Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline (2023) Flashcards

Question

What insights do genomic studies provide about concomitant upper and lower tract tumors?

Answer 1

Genomic studies have shown clonal similarity between upper and lower tract tumors, which indicates a potential downstream or upstream tumor implantation mechanism. This finding underscores the interconnected nature of these tumors and justifies treating them in the same surgical setting when they are discovered concurrently. It's important to note, however, that while bladder tumor pathology often reflects that of upper tract tumors, it is not reliable enough to avoid separate upper tract endoscopy and biopsy when feasible.

Answer 2

The guideline recommends minimizing the risk of ureteral injury in patients with existing ureteral strictures or difficult access to the upper tract by using gentle dilation techniques, such as temporary stenting (pre-stenting), and limiting the use of aggressive dilation access techniques like ureteral access sheaths. This is crucial because perforation or disruption of the urothelium in patients with upper tract urothelial carcinoma (UTUC) can risk tumor seeding outside the urinary tract. Pre-stenting can decrease the risk of iatrogenic injury and allow for a safer and more successful procedure. If perforation or injury events occur, they should be immediately documented and the procedure should be stopped as soon as safely possible, with additional steps taken to limit complications.

Answer 3

b) Use of gentle dilation techniques such as temporary stenting (pre-stenting)

Answer 4

b) Document the injury event immediately and cease the procedure as soon as safely possible

Answer 5

In patients with upper tract urothelial carcinoma (UTUC) who have existing ureteral strictures or difficulty accessing the upper tract, gentle dilation techniques such as temporary stenting or pre-stenting can decrease the risk of iatrogenic injury. This is critical as perforation or disruption of the urothelium in patients with UTUC can risk seeding the tumor outside the urinary tract. Pre-stenting provides an opportunity for a safer and more successful procedure.

Answer 6

If a perforation or injury event is recognized during the procedure, it should be immediately documented, and the procedure should be stopped as soon as it is safe to do so. Additional measures to limit complications should be undertaken, such as stenting, bladder decompression with urethral catheter drainage to limit reflux, and placement of a nephrostomy tube in cases of a completely obstructive ureteral tumor and evidence of contrast extravasation. These measures are important to manage the injury and prevent further complications.

Answer 7

The guideline suggests that in cases where ureteroscopy can't be performed safely or isn't possible, attempts at selective upper tract washing or barbotage for cytology can be made, and pyeloureterography could be performed in cases where high-quality imaging such as CT or MR urography cannot be obtained. The findings from these procedures may provide useful and objective information for risk stratification when endoscopic examination of the involved upper tract isn't feasible. This guidance is considered a conditional recommendation due to limited data from endoscopy, biopsy, and imaging, but is supported by the evidence associated with Statement 2.

Answer 8

b) When ureteroscopy cannot be safely performed or is not possible

Answer 9

c) When high-quality imaging such as CT or MR urography cannot be obtained

Answer 10

In cases where ureteroscopy can't be performed safely or isn't possible, attempts at selective upper tract washing or barbotage for cytology can provide useful, objective information for risk stratification. Furthermore, pyeloureterography can be beneficial in scenarios where high-quality imaging such as CT or MR urography is not obtainable. These methods provide an alternative approach to gather critical information about the patient's condition when traditional methods are not viable.

Answer 11

The guideline advises against performing ureteroscopic inspection of a radiographically and clinically normal contralateral upper tract at the time of ureteroscopy for suspected upper tract urothelial carcinoma (UTUC). Indications for upper urinary tract ureteroscopy or percutaneous endoscopy include lateralizing hematuria, suspicious selective cytology, and radiographic presence of a mass or urothelial thickening. These endoscopic procedures carry risks for patient injury and potential for tumor seeding in the presence of urothelial cancer. Unnecessary upper tract endoscopy in the setting of a completely normal contralateral upper urinary tract, without clinical indication or as a "screening" procedure, puts patients at undue risk and is not recommended.

Answer 12

b) When there are findings such as lateralizing hematuria, suspicious selective cytology, and radiographic presence of a mass or urothelial thickening

Answer 13

b) Potential risks include patient injury and the possibility of tumor seeding in the presence of urothelial cancer

Answer 14

Performing a ureteroscopic inspection of a radiographically and clinically normal contralateral upper tract is not recommended because it unnecessarily exposes the patient to risks associated with the procedure. These risks include potential injury to the patient and the possibility of tumor seeding in the presence of urothelial cancer. The guideline suggests that this procedure should only be performed when there are specific indications such as lateralizing hematuria, suspicious selective cytology, and radiographic presence of a mass or urothelial thickening.

Answer 15

Ureteroscopy or percutaneous endoscopy of the upper urinary tract should be performed when there are specific clinical indications. These indications include lateralizing hematuria, suspicious selective cytology, and the radiographic presence of a mass or urothelial thickening. The decision to perform these procedures should be guided by the need to diagnose and treat suspected upper tract urothelial carcinoma, balanced against the potential risks associated with the procedures.

Answer 16

Clinicians should obtain a personal and family history from patients with suspected or diagnosed upper tract urothelial carcinoma (UTUC) to identify known hereditary risk factors for familial diseases associated with Lynch Syndrome (LS), including colorectal, ovarian, endometrial, gastric, biliary, small bowel, pancreatic, prostate, skin, and brain cancer. If such risks are identified, referral for genetic counseling should be offered. LS is common among UTUC patients, accounting for 7-20% of U.S. cases. It's an autosomal-dominant multi-organ cancer syndrome affecting approximately 1 in 280 individuals in the U.S. LS is associated with several cancers, with patients recommended to undergo routine screening due to increased life-long risk for developing associated malignancies. For UTUC patients with familial risk factors, clinical suspicion, or interest in further testing for hereditary syndromes, clinicians can perform initial screening tests and should offer referral for genetic counseling and, if indicated, genetic testing.

Answer 17

d) All of the above

Answer 18

Clinicians should obtain a detailed personal and family history from patients with suspected or diagnosed UTUC to identify known hereditary risk factors for familial diseases associated with Lynch Syndrome. If such risk factors are identified, clinicians should offer referral for genetic counseling and, if indicated, genetic testing. Routine evaluation should include specific questions about Lynch Syndrome associated cancers to help identify at-risk patients and their family members. In UTUC specifically, Lynch Syndrome may increase the possibility of contralateral upper tract involvement, which should be considered when developing a treatment plan.

Answer 19

It's important to recognize Lynch Syndrome as a potential risk factor in patients with UTUC as it's common among such patients, accounting for an estimated 7-20% of U.S. cases. Moreover, Lynch Syndrome is an autosomal-dominant multi-organ cancer syndrome that increases the lifetime risk for developing associated malignancies. Therefore, recognition of this syndrome can help guide clinical decision-making, including routine screening, development of treatment plans, and referral for genetic counseling and testing. It's particularly important to consider when LS might increase the risk of contralateral upper tract involvement in UTUC. Also, future therapeutic options are likely to target LS-associated cancers, further emphasizing the importance of aligning clinical guidelines with genetic risk factors for the preventative and therapeutic management of UTUC in patients with LS.

Answer 20

Universal histologic testing of upper tract urothelial carcinoma (UTUC) should be performed, using additional studies like immunohistochemical (IHC) or microsatellite instability (MSI) testing. This helps identify patients with high probability of Lynch-related cancers, who should then be referred for genetic counseling and germline testing. Lynch Syndrome (LS) results from inherited germline mutations in DNA damage response genes responsible for mismatch repair (MMR), specifically MLH1, MSH2, MSH6, PMS2, or EPCAM. Histologic studies like IHC can indicate loss of these specific MMR proteins or evaluate for MSI status as a standard means to assess for the possibility of LS association. Recommendations in other LS-related cancers strongly endorse universal MMR and MSI testing. The panel recommends genetic testing to all patients with UTUC due to the higher identified prevalence of LS association in UTUC relative to colorectal cancer.

Answer 21

d) All of the above

Answer 22

Which genetic mutations are commonly associated with Lynch Syndrome? a) BRCA1 and BRCA2 b) TP53 and PTEN c) MLH1, MSH2, MSH6, PMS2, or EPCAM d) FLT3 and IDH1

Answer 23

Universal histologic testing of UTUC is crucial as it helps to identify patients with a high probability of Lynch-related cancers. It's the first-line means to detect Lynch Syndrome-associated features in tumor samples, thus providing clinically significant information for patient counseling, management, and screening for family members. Additional studies that should be performed include immunohistochemical (IHC) testing and microsatellite instability (MSI) testing. IHC testing can preliminarily identify the altered proteins associated with Lynch Syndrome, while MSI testing can assess the genome stability. These tests serve as a standard means to assess for the possibility of LS association, and suspicious findings with these tests require further confirmatory testing.

Answer 24

Genetic testing is recommended for all patients with UTUC due to the higher identified prevalence of Lynch Syndrome association in UTUC relative to colorectal cancer. Lynch Syndrome results from inherited germline mutations in mismatch repair (MMR) genes, specifically MLH1, MSH2, MSH6, PMS2, or EPCAM. Alterations in these genes can lead to the accumulation of DNA errors and increase the potential for cancer development. Therefore, genetic testing can help to identify patients who have a high probability of Lynch-related cancers, leading to more effective patient counseling, management strategies, and familial screening. Furthermore, recommendations and guidelines in other LS-related cancers strongly endorse universal MMR and MSI testing.

Answer 25

At the time of identifying upper tract urothelial carcinoma (UTUC), a standardized assessment documenting endoscopic (focality, location, appearance, size) and radiographic (invasion, obstruction, lymphadenopathy) features should be performed to facilitate clinical staging and risk assessment. Such tumor features identified by endoscopic and radiologic assessment are strongly associated with disease risk, hence vital for proper risk stratification, treatment decision-making, and treatment response assessment. Key features to document include sites of involvement, number of tumors or presence of multifocality, and tumor appearance. Quality of visualization and possible impacts on accuracy should be documented. Radiographic characterization of tumor features is also important for clinical staging, including details of tumor characteristics suggesting invasive features, obstruction of the urinary tract, locoregional progression, and presence of metastatic disease.

Answer 26

d) All of the above

Answer 27

d) All of the above

Answer 28

The endoscopic and radiographic features of a UTUC are strongly associated with disease risk, which is crucial for proper risk stratification, guiding treatment decisions, and assessing the response to treatment. By standardizing the assessment and documentation of these features, clinicians can better communicate and evaluate the objective clinical findings, enhancing patient management and treatment outcomes.

Answer 29

Radiographic characterization of tumor features is crucial for clinical staging of UTUC. It provides details about tumor characteristics suggesting invasive features, obstruction of the urinary tract, locoregional progression, and the presence of metastatic disease. This information assists in determining the extent of the disease, helping to inform the appropriate treatment strategy and assess the potential treatment response. Moreover, these radiographic features can aid in the monitoring of disease progression and response to therapy over time.

Answer 30

After standardized assessment, clinicians should categorize patients into "low-" or "high" risk for invasive disease (pT2 or greater) based on endoscopic, cytologic, pathologic, and radiographic findings. Further stratification into favorable and unfavorable risk groups should be based on standard identified features. The factors assisting sub-stratification include biopsy, cytology, fluorescence in situ hybridization (FISH), and CT imaging. Biopsy has a positive predictive value (PPV) of 60% and negative predictive value (NPV) of 77% for high-stage (HS) disease. FISH may have value as an adjunct test where tissue sampling is challenging and cytology is indeterminate. The sensitivity and specificity of specific CT findings for identifying high-grade (HG) disease varies; heterogenous texture (versus homogeneous) has a sensitivity of 70% and specificity of 100%. Moreover, retrograde pyelograms, MRI, and features such as tumor appearance, growth characteristics, and lower tract involvement also contribute to risk stratification. However, the panel advises that studies like endoluminal US and MRI should only be used as supplements to current standards of care.

Answer 31

e) All of the above

Answer 32

b) Heterogeneous texture

Answer 33

Selective ipsilateral upper tract cytology provides supplemental histologic data to tumor biopsies. If high-grade cytology is found in the setting of low-grade biopsy findings, it indicates the likely presence of higher-risk features, such as a high-grade tumor, that were missed on biopsy sampling. Obtaining selective cytology after tumor biopsy can improve the yield of cells for cytologic analysis, providing more accurate and detailed information about the tumor.

Answer 34

Specific CT findings, such as the presence of heterogeneous texture, can be indicative of high-grade disease in UTUC. It's important to note that the sensitivity and specificity of CT findings for identifying high-stage UTUC vary widely. MRI can provide some soft tissue details in patients who cannot receive contrast, offering some advantages by identifying features of fat invasion with diffusion-weighted imaging associated with very advanced, T3 disease. However, MRI can falsely overestimate tumor stage due to surrounding tissue effects that may mimic tumor invasion. At present, the guidelines recommend such studies only as supplements to current standards of care.

Answer 35

The 11th guideline emphasizes the assessment of patients with Upper Tract Urothelial Carcinoma (UTUC) for risk of Chronic Kidney Disease (CKD) or dialysis following nephroureterectomy (NU). This process is crucial for operative decision-making and systemic therapy administration. An estimated glomerular filtration rate (eGFR) should be obtained before surgery. If hydronephrosis or renal atrophy is present, these may affect accurate preoperative renal function estimation. Hence, renal decompression may be needed. Considerations for postoperative renal function, especially for patients needing perioperative systemic treatment, must be taken into account. Regular monitoring and management of CKD risks, such as Diabetes Mellitus (DM) and hypertension, are also crucial.

Answer 36

d) All of the above. All these tests are recommended to assess the renal function before surgery.

Answer 37

c) Both a and b. Hydronephrosis may falsely under-estimate, and renal atrophy may overestimate the preoperative renal function.

Answer 38

Assessing UTUC patients for the risk of post-NU CKD or dialysis is crucial because the operative approach and administration of systemic therapy are decided based on the patient's baseline renal function and their estimated post-operative glomerular filtration rate (eGFR). Further, since the postoperative renal function can diminish due to the loss of a renal unit in NU, this can exacerbate CKD and affect a patient's eligibility to receive adjuvant chemotherapy. Thus, an accurate preoperative assessment helps in planning the treatment strategy and managing the risks effectively.

Answer 39

Optimizing glycemic and blood pressure control is essential in managing postoperative renal function in UTUC patients because it helps reduce the degree of renal dysfunction in the perioperative period. Particularly in patients with diabetes mellitus, maintaining good glycemic control can prevent the risk of acute kidney injury. Similarly, effective blood pressure control can mitigate the risk of hypertensive nephropathy. These measures, along with smoking cessation and minimizing the risk of acute kidney injury, can significantly contribute to preserving renal function and managing CKD in the postoperative period.

Answer 40

The 12th guideline underlines the importance of informing patients about the short- and long-term risks associated with diagnostic and therapeutic options for Upper Tract Urothelial Carcinoma (UTUC). These risks include the need for endoscopic follow-up, possible complications like significant strictures, surgical treatment toxicities, and side effects from neoadjuvant and adjuvant therapies. Urothelial recurrences are common in UTUC management, necessitating long-term surveillance and possible additional treatments. Ablative therapies, while providing local control and durable long-term kidney-sparing outcomes, come with added endoscopic surveillance requirements and associated risks such as stricture and infection. Treatment options such as chemoablative treatment with reverse thermo-hydrogel preparation of mitomycin carry specific risks and require appropriate patient counseling.

Answer 41

d) All of the above. Long-term surveillance is necessary to monitor the effectiveness of the therapy, due to the common occurrence of urothelial recurrences, and to check for possible complications from therapies.

Answer 42

d) All of the above. Ablative therapies for UTUC can lead to a need for additional endoscopic surveillance, risk of significant stricture formation, and the risk of infection.

Answer 43

Informing patients about the short- and long-term risks associated with diagnostic and therapeutic options for UTUC is a crucial part of care as it enables the patient to understand the potential consequences and complications of the treatment. It allows the patients to make informed decisions about their treatment options, prepare for possible long-term surveillance and additional treatments, and manage their expectations. Additionally, this information helps patients to adhere to the treatment plan and encourages them to promptly report any side effects or complications, which contributes to better overall management of UTUC.

Answer 44

The specific risks associated with the use of chemoablative treatment with reverse thermo-hydrogel preparation of mitomycin for pyelocaliceal instillation for low-grade tumors include a high risk of ureteral obstruction (over 44%), potential bone marrow suppression, and embryo-fetal toxicity. These risks necessitate specific patient counseling and careful monitoring of the patient's condition during the treatment.

Answer 45

The 13th guideline states that tumor ablation should be the initial management option for patients with low-risk (LR) favorable Upper Tract Urothelial Carcinoma (UTUC) due to low rates of metastatic progression. Endoscopic management is recommended as the first-line treatment when feasible. Observational studies have shown comparable cancer-specific survival (CSS) and improved renal functional outcomes with endoscopic ablation compared to nephroureterectomy (NU). However, there is strong case-selection bias, and outcomes should be interpreted within this context. There have been instances where complete endoscopic ablation may not be feasible, and chemoablation can serve as an alternative. The benefits of chemoablation, however, need to be balanced against the risk of potential ureteral stricture. Whenever possible, complete endoscopic ablation is preferred over chemoablation.

Answer 46

d) Both a and b. Tumor ablation is the initial management option because it is associated with lower rates of metastatic progression and helps preserve kidney function.

Answer 47

a) When complete endoscopic ablation is not feasible. Chemoablation is considered when specific tumor (location and focality) and patient factors (age, comorbidities, baseline renal function, procedural risk) make complete endoscopic ablation unfeasible.

Answer 48

Observational studies have found endoscopic management to have similar cancer-specific survival (CSS) outcomes as nephroureterectomy (NU) in patients with low-risk UTUC. Additionally, endoscopic management has been shown to lead to improved renal functional outcomes compared to NU. However, these findings must be interpreted in the context of strong case-selection bias inherent in retrospective studies. Therefore, while the endoscopic approach can be advantageous, especially in terms of preserving renal function, the decision between endoscopic management and NU must be made on a case-by-case basis.

Answer 49

The primary drawback of using chemoablation is the potential risk of ureteral stricture. However, it can be considered in situations where complete endoscopic ablation is not feasible due to specific tumor characteristics (such as location and focality) or patient factors (like age, comorbidities, baseline renal function, and procedural risk). Despite these drawbacks, chemoablation can be a beneficial treatment alternative in certain clinical scenarios. But it's important to note that chemoablation should not be used as a substitute for complete endoscopic ablation when the latter is feasible.

Answer 50

The 14th guideline proposes that tumor ablation may be the initial management option offered to patients with low-risk (LR) unfavorable UTUC and select patients with high-risk (HR) favorable disease with low-volume tumors or those who cannot undergo radical nephroureterectomy (RNU). There's no high-quality evidence comparing endoscopic management versus RNU for these patients. Nonetheless, comparable cancer-specific survival and improved renal functional outcomes have been reported for endoscopic management compared to RNU. Certain considerations need to be factored, such as tumor size. Tumors less than 1.5 cm may be optimal for endoscopic ablation due to a lower risk of invasive disease. However, larger tumors (≥ 1.5 cm) could also be considered for ablation based on provider's experience and assessment for kidney sparing surgery. For LR unfavorable disease showing progression in tumor size, focality, or grade, further endoscopic-assisted attempts are discouraged, and definitive resection via segmental ureterectomy (SU) or NU is recommended.

Answer 51

d) All of the above. Tumor ablation can be considered for patients with LR unfavorable UTUC, select patients with HR favorable disease with low-volume tumors, and patients who cannot undergo RNU.

Answer 52

b) When the provider's experience supports it and there is a need for kidney sparing surgery. Larger tumors may be considered for ablation based on provider’s experience and assessment of the need for kidney sparing surgery.

Answer 53

Several factors need to be considered when deciding the initial management for LR unfavorable or HR favorable UTUC. These include the size of the tumor, the volume of the tumor, and the patient's ability to undergo radical nephroureterectomy (RNU). Tumors less than 1.5 cm in size may be more optimal for endoscopic ablation due to a lower risk of invasive disease. However, larger tumors (greater or equal to 1.5 cm) may also be considered for ablation based on the provider's experience and the need for kidney-sparing surgery. For patients with LR unfavorable disease showing progression in size, focality, or grade, further endoscopic attempts are discouraged, and definitive resection via segmental ureterectomy (SU) or NU is recommended.

Answer 54

For patients with low-risk unfavorable disease who demonstrate progression in tumor size, focality, or grade, further endoscopic-assisted attempts are discouraged. Instead, consideration should be given to definitive resection via segmental ureterectomy (SU) or radical nephroureterectomy (NU). This decision must be made based on the individual patient's circumstances, the extent of disease progression, and the potential benefits and risks of the different surgical approaches.

Answer 55

Guideline 15 emphasizes that tumor ablation in UTUC can be accomplished via either a retrograde or antegrade percutaneous approach, and it's crucial to repeat endoscopic evaluation within three months. Retrograde approaches, including ureteroscopy with pyeloscopy, are common, while percutaneous techniques are typically reserved for larger tumors, those difficult to access in a retrograde fashion, or in patients who have undergone prior radical cystectomy or urinary diversion. The energy source for ablation can vary, including thulium laser, holmium laser, Neodymium (Nd:YAG), electrocautery devices, or chemoablation. Using a ureteral access sheath during ureteroscopic ablation can provide advantages, such as allowing repeated scope passage and managing irrigation solutions. Because UTUC has a high chance of recurrence and residual disease after the first ablation, repeat endoscopic evaluation should take place within three months, with a 30-day window on either side of this period. Clinicians may opt for shorter intervals for more challenging cases.

Answer 56

c) For patients who have undergone prior radical cystectomy or urinary diversion. Percutaneous techniques are typically reserved for larger tumors, those difficult to access in a retrograde fashion, or in patients who have undergone prior radical cystectomy or urinary diversion.

Answer 57

b) Allows for repeated scope passage up and down the ureter. The use of a ureteral access sheath allows for repeated scope passage up and down the ureter and provides a means of fluid egress from the upper tract to avoid excess pelvicalyceal hydrostatic pressure from irrigation solutions.

Answer 58

The choice of approach for tumor ablation in UTUC depends on the size and accessibility of the tumor and the patient's past surgical history. Retrograde approaches, including ureteroscopy with pyeloscopy, are commonly used, while percutaneous techniques are usually reserved for larger tumors, those difficult to access in a retrograde fashion, or in patients who have undergone prior radical cystectomy or urinary diversion. The choice of energy source for ablation can vary based on the availability of instrumentation and tumor characteristics. These can include the thulium laser, holmium laser, Neodymium (Nd:YAG), and electrocautery devices. Additionally, chemoablation can be employed either through retrograde ureteral catheter instillation or percutaneous access with fluoroscopic imaging guidance.

Answer 59

The recommendation to perform a repeat endoscopic evaluation within three months of the initial treatment is due to the propensity of UTUC to recur and for residual disease to remain after the first ablation. Optimal timing of follow-up endoscopic evaluation has not been definitively established, but several factors such as tumor size, visualization, access, treatment efficacy, etc., could influence this decision. A 30-day window on either side of the three-month period is justified to allow for timely identification of recurrences. Especially for more challenging cases or when incomplete treatment is a possibility, clinicians may opt for a more conservative approach with shorter interval endoscopic diagnostic and therapeutic procedures.

Answer 60

Guideline 16 advocates for the instillation of adjuvant pelvicalyceal chemotherapy or intravesical chemotherapy following the ablation of UTUC tumors, provided there is no bladder or upper tract perforation. This recommendation is aimed at decreasing the risk of urothelial cancer recurrence. The principle of immediate instillation of chemotherapy after endoscopic tumor ablation for UTUC comes from extrapolation of data related to urothelial carcinoma of the lower tract. Despite limited compelling evidence, some studies show a trend towards improved urothelial recurrence-free survival with the use of chemotherapy post-ablation. Technical aspects are still not fully established, but the guideline considers three approaches to be acceptable: 1) antegrade perfusion by nephrostomy tube, 2) retrograde perfusion via ureteral catheter, and 3) bladder instillation by transurethral catheter with reflux via a double J ureteral stent. While bacillus Calmette-Guerin (BCG) is the primary topical therapy for UTUC, other agents have been described including mitomycin c, gemcitabine, docetaxel, epirubicin, adriamycin, thiotepa, and BCG with interferon.

Answer 61

b) To decrease the risk of urothelial cancer recurrence. The purpose of instilling adjuvant pelvicalyceal or intravesical chemotherapy after UTUC tumor ablation is to reduce the risk of urothelial cancer recurrence.

Answer 62

a) Antegrade perfusion by nephrostomy tube, retrograde perfusion via ureteral catheter, and bladder instillation by transurethral catheter with reflux via a double J ureteral stent. These are the three approaches considered acceptable for the administration of chemotherapy following UTUC tumor ablation.

Answer 63

The purpose of instilling adjuvant pelvicalyceal or intravesical chemotherapy following UTUC tumor ablation is to decrease the risk of urothelial cancer recurrence. The recommendation is largely based on extrapolation of data from the management of urothelial carcinoma of the lower tract, where an immediate instillation of intravesical chemotherapy after transurethral resection has been shown to reduce the rate of intravesical tumor recurrence. Some small studies specifically investigating UTUC have shown a trend towards improved urothelial recurrence-free survival with the use of chemotherapy post-ablation.

Answer 64

The three approaches to chemotherapy instillation considered acceptable by the Panel following UTUC tumor ablation are: 1) Antegrade perfusion by nephrostomy tube, where the chemotherapy is instilled directly into the kidney via a tube; 2) Retrograde perfusion via a ureteral catheter, where the chemotherapy is instilled upwards through the ureter into the kidney; 3) Bladder instillation by transurethral catheter with reflux via a double J ureteral stent, where the chemotherapy is instilled into the bladder and then allowed to reflux back into the kidneys via a stent.

Answer 65

Guideline 17 suggests that pelvicalyceal therapy with Bacillus Calmette-Guerin (BCG) can be offered to patients with high-risk but favorable Upper Tract Urothelial Carcinoma (UTUC) after complete tumor ablation, or to patients with upper tract carcinoma in situ (CIS). This is particularly beneficial for patients with imperative indications such as solitary kidney status, bilateral UTUC, or the risk of progression to end-stage renal disease. However, there is limited literature specifically addressing the treatment of such UTUC with topical therapy like BCG. The outcomes of studies vary widely, with complete response rates ranging from 41% to 100%, and adverse effects reported in 0% to 92% of patients. Systematic reviews indicate that the treatment of UTUC Ta/T1 disease with BCG yields a cancer-specific survival and overall survival rate of 94% and 71% respectively. Furthermore, there seems to be no significant differences in outcomes when other therapeutic agents are used.

Answer 66

d) To reduce the risk of UTUC recurrence post-ablation. Bacillus Calmette-Guerin (BCG) therapy may be offered to patients with high-risk but favorable UTUC after complete tumor ablation to reduce the risk of UTUC recurrence.

Answer 67

BCG therapy is considered for patients with high-risk but favorable UTUC following complete tumor ablation to reduce the risk of UTUC recurrence. This therapy is particularly beneficial for patients with solitary kidney status, bilateral UTUC, or the risk of progression to end-stage renal disease. However, outcomes from the studies are highly variable, with complete response rates ranging from 41% to 100%. Adverse effects have been reported in 0% to 92% of patients, including complications such as cystitis, fever, sepsis, renal tuberculosis, ureteral stricture, and pericarditis.

Answer 68

Guideline 18 suggests that when tumor ablation is not feasible or evidence of risk group progression is identified in patients with low-risk Upper Tract Urothelial Carcinoma (UTUC), surgical resection of all involved sites, either by radical nephroureterectomy (RNU) or segmental resection of the ureter, should be offered. This is due to the potential risk of cancer progression from curable to an incurable form of UTUC. Any signs of a change in tumor growth pattern toward a more aggressive subtype should lead to a reconsideration of the management strategy. Studies have shown mixed results when comparing endoscopic management versus RNU. Despite these disparities, clear communication with patients is essential to manage their expectations and make a shared decision about their treatment plan.

Answer 69

c) Perform surgical resection of all involved sites. If tumor ablation is not feasible or if there's evidence of progression from low-risk UTUC, surgical resection of all involved sites should be considered to avoid the risk of cancer progression to an incurable state.

Answer 70

b) Risk of progression to incurable UTUC. If conservative strategies for kidney preservation in UTUC fail, there's a potential risk of cancer progression from a curable to an incurable form of UTUC.

Answer 71

If a more aggressive tumor growth pattern is observed in a patient with low-grade UTUC, the management strategy should be reassessed. This could prompt a consideration for a more definitive treatment with extirpative surgical resection, either by radical nephroureterectomy (RNU) or segmental resection of the ureter. The observed findings and their clinical significance suggesting a shift in disease risk should be thoroughly discussed with the patient, and a decision for the change in strategy should be made collaboratively.

Answer 72

c) 94% and 71% respectively. According to the meta-analysis by Foerster et al., the cancer-specific survival and overall survival rates following the treatment of UTUC Ta/T1 disease with BCG were 94% and 71% respectively.

Answer 73

c) 94% and 71% respectively. According to the meta-analysis by Foerster et al., the cancer-specific survival and overall survival rates following the treatment of UTUC Ta/T1 disease with BCG were 94% and 71% respectively.

Answer 74

Studies comparing endoscopic management versus RNU in different risk groups of UTUC have shown mixed results. For instance, one study found that endoscopic management was associated with an increased risk of any local, intravesical, or distant recurrence, while another study found endoscopic management associated with improved intravesical recurrence-free survival. Yet another study found endoscopic management associated with an increased risk of local recurrence but no difference in the risk of intravesical recurrence-free survival. Regarding cancer-specific survival or all-cause mortality, some studies have found endoscopic management to be associated with worse outcomes. These mixed findings underscore the importance of vigilance in follow-up and recognizing clinical signs indicating thresholds for recommending altering care.

Answer 75

Guideline 19 suggests that clinicians may offer watchful waiting or surveillance alone to selected patients with Upper Tract Urothelial Carcinoma (UTUC) who have significant comorbidities, competing risks of mortality, or at significant risk of End-Stage Renal Disease (ESRD) with any intervention resulting in dialysis. These are patients for whom the risk of treatment-related complications may outweigh the potential benefits. Rates of complications following radical nephroureterectomy (RNU) range from 15% to 50%, including a 30-day mortality risk of 1%. Discussions should involve treatment-related risks, including perioperative mortality, leading to a shared decision for active surveillance or watchful waiting/expectant management. However, patients and families should be prepared for potential disease-related events like bleeding, obstruction, infection, and pain. Studies comparing non-surgical management versus surgery for UTUC have generally found worse overall survival (OS) associated with non-surgical management, likely due to the compromised medical condition of these patients.

Answer 76

b) Patients with significant comorbidities, competing risks of mortality, or at significant risk of End-Stage Renal Disease (ESRD) with any intervention resulting in dialysis.

Answer 77

c) Bleeding, obstruction, infection, and pain.

Answer 78

c) 94% and 71% respectively. According to the meta-analysis by Foerster et al., the cancer-specific survival and overall survival rates following the treatment of UTUC Ta/T1 disease with BCG were 94% and 71% respectively.

Answer 79

c) 94% and 71% respectively. According to the meta-analysis by Foerster et al., the cancer-specific survival and overall survival rates following the treatment of UTUC Ta/T1 disease with BCG were 94% and 71% respectively.

Answer 80

Studies utilizing large databases have shown that non-surgical management is generally associated with worse overall survival (OS) compared to surgical treatment for UTUC. For example, an analysis of the Surveillance, Epidemiology, and End Results (SEER) database found that non-surgical management was associated with worse OS and 3-year cancer-specific survival (CSS). Similarly, a study using the National Cancer Database found non-surgical management to be associated with worse OS. These results, however, likely reflect the compromised medical condition of the patients who opt for non-surgical management.

Answer 81

Guideline 20 suggests that clinicians should recommend radical nephroureterectomy (RNU) or segmental ureterectomy (SU) for surgically eligible patients with high-risk UTUC. RNU with complete bladder cuff excision (BCE) and lymphadenectomy is the standard of care for patients with high-risk UTUC. Oncological principles should be maintained whether an open, robotic, or laparoscopic approach is used. Minimally invasive approaches are favored for most patients as they offer shorter lengths of stay and fewer complications. However, open surgical approaches might be preferred for large, bulky UTUC with clinical evidence for direct invasion to adjacent structures. Complete BCE is important, as studies have shown worse outcomes for patients who did not receive it. Distal ureterectomy or SU are reasonable alternatives to RNU for well-selected patients. The best candidates for distal ureterectomy have ureteral tumors in the lower third of the ureter and a mobile bladder with sufficient capacity for reimplantation. Those suitable for SU have small, unifocal tumors (typically 1 cm or smaller) isolated to a short segment of the proximal or mid-ureter.

Answer 82

b) Radical nephroureterectomy (RNU) with complete bladder cuff excision (BCE) and lymphadenectomy.

Answer 83

c) Shorter length of stay and fewer complications.

Answer 84

The basic principles of an RNU include complete excision of the ipsilateral upper tract urothelium, including the intramural portion of the ureter and ureteral orifice with negative margins. It's also crucial to avoid urinary spillage by, for example, early low ligation of the ureter, to minimize the risk of seeding urothelial cancer outside the urinary tract. The RNU specimen should be removed en bloc whenever technically feasible. These principles must be adhered to regardless of whether an open, robotic, or laparoscopic approach is used.

Answer 85

The most suitable patients for SU are those with small, unifocal tumors (typically 1 cm or smaller) that are isolated to a short segment of the proximal or mid-ureter. The requirement is that the resection involves 2 cm or less of ureteral length to allow for primary ureteroureterostomy. Longer sections of ureteral involvement and resection may require more complex reconstruction techniques when kidney sparing is desired.

Answer 86

GUIDELINE STATEMENT 21 For surgically eligible patients with HR and unfavorable LR cancers endoscopically confirmed as confined to the lower ureter in a functional renal unit, distal ureterectomy and ureteral reimplantation is the preferred treatment. (Expert Opinion)

Answer 87

b) Distal ureterectomy and ureteral reimplantation

Answer 88

d) Both a) and c)

Answer 89

Distal ureterectomy and ureteral reimplantation is preferred because it offers definitive curative management for tumors confined to the lower ureter while preserving kidney function. It is ideal for patients with localized cancers in this location who have an increased risk of disease recurrence and progression.

Answer 90

Carcinoma in situ (CIS) that is limited to the region within the ureteral orifice can be managed with topical therapies such as BCG. Additionally, transurethral resection of the transmural portion of the ureter can be used for very distal tumors, when the tumor is limited to the region inside the ureteral orifice and not beyond the bladder wall, thus it can be anatomically managed as bladder cancer.

Answer 91

Guideline 22 advises that when performing nephroureterectomy (NU) or distal ureterectomy, the entire distal ureter, including the intramural ureteral tunnel and ureteral orifice, should be excised. Moreover, the urinary tract should be closed in a watertight manner to avoid urinary extravasation, facilitate more rapid catheter removal, and allow for instillation of intravesical adjuvant chemotherapy in the perioperative setting. Various surgical approaches have been described for managing the ureteral orifice during these procedures, but there are insufficient data to recommend one over the other. Retrospective observational studies have shown that formal bladder cuff excision (BCE) is associated with improved survival rates compared to no BCE. No randomized controlled trial has compared the different surgical techniques for managing the distal ureter and ureteral orifice during NU or distal ureterectomy for upper tract urothelial carcinoma (UTUC).

Answer 92

b) Excision of the entire distal ureter, including the intramural ureteral tunnel and ureteral orifice

Answer 93

d) All of the above

Answer 94

c) 94% and 71% respectively. According to the meta-analysis by Foerster et al., the cancer-specific survival and overall survival rates following the treatment of UTUC Ta/T1 disease with BCG were 94% and 71% respectively.

Answer 95

Retrospective observational studies have shown that formal bladder cuff excision (BCE) is associated with improved 5-year overall survival rates compared to no BCE in patients undergoing these procedures for upper tract urothelial carcinoma.

Answer 96

Closing the urinary tract in a watertight fashion during these procedures is recommended to avoid urinary extravasation, facilitate more rapid catheter removal, and permit the instillation of intravesical adjuvant chemotherapy in the perioperative setting.

Answer 97

Guideline 23 recommends administering a single dose of perioperative intravesical chemotherapy to patients undergoing radical nephroureterectomy (RNU) or segmental ureterectomy (SU), including distal ureterectomy, for upper tract urothelial carcinoma (UTUC). This is done to reduce the risk of bladder recurrence. Two prospective randomized controlled trials (RCTs) have shown that a single instillation of intravesical chemotherapy around the time of NU reduces the risk of subsequent bladder recurrence of urothelial carcinoma. Although there's little data to support one intravesical chemotherapeutic over another, many clinicians have started using gemcitabine due to compelling evidence supporting its use and concerns about potential chemical peritonitis from extravesical extravasation of mitomycin-C.

Answer 98

b) To reduce the risk of bladder recurrence

Answer 99

b) Gemcitabine

Answer 100

The evidence comes from two prospective randomized controlled trials (RCTs). The ODMIT-C trial by O’Brien et al. showed that 17% of patients who received a single post-operative intravesical dose of mitomycin-C developed a bladder recurrence in the first year, compared to 27% in the standard treatment arm. Another phase II trial by Ito et al. showed similar results with a single intravesical instillation of pirarubicin.

Answer 101

There are compelling data supporting the use of a single dose of intravesical gemcitabine at the time of trans urethral resection of bladder tumor to reduce the rate of intravesical recurrences. Additionally, there are concerns about potential chemical peritonitis if there is extravesical extravasation of mitomycin-C. These factors have led many clinicians to prefer gemcitabine over mitomycin-C.

Answer 102

Guideline 24 suggests that clinicians may perform a lymph node dissection (LND) at the time of nephroureterectomy (NU) or ureterectomy in patients with low-risk (LR) upper tract urothelial carcinoma (UTUC). However, the evidence supporting this approach is limited. No randomized controlled trials (RCTs) have compared LND versus no LND concerning oncologic outcomes. Two recent systematic reviews of observational studies also showed no significant differences in oncologic outcomes whether LND was performed or not. Given these findings, the benefit of LND among patients with LR UTUC remains unclear. Thus, the decision to perform LND may be left to the clinician's discretion based on clinically or radiographically suspicious regional lymphadenopathy or other intraoperative findings suggesting more advanced disease.

Answer 103

c) When there are clinically or radiographically suspicious regional lymphadenopathy or other intraoperative findings suggesting more advanced disease

Answer 104

c) The evidence is limited, with no randomized controlled trials available, and observational studies showing no significant differences in oncologic outcomes

Answer 105

Guideline 24 suggests that for patients with low-risk UTUC, clinicians may perform lymph node dissection (LND) at the time of nephroureterectomy (NU) or ureterectomy. However, the decision to perform LND should be based on clinically or radiographically suspicious regional lymphadenopathy or other intraoperative findings suggesting more advanced disease.

Answer 106

The evidence supporting LND in patients with low-risk UTUC is limited. No randomized controlled trials have compared LND versus no LND in terms of oncologic outcomes. Also, two recent systematic reviews of observational studies did not find statistically significant differences in oncologic outcomes between patients who had LND and those who did not. Therefore, the benefit of LND among patients with low-risk UTUC is unclear.

Answer 107

Guideline 25 advises that for patients with high-risk (HR) upper tract urothelial carcinoma (UTUC), clinicians should perform a lymph node dissection (LND) at the time of nephroureterectomy (NU) or ureterectomy. Although there are no randomized controlled trials (RCTs) that evaluate the effect of LND on oncologic outcomes, the panel conducted a re-analysis of some studies described in the systematic review. The results indicate an association between LND and better recurrence-free survival (RFS). Two additional recent cohort studies also found LND was associated with improved overall survival (OS) and cancer-specific survival (CSS), especially in patients with T3 and T4 tumors. However, there's no consensus yet on the appropriate template to yield maximal oncologic outcomes and prognostic information.

Answer 108

b) LND should be performed at the time of NU or ureterectomy

Answer 109

c) LND was associated with better oncologic outcomes, specifically better recurrence-free survival

Answer 110

Guideline 25 strongly recommends that for patients with high-risk UTUC, clinicians should perform lymph node dissection (LND) at the time of nephroureterectomy (NU) or ureterectomy.

Answer 111

Despite the lack of randomized controlled trials (RCTs), recent systematic reviews and a re-analysis conducted by the panel suggest a potential benefit of LND in patients with high-risk UTUC. The re-analysis revealed that LND was associated with better recurrence-free survival (RFS). Moreover, additional cohort studies found LND to be associated with improved overall survival (OS) and cancer-specific survival (CSS), especially in patients with T3 and T4 tumors.

Answer 112

Guideline 26 recommends offering cisplatin-based neoadjuvant chemotherapy (NAC) to patients undergoing radical nephroureterectomy (RNU) or ureterectomy with high-risk (HR) upper tract urothelial carcinoma (UTUC). This is particularly important for patients whose post-operative estimated glomerular filtration rate (eGFR) is expected to be less than 60 mL/min/1.73m2 or those with other medical comorbidities that would prevent platinum-based chemotherapy in the post-operative setting. This strong recommendation is supported by evidence from several meta-analyses and two recent NAC trials, which show improved pathologic outcomes, cancer-specific survival (CSS), and overall survival (OS) with this approach. The guideline highlights that alternatives to cisplatin-based chemotherapy, such as immune checkpoint inhibitors, carboplatin, antibody drug conjugates, targeted FGFR therapies, are not recommended in the neoadjuvant setting outside of clinical trials.

Answer 113

a) NAC can be better tolerated in the neoadjuvant setting, allowing for more complete courses and enabling patients to proceed to the surgical intervention

Answer 114

b) It leads to improved pathologic outcomes, cancer-specific survival (CSS), and overall survival (OS)

Answer 115

Guideline 26 strongly recommends that clinicians should offer cisplatin-based neoadjuvant chemotherapy (NAC) to high-risk (HR) upper tract urothelial carcinoma (UTUC) patients undergoing radical nephroureterectomy (RNU) or ureterectomy. This recommendation is particularly crucial for patients whose post-operative estimated glomerular filtration rate (eGFR) is expected to be less than 60 mL/min/1.73m2 or for those with other medical comorbidities that would preclude the use of platinum-based chemotherapy in the post-operative setting.

Answer 116

c) 94% and 71% respectively. According to the meta-analysis by Foerster et al., the cancer-specific survival and overall survival rates following the treatment of UTUC Ta/T1 disease with BCG were 94% and 71% respectively.

Answer 117

There are several meta-analyses and recent neoadjuvant chemotherapy trials supporting the use of cisplatin-based NAC for high-risk UTUC patients. These studies have shown that NAC improves pathologic outcomes, cancer-specific survival (CSS), and overall survival (OS) in these patients. Two recently completed NAC trials of cisplatin-based chemotherapy prior to RNU strongly support the use of this approach. Additionally, it's important to note that alternative treatments to cisplatin-based chemotherapy are not recommended in the neoadjuvant setting outside of clinical trials.

Answer 118

Guideline 27 recommends offering platinum-based adjuvant chemotherapy to patients with advanced pathological stage (pT2–T4 pN0–N3 M0 or pTany N1–3 M0) UTUC after RNU or ureterectomy who have not received neoadjuvant platinum-based therapy. This strong recommendation is based on the results from the randomized phase III POUT trial, which showed that adjuvant platinum-based chemotherapy improved disease-free survival (DFS) compared with observation. Patients in the adjuvant chemotherapy arm had a significantly lower risk of metastases or death. However, the trial also showed that outcomes for patients with lymph node involvement and those treated with carboplatin chemotherapy were worse than those without positive nodes or treated with cisplatin chemotherapy. Therefore, carboplatin remains a reasonable choice for HR cisplatin-ineligible patients post-RNU if neoadjuvant chemotherapy was not given.

Answer 119

b) It leads to improved disease-free survival (DFS) and lower risk of metastases or death.

Answer 120

c) It is a reasonable choice for cisplatin-ineligible patients.

Answer 121

Guideline 27 strongly recommends that clinicians should offer platinum-based adjuvant chemotherapy to advanced pathological stage (pT2–T4 pN0–N3 M0 or pTany N1–3 M0) UTUC patients after radical nephroureterectomy (RNU) or ureterectomy who have not received neoadjuvant platinum-based therapy. The chemotherapy can improve disease-free survival (DFS) and reduce the risk of metastases or death.

Answer 122

The strong recommendation for platinum-based adjuvant chemotherapy in advanced pathological stage UTUC patients is supported by results from the randomized phase III POUT trial. This trial found that adjuvant platinum-based chemotherapy improved disease-free survival (DFS) and lowered the risk of metastases or death compared to observation. However, it also showed that outcomes were worse for patients with lymph node involvement and those treated with carboplatin chemotherapy, suggesting that carboplatin remains a reasonable choice for cisplatin-ineligible patients if neoadjuvant chemotherapy was not given.

Answer 123

Guideline 28 suggests that adjuvant nivolumab therapy can be offered to patients who have either received neoadjuvant platinum-based chemotherapy or are ineligible for or refuse perioperative cisplatin. This recommendation is based on the results of two RCTs - IMvigor 010 and CheckMate 274, which involved patients with high-risk non-metastatic urothelial carcinoma, including a subset with upper tract urothelial carcinoma (UTUC). The IMvigor 010 trial, with adjuvant atezolizumab, did not meet its primary endpoint of improved disease-free survival (DFS) compared to observation. In contrast, the CheckMate 274 study demonstrated that adjuvant nivolumab did improve DFS compared to placebo. The approval of adjuvant nivolumab for UTUC and urothelial carcinoma of the bladder is based on these overall findings, despite the lack of a distinct difference in DFS for renal pelvic cancers or ureter in either arm within a UTUC subgroup. However, the small sample size limits the statistical power of this subgroup analysis. Nivolumab was well tolerated, with toxicities similar to other checkpoint inhibitor studies. Adjuvant platinum-based chemotherapy is still recommended over adjuvant nivolumab for eligible patients who did not receive neoadjuvant chemotherapy, while nivolumab might be more suitable for those with contraindications to platinum-based chemotherapy, high-risk pathology after neoadjuvant chemotherapy, or those who refuse standard adjuvant chemotherapy.

Answer 124

c) For patients who have received neoadjuvant platinum-based chemotherapy, are ineligible for or refuse perioperative cisplatin, or who refuse standard forms of adjuvant chemotherapy after appropriate counseling.

Answer 125

b) Adjuvant nivolumab improved DFS compared to placebo in the intention to treat population.

Answer 126

The IMvigor 010 trial and the CheckMate 274 study yielded different results. The IMvigor 010 trial, which used adjuvant atezolizumab, did not meet its primary endpoint of improved disease-free survival (DFS) compared to observation. On the other hand, the CheckMate 274 study, which used adjuvant nivolumab, did meet its co-primary endpoints and showed improved DFS compared to placebo.

Answer 127

Adjuvant nivolumab might be considered over adjuvant platinum-based chemotherapy for UTUC patients in the following cases: 1) patients with contraindications to platinum-based chemotherapy, such as poor renal function, poor performance status, sensorineural hearing loss, neuropathy or congestive heart failure, or allergy, 2) patients with high-risk pathology after receiving neoadjuvant chemotherapy, 3) patients who refuse standard forms of adjuvant chemotherapy after they have been properly counseled.

Answer 128

Nivolumab is an immune checkpoint inhibitor.

Answer 129

Nivolumab targets the programmed cell death protein 1 (PD-1) receptor on T cells.

Answer 130

The interaction between PD-1 on T cells and PD-L1 on normal and cancerous cells sends an "off" signal that prevents T cells from attacking these cells.

Answer 131

By blocking the PD-1 receptor, Nivolumab prevents the interaction between PD-1 and PD-L1, effectively removing the "off" signal. This allows T cells to recognize and attack cancer cells.

Answer 132

Nivolumab can be used to treat non-small cell lung cancer, renal cell carcinoma, melanoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colorectal cancer, and hepatocellular carcinoma, among others.

Answer 133

Guideline 29 advises against offering radical nephroureterectomy (RNU) or ureterectomy as initial therapy in patients with metastatic upper tract urothelial carcinoma (UTUC). There is no clear evidence supporting upfront surgery without chemotherapy for metastatic UTUC, as oncologic outcomes are primarily determined by the response to systemic therapy. Surgical treatment does not have demonstrable therapeutic efficacy for cytoreduction or as a stand-alone modality in this setting. Additionally, the potential harms, such as delays or an inability to receive systemic therapy due to surgical consequences, can significantly and negatively impact oncologic outcomes and overall survival. Instead, systemic therapy and alternative approaches, such as radiotherapy with or without chemotherapy, should be considered for inoperable or symptomatic patients with metastatic UTUC. The retrospective studies that suggest a clinical benefit from surgery to the primary site in metastatic UTUC patients typically involve those who have already received first-line chemotherapy or lack well-documented use of perioperative chemotherapy. This limits the interpretation and applicability of these studies due to strong selection biases and significant weaknesses in the data sets.

Answer 134

c) Surgery can delay or prevent the receipt of systemic therapy, which can negatively impact oncologic outcomes and overall survival.

Answer 135

a) Systemic therapy and radiotherapy, potentially with chemotherapy.

Answer 136

Guideline 29 advises against offering RNU or ureterectomy as initial therapy in patients with metastatic UTUC because there is no clear evidence supporting upfront surgery without chemotherapy in these patients. Oncologic outcomes are primarily determined by the response to systemic therapy. Surgical treatment does not have demonstrable therapeutic efficacy for cytoreduction or as a single modality in this setting. Furthermore, surgery can potentially delay or prevent the receipt of systemic therapy, which can significantly and negatively impact oncologic outcomes and overall survival.

Answer 137

For inoperable or symptomatic patients with metastatic UTUC, the guideline suggests considering systemic therapy and alternative approaches, such as radiotherapy with or without chemotherapy.

Answer 138

Guideline 30 recommends that patients with clinical, regional node-positive (cN1-3, M0) upper tract urothelial carcinoma (UTUC) should first be treated with systemic therapy. In cases where the patients have a partial or complete response to the systemic therapy, consolidative radical nephroureterectomy (RNU) or ureterectomy with lymph-node dissection may be performed. Patients with clinically suspicious lymph nodes are considered to have high-risk unfavorable disease with likely locally advanced or metastatic disease. In patients whose disease is converted to a surgically resectable state following a response to systemic therapy, surgical treatment should be offered if they are medically suitable. Comparative data supports this approach, with three reviews of up to six studies indicating that neoadjuvant chemotherapy (NAC) improves oncologic outcomes compared to nephroureterectomy alone.

Answer 139

b) Systemic therapy.

Answer 140

c) 94% and 71% respectively. According to the meta-analysis by Foerster et al., the cancer-specific survival and overall survival rates following the treatment of UTUC Ta/T1 disease with BCG were 94% and 71% respectively.

Answer 141

b) In patients who have either a partial or complete response to the systemic therapy.

Answer 142

Guideline 30 recommends treating patients with clinical, regional node-positive (cN1-3, M0) UTUC initially with systemic therapy. If these patients respond partially or completely to the systemic therapy, consolidative radical nephroureterectomy or ureterectomy with lymph-node dissection can be performed.

Answer 143

The data supporting Guideline 30, derived from a pooled analysis of various studies, indicates that neoadjuvant chemotherapy is associated with significantly better overall survival and cancer-specific survival compared to nephroureterectomy alone. In the subgroup of patients with locally advanced tumors (≥cT3 or cN+), the findings for overall survival were similar. Additionally, a review found neoadjuvant chemotherapy associated with improved recurrence-free survival compared to nephroureterectomy.

Answer 144

Guideline 31 recommends that patients with unresectable upper tract urothelial carcinoma (UTUC) or those who are ineligible for or refuse surgical treatment should be offered a clinical trial or best supportive care, including palliative management. Unresectable disease may be due to significant medical comorbidities, or other factors such as refusal of surgical treatment or possession of a solitary kidney. Treatment options should be determined with a multidisciplinary approach, focusing on achieving realistic care goals like local control for functional preservation (for instance, renal function) and palliation (such as bleeding, infection). Treatment plans should be explained clearly to patients, and their understanding and acceptance of the goals and expectations should be documented. Clinical trials should be sought and offered to eligible patients where available. Multimodal approaches may involve a combination of endoscopic management, systemic treatment options, and in rare cases, radiation, angioembolization, or percutaneous ablation for palliation of bleeding.

Answer 145

b) A clinical trial or best supportive care including palliative management.

Answer 146

b) Achieving realistic care goals such as local control for functional preservation and palliation.

Answer 147

Guideline 31 recommends that patients with unresectable UTUC or those who are ineligible or refuse surgery should be offered a clinical trial or best supportive care, including palliative management. Multimodal approaches may involve a combination of endoscopic management and systemic treatment options. In rare cases, radiation, angioembolization, or percutaneous ablation can be offered for palliation of bleeding.

Answer 148

When formulating alternative care options for patients with unresectable UTUC or those who are ineligible or refuse surgery, a multi-disciplinary approach should be taken. The focus should be on achieving realistic care goals such as local control for functional preservation (like renal function) and palliation (for example, bleeding, infection). It's crucial to provide appropriate patient counseling to explain goals and expectations, and document these discussions. If available, clinical trials should be discussed and offered to eligible patients.

Answer 149

Guideline 32 advises that low-risk patients treated with kidney-sparing treatments should undergo a follow-up cystoscopy and upper tract endoscopy within one to three months to confirm successful treatment. Upon confirmation, these patients should continue cystoscopic surveillance of the bladder at least every six to nine months for the first two years, and then at least annually afterwards. Endoscopy should be repeated at six months and one year. Upper tract imaging should be performed at least every six to nine months for two years, then annually up to five years. Surveillance after five years in the absence of recurrence should be based on shared decision-making between the patient and clinician. The follow-up evaluation schedule aims to balance the morbidity and cost of follow-up with the risk of disease recurrence. Clinicians may elect to increase the intensity of surveillance according to their assessment of an individual patient’s risk and shared decision-making.

Answer 150

a) They should undergo a follow-up cystoscopy and upper tract endoscopy within one to three months, followed by continued cystoscopic surveillance of the bladder at least every six to nine months for the first two years and then at least annually thereafter.

Answer 151

b) It should aim to balance the morbidity and cost of follow-up with the risk of disease recurrence.

Answer 152

According to Guideline 32, low-risk patients managed with kidney sparing treatment should undergo a follow-up cystoscopy and upper tract endoscopy within one to three months to confirm successful treatment. Once confirmed, these patients should undergo continued cystoscopic surveillance of the bladder at least every six to nine months for the first two years and then at least annually thereafter. Endoscopy should be repeated at six months and one year. Upper tract imaging should be performed at least every six to nine months for two years, then annually up to five years. Surveillance after five years in the absence of recurrence should be based on shared decision-making between the patient and clinician.

Answer 153

When deciding the intensity of surveillance for low-risk patients treated with kidney sparing treatment for UTUC, clinicians should balance the morbidity and cost of follow-up with the risk of disease recurrence. They can elect to increase the intensity of surveillance above the minimum recommendations according to their assessment of an individual patient’s risk and shared decision-making with the patient.

Answer 154

Guideline 33 suggests that high-risk patients managed with kidney sparing treatment should undergo a follow-up cystoscopy and upper tract endoscopy with cytology within one to three months. If there's no evidence of disease, these patients should undergo cystoscopic surveillance of the bladder and cytology at least every three to six months for the first three years and then at least annually thereafter. Endoscopy should be repeated at least at six months and one year. Upper tract imaging should be performed every three to six months for three years, then annually up to five years. Surveillance after five years in the absence of recurrence should be encouraged and based on shared decision-making between the patient and clinician. Risk-adapted surveillance reflecting high recurrence risk within this patient population should incorporate cross-sectional imaging of the abdomen, pelvis, and chest to evaluate sites of metastasis.

Answer 155

b) They should undergo a follow-up cystoscopy and upper tract endoscopy within one to three months, followed by cystoscopic surveillance of the bladder and cytology at least every three to six months for the first three years and then at least annually thereafter.

Answer 156

b) It should aim to balance the morbidity and cost of follow-up with the risk of disease recurrence and metastasis.

Answer 157

According to Guideline 33, high-risk patients managed with kidney sparing treatment should undergo a follow-up cystoscopy and upper tract endoscopy with cytology within one to three months. If there's no evidence of disease, these patients should undergo cystoscopic surveillance of the bladder and cytology at least every three to six months for the first three years and then at least annually thereafter. Endoscopy should be repeated at least at six months and one year. Upper tract imaging should be performed every three to six months for three years, then annually up to five years. Surveillance after five years in the absence of recurrence should be encouraged and based on shared decision-making between the patient and clinician.

Answer 158

Clinicians should tailor the surveillance regimen for high-risk patients managed with kidney sparing treatment for UTUC based on disease risk and treatment modalities received. The regimen includes cystoscopic surveillance starting within three months after treatment, continuing every 3-6 months for 3 years, and then every 6-12 months through year 5. Follow-up ureteroscopy should be performed at least once within three to six months of endoscopic therapy and subsequently at the discretion of the clinician. Upper tract imaging with CT urogram and basic metabolic panel should be performed every 3-6 months for 3 years, then every 6-12 months for 2 years, and annually thereafter. Chest imaging with chest X-ray or CT of the chest is recommended every 6-12 months to evaluate for intrathoracic metastasis up to 5 years following the last diagnosis/treatment.

Answer 159

Guideline 34 suggests that if a patient with a history of UTUC develops urothelial recurrence in the bladder or urethra, or shows positive cytology, there might be a possibility of recurrent disease in the upper tracts. In such cases, an evaluation of the upper tracts should be carried out. This evaluation can be done through cross-sectional imaging or retrograde pyelography with or without selective upper tract cytology. If these tests suggest the presence of upper tract involvement, then further endoscopic evaluation is warranted.

Answer 160

c) Conduct an evaluation of the upper tracts, as there may be a recurrence of the disease there.

Answer 161

c) 94% and 71% respectively. According to the meta-analysis by Foerster et al., the cancer-specific survival and overall survival rates following the treatment of UTUC Ta/T1 disease with BCG were 94% and 71% respectively.

Answer 162

c) Conduct further endoscopic evaluation.

Answer 163

According to Guideline 34, if a patient with a history of UTUC develops urothelial recurrence in the bladder or urethra, or shows positive cytology, it's recommended to conduct an evaluation of the upper tracts, as there may be a recurrence of the disease there.

Answer 164

Guideline 34 suggests conducting an evaluation of the upper tracts in such cases. This evaluation could be carried out through cross-sectional imaging or retrograde pyelography with or without selective upper tract cytology. If these tests suggest the presence of upper tract involvement, then a further endoscopic evaluation is warranted.

Answer 165

Guideline 35 recommends post-radical nephroureterectomy (NU) surveillance for patients with

Answer 166

a) Every three to six months

Answer 167

b) Approximately 5%

Answer 168

According to Guideline 35, after NU, cystoscopy and cytology should be performed within three months. For Low-Grade (LG) disease, these tests should be repeated every six to nine months for the first two years and then annually. For High-Grade (HG) disease, tests should be performed every three to six months for the first three years, then annually. Cross-sectional imaging of the abdomen and pelvis should be done within six months after surgery and annually for a minimum of five years due to metastasis risk and a 5% probability for contralateral disease.

Answer 169

The studies indicate that the rate of intravesical recurrence after NU is approximately 29% with a median time to recurrence of 6-12 months. The overall risk of recurrence to the contralateral upper tract is 2.2% (with a range of 0% to 4.6%). Local recurrence rates are around 24% with a median time to recurrence of 7 months. Also, most local recurrences were identified within the first two years. These findings highlight the need for regular attention to monitoring for intravesical recurrence through regular cystoscopic surveillance.

Answer 170

Guideline 36 provides post-operative surveillance recommendations for patients who have undergone nephroureterectomy (NU) for >pT2 Nx/0 disease. Surveillance includes cystoscopy with cytology, cross-sectional imaging of the abdomen and pelvis, and chest imaging. The frequency varies based on the years passed since surgery. Beyond five years without recurrence, annual surveillance may be continued based on shared/informed decision-making. A systematic review and meta-analysis of studies highlighted the need for such surveillance due to the significant risk of intravesical recurrence and retroperitoneal or distant metastasis. A range of risk factors associated with recurrences were identified, including male sex, prior bladder cancer, positive preoperative urinary cytology, multifocality, necrosis, positive surgical margins, etc. In addition to monitoring for cancer recurrence or metastasis, patients should also be observed for any health complications arising from the NU procedure. Periodic laboratory assessments, including serum creatinine level, eGFR, and urinalysis, are recommended. Referrals to nephrology should be considered in patients who develop progressive renal insufficiency or proteinuria.

Answer 171

b) Every three to six months

Answer 172

d) Positive surgical margins

Answer 173

The key elements of post-operative surveillance as per Guideline 36 include performing cystoscopy with cytology every three to six months for the first three years, then annually thereafter. Additionally, cross-sectional imaging of the abdomen and pelvis with multiphasic contrast-enhanced CT urography should be performed every three to six months for years one and two, every six months in year three, and annually up to year five. Chest imaging should be performed every 6-12 months for the first 5 years. Beyond five years without recurrence, annual surveillance may be continued based on shared/informed decision-making.

Answer 174

Some of the risk factors for intravesical recurrence after NU include male sex, previous bladder cancer, preoperative chronic kidney disease, positive preoperative urinary cytology, ureteral tumor site, multifocality, invasive pathologic T-stage, presence of necrosis, laparoscopic approach, extravesical bladder cuff removal, and positive surgical margins.

Answer 175

Guideline 37 emphasizes the importance of postoperative renal function monitoring in patients who have undergone nephroureterectomy (NU) or other interventions. If patients display reduced or deteriorating renal function, clinicians are recommended to consider a referral to nephrology. This is particularly crucial for patients with an estimated Glomerular Filtration Rate (eGFR) less than 45 mL/min/1.73m^2, confirmed proteinuria, diabetics with preexisting Chronic Kidney Disease (CKD), or if eGFR is projected to be less than 30 mL/min/1.73m^2 post-intervention. Long-term renal dysfunction can heighten the risk of osteoporosis, anemia, metabolic and cardiovascular disease, hospitalization, and death. However, early detection of progressing renal dysfunction or proteinuria can provide opportunities for medical interventions to slow CKD progression and reduce cardiovascular risks. The Modification of Diet in Renal Disease and CKD – Epidemiology Collaboration (CKDEPI) equations are commonly used formulas for monitoring eGFR.

Answer 176

b) eGFR less than 45 mL/min/1.73m^2

Answer 177

c) 94% and 71% respectively. According to the meta-analysis by Foerster et al., the cancer-specific survival and overall survival rates following the treatment of UTUC Ta/T1 disease with BCG were 94% and 71% respectively.

Answer 178

b) Modification of Diet in Renal Disease and CKD – Epidemiology Collaboration (CKDEPI) equations

Answer 179

c) 94% and 71% respectively. According to the meta-analysis by Foerster et al., the cancer-specific survival and overall survival rates following the treatment of UTUC Ta/T1 disease with BCG were 94% and 71% respectively.

Answer 180

According to Guideline 37, a referral to nephrology should be considered for patients with reduced or deteriorating renal function following nephroureterectomy (NU) or other interventions. Specifically, a nephrology referral should be considered for patients with an eGFR less than 45 mL/min/1.73m^2, confirmed proteinuria, diabetics with preexisting CKD, or when eGFR is expected to be less than 30 mL/min/1.73m^2 after intervention.

Answer 181

Long-term renal dysfunction can increase the risk of various health conditions, including osteoporosis, anemia, metabolic and cardiovascular disease. It can also increase the likelihood of hospitalization and death.

Answer 182

Guideline 38 advises clinicians to discuss disease-related stressors and risk factors with patients who have urothelial cancer. Clinicians should also encourage these patients to adopt healthy lifestyle habits, such as quitting smoking, exercising regularly, and maintaining a healthy diet, to promote long-term health benefits and enhance their quality of life. Certain risk factors like smoking are linked to advanced disease stage, recurrence, and worse cancer-specific mortality (CSM) among patients with Upper Tract Urothelial Carcinoma (UTUC), especially for current smokers. UTUC is also associated with metabolic syndrome and obesity. Obesity has been found to negatively impact disease-specific outcomes among patients undergoing Radical Nephroureterectomy (RNU). As such, clinicians should emphasize the adoption of healthy lifestyle habits to UTUC patients to foster long-term health benefits and improve their quality of life. Clinicians should also collaborate with patients and their primary care providers to optimally manage comorbidities throughout the UTUC treatment and surveillance process, ensuring a better quality of life during survivorship.

Answer 183

b) Smoking

Answer 184

a) Metabolic syndrome and obesity

Answer 185

According to Guideline 38, clinicians should encourage UTUC patients to adopt healthy lifestyle habits such as quitting smoking, regularly exercising, and maintaining a healthy diet. These habits are associated with long-term health benefits and improved quality of life.

Answer 186

Obesity is associated with UTUC and it has been found to negatively impact disease-specific outcomes among patients undergoing Radical Nephroureterectomy (RNU). Therefore, maintaining a healthy weight can be a crucial aspect of managing UTUC.

Answer 187

a) High prevalence of activating FGFR3 mutations in UTUC

Answer 188

c) It provides optimal care by integrating various fields of expertise

Answer 189

Genomic markers and urinary biomarkers have the potential to improve UTUC management by providing less invasive methods of grading and staging tumors, as well as identifying potential treatment pathways. Urinary biomarkers may also be beneficial for refining post-treatment follow-up procedures and enabling better-informed decisions about endoscopic surveillance.

Answer 190

Advancements in flexible digital endoscopes have improved the visualization and accessibility of upper urinary tract tumors. In terms of treatment, the development of new therapies such as reverse thermo-hydrogel preparation of mitomycin offers a new method of treating low-risk tumors. Energy devices like the thulium:YAG laser have also been approved for thermal ablative procedures, and photodynamic treatments are currently being tested in Phase III clinical trials.

Answer 191

c) 94% and 71% respectively. According to the meta-analysis by Foerster et al., the cancer-specific survival and overall survival rates following the treatment of UTUC Ta/T1 disease with BCG were 94% and 71% respectively.

Answer 192

Clinicians may consider watchful waiting or surveillance alone for patients with UTUC who have significant comorbidities, competing risks of mortality, or are at significant risk of End-Stage Renal Disease (ESRD) with any intervention resulting in dialysis. These patients have a higher risk of severe treatment-related complications, which could outweigh the potential benefits of treatment. Also, if the patient has a very limited life expectancy, interventions might be limited to palliation or awaiting symptomatic progression.

Answer 193

The meta-analysis conducted by Foerster et al. reported cancer-specific survival and overall survival rates of 94% and 71% respectively for the treatment of UTUC Ta/T1 disease with BCG. These figures suggest that BCG therapy can be effective in managing high-risk but favorable UTUC.