Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery in Patients with High Grade Upper Tract Urothelial Carcinoma

No AccessJournal of UrologyAdult Urology1 Apr 2020Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery in Patients with High Grade Upper Tract Urothelial CarcinomaThis article is commented on by the following:Editorial Comment Vitaly Margulis, Maneka Puligandla, Edouard J. Trabulsi, Elizabeth R. Plimack, Elizabeth R. Kessler, Surena F. Matin, Guilherme Godoy, Ajjai Alva, Noah M. Hahn, Michael A. Carducci, Jean Hoffman-Censits, Nirmish Singla, MD, MSCS Antony Ruggeri, MD Leslie Howard, MD John McCann, MD Scott Delacroix, MD Matthew Matthew, MD Yagnesh Oza, MD Jennifer Wang, MD Benjamin Gartrell, MD Maha Hussain, MD Marc Matrana, MD Sam Benjamin, MD Guru Sonpavde, MD Elaine Lam, MD Brandon Bernard, MD Yousef Zakharia, MD Sarah Taylor, MD Matthew Milowsky, Sofia Ghani, MD Sindhu Singh, MD Kevin Kane, MD Yull Arriaga, MD Alicia Morgans, andMD, MPH David Chism Vitaly MargulisVitaly Margulis *Correspondence: Department of Urology, University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., J8.130, Dallas, Texas 75390-9110 telephone: 214-648-0567; FAX: 214-648-8786; E-mail Address: [email protected] Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas Institute of Urology and Reproductive Health, Sechenov University, Moscow, Russia More articles by this author , Maneka PuligandlaManeka Puligandla Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts More articles by this author , Edouard J. TrabulsiEdouard J. Trabulsi Department of Urology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania More articles by this author , Elizabeth R. PlimackElizabeth R. Plimack Department of Hematology-Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania More articles by this author , Elizabeth R. KesslerElizabeth R. Kessler Division of Medical Oncology, Department of Internal Medicine, University of Colorado, Aurora, Colorado More articles by this author , Surena F. MatinSurena F. Matin Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas Financial and/or other relationship with QED Therapeutics, Taris Bio, UroGen, AT&T Foundation and Specialized Programs in Oncology Research. More articles by this author , Guilherme GodoyGuilherme Godoy Department of Urology, Baylor College of Medicine, Houston, Texas More articles by this author , Ajjai AlvaAjjai Alva Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan (AA), Ann Arbor, Michigan More articles by this author , Noah M. HahnNoah M. Hahn Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland More articles by this author , Michael A. CarducciMichael A. Carducci Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland More articles by this author , and Jean Hoffman-CensitsJean Hoffman-Censits Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland More articles by this author and Collaborators View All Author Informationhttps://doi.org/10.1097/JU.0000000000000644AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Data supporting neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma are scant. In this multi-institution, prospective, phase II trial we investigated pathological complete responses after neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma. Materials and Methods: Patients with high grade upper tract urothelial carcinoma in whom nephroureterectomy was planned were assigned to 4 neoadjuvant chemotherapy cycles of accelerated methotrexate, vinblastine, doxorubicin and cisplatin in those with baseline creatinine clearance greater than 50 ml per minute or gemcitabine and carboplatin in those with creatinine clearance 30 to 50 ml per minute or less. The study primary end point was a pathological complete response (ypT0N0). The accrual goal was 30 patients per arm. An 18% pathological complete response was considered worth further study while a 4% pathological complete response would not have justified pursuing this regimen. With 28 eligible patients per arm success was defined as 3 or more pathological complete responses (10.7%) in a given arm. Secondary end points included safety, renal function and oncologic outcomes. Results: A total of 30 patients enrolled in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm from 2015 to 2017. Six patients enrolled in the gemcitabine and carboplatin arm, which closed due to poor accrual. Of the 29 patients eligible for accelerated methotrexate, vinblastine, doxorubicin and cisplatin, including 23 men and 6 women with a median age of 65 years (range 40 to 84), 80% completed all planned treatments, 3 (10.3%) achieved ypT0N0 and 1 achieved ypT0Nx for a pathological complete response in 13.8% (90% CI 4.9–28.8). In 1 patient receiving accelerated methotrexate, vinblastine, doxorubicin and cisplatin nephroureterectomy was deferred due to grade 4 sepsis. The grade 3-4 toxicity rate was 23% in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm with no grade 5 event. Conclusions: Accelerated methotrexate, vinblastine, doxorubicin and cisplatin neoadjuvant chemotherapy in patients with high grade upper tract urothelial carcinoma and creatinine clearance greater than 50 ml per minute was safe and demonstrated predefined activity with a 14% pathological complete response rate. Final pathological stage ypT1 or less in more than 60% of patients is encouraging. Together the results of this prospective trial support the use of neoadjuvant chemotherapy in eligible patients with high grade upper tract urothelial carcinoma. References 1. : European Association of Urology guidelines on upper urinary tract urothelial carcinoma: 2017 Update. Eur Urol 2018; 73: 111. Google Scholar 2. : Cancer statistics, 2018. CA Cancer J Clin 2018; 68: 7. Google Scholar 3. : Comparing changes in renal function after radical surgery for upper tract urothelial carcinoma and renal cell carcinoma. Urology 2016; 96: 44. Google Scholar 4. : Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349: 859. Google Scholar 5. : Guideline on muscle-invasive and metastatic bladder cancer (European Association of Urology Guideline): American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 2016; 34: 1945. Google Scholar 6. : Impact of neoadjuvant chemotherapy on pathologic response in patients with upper tract urothelial carcinoma undergoing extirpative surgery. Clin Genitourin Cancer 2018: 16: e1237. Google Scholar 7. : Perioperative chemotherapy in upper tract urothelial carcinoma: a comprehensive review. World J Urol 2017; 35: 1401. Google Scholar 8. : A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma. Eur Urol 2014; 66: 529. Google Scholar 9. : Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma. Cancer 2010; 116: 3127. Google Scholar 10. : Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma. Cancer 2014; 120: 1794. Google Scholar 11. : Results of POUT: a phase III randomised trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). J Clin Oncol, suppl., 2018; 36: 407, abstract 407. Google Scholar 12. : Adjuvant chemotherapy after radical nephroureterectomy does not improve survival in patients with upper tract urothelial carcinoma: a joint study by the European Association of Urology-Young Academic Urologists and the Upper Tract Urothelial Carcinoma Collaboration. BJU Int 2018; 121: 252. Google Scholar 13. : Effectiveness of adjuvant chemotherapy for locally advanced bladder cancer. J Clin Oncol 2016; 34: 825. Google Scholar 14. : Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 2014; 66: 42. Google Scholar 15. : Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol 2015; 16: 76. Google Scholar 16. : Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. J Clin Oncol 2011; 29: 3443. Google Scholar 17. : Multi-institutional analysis of renal function outcomes following radical nephroureterectomy and partial ureterectomy for upper tract urothelial carcinoma. Urol Oncol 2015; 33: 268. Google Scholar 18. : Impact of renal function on eligibility for chemotherapy and survival in patients who have undergone radical nephro-ureterectomy. BJU Int 2013; 112: 453. Google Scholar 19. : Patterns of lymphatic metastases in upper tract urothelial carcinoma and proposed dissection templates. J Urol 2015; 194: 1567. Link, Google Scholar 20. : Complications following radical nephroureterectomy. Curr Urol Rep 2016; 17: 36. Google Scholar 21. : Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer 2006; 107: 506. Google Scholar 22. : Preoperative multiplex nomogram for prediction of high-risk nonorgan-confined upper-tract urothelial carcinoma. Urol Oncol 2019; 37: 292. Google Scholar 23. : Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma. Clin Cancer Res. 2019; 25: 967. Google Scholar 24. : Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 2017; 171: 540. Google Scholar 25. : Comprehensive genomic characterization of upper tract urothelial carcinoma. Eur Urol 2017; 72: 641. Google Scholar 26. : Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J Urol 2017; 198: 552. Link, Google Scholar 27. : Organ preservation for muscle-invasive bladder cancer by transurethral resection. Urology 2007; 70: 473. Google Scholar 28. : Conservative management following complete clinical response to neoadjuvant chemotherapy of muscle invasive bladder cancer: contemporary outcomes of a multi-institutional cohort study. J Urol 2018; 200: 1005. Link, Google Scholar 29. : Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol 2014; 32: 1895. Google Scholar 30. : Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol 2014; 32: 1889. Google Scholar The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. Supported by the NIH (National Institutes of Health) NCI (National Cancer Institute) CA180820, CA180794, CA180834, CA180870, CA180801, CA180802, CA180858 and CA180888. Presented at the American Urological Association Annual Meeting, May 21, 2018. ClinicalTrials.gov NCT02412670. Coordinated by the ECOG-ACRIN™ Cancer Research Group, Drs. Petr J. O’Dwyer and Mitchell D. Schnall, Group Co-Chairs, with study ID EA8141. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. government. No direct or indirect commercial, personal, academic, political, religious or ethical incentive is associated with publishing this article. Editor’s Note: This article is the second of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 843 and 844. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited BySmith J (2020) This Month in Adult UrologyJournal of Urology, VOL. 203, NO. 4, (635-636), Online publication date: 1-Apr-2020.Related articlesJournal of UrologyJan 22, 2020, 12:00:00 AMEditorial Comment Volume 203Issue 4April 2020Page: 690-698Supplementary Materials Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.Keywordsurotheliumurinary tractcarcinomadrug therapynephroureterectomyMetricsAuthor Information Vitaly Margulis Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas Institute of Urology and Reproductive Health, Sechenov University, Moscow, Russia *Correspondence: Department of Urology, University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., J8.130, Dallas, Texas 75390-9110 telephone: 214-648-0567; FAX: 214-648-8786; E-mail Address: [email protected] More articles by this author Maneka Puligandla Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts More articles by this author Edouard J. Trabulsi Department of Urology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania More articles by this author Elizabeth R. Plimack Department of Hematology-Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania More articles by this author Elizabeth R. Kessler Division of Medical Oncology, Department of Internal Medicine, University of Colorado, Aurora, Colorado More articles by this author Surena F. Matin Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas Financial and/or other relationship with QED Therapeutics, Taris Bio, UroGen, AT&T Foundation and Specialized Programs in Oncology Research. More articles by this author Guilherme Godoy Department of Urology, Baylor College of Medicine, Houston, Texas More articles by this author Ajjai Alva Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan (AA), Ann Arbor, Michigan More articles by this author Noah M. Hahn Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland More articles by this author Michael A. Carducci Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland More articles by this author Jean Hoffman-Censits Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland More articles by this author Expand All The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. Supported by the NIH (National Institutes of Health) NCI (National Cancer Institute) CA180820, CA180794, CA180834, CA180870, CA180801, CA180802, CA180858 and CA180888. Presented at the American Urological Association Annual Meeting, May 21, 2018. ClinicalTrials.gov NCT02412670. Coordinated by the ECOG-ACRIN™ Cancer Research Group, Drs. Petr J. O’Dwyer and Mitchell D. Schnall, Group Co-Chairs, with study ID EA8141. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. government. No direct or indirect commercial, personal, academic, political, religious or ethical incentive is associated with publishing this article. Editor’s Note: This article is the second of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 843 and 844. 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