–47% of patients with UTUC after RNU.[51] 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.[50] These predictors may guide postoperative decision making to perform adjuvant intravesical chemotherapy instillation or cystoscopy surveillance.

Contralateral recurrence

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%).[52] 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.[53] In a Taiwanese study, renal insufficiency patients, especially patients on dialysis, have a higher incidence of developing contralateral UTUC.[54]

Disease recurrence outside the urinary tract system

Local recurrence

The rate of local failure is as high as 30%–50% in locally advanced patients with UTUC following RNU, which is associated with mortality.[55] Tumor stage, grade, and location were investigated to be associated with local recurrence.[23],[56] Adjuvant radiotherapy can reduce local recurrence and may improve survival.[56] Template-based and complete lymphadenectomy also seems to reduce the risk of local recurrence and improve CSS in patients with muscle-invasive UTUC.[57]

Distant metastasis

At the time of diagnosis, most UTUC tumors are invasive,[17] and metastatic recurrence occurs in more than 25% of patients treated with RNU.[17],[58] The survival of patients experiencing metastatic recurrence is poor, with survival time rarely exceeding 2 years.[59] 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.[60]

  Surgical Management Top

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.[2] For low-risk UTUC, KSS has similar survival outcomes and reduced morbidities, such as impaired renal function, compared with radical surgery.[61] Therefore, KSS should be considered in all low-risk patients regardless of the status of the contralateral kidney.

Ureteroscopy

For patients with low-risk tumors, endoscopic ablation of UTUC should be considered a treatment option.[61] Flexible URS represents a valid treatment option for pelvicalyceal tumors.[62] Early repeated URS and strict surveillance are necessary for tumor recurrence detection and disease aggressiveness characterization.[63] Of note, due to the limitations of endoscopic surveillance and biopsy, the risk of progression remains after endoscopic management.[64]

Percutaneous access

For low-risk or superficial UTUC located in the renal pelvis, percutaneous management can be recommended.[61] 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.[61] 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.

Ureteral resection

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.[2],[65] 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.[2],[66] Total ureterectomy with ileal ureteral substitution is a feasible choice, especially for CKD patients with multifocal or long-segment ureteral UC.[67]

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.[68] 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.[69] 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).[70]

Management of high-risk nonmetastatic urinary tract urothelial carcinomas

Surgical approach

  Open radical nephroureterectomy Top

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.[17] RNU performed according to oncological principles may lower the risk of tumor seeding.[17]

  Minimally invasive radical nephroureterectomy Top

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.[71] 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.[2] 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.[72]

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.[73] Despite staging, surgical refinements, and availability of active systemic treatment strategies, patient survival after RNU has not changed significantly over the past three decades.,[74] In recent data, the robotic-assisted laparoscopic approach for UTUC seems to have equivalent oncological outcomes to open and laparoscopic approaches.[75]

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.[76] 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.[76]

Lymph node dissection

LND, according to the template, shows a greater impact on patient survival than the number of LNs removed.[77] Anatomical template-based and complete LND improves CSS in muscle-invasive disease of the renal pelvis and reduces the risk of local recurrence.[57] To ensure accurate nodal staging, all patients should be offered a template-based LND during RNU.[78]

  Perioperative Treatment Top

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.[79] NAC is also associated with improved survival and lower disease recurrence than RNU alone.[79] 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.[80] 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.[5] 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.[81] 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.[82]

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.[83] In addition, in a recent systematic review, ART combined with chemotherapy has a beneficial effect on oncologic outcomes in patients with UTUC.[83] 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%.[51] A meta-analysis evaluated the use of a single postoperative intravesical chemotherapy instillation following RNU, and it reduced the risk of bladder tumor recurrence.[84] 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.[2]

  Metastatic Disease Top

Radical nephroureterectomy

The role of RNU in metastatic patients has been evaluated recently.[85] It is noteworthy that surgery may have survival benefits in patients with single-site metastatic UTUC.[85] RNU may be considered in patients who have a partial or complete response to induction chemotherapy.

Metastasectomy

Metastasectomy may be advantageous in selected patients with advanced UTUC. However, metastasectomy is rarely performed, and the supporting data are scarce.

Systemic therapies

First-line monotherapy

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.[2] 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.[86] 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.[87] 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.[88]

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.[89] 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.[90]

Second-line setting

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.[91] 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.[92]

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.[93] 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.[94] However, atezolizumab failed to prolong OS compared to second-line chemotherapy for patients with high PDL-1 expression in the phase III trial IMvigor211.[95]

Other immune-checkpoint inhibitors such as nivolumab,[96] avelumab,[97] and durvalumab[98] 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.[97] 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.[99]

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%.[100]

Financial support and sponsorship

Nil.

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.

 

  References Top
1.Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin 2021;71:7-33.  Back to cited text no. 1
    2.Rouprêt M, Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, et al. European Association of Urology guidelines on upper urinary tract urothelial carcinoma: 2020 update. Eur Urol 2021;79:62-79.  Back to cited text no. 2
    3.Munoz JJ, Ellison LM. Upper tract urothelial neoplasms: Incidence and survival during the last 2 decades. J Urol 2000;164:1523-5.  Back to cited text no. 3
    4.Chen JS, Lu CL, Huang LC, Shen CH, Chen SC. Chronic kidney disease is associated with upper tract urothelial carcinoma: A nationwide population-based cohort study in Taiwan. Medicine (Baltimore) 2016;95:e3255.  Back to cited text no. 4
    5.Necchi A, Lo Vullo S, Mariani L, Moschini M, Hendricksen K, Rink M, et al. Adjuvant chemotherapy after radical nephroureterectomy does not improve survival in patients with upper tract urothelial carcinoma: A joint study by the European Association of Urology-Young Academic Urologists and the Upper Tract Urothelial Carcinoma Collaboration. BJU Int 2018;121:252-9.  Back to cited text no. 5
    6.Luo HL, Ohyama C, Hatakeyama S, Wang HJ, Yoneyama T, Yang WC, et al. Unusual presentation of upper urinary tract urothelial carcinoma in Taiwan: Direct comparison from Taiwan-Japan UTUC Collaboration Cohort. Int J Urol 2020;27:327-32.  Back to cited text no. 6
    7.Audenet F, Isharwal S, Cha EK, Donoghue MT, Drill EN, Ostrovnaya I, et al. Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma. Clin Cancer Res 2019;25:967-76.  Back to cited text no. 7
    8.Colin P, Koenig P, Ouzzane A, Berthon N, Villers A, Biserte J, et al. Environmental factors involved in carcinogenesis of urothelial cell carcinomas of the upper urinary tract. BJU Int 2009;104:1436-40.  Back to cited text no. 8
    9.Jadot I, Declèves AE, Nortier J, Caron N. An integrated view of aristolochic acid nephropathy: Update of the literature. Int J Mol Sci 2017;18:297.  Back to cited text no. 9
    10.Nortier JL, Vanherweghem JL. Renal interstitial fibrosis and urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). Toxicology 2002;181-182:577-80.  Back to cited text no. 10
    11.Chen CH, Dickman KG, Huang CY, Moriya M, Shun CT, Tai HC, et al. Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: Clinical characteristics and outcomes. Int J Cancer 2013;133:14-20.  Back to cited text no. 11
    12.Rink M, Xylinas E, Margulis V, Cha EK, Ehdaie B, Raman JD, et al. Impact of smoking on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. Eur Urol 2013;63:1082-90.  Back to cited text no. 12
    13.McLaughlin JK, Silverman DT, Hsing AW, Ross RK, Schoenberg JB, Yu MC, et al. Cigarette smoking and cancers of the renal pelvis and ureter. Cancer Res 1992;52:254-7.  Back to cited text no. 13
    14.Rink M, Robinson BD, Green DA, Cha EK, Hansen J, Comploj E, et al. Impact of histological variants on clinical outcomes of patients with upper urinary tract urothelial carcinoma. J Urol 2012;188:398-404.  Back to cited text no. 14
    15.Perez-Montiel D, Wakely PE, Hes O, Michal M, Suster S. High-grade urothelial carcinoma of the renal pelvis: Clinicopathologic study of 108 cases with emphasis on unusual morphologic variants. Mod Pathol 2006;19:494-503.  Back to cited text no. 15
    16.Tang Q, Xiong G, Li X, Fang D, Xi C, Zhang L, et al. The prognostic impact of squamous and glandular differentiation for upper tract urothelial carcinoma patients after radical nephroureterectomy. World J Urol 2016;34:871-7.  Back to cited text no. 16
    17.Margulis V, Shariat SF, Matin SF, Kamat AM, Zigeuner R, Kikuchi E, et al. Outcomes of radical nephroureterectomy: A series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer 2009;115:1224-33.  Back to cited text no. 17
    18.Lughezzani G, Burger M, Margulis V, Matin SF, Novara G, Roupret M, et al. Prognostic factors in upper urinary tract urothelial carcinomas: A comprehensive review of the current literature. Eur Urol 2012;62:100-14.  Back to cited text no. 18
    19.Wu YT, Luo HL, Wang HJ, Chen YT, Cheng YT, Chiang PH. Gender effect on the oncologic outcomes of upper urinary tract urothelial carcinoma in Taiwan. Int Urol Nephrol 2020;52:1043-8.  Back to cited text no. 19
    20.Xylinas E, Kluth LA, Rieken M, Lee RK, Elghouayel M, Ficarra V, et al. Impact of smoking status and cumulative exposure on intravesical recurrence of upper tract urothelial carcinoma after radical nephroureterectomy. BJU Int 2014;114:56-61.  Back to cited text no. 20
    21.Waseda Y, Saito K, Ishioka J, Matsuoka Y, Numao N, Fujii Y, et al. Ureteral involvement is associated with poor prognosis in upper urinary tract urothelial carcinoma patients treated by nephroureterectomy: A multicenter database study. Eur Urol Focus 2016;2:296-302.  Back to cited text no. 21
    22.Ouzzane A, Colin P, Xylinas E, Pignot G, Ariane MM, Saint F, et al. Ureteral and multifocal tumours have worse prognosis than renal pelvic tumours in urothelial carcinoma of the upper urinary tract treated by nephroureterectomy. Eur Urol 2011;60:1258-65.  Back to cited text no. 22
    23.Chen TS, Chen YT, Wang HJ, Chiang PH, Yang WC, Lee WC, et al. The prognostic impact of tumor location in pT3N0M0 upper urinary tract urothelial carcinoma: A retrospective cohort study. Front Oncol 2022;12:850874.  Back to cited text no. 23
    24.Park J, Park S, Song C, Hong JH, Kim CS, Ahn H. Peripelvic/periureteral fat invasion is independently associated with worse prognosis in pT3 upper tract urothelial carcinoma. World J Urol 2014;32:157-63.  Back to cited text no. 24
    25.Shibing Y, Liangren L, Qiang W, Hong L, Turun S, Junhao L, et al. Impact of tumour size on prognosis of upper urinary tract urothelial carcinoma after radical nephroureterectomy: A multi-institutional analysis of 795 cases. BJU Int 2016;118:902-10.  Back to cited text no. 25
    26.Collà Ruvolo C, Nocera L, Stolzenbach LF, Wenzel M, Califano G, Tian Z, et al. Tumor size predicts muscle-invasive and non-organ-confined disease in upper tract urothelial carcinoma at radical nephroureterectomy. Eur Urol Focus 2022;8:498-505.  Back to cited text no. 26
    27.Kohada Y, Hayashi T, Goto K, Kobatake K, Abdi H, Honda Y, et al. Preoperative risk classification using neutrophil-lymphocyte ratio and hydronephrosis for upper tract urothelial carcinoma. Jpn J Clin Oncol 2018;48:841-50.  Back to cited text no. 27
    28.Marchioni M, Primiceri G, Cindolo L, Hampton LJ, Grob MB, Guruli G, et al. Impact of diagnostic ureteroscopy on intravesical recurrence in patients undergoing radical nephroureterectomy for upper tract urothelial cancer: A systematic review and meta-analysis. BJU Int 2017;120:313-9.  Back to cited text no. 28
    29.Luo HL, Kang CH, Chen YT, Chuang YC, Lee WC, Cheng YT, et al. Diagnostic ureteroscopy independently correlates with intravesical recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma. Ann Surg Oncol 2013;20:3121-6.  Back to cited text no. 29
    30.Ehdaie B, Chromecki TF, Lee RK, Lotan Y, Margulis V, Karakiewicz PI, et al. Obesity adversely impacts disease specific outcomes in patients with upper tract urothelial carcinoma. J Urol 2011;186:66-72.  Back to cited text no. 30
    31.Sato G, Yoshida T, Yanishi M, Saito R, Murota T, Kawa G, et al. Preoperative pyuria predicts for intravesical recurrence in patients with urothelial carcinoma of the upper urinary tract after radical nephroureterectomy without a history of bladder cancer. Clin Genitourin Cancer 2020;18:e167-73.  Back to cited text no. 31
    32.Berod AA, Colin P, Yates DR, Ouzzane A, Audouin M, Adam E, et al. The role of American Society of Anesthesiologists scores in predicting urothelial carcinoma of the upper urinary tract outcome after radical nephroureterectomy: Results from a national multi-institutional collaborative study. BJU Int 2012;110:E1035-40.  Back to cited text no. 32
    33.Vartolomei MD, Kimura S, Ferro M, Vartolomei L, Foerster B, Abufaraj M, et al. Is neutrophil-to-lymphocytes ratio a clinical relevant preoperative biomarker in upper tract urothelial carcinoma? A meta-analysis of 4385 patients. World J Urol 2018;36:1019-29.  Back to cited text no. 33
    34.Liu J, Wang F, Li S, Huang W, Jia Y, Wei C. The prognostic significance of preoperative serum albumin in urothelial carcinoma: A systematic review and meta-analysis. Biosci Rep 2018;38:BSR20180214.  Back to cited text no. 34
    35.Sharma G, Yadav AK, Pareek T, Kaundal P, Tyagi S, Devana SK, et al. Impact of pathological factors on survival in patients with upper tract urothelial carcinoma: A systematic review and meta-analysis. Int Braz J Urol 2022;48:406-55.  Back to cited text no. 35
    36.Gandaglia G, Bianchi M, Trinh QD, Becker A, Larouche A, Abdollah F, et al. Sur

留言 (0)

沒有登入
gif