Phase 1b Trial Evaluating Tolerability and Activity of Targeted Fibroblast Growth Factor Receptor Inhibition in Localized Upper Tract Urothelial Carcinoma.

PURPOSE: We initiated a biomarker-informed preoperative study of infigratinib, a fibroblast growth factor receptor (FGFR) inhibitor, in patients with localized upper tract urothelial carcinoma (UTUC), a population with high unmet needs and tumor with a high frequency of FGFR3 alterations. MATERIALS AND METHODS: Patients with localized UTUC undergoing ureteroscopy or nephroureterectomy/ureterectomy were enrolled on a phase 1b trial (NCT04228042). Once-daily infigratinib 125 mg by mouth × 21 days (28-day cycle) was given for 2 cycles. Tolerability was monitored by Bayesian design and predefined stopping boundaries. The primary endpoint was tolerability, and the secondary endpoint was objective response based on tumor mapping, done after endoscopic biopsy and post-trial surgery. Total planned enrollment: 20 patients. Targeted sequencing performed using a NovaSeq 6000 solid tumor panel. RESULTS: From May 2021 to November 2022, 14 patients were enrolled, at which point the trial was closed due to termination of all infigratinib oncology trials. Two patients (14.3%) had treatment-terminating toxicities, well below the stopping threshold. Responses occurred in 6 (66.7%) of 9 patients with FGFR3 alterations. Responders had median tumor size reduction of 67%, with 3 of 5 patients initially planned for nephroureterectomy/ureterectomy converted to ureteroscopy. Median follow-up in responders was 24.7 months (14.9-28.9). CONCLUSIONS: In this first trial of targeted therapy for localized UTUC, FGFR inhibition was well tolerated and had significant activity in FGFR3 altered tumors. Renal preservation was enabled in a substantial proportion of participants. These data support the design of a biomarker-driven phase 2 trial of FGFR3 inhibition in this population with significant unmet clinical needs.

Real world evidence of enfortumab vedotin in patients with advanced urothelial cancer: A multicenter observational study.

OBJECTIVES: To explore the characteristics of patients and assess the effectiveness of enfortumab vedotin (EV) in those with treatment-resistant advanced urothelial cancer in a real-world setting. PATIENTS AND METHODS: A multicenter observational study was conducted on 103 evaluable patients with advanced urothelial cancer who received EV. Outcomes were assessed by radiographic response, progression-free survival (PFS), and overall survival (OS), with treatment-related adverse events (trAEs). Radiographic response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1, while trAEs were studied in line with Common Terminology Criteria for Adverse Events version 5.0. RESULTS: The median follow-up was 8.9 months (range, 0.1-16.4). The observed objective response rate was 50.5%. The median PFS was 6.0 months (95% CI: 4.7-9.8), and the median OS was 14.5 months (95% CI: 12.4-not reached). Out of the 103 patients, 19 (18.4%) had an Eastern Cooperative Oncology Group performance status of 2 or more, 14 (14.7%) had an non-urothelial carcinoma histology, and 40 (38.3%) had at least one pre-existing comorbidity. There were 26 (25.2%) patients who reported 49 trAEs, with 9 (18.3%) being grade 3 or higher. The most common trAEs included rash, occurring in 18.4%. CONCLUSIONS: This study describes the characteristics and outcomes of patients with previously treated advanced urothelial cancer receiving EV. The findings demonstrate that EV showed robust anti-tumor activity and had manageable safety profiles outside the clinical trial setting.

Carbon-ion radiotherapy for inoperable upper tract ureteral cancer.

AIM: This study aimed to report initial results of hypofractionated carbon-ion radiotherapy (C-ion RT) for inoperable upper tract ureteral cancer. METHODS: Retrospective chart review was performed for five consecutive patients with medically inoperable ureter cancer that was treated with radical C-ion RT between December 2013 and December 2014. The median age of the patients was 80 years (range, 68-84 years). The reasons for inoperability were advanced age, post-contralateral nephrectomy, alcoholic cirrhosis, both advanced age and contralateral renal function degeneracy, and pneumonia. The median size of tumor was 2.8 cm (range, 2.2-4.0 cm). Diagnostic imaging did not identify lymph node metastases or distant metastases in any case. All patients underwent C-ion RT (52.8 Gy relative biological effectiveness; 12 fractions in 3 weeks). The clinical target volume encompassed the growth tumor volume with a 5-mm margin bilaterally; there was a 40-mm margin craniocaudally but the clinical target volume did not encompass the whole ureter. RESULTS: Within a median follow-up time of 32.9 months (range, 24-36 months), two patients died and three remained alive. Neither local recurrence nor regional lymph node metastases were observed. Secondary bladder tumor was observed in four patients, and one patient had a liver metastasis. Grade 1 hematuria was observed in two patients, and Grade 3 pyelonephritis was observed in one patient as acute toxicity. Ureteral obstruction was observed in two patients. CONCLUSION: C-ion RT might be a useful treatment option for inoperable ureter cancer.

Is Segmental Ureterectomy Associated with Inferior Survival for Localized Upper-Tract Urothelial Carcinoma of the Ureter Compared to Radical Nephroureterectomy?

Segmental ureterectomy (SU) is an alternative to radical nephroureterectomy (RNU) in the treatment of upper-tract urothelial carcinoma (UTUC) of the ureter. SU generally preserves renal function, at the expense of less intensive cancer control. We aim to assess whether SU is associated with inferior survival compared to RNU. Using the National Cancer Database (NCDB), we identified patients diagnosed with localized UTUC of the ureter between 2004-2015. We used a propensity-score-overlap-weighted (PSOW) multivariable survival model to compare survival following SU vs. RNU. PSOW-adjusted Kaplan-Meier curves were generated and we performed a non-inferiority test of overall survival. A population of 13,061 individuals with UTUC of the ureter receiving either SU or RNU was identified; of these, 9016 underwent RNU and 4045 SU. Factors associated with decreased likelihood of receiving SU were female gender (OR, 0.81; 95% CI, 0.75-0.88; p < 0.001), advanced clinical T stage (cT4) (OR, 0.51; 95% CI, 0.30-0.88; p = 0.015), and high-grade tumor (OR, 0.76; 95% CI, 0.67-0.86; p < 0.001). Age greater than 79 years was associated with increased probability of undergoing SU (OR, 1.18; 95% CI, 1.00-1.38; p = 0.047). There was no statistically significant difference in OS between SU and RNU (HR, 0.98; 95% CI, 0.93-1.04; p = 0.538). SU was not inferior to RNU in PSOW-adjusted Cox regression analysis (p < 0.001 for non-inferiority). In weighted cohorts of individuals with UTUC of the ureter, the use of SU was not associated with inferior survival compared to RNU. Urologists should continue to utilize SU in appropriately selected patients.

Kidney-sparing surgery for distal high-risk ureteral carcinoma: Clinical efficacy and preliminary experiences in 22 patients.

BACKGROUND: Several groups proved kidney-sparing surgery (KSS) had equivalent oncological outcomes compared with radical nephroureterectomy (RNU) for the low-risk upper urinary tract urothelial carcinoma (UTUC) patients. Whereas, the clinical efficacy of KSS for high-risk UTUC, especially for distal high-risk ureteral carcinoma, remains unclear. OBJECTIVE: To evaluate the feasibility of KSS for patients with distal high-risk ureter cancer. MATERIALS AND METHODS: Our study included 22 patients who diagnose the distal high-risk ureter cancer and underwent KSS between May 2012 and July 2021 in the First Affiliated Hospital of Chongqing Medical University. Overall survival (OS), confirmed as the primary endpoint of present study, was assessed by a blinded independent review committee (BIRC). The secondary endpoints included the postoperative SF-36 (the short form 36 health survey questionnaire) score, progression-free survival (PFS), postoperative complications, and so on. RESULTS: Overall, 17 (77.3%) and 5 (22.7%) patients underwent segmental ureterectomy (SU) and endoscopic ablation (EA), respectively. By the cut-off date, the mean OS was 76.3 months (95% Cl: 51.3-101.1 months) and the mean PFS was 47.0 months (95% Cl: 31.1-62.8 months), respectively. And the SF-36 score in a majority of patients was >300 (90.9%). CONCLUSION: This is a daring endeavor to explore the clinical efficacy of KSS in distal high-risk ureter cancer based on the high-risk UTUC criteria, which shows satisfactory results in the long-term prognosis and operation-associated outcomes. However, future randomized or prospective multicenter studies are necessary to validate our conclusions.

Significant impact of a history of prior or concomitant upper urinary tract cancer on the recurrence and progression of non-muscle invasive bladder cancer.

BACKGROUND: The objective of the present study was to evaluate the prognostic impact of the upper urinary tract cancer status on recurrence-free survival and progression-free survival, and to develop risk stratification systems that include the upper urinary tract cancer status for patients with non-muscle invasive bladder cancer. PATIENTS AND METHODS: The present study included 40 (upper urinary tract cancer-non-muscle invasive bladder cancer group) and 285 (non-muscle invasive bladder cancer alone group) patients with and without a history of prior or concomitant upper urinary tract cancer, respectively. Nine clinicopathological findings between the two groups were compared, and risk stratification systems for the recurrence and progression of non-muscle invasive bladder cancer were developed. RESULTS: Recurrence-free survival and progression-free survival in the upper urinary tract cancer-non-muscle invasive bladder cancer group were significantly inferior to those in the NMIBC alone group (P < 0.001 and P = 0.006, respectively). Multivariate analyses identified the following independent prognosticators: multiplicity and upper urinary tract cancer status for recurrence-free survival, and pT category and upper urinary tract cancer status for progression-free survival. Significant differences were noted by the risk stratification systems based on the positive number of independent predictors of recurrence-free survival and progression-free survival (P < 0.001 and P = 0.007, respectively). The concordance indices of recurrence-free survival were 0.627, 0.588 and 0.499 in this study stratification, EORTC risk table and CUETO model, respectively. Those of progression-free survival were 0.752, 0.740 and 0.714, respectively. CONCLUSION: The present results suggest the significant impact of a history of prior or concomitant UUTC on recurrence-free survival and progression-free survival in non-muscle invasive bladder cancer patients, and risk stratification systems that include the upper urinary tract cancer status for the recurrence and progression of non-muscle invasive bladder cancer are promising tools for predicting the outcomes of these patients.

Five and Ten-Year Outcomes of Neoadjuvant Chemotherapy and Surgery for High-Risk Upper Tract Urothelial Carcinoma.

BACKGROUND: Emerging data suggests improved outcomes in patients receiving neoadjuvant chemotherapy (NAC) prior to radical nephroureterectomy (RNU) for high-risk upper tract urothelial carcinoma. In one of the largest single-center experiences to date, we provide an updated analysis of outcomes of patients receiving NAC followed by RNU. PATIENTS AND METHODS: A retrospective review of patients with high-risk UTUC who received NAC followed by surgery between 2004 to 2017 was conducted. 126 patients were evaluated as part of the analysis. Kaplan-Meier method was used to estimate survival probabilities. Multivariable Cox modeling was used to evaluate for association with outcomes, and the cumulative incidence factor was used for competing risk analysis. RESULTS: Median OS time was 106 months. 14.3% of patients had a pathologic complete response and 60% were down-staged to ypT0-1 ypN0. The estimated 5 and 10-year DSS rates were 89.8% and 80.6%, respectively. The estimated 5 and 10-year metastasis-free survival rates were 81% and 75.4%, respectively. The estimated 5 and 10-year OS rates were 73.7% and 35.9 %, respectively. Recurrences mainly occurred in lymph nodes and lung at a median time of 15.5 months (IQR 8.9-27). The estimated 5 and 10-year cumulative incidence factor for death from UTUC was 9.5% and 16.1%, respectively. Limitations include retrospective nature and challenge of accurate pre-surgical staging. CONCLUSIONS: NAC prior to RNU in high-risk UTUC shows durable 5 and 10-year OS and DSS rates in a large single-institution series, confirming prior findings in prospective trials and retrospective studies.

Bladder and upper urinary tract cancers as first and second primary cancers.

BACKGROUND: Previous population-based studies on second primary cancers (SPCs) in urothelial cancers have focused on known risk factors in bladder cancer patients without data on other urothelial sites of the renal pelvis or ureter. AIMS: To estimate sex-specific risks for any SPCs after urothelial cancers, and in reverse order, for urothelial cancers as SPCs after any cancer. Such two-way analysis may help interpret the results. METHODS: We employed standardized incidence ratios (SIRs) to estimate bidirectional relative risks of subsequent cancer associated with urothelial cancers. Patient data were obtained from the Swedish Cancer Registry from years 1990 through 2015. RESULTS: We identified 46 234 urinary bladder cancers (75% male), 940 ureteral cancers (60% male), and 2410 renal pelvic cancers (57% male). After male bladder cancer, SIRs significantly increased for 9 SPCs, most for ureteral (SIR 41.9) and renal pelvic (17.2) cancers. In the reversed order (bladder cancer as SPC), 10 individual FPCs were associated with an increased risk; highest associations were noted after renal pelvic (21.0) and ureteral (20.9) cancers. After female bladder cancer, SIRs of four SPCs were significantly increased, most for ureteral (87.8) and pelvic (35.7) cancers. Female bladder, ureteral, and pelvic cancers associated are with endometrial cancer. CONCLUSIONS: The risks of recurrent urothelial cancers were very high, and, at most sites, female risks were twice over the male risks. Risks persisted often to follow-up periods of >5 years, motivating an extended patient follow-up. Lynch syndrome-related cancers were associated with particularly female urothelial cancers, calling for clinical vigilance.

Chronic hepatitis C virus infection and genitourinary cancers: A case-control study.

BACKGROUND: Chronic Hepatitis C virus (HCV) infection has been associated with extrahepatic cancers. Few studies have reported associations between HCV and genitourinary cancers such as kidney and prostate cancers with inconsistent findings. We sought to study associations between HCV and the most common genitourinary cancers including kidney, prostate and urinary bladder. MATERIAL AND METHODS: This case-control study included adult (≥18 years at diagnosis) cancer patients who were screened for HCV antibody (anti-HCV) at MD Anderson Cancer Center from June 2004 through January 2018. Cases had incident primary genitourinary cancers (cancers of the kidney, prostate, renal pelvis and ureter, or urinary bladder). Controls had smoking-associated cancers (esophagus, lung and pancreas). Multivariate logistic regression models were used. RESULTS: Among 42,244 patients screened for anti-HCV, 1,493 cases (527 kidney, 691 prostate, 58 renal pelvis and ureter, and 217 urinary bladder cancer) and 1,187 controls (242 esophagus, 709 lung, and 236 pancreas cancer) were studied. In the univariate analysis, the prevalence of anti-HCV positivity did not differ significantly between the controls and the cases with cancers of the renal pelvis and ureter (8% v9%, P = .81), prostate (10% v8%, P = .34), or urinary bladder (8% v 6%, P = .18). In contrast, the prevalence of anti-HCV positivity was lower among the cases with kidney cancer than among the controls (4% v 8%, P< .001). However, in the multivariate analyses after adjustment for cofounders, no significant association between anti-HCV positivity and any genitourinary cancer we evaluated. CONCLUSION: Our results do not support an association between chronic HCV and common genitourinary cancers.

Primary small cell carcinoma of the upper urinary tract: A case report.

Small cell carcinoma of the urinary tract is an aggressive malignancy that comprises less than 1% of urinary bladder cancers. The renal pelvis and ureter, also lined by urothelium, are rare sites for small cell carcinoma. The diagnosis and staging of upper tract cancer are difficult due to the need for small, atraumatic instrument to access the upper tract. There are fewer than 40 reported cases of upper urinary tract small cell carcinoma. These include both pure and variant histologies. We present the management of a 72 year old male with small cell carcinoma of the upper urinary tract.

Proton beam therapy for renal pelvis and ureter cancer: A report of 5 cases and a literature review.

Standard treatment for localized renal pelvis and ureter cancer is surgery. Previously, the primary role of radiation therapy (RT) in cancer treatment was to control pain and hemostasis as palliative or as adjuvant therapy following surgery. In this report, we describe 5 patients with the disease treated with proton beam therapy (PBT) as curative treatment. Between September 2009 and July 2013, 5 males with renal pelvis (n=3) or ureter (n=2) cancer were treated by PBT with hypofractionated [72.6 Gy relative biological effectiveness (RBE)/22 fractions] or conventional [64-66 Gy (RBE)/32-33 fractions] fractionation. The median patient age was 72 years (range, 59-85 years). Three patients were deemed unfit for surgery. Local hypofractionated PBT was performed in 2 patients with T1-2N0M0 diseases, while prophylactic lymph node irradiation using a patch irradiation technique was performed for the remaining 3 patients, who had T3-4 disease. Two patients with T3-4 disease received chemotherapy prior to definitive PBT. No serious acute or late toxicities were observed in any patient. Local tumor control was achieved in 3 patients (60%); however, distant metastases were observed in 2 patients. Four of the five patients (80%) evaluated in the present study survived for >3 years. The data is limited; however, PBT appears to be a potential option for patients with renal pelvis or ureter cancer, especially for those who are unsuitable for radical surgery.

The single-base-pair deletion, MSH2 c.2635-3delC affecting intron 15 splicing can be a cause of Lynch syndrome.

The proband was a 62-year-old man with ureter cancer. He had a history of metachronous colorectal and gastric cancer. Immunohistochemical staining showed the absence of both MSH2 and MSH6 proteins in the ureter cancer and other available cancer tissue specimens. Genetic testing was conducted to identify the causative genes of hereditary gastrointestinal cancer syndromes including mismatch repair genes. We detected a germline variant, c.2635-3delC, within the splice acceptor site of exon 16, in the MSH2 gene. To investigate whether this variant affected splicing of the gene, RNA sequencing was performed using blood samples. We observed a substantial amount of the transcripts that lacked proper splicing of intron 15 in the indexed case, whereas, a very low amount of such aberrant transcripts was detected in the controls, strongly indicating an association between the variant and splicing defect. These results indicate that MSH2 c.2635-3delC affects normal splicing and might be a cause of Lynch syndrome.

Outcomes of nonmetastatic micropapillary variant upper tract urothelial carcinoma.

PURPOSE: Micropapillary variant upper tract urothelial cancer (MP-UTUC) is a rare malignancy with little known regarding its clinical course and/or optimal treatment. In this case series, we describe patient characteristics, surgical treatment, oncologic outcomes, and response to perioperative chemotherapy. MATERIALS AND METHODS: We conducted a review to identify patients with MP-UTUC treated at our center between January 1994 and October 2017. Clinicopathologic data was obtained. Descriptive statistics, Kaplan-Meier analysis, Cox proportional hazards, and nearest neighbor matching were used to examine the cohort. RESULTS: Eighteen, (4.3%) of 416 patients were found to have MP-UTUC at our institution over a 23-year period. The majority of patients had ≥pT3 disease at the time of extirpative surgery (13/18, 72%) and one was identified as MP-UTUC prior to surgery. Seven patients received neoadjuvant chemotherapy and six patients received adjuvant chemotherapy. Median overall, cancer specific, and recurrence free survival were 3.29, 3.29, and 1.69 years, respectively for MP-UTUC. There was no survival difference between conventional UTUC and MP-UTUC when matched for age, stage, grade, lymphovascular invasion, and margins (HR 1.18, P = 0.567). No MP-UTUC patients receiving neoadjuvant and adjuvant chemotherapy had apparent pathologic down staging, and of those receiving adjuvant chemotherapy two-thirds died of disease within 2 years. CONCLUSIONS: MP-UTUC is a rare, and in most cases aggressive malignancy that commonly presents as locally advanced disease. In this case series, MP-UTUC does not appear to respond to perioperative chemotherapy as neoadjuvant and adjuvant chemotherapy did not result in apparent pathologic down staging and the majority of those receiving adjuvant chemotherapy died from MP-UTUC.

Usefulness of multi-parametric MRI for diagnosis of invasive urothelial cancer: Case reports of bladder and ureteral cancer.

The presence or absence of metastasis has critical implications for therapeutic decision-making in urothelial cancer (UC). Conventional magnetic resonance imaging (MRI) utilizing anatomic T1- and T2-weighted images has modest efficacy in detecting lymph node and distant metastases in UC. However, incorporation of functional techniques including diffusion weighted imaging and dynamic contrast-enhanced imaging, may improve the accuracy of lesion detection and staging. Multiparametric (mp)MRI is widely used in the imaging of prostate and breast cancers, though its usefulness in UC has yet to be fully elucidated. The present study reports on mpMRI in the context of two cases of bladder and ureteral cancer, and imaging results with pathological diagnosis.

Prognostic Value of Leptin Receptor Overexpression in Upper Tract Urothelial Carcinomas in Taiwan.

OBJECTIVES: Leptin and its receptor (LEPR) are key players in the regulation of energy balance and body weight control and act as a growth factor for specific organs in both normal and disease states. However, LEPR accumulation may be involved in carcinogenesis, progression, and metastasis in many cancers. This study evaluated the clinical significance of LEPR expression in upper tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: LEPR expression was examined in 110 tissue samples from patients with UTUC, using immunohistochemistry, and an analysis was performed to identify evidence of association between LEPR expression and different clinicopathologic variables. RESULTS: LEPR expression was significantly correlated with patients with increased body mass index (P < .001) and high serum creatinine levels (P = .005). We found, using the log-rank test, that high LEPR expression was associated with poor recurrence-free (P = .009) and cancer-specific survival (P = .001). This finding was supported by our results using Cox regression analysis, which showed that LEPR expression was an independent predictor of poor recurrence-free survival (hazard ratio = 2.55; P = .011) and cancer-specific survival (hazard ratio = 2.26; P = .006). CONCLUSIONS: Our findings indicate that LEPR expression is a potential biomarker for predicting patient survival in UTUC. Further study is necessary to investigate the role of LEPR in carcinogenesis of UTUC.

Clinical significance of a second-line chemotherapy regimen with paclitaxel, ifosfamide and nedaplatin for metastatic urothelial carcinoma after failure of cisplatin-based chemotherapy.

OBJECTIVE: Cisplatin-based chemotherapy has been commonly used as the first-line chemotherapy for metastatic urothelial carcinoma. However, after failure of the first-line cisplatin-based chemotherapy, there is no established standard second-line chemotherapy. Starting in 2006, paclitaxel, ifosfamide and nedaplatin chemotherapy has been performed as the second-line chemotherapy in our institution. Here, we report the treatment results of paclitaxel, ifosfamide and nedaplatin chemotherapy. METHODS: From 2006 to 2015, 33 patients with metastatic urothelial carcinoma were treated with paclitaxel, ifosfamide and nedaplatin chemotherapy after failure of first-line cisplatin-based chemotherapy in our institution. We retrospectively examined the treatment outcome and predictive factors for therapeutic effects of paclitaxel, ifosfamide and nedaplatin. The median age, treatment cycle and follow-up period were 62.5 years, 3 cycles and 10.4 months, respectively. RESULTS: The median overall survival and progression-free survival were 10.4 and 3.5 months, respectively. Complete and partial responses were found in 3 and 7 patients, respectively, with an overall response rate of 30%. All patients developed grade 3-4 neutropenia, but there was no treatment-related death. In multivariate analysis, the only prognostic factor for progression-free survival was 24-hour urinary creatinine clearance. CONCLUSIONS: A paclitaxel, ifosfamide and nedaplatin regimen as second-line chemotherapy for metastatic urothelial carcinoma was effective and tolerable. Moreover, paclitaxel, ifosfamide and nedaplatin chemotherapy may be more effective in patients with satisfactory renal function.

Mycosis Fungoides with Coincidental Ureter Cancer / 대한피부과학회지

An 82-year-old woman presented with a 5-year history of erythematous to brown patches and plaques on both legs, arms and trunk. Histopathological findings of biopsy specimens were consistent with mycosis fungoides, and the tumor cells were positive for CD3 and negative for CD20 in immunohistochemical stain. Imaging studies proposed the suspicion of ureter cancer, and the result of cystoscopic biopsy showed papillary urothelial carcinoma. Mycosis fungoides is the most common type of cutaneous T-cell lymphoma, characterized by variable cutaneous manifestations, including patches, plaques, tumors, and erythroderma. There were several studies concerning the evaluation of the second malignancy risk after cutaneous T-cell lymphoma, however the relationship between mycosis fungoides and ureter cancer is not revealed. This patient is considered a case of mycosis fungoides with coincidental ureter cancer.