Topic: Upper Tract Urothelial Carcinoma

FGFR3 Inhibitors for Upper Tract Urothelial Cancer

E. David Crawford, MD, Professor of Urology at the University of California, San Diego, and Editor-in-Chief of Grand Rounds in Urology, interviews Sumanta Kumar Pal, MD, Clinical Professor in the Department of Medical Oncology & Therapeutics Research and Co-Director of the Kidney Cancer Program at City of Hope in Duarte, California, about his recent paper looking at FGFR3 inhibitors for treating upper tract urothelial cancer. Dr. Pal explains that upper tract urothelial cancer, which is both more rare and more aggressive than lower tract urothelial cancers, seems to be enriched in mutations in FGFR3, making FGFR3 inhibition a potentially good treatment for this disease state. While one such inhibitor, erdafitinib, is already approved for treating upper tract urothelial cancer, Dr. Pal suggests that a different inhibitor, infigratinib, has a profile that might lend itself better to clinical practice, with lower incidence of hyperphosphatemia and other side effects. He goes over the results of the initial phase 1 study of infigratinib, noting the 25% response rate and considering different biomarkers as indicators of response. Dr. Pal concludes by introducing the Proof 302 study, a phase 3 trial looking at infigratinib for upper tract urothelial cancer which he hopes urologists will consider signing eligible patients up for.

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Advances in Treating Upper Tract Urothelial Cancer

Seth P. Lerner, MD, Professor of Urology and holder of the Beth and Dave Swalm Chair in Urologic Oncology in the Scott Department of Urology at Baylor College of Medicine, discusses developments in upper tract urothelial carcinoma (UTUC) treatment. He delivers a rationale for adjuvant therapy based on a lack of clinical staging accuracy, a lack of high-level evidence to support perioperative systemic therapy, the perceived benefit in cases of high-risk bladder cancer, and the ability of pathologic staging to identify patients most likely to benefit. He then reviews the POUT trial of adjuvant chemotherapy, noting that it found a statistically significant benefit in disease-free survival and metastasis-free survival. Dr. Lerner continues by summarizing guideline statements. The EAU statement recommends perioperative chemo to patients with muscle invasive UTUC. ICUD states that it is unknown if adjuvant chemotherapy or waiting for the development of clinically evident disease is better. The French ccAFU recommends adjuvant chemotherapy after radical nephroureterectomy in pT2-T4 N0-3 M0 disease. Dr. Lerner then discusses neoadjuvant therapy, which studies suggest is beneficial to patients with optimized renal function. A Hopkins study specifically displayed a pathologic complete response of 9.4%, while the EA8141 trial found a total pathologic complete response of 13.8%. Dr. Lerner continues with a review of management options for low-grade UTUC, a rare disease with limited treatment options. He posits that a kidney-sparing treatment option is needed for patients, as there is a high chance of recurrence and kidney damage with the treatments currently available. Dr. Lerner theorizes that if durability of complete response following ablation with UGN-101 is demonstrated, this could provide a potential new kidney-sparing treatment for patients with low-grade UTUC. Dr. Lerner concludes with a discussion of the OLYMPUS study on UGN-101, which found a complete response in 59% of patients.

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Updates in Upper Tract Urothelial Cancer: Challenges in Diagnosis and Treatment

Surena F. Matin, MD, the Monteleone Family Foundation Distinguished Professor in the Department of Urology at MD Anderson Cancer Center, gives an overview of upper tract urothelial carcinoma (UTUC), comparing it to bladder UC and outlining risk factors, imaging options, and possible treatment paths. He posits that the lack of research on UTUC is a major reason for the challenges in diagnosing and treating the illness. When compared to bladder UC, UTUC has more imprecise staging options, more anatomical barriers for therapy, and unclear lymphadenectomy templates. Dr. Matin identifies UTUC risk factors such as tobacco, exposure to aromatic amines and arsenic, and also discusses classification issues related to patients with hereditary UTUCs. He then discusses how imaging is the backbone of staging and grading, but has limitations, recommending a CT chest scan or chest X-ray to rule out metastases, a cystoscopy to assess bladder capacity, and a ureteroscopy to assess tumor size. Dr. Matin concludes with a discussion of radical nephroureterectomy as a treatment option, stating that it is highly curative but at the cost of kidney function. He believes that adjuvant topical therapy could help solve the problem of treatment options but notes that there is not enough data to be certain of this yet.

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The Unique Experience of Upper Tract Urothelial Carcinoma in Taiwan

Hsiang Ying Lee, MD, Assistant Professor of Urology at Kaohsiung Medical University Hospital, discusses upper tract urothelial carcinoma’s (UTUC) unusual prevalence in the Taiwanese population, along with the national effort to gather more information on the disease. She explains that while there are 1-2 cases of UTUC per 100,000 people in Western countries, there are 4.09-4.37 cases per 100,000 people in Taiwan, as well as a much higher ratio of UTUC to all urothelial carcinomas and a higher proportion of men with the disease compared to the West. Dr. Lee notes several possible reasons for this, including the high rates of exposure to aristolochic acid and arsenic in Taiwan. She then discusses the efforts of a whole Taiwan collaborative clinical study designed to identify high-risk patients in the country, explore new treatments, and develop a UTUC guideline for Taiwan. The presentation concludes with a Q&A session in which Dr. Lee emphasizes the need to find better biomarkers for UTUC.

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Updates in Upper Tract Urothelial Carcinoma

Seth P. Lerner, MD, Professor of Urology, Director of Urologic Oncology and the Multidisciplinary Bladder Cancer Program, and Faculty Group Practice Medical Director for the Urology Clinic at Baylor College of Medicine discusses the impact of several upper tract urothelial carcinoma studies on the treatment of the disease. The POUT phase III trial used adjuvant therapy for high-risk patients who didn’t receive neoadjuvant therapy and through increased survival rates supported the establishment of the new adjuvant therapy standard of care. ECOG, a phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery in high-risk upper tract urothelial carcinoma found about a 10% pathological complete response rate from treatment. QED, an ongoing adjuvant trial, tested infigratinib, an oral FGFR1-3 selective kinase inhibitor, so far finding increased survival rates in patients. Dr. Lerner concludes with the Olympus Study, a phase III prospective study on patients with low-grade disease in the renal pelvis using mitomycin gel for treatment and found a 58% complete response rate and led to the treatment’s approval by the FDA.

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Ureterocutaneostomy: A Valuable Option for Urinary Diversion in the Elderly Patient?

Margit Fisch, MD, FEAPU, FEBU, Director and Chair of the Department of Urology and Pediatric Urology at University Medical Center Hamburg-Eppendorf in Hamburg, Germany, discusses the value of ureterocutaneostomy as a urinary diversion technique for the increasing number of older, sicker patients with urothelial carcinoma of the bladder. Dr. Fisch explains that, compared with other urinary diversions, ureterocutaneostomy is a simpler, shorter procedure with no significant quality of life differences. She then summarizes the findings of a cystectomy series, which showed that even though patients who had undergone ureterocutaneostomy were older, more likely to have comorbidities, and more likely to have had prior pelvic/abdominal surgeries and irradiation compared with patients who had received ilial/colonic conduit or continent diversion, they had the shortest surgeries and hospital stays during cystectomy, as well as no difference in 30-day complication rate. The benefits of ureterocutaneostomy are further corroborated by a study which compared ureterocutaneostomy to urinary diversion with use of bowel, and found that ureterocutaneostomy patients had shorter operating room time, shorter time in the ICU, and fewer serious complications, although they did experience higher long-term morbidity, probably because of comorbidities. Dr. Fisch notes that ureterocutaneostomy has late complications such as abscess formation, ureteral necrosis, stoma stenosis, and pyelonephritis, but concludes that conduits are no better in this area, and that the benefits of ureterocutaneostomy make it a valuable and useful diversion in elderly patients.

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Mitomycin Gel (UGN-101) Approved for Treating Low-Grade Upper Tract Urothelial Carcinoma: The OLYMPUS Trial

Surena F. Matin, MD, Professor in the Department of Urology at MD Anderson Cancer Center in Houston, Texas, discusses the OLYMPUS Trial which studied the effects of mitomycin gel (UGN-101) in treating low-grade upper tract urothelial carcinoma. The FDA has recently approved this drug for treatment after the trial’s successful results. Prior to approval, there was no method of treatment that allowed for topical therapies in upper-tract cancer cases like there is for the bladder, and there had been little research into potential treatments. Dr. Matin was an investigator on the trial and discusses the selection of participants, the procedures of the trial, and the conclusions that were drawn. He highlights that during the trial, 58% of participants had a complete response, and that fully optimizing the drug plays an important role in those high numbers of success. He also discusses some of the adverse events that occurred during the trial and considerations for using mitomycin gel as a treatment.

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Management of High-Grade Upper Tract Urothelial Cell Carcinoma

Brian W. Cross, MD, Assistant Professor of Urology at the University of Oklahoma College of Medicine, discusses chemotherapy options in patients undergoing nephroureterectomy (NU). He goes on to discuss the advantages of perioperative chemotherapy following NU, the role of neoadjuvant chemotherapy in patients with high-risk upper tract urothelial carcinoma prior to NU, and surgical techniques for the management of the distal ureter during NU.

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Clinical Implications of Similarities and Differences Between Upper-Tract and Bladder Urothelial Carcinoma

Peter Black, MD, FACS, FRCSC, a Urologic Oncologist at Vancouver General Hospital, a Senior Research Scientist at the Vancouver Prostate Centre, and a Professor in the Department of Urologic Sciences at the University of British Columbia, examines key differences between upper-tract and bladder urothelial carcinomas, and their impact on diagnosis and treatment of each respective disease. He discusses subtle molecular differences between each disease, how these variations’ relationship to genetic alterations could lead to marker-based therapy, as well as treatments that are effective in treating both diseases.

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Upper Tract Urothelial Cancer: Challenges and Opportunities for Treating the Unmet Medical Need

David S. Morris, MD, FACS, discusses current methods of diagnosing and risk-stratifying upper tract urothelial cancer (UTUC), as well as the implications of disease risk on treatment decisions. He notes the unmet need for an effective kidney-sparing option for low-risk patients, and the potential for chemoablation with UGN-101 to address this need based on findings from the OLYMPUS trial.

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Current Treatment Options and Future Treatment Options: Addressing the Unmet Needs in Treating UTUC

Jennifer A. Linehan, MD, surveys the current landscape of treatment for upper tract urothelial cancer (UTUC), difficulties with current methods, and promising future treatment options, including kidney-sparing options for low-grade disease. She details the current European Association of Urology (EAU) prognostic algorithm and National Comprehensive Cancer Network (NCCN) guidelines, and discusses the benefits and risks of the “watchful waiting” method of disease management as well as updated approaches to treatment algorithms for UTUC.

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