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Updating the Definitions, Endpoints, and Clinical Trial Designs for Bladder Cancer

Posted by | Apr 2022

Amirali Salmasi, MD, Assistant Professor of Urology at the University of California, San Diego, reviews risk stratification guidelines for non-muscle invasive bladder cancer (NMIBC) from the American Urological Association (AUA) and European Association of Urology (EAU); pointing out that the AUA classifies solitary high-grade (HG) Ta lesions ≤3cm classified as intermediate risk (IR-Ta) while the EAU recommends all HG tumors be classified as high-risk. Dr. Salmasi then presents data suggesting that, indeed, all HG Ta lesions should be considered high risk, supporting the EAU risk stratification model. He then reviews recommendations from the International Bladder Cancer Group, including definitions, end points, and clinical trial designs for NMIBC for both BCG-naive and BCG-unresponsive patients. For BCG-naive patients, Dr. Salmasi defines the clinically significant outcome of an absolute difference of 10 percent in the percentage of patients with recurrence at two years. For BCG-unresponsive patients with carcinoma in situ (CIS), a clinically meaningful magnitude of effect is an initial complete response rate of 50 percent at six months and a durable response rate of 30 percent at 12 months and 25 percent at 18 months; for those with papillary disease, it is a recurrence-free rate of 30 percent at 12 months and 25 percent at 18 months. Dr. Salmasi then shares information refining neoadjuvant therapy clinical trial design for muscle-invasive bladder cancer (MIBC) before cystectomy, citing level-one evidence that says neoadjuvant chemotherapy (NAC) should be offered to any “fit” patient before radical cystectomy (RC). He discusses eligibility and staging before discussing treatment options, posing questions about appropriate control arms for neoadjuvant trials as well as what number of neoadjuvant therapy cycles might be ideal, acknowledging that the best combination of treatment options remains uncertain. Dr. Salmasi discusses primary endpoints for neoadjuvant trials before shifting to a discussion on the future of trial design. He outlines some potential improvements to trial design, including sample size re-estimation; adaptive enrichment; seamless design; multi-arm, multistage (MAMS) trials; and biomarker-based adaptive study. Dr. Salmasi then outlines the benefits and limitations of MAMS trials and describes the characteristics of umbrella trials and basket trials. He discusses the BISCAY flowchart and the trial’s limitations and discusses the future of biomarker-based trial design in bladder cancer, citing two successful, meaningful biomarker-adaptive trials (PROOF 302 and IMvigor 011). Dr. Salmasi concludes by outlining future directions in the field, including ongoing trials for treatments for BCG-unresponsive NMIBC as well as neoadjuvant therapy for MIBC, where he asserts that work must be done to find the biomarkers of response, the need for improvements in molecular subtyping and treatment selection, and the need to identify optimal treatment. Finally, he asserts that improved patient outcomes would stem from an improved patient selection for radical cystectomy versus chemoradiation; there is also a need to continue to design adaptive trials to personalize treatment for those with metastatic urothelial cancer.

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A Biochemical Definition of Cure Following Brachytherapy of Prostate Cancer

Posted by | Apr 2022

As part of a special course on brachytherapy for prostate cancer from the American Brachytherapy Society (ABS) and Grand Rounds in Urology, Juanita M. Crook, MD, FRCPC, Professor of Radiation Oncology at the University of British Columbia in Kelowna, discusses the development of a biochemical definition of cure following low-dose-rate (LDR) prostate brachytherapy. She begins with some background, explaining that the interpretation of post-radiation PSA values has been challenging. She relates that the 1996 ASTRO consensus conference defined biochemical failure as 3 consecutive rises after the nadir with failure backdated to midway between the nadir and the first rise, while the 2005 Phoenix consensus conference defined biochemical failure as 2 ng/ml > nadir, a definition still widely used today. Dr. Crook emphasizes that neither definition was meant to be a trigger for intervention, and neither attempted to define cure. She then discusses research on the importance of PSA nadir in LDR brachytherapy which showed that if PSA at 4 years was less than 0.2 to 0.4 ng/ml, patients tended to do well, but if it was greater than 1.0, the majority were going to fail. Dr. Crook considers another study on long-term PSA stability after LDR brachytherapy which found that 86% of patients had stable PSA at a median followup of 89 months. She also briefly notes that a study of intermediate-risk patients undergoing external beam radiation therapy (EBRT) + high-dose-rate brachytherapy boost found similar results to the studies of LDR brachytherapy regarding the importance of PSA nadir. Dr. Crook then goes into detail about a study she and her colleagues conducted to define a biochemical definition of cure following LDR brachytherapy by identifying a PSA threshold value at an intermediate follow-up time that is associated with long-term (10-15 year) freedom from prostate cancer. She explains that by using prospectively-collected data sets combined from 7 institutions, she and her colleagues were able to determine that patients with a PSA ≤ 0.2 ng/ml by 4-5 years have a 99% probability of being free of clinical failure at 10-15 years. Dr. Crook concludes that PSA ≤ 0.2 ng/ml should be adopted as biochemical definition of cure for comparison with surgical series, but highlights that those patients not achieving this threshold PSA should not be considered as having “failed” but should continue to be monitored with the understanding that they are at higher risk of subsequent clinical failure.

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Overview of the State of Genetic Testing and Future Applications in Prostate Cancer

Posted by | Apr 2022

Brian T. Helfand, MD, PhD, Chief of the Division of Urology and the Ronald L. Chez Family and Richard Melman Family Endowed Chair at NorthShore University HealthSystem in Evanston, Illinois, discusses current and potential future applications of genetic testing in prostate cancer screening and treatment. He explains that genetic testing has applications throughout the patient journey. At the prevention and screening stage, genetic testing can determine which men will benefit from screening. At the diagnosis stage, it can determine which men will benefit from biopsy. During early-stage disease, genetic testing can help identify which men will benefit from definitive treatment. Finally, during late-stage disease, genetic testing can identify the men that will benefit from advanced therapies. Dr. Helfand notes that there are two kinds of genetic testing, germline and somatic, and not all tests are relevant at all stages of the patient journey. He then gives an overview of germline genetic testing’s role in screening, arguing that because family history, rare pathogenic mutations (RPMs), and genetic risk score (GRS) all measure risk independently, a comprehensive inherited risk assessment should include all three tools. Dr. Helfand particularly focuses on GRS, defining it as a number calculated based on the cumulative variation across multiple single nucleotide polymorphisms (SNPs), which is then used to provide an estimate of disease risk. He notes that GRS is simple to interpret and more informative than family history. Dr. Helfand also observes that GRS is correlated with number and laterality of tumor cores. GRS, he argues, is useful for risk stratification for both screening and active surveillance. He notes that RPMs can help with stratification in terms of disease aggressiveness. Dr. Helfand concludes by arguing that genetic testing for prostate cancer will be pivotal in the future and should be included in guidelines for both prevention and screening.

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Lyndon Johnson and His Kidney Stone

Posted by | Apr 2022

Grand Rounds in Urology Contributing Editor Neil H. Baum, MD, Professor of Urology at Tulane Medical School, highlights the importance of imagining how the United States healthcare system could change by reflecting on how different the world would be had Lyndon Johnson’s kidney stone not been successfully removed. He explains that in 1948, Johnson was running for a US Senate seat and was deadlocked against the favorite, when he developed an obstructing kidney stone in the upper third of his ureter. He thought he would require a ureterolithotomy, but did not want to since that might require him to drop out of the race. Dr. Baum explains that Johnson met with Dr. Gershom Thompson at the Mayo Clinic for a second opinion, and Thompson agreed to try an endoscopic stone removal, even though he had never before removed a stone in the upper third of the ureter. Thompson was successful, and Johnson had a prompt recovery, allowing him to return to the campaign and win. Dr. Baum notes that Johnson’s recovery raises several “what if” questions, such as “how might the world have changed if LBJ had not had a successful endoscopic retrieval of a proximal ureteral stone and been unable to win his Senate race?” Dr. Baum considers Johnson’s legacy as President of the United States, from passing the Civil Rights Act to accelerating US military involvement in Vietnam. He then asks, “what if we did not have the two government healthcare programs, Medicare and Medicaid, that were instituted and approved during the Johnson Administration?” This leads him to ask a whole series of “what if” questions, such as “what if we had a single payer system?” and “what if we could put more enjoyment back in the practice of medicine?” He concludes that it may be time to ask some “what if” questions, and he suggests that by doing so, it may be possible to find ways to repair the current healthcare system rather than seeing it as fundamentally immutable.

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