Adjuvant Radiotherapy for Upper Tract Urothelial Carcinoma: Systematic Review and Meta-Analysis

Purpose: Upper tract urothelial carcinoma (UTUC) is a rare form of malignancy comprising only 5% of urothelial cancers. The mainstay of treatment is radical nephroureterectomy (RNU) with bladder cuff excision. Neoadjuvant or adjuvant chemotherapy is often used in locally advanced disease. The role of adjuvant radiotherapy (RT), however, remains controversial. To further explore the potential role of adjuvant RT, we performed a systematic review and meta-analysis of the literature from 1990 to present. Methods and Materials: We identified 810 candidate articles from database searches, of which 67 studies underwent full-text review, with final inclusion of 20 eligible studies. Among the included studies, there were no randomized controlled trials and a single prospective trial, with the remainder being retrospective series. We performed quantitative synthesis of the results by calculating the pooled odds ratios (OR) for the primary outcome of locoregional recurrence (LRR) and secondary outcomes of overall survival (OS), cancer-specific survival (CSS) and distant recurrence (DR). Results: Adjuvant RT, which was mostly prescribed for locally advanced or margin-positive disease following RNU, significantly reduced locoregional recurrence risk OR 0.43 (95% CI: 0.23–0.70), and the effect remained significant even following subgroup analysis to account for adjuvant systemic therapy. The effect of adjuvant RT on 3-year OS, 5-year CSS and DR was non-significant. However, 5-year OS was unfavourable in the adjuvant RT arm, but study heterogeneity was high, and analysis of small-study effects and subgroups suggested bias in reporting of outcomes. Conclusions: Adjuvant RT in the setting of locally advanced UTUC improves locoregional control following definitive surgery, but does not appear to improve OS. Higher-quality studies, ideally randomized controlled trials, are needed to further quantify its benefit in this setting, and to explore multi-modal treatments that include systemic agents given concomitantly or sequentially with RT, which may offer an OS benefit in addition to the locoregional control benefit of RT.

[1]  E. Rammant,et al.  The incidence and prevalence of upper tract urothelial carcinoma: a systematic review , 2021, BMC Urology.

[2]  T. Powles,et al.  Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. , 2021, The Lancet. Oncology.

[3]  G. Facchini,et al.  Urologic malignancies: advances in the analysis and interpretation of clinical findings , 2021, Future science OA.

[4]  D. Pieper,et al.  Managing overlap of primary study results across systematic reviews: practical considerations for authors of overviews of reviews , 2021, BMC Medical Research Methodology.

[5]  Huina Wang,et al.  Comparison of genomic characterization in upper tract urothelial carcinoma and urothelial carcinoma of the bladder. , 2021, The oncologist.

[6]  Ming-Hong Chen,et al.  Aristolochic acid-associated urinary tract cancers: an updated meta-analysis of risk and oncologic outcomes after surgery and systematic review of molecular alterations observed in human studies , 2021, Therapeutic advances in drug safety.

[7]  F. Petros Epidemiology, clinical presentation, and evaluation of upper-tract urothelial carcinoma , 2020, Translational andrology and urology.

[8]  Kun-lin Yang,et al.  Pattern and risk factors of local recurrence after nephroureterectomy for upper tract urothelial carcinoma , 2020, World Journal of Surgical Oncology.

[9]  Yee Mun Lee,et al.  Optimal Management of Upper Tract Urothelial Carcinoma: Current Perspectives , 2020, OncoTargets and therapy.

[10]  Chung‐Han Ho,et al.  Concurrent chemoradiotherapy in patients with non‐metastatic upper urinary tract urothelial carcinoma: Report from a single institution in Taiwan , 2020, International journal of urology.

[11]  Chun-Chieh Huang,et al.  Aristolochic Acid Affects Upper Tract Urothelial Cancer Behavior through the MAPK Pathway , 2019, Molecules.

[12]  Young Seok Kim,et al.  Adjuvant Treatments for Advanced Stage, Non-metastatic Upper Tract Urothelial Carcinoma: A Multicenter Study. , 2019, International journal of radiation oncology, biology, physics.

[13]  W. Hwang,et al.  Randomized trial of adjuvant chemotherapy versus adjuvant radiation therapy for locally advanced bladder cancer after radical cystectomy. , 2019, Journal of Clinical Oncology.

[14]  Jianguo Wen,et al.  Prognosis and risk factors of patients with upper urinary tract urothelial carcinoma and postoperative recurrence of bladder cancer in central China , 2019, BMC Urology.

[15]  T. Sio,et al.  Gender Is a Significant Prognostic Factor for Upper Tract Urothelial Carcinoma: A Large Hospital-Based Cancer Registry Study in an Endemic Area , 2019, Front. Oncol..

[16]  M. Brundage,et al.  Perioperative chemotherapy for urothelial carcinoma of the upper urinary tract: A systematic review and meta-analysis. , 2018, Critical reviews in oncology/hematology.

[17]  H. Cathro,et al.  Universal Lynch Syndrome Screening Should be Performed in All Upper Tract Urothelial Carcinomas , 2018, The American journal of surgical pathology.

[18]  E. B. Butler,et al.  The Role of Adjuvant Radiation Therapy in Locally Advanced Bladder Cancer , 2018, Bladder cancer.

[19]  W. Hsueh,et al.  Adjuvant Radiation Therapy for High Stage Urothelial Carcinoma of the Upper Urinary Tract , 2017 .

[20]  Zhuojun Zheng,et al.  Prognostic factors and outcomes of primary transitional cell carcinoma of the ureter: a population-based study , 2017, Oncotarget.

[21]  X. Yang,et al.  Perioperative treatments for resected upper tract urothelial carcinoma: a network meta-analysis , 2016, Oncotarget.

[22]  Ying-Hsu Chang,et al.  Adjuvant radiotherapy for locally advanced upper tract urothelial carcinoma , 2016, Scientific Reports.

[23]  Steven L. Chang,et al.  Upper tract urothelial carcinoma: a different disease entity in terms of management , 2016, ESMO Open.

[24]  V. Bhatt,et al.  Effect of Adjuvant Radiotherapy on Survival in Patients with Locoregional Urothelial Malignancies of the Upper Urinary Tract. , 2016, Anticancer research.

[25]  S. Hussain,et al.  Bladder Sparing Approaches for Muscle-Invasive Bladder Cancers , 2016, Current Treatment Options in Oncology.

[26]  S. Shariat,et al.  Effect of smoking on outcomes of urothelial carcinoma: a systematic review of the literature. , 2014, European urology.

[27]  Young Seok Kim,et al.  Adjuvant radiotherapy for stage III/IV urothelial carcinoma of the upper tract. , 2014, Anticancer research.

[28]  M. Babjuk,et al.  Impact of smoking on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. , 2013, European urology.

[29]  David A. Green,et al.  Stage-specific impact of tumor location on oncologic outcomes in patients with upper and lower tract urothelial carcinoma following radical surgery. , 2012, European urology.

[30]  C. Chuang,et al.  Adjuvant and salvage radiotherapy for urothelial cell carcinoma of the upper urinary tract: experience in a single institution. , 2012, Chang Gung medical journal.

[31]  A. Niemierko,et al.  Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. , 2012, European urology.

[32]  A. Kibel,et al.  Radiotherapy with or Without Chemotherapy in Muscle-Invasive Bladder Cancer , 2012 .

[33]  K. Bensalah,et al.  Predicting clinical outcomes after radical nephroureterectomy for upper tract urothelial carcinoma. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  J. Raman,et al.  Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, 1973–2005 , 2011, BJU international.

[35]  Yuan Ji,et al.  Radiotherapy may improve overall survival of patients with T3/T4 transitional cell carcinoma of the renal pelvis or ureter and delay bladder tumour relapse , 2011, BMC Cancer.

[36]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.

[37]  S. Nakatsuka,et al.  [Clinical study of upper urinary tract carcinoma]. , 2009, Nihon Hinyokika Gakkai zasshi. The japanese journal of urology.

[38]  Y. Lotan,et al.  Outcomes of radical nephroureterectomy: A series from the Upper Tract Urothelial Carcinoma Collaboration , 2009, Cancer.

[39]  K. Bensalah,et al.  Evidence-based sex-related outcomes after radical nephroureterectomy for upper tract urothelial carcinoma: results of large multicenter study. , 2009, Urology.

[40]  Roger M Harbord,et al.  A modified test for small‐study effects in meta‐analyses of controlled trials with binary endpoints , 2006, Statistics in medicine.

[41]  C. Sternberg Muscle invasive and metastatic bladder cancer. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[42]  T. Sun,et al.  Urothelial umbrella cells of human ureter are heterogeneous with respect to their uroplakin composition: different degrees of urothelial maturity in ureter and bladder? , 2005, European journal of cell biology.

[43]  A. Zietman,et al.  Adjuvant radiotherapy with and without concurrent chemotherapy for locally advanced transitional cell carcinoma of the renal pelvis and ureter. , 2004, The Journal of urology.

[44]  R. Sylvester,et al.  EAU guidelines on diagnosis and treatment of upper urinary tract transitional cell carcinoma. , 2004, European urology.

[45]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[46]  K. Slim,et al.  Methodological index for non‐randomized studies (MINORS): development and validation of a new instrument , 2003, ANZ journal of surgery.

[47]  A. Zietman,et al.  Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. , 2002, Urology.

[48]  L. Ellison,et al.  Upper tract urothelial neoplasms: incidence and survival during the last 2 decades. , 2000, The Journal of urology.

[49]  R. Mirimanoff,et al.  Prognostic factors in urothelial renal pelvis and ureter tumours: a multicentre Rare Cancer Network study. , 1999, European journal of cancer.

[50]  C. Roehrborn,et al.  Advanced transitional cell carcinoma of the upper urinary tract: patterns of failure, survival and impact of postoperative adjuvant radiotherapy. , 1998, The Journal of urology.

[51]  M. Arrabal Martín,et al.  [Efficacy of radiotherapy for upper urinary tract tumor following radical surgery]. , 1998, Archivos españoles de urología.

[52]  C. Catton,et al.  Transitional cell carcinoma of the renal pelvis and ureter: Outcome and patterns of relapse in patients treated with postoperative radiation. , 1996, Urologic oncology.

[53]  M. Housset,et al.  Postoperative radiation therapy in 26 patients with invasive transitional cell carcinoma of the upper urinary tract: no impact on survival? , 1996, The Journal of urology.

[54]  S. Smalley,et al.  Transitional cell carcinoma of the renal pelvis or ureter: patterns of failure. , 1995, Urology.

[55]  K. Matsuoka,et al.  Analysis of Prognostic Factors in Patients with Pyeloureteral Carcinoma , 1991, American Journal of Clinical Oncology.

[56]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[57]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[58]  J. Gart,et al.  On the bias of various estimators of the logit and its variance with application to quantal bioassay. , 1967, Biometrika.

[59]  Nathan Mantel,et al.  Chi-square tests with one degree of freedom , 1963 .

[60]  B. Woolf ON ESTIMATING THE RELATION BETWEEN BLOOD GROUP AND DISEASE , 1955, Annals of human genetics.