Guidelines Summary
Guidelines on the diagnosis and treatment of urothelial tumors of the renal pelvis and ureters have been published by the following organizations:
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National Comprehensive Cancer Network (NCCN)
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European Association of Urology (EAU)
Diagnosis
The NCCN guidelines recommend including the following tests in the workup of suspected renal pelvic and ureteral tumors [24] :
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Cystoscopy
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CT or MR urography
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Renal ultrasound or CT without contrast with retrograde pyelography for patients who cannot receive iodinated or gadolinium-based contrast agentsl.
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Ureteroscopy with biopsy and/or selective washings.
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Kidney function tests
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Chest x-ray to help evaluate for possible metastasis and assess for comorbidities
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Urine cytology to help identify carcinoma cells
Additional imaging studies, such as renal or bone scanning, may be indicated by the test results or presence of specific symptoms. Evaluation for Lynch syndrome should be considered for those at high risk.
The EAU guidelines in general concur with NCCN and include the following key recommendations [1] :
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Cystoscopy is performed to rule out concurrent bladder tumor
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CT urography is performed for upper tract evaluation and staging
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Diagnostic ureteroscopy and biopsy are performed only in cases where additional information will impact treatment decisions
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Magnetic resonance urography or 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/CT may be used when CT is contraindicated.
Treatment
The NCCN guidelines provide treatment recommendations based on grade and tumor location. For low-grade renal pelvic tumors, the guidelines recommend the following treatment [24] :
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Nephroureterectomy with cuff of bladder with or without perioperative intravesical chemotherapy or
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Endoscopic resection with or without postsurgical intrapelvic chemotherapy or bacillus Calmette-Guerin (BCG)
For high-grade renal pelvic tumors and upper ureter tumors, NCCN treatment recommendations include the following [24] :
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Nephroureterectomy with cuff of bladder and regional lymphadenectomy with or without perioperative intravesical chemotherapy
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Neoadjuvant chemotherapy may be considered in selected patients
For low-grade upper- and mid-ureter tumors, NCCN recommended treatment options include the following [24] :
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Endoscopic resection
For high-grade upper- and mid-ureter tumors, NCCN recommended treatment options include the following [24] :
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Nephroureterectomy with cuff of bladder and regional lymphadenectomy
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Consider neoadjuvant chemotherapy in selective patients
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Excision and ureteroureterostomy/ileal ureter in highly selected patients
For distal ureter tumors, NCCN recommended treatment options include the following [24] :
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Distal ureterectomy and regional lymphadenectomy (high grade) and reimplantation of ureter (preferred if clinically feasible) and consider neoadjuvant chemotherapy in selected patients
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Endoscopic resection (low grade)
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Nephroureterectomy with cuff of bladder and regional lymphadenectomy and consider neoadjuvant chemotherapy in selected patients
For metastatic disease in both renal pelvis and ureter tumors, systemic therapy is recommended by both guidelines. [1, 24]
The EAU guidelines include the following key treatment recommendations [1]
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Kidney-sparing management (flexible ureteroscopy or segmental resection or percutaneous approach) is the primary treatment option for low-risk tumors.
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Offer kidney-sparing management to high-risk patients with imperative indication on a case-by-case basis, in consultation with the patient.
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Perform radical nephroureterectomy (RNU) in patients with high-risk non-metastatic UTUC.
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Perform open RNU in non–organ-confined UTUC (cT3, cN+).
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Perform a template-based lymphadenectomy in patients with high-risk non-metastatic UTUC.
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Deliver a postoperative bladder instillation of chemotherapy to lower the intravesical recurrence rate.
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Offer adjuvant platinum-based systemic chemotherapy after RNU to patients with pT2–T4 and/or pN+ disease; offer gemcitabine/carboplatin chemotherapy to cisplatin-ineligible patients.
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Discuss adjuvant nivolumab with patients who are unfit for, or who declined, platinum-based adjuvant chemotherapy for > pT3 and/or pN+ disease after RNU alone or > ypT2 and/or ypN+ disease after neoadjuvant chemotherapy, followed by RNU.
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Offer the checkpoint inhibitors pembrolizumab or atezolizumab to patients with programmed death ligand 1 (PD-L1)–positive tumors.
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Offer enfortumab vedotin to patients previously treated with platinum-containing chemotherapy and who had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor.
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Offer erdafitinib as subsequent-line therapy to patients with platinum-refractory UTUC with FGFR DNA genomic alterations (FGFR2/3 mutations or FGFR3 fusions).
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Intravenous pyelogram (IVP) demonstrating an upper calyx filling defect characteristic of upper tract urothelial carcinoma (UTUC). Blunting of the involved calyx is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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CT scan demonstrating right renal pelvis upper tract urothelial carcinoma (UTUC). Contrast in the renal pelvis is displaced by the tumor. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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CT scan demonstrating left distal ureteral upper tract urothelial carcinoma (UTUC). The left ureter is dilated and a medial filling defect is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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Left retrograde ureterogram demonstrating the classic "goblet" sign of ureteral upper tract urothelial carcinoma (UTUC). Ureteral dilation distally and proximally to the tumor is present. The narrowed wall of the ureter is irregular. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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CT scan demonstrating bulky right renal pelvis upper tract urothelial carcinoma (UTUC) replacing the majority of the renal parenchyma. A pericaval lymph node metastasis is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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CT scan demonstrating metastatic upper tract urothelial carcinoma (UTUC) of the right adrenal gland. A heterogeneous adrenal mass is noted adjacent to the spine. The superior portion of the right kidney is observed. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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Graphic representation of templates for lymph node dissection in patients with upper tract urothelial carcinoma, as proposed by Matin et al. For tumors in the right pelvis and upper ureter, dissection encompassing the right hilar, paracaval, and retrocaval regions (orange) will remove 82.9% of the involved lymph nodes. Adding the inter-aortocaval region (green) will improve coverage to 95.8%. For left-sided pelvic tumors, removal of hilar and para-aortic lymph nodes (violet) will ensure removal of 86.9% of the involved nodes. Adding inter-aortocaval lymph nodes (green) will increase the coverage to 90.2% of involved nodes. The level of dissection along the great vessels varies for pelvic tumors. The lower limit is the inferior mesenteric artery. For upper ureteric tumors, dissection should extend up to the aortic bifurcation. For distal ureteric tumors, pelvic template dissection involving the common iliac, external iliac, obturator, and internal iliac nodes will remove 75% of involved nodes on the right side and 83.3% of involved nodes on the left side (orange and violet circles). However, adding paracaval groups for tumors on the left side (orange rectangle) and para-aortic groups for those on the right side (violet rectangle) will improve coverage to almost 100%.
Tables
Stage |
Tumor |
Node |
Metastasis |
0a |
Ta |
N0 |
M0 |
0is |
Tis |
N0 |
M0 |
I |
T1 |
N0 |
M0 |
II |
T2 |
N0 |
M0 |
III |
T3 |
N0 |
M0 |
IV |
T4 |
NX, N0 |
M0 |
Any T |
N1 |
M0 |
|
Any T |
N2 |
M0 |
|
Any T |
Any N |
M1 |
Reference |
Study design |
Outcome |
Number of patients enrolled |
Leow JJ, Martin-Doyle W, Fay AP, et al. 2014
|
Systematic review and meta-analysis |
Pooled hazard ratio (HR) for overall survival (OS) was 0.43 (95% confidence interval [CI], 0.21–0.89; P = 0.023) for adjuvant therapy group compared with controls without adjuvant therapy |
Prospective study (n = 36) investigating adjuvant carboplatin–paclitaxel and nine retrospective studies, with a total of 482 patients receiving cisplatin-based or non-cisplatin–based AC after nephroureterectomy |
Porten S, Siefker-Radtke AO, Xiao L, et al. 2014
|
Retrospective review between neoadjuvant chemotherapy group and initial surgery group |
Neoadjuvant chemotherapy had improved OS and disease-specific survival (DSS) with a 5-year DSS rate of 90.1% and a 5-year OS rate of 80.2% versus DSS and OS rates of 57.6% for those who underwent initial surgery (P = 0.0204 and P = 0.0015, respectively |
Neoadjuvant chemotherapy +surgery (n =31) and surgery only (n= 81)
|
Huang YC, Chen MF, Shi CS, et al. 2015
|
Retrospective review of patient records with pT3N0M0 upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy and adjuvant therapy versus control group |
Statistically significant differences were found between the adjuvant and control groups in 5-year cancer-specific survival rates (80.5% vs 57.6%, P = 0.010) and recurrence-free survival rates (74.4% vs 52.9%, P = 0.026), but no statistically significant difference in overall survival (71.9% vs 49.0%, P = 0.072) |
Postoperative adjuvant chemotherapy (n= 60) vs surgery only (n=111) |
Urakami S, Yuasa T, Yamamoto S, et al. 2015 |
Retrospective analysis of clinicopathological response to induction chemotherapy and identification of prognostic factors for OS |
Clinically objective response to the induction chemotherapy occurred in 75% of patients. Histopathological analysis indicated pT0 status in 20% and pN0 in 33%. Clinical tumor response correlated significantly with achievement of pathological complete response |
60 urothelial cancer patients; primary cancer site was the urinary bladder (n= 31; 52%) and upper urinary tract (n=29; 48%) |
Lucca I, Kassouf W, Kapoor A, et al. 2015
|
Retrospective analysis of data of patients with lymph node (LN)–positive UTUC, who underwent full surgical resection followed by adjuvant chemotherapy (AC) |
In all patients (T(all) N+), administration of AC had no significant impact on UTUC-related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3-4 disease benefited from AC. In this subgroup, AC reduced UTUC-related mortality by 34% (P = 0.019). |
263 patients with LN-positive UTUC underwent full surgical resection. Study group (n=107, 41%) received three to six cycles of AC, while controls (n=156; 59.3%) were treated with RNU alone |
Kim DK, Kim JW, Jung HD, et al. 2019 |
Systematic review and meta-analysis of adjuvant therapy after radical nephroureterectomy (RNU) in patients with locally advanced UTUC
|
Compared with patients who underwent RNU only, those who received adjuvant chemotherapy after RNU had HRs for disease-free survival of 0.59 (P = 0.001), cancer-specific survival of 0.73 (P = 0.02), and OS of 0.84 (P = 0.02) |
11 studies, comprising 1496 patients who underwent RNU alone and 798 patients who received ACH after RNU |
Margulis V, Puligandla M, Trabulsi EJ, et al. 2020
|
Prospective phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery for patients with high-grade UTUC
|
Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy in patients with high-grade UTUC and creatinine clearance > 50 mL/min was safe and demonstrated predefined activity with a 14% pathologic complete response rate. |
23 men and 6 women with a median age of 65 years (range 40 to 84); 80% completed all planned treatments |
NCT01261728 |
Prospective phase II study of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade UTUC |
Expected to complete by Dec 2023 |
NA |
