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Article of the week: Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23‐gene panel with utility for non‐invasive diagnosis and risk stratification

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Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urological community and a video prepared by the authors. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23‐gene panel with utility for non‐invasive diagnosis and risk stratification

Douglas G. Ward*, Naheema S. Gordon*, Rebecca H. Boucher*, Sarah J. Pirrie*, Laura Baxter†, Sascha Ott†, Lee Silcock‡, Celina M. Whalley*, Joanne D. Stockton*, Andrew D. Beggs*, Mike Griffiths§, Ben Abbotts*, Hanieh Ijakipour*, Fathimath N.Latheef*, Robert A. Robinson*, Andrew J. White*, Nicholas D. James*, Maurice P.Zeegers, K. K. Cheng** and Richard T. Bryan*

 

*Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, †Department of Computer Science, University of Warwick, Coventry, ‡Nonacus Limited, Birmingham Research Park, §West Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK, NUTRIM School for Nutrition and Translational Research in Metabolism and CAPHRI Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands and **Institute of Applied Health Research, University of Birmingham, Birmingham, UK

Read the full article

Abstract

Objectives

To develop a focused panel of somatic mutations (SMs) present in the majority of urothelial bladder cancers (UBCs), to investigate the diagnostic and prognostic utility of this panel, and to compare the identification of SMs in urinary cell‐pellet (cp) DNA and cell‐free (cf) DNA as part of the development of a non‐invasive clinical assay.

Patients and Methods

A panel of SMs was validated by targeted deep‐sequencing of tumour DNA from 956 patients with UBC. In addition, amplicon and capture‐based targeted sequencing measured mutant allele frequencies (MAFs) of SMs in 314 urine cpDNAs and 153 urine cfDNAs. The association of SMs with grade, stage and clinical outcomes was investigated by univariate and multivariate Cox models. Concordance between SMs detected in tumour tissue and cpDNA and cfDNA was assessed.

 

Results

The panel comprised SMs in 23 genes: TERT (promoter), FGFR3, PIK3CA, TP53, ERCC2, RHOB, ERBB2, HRAS, RXRA, ELF3, CDKN1A, KRAS, KDM6A, AKT1, FBXW7, ERBB3, SF3B1, CTNNB1, BRAF, C3orf70, CREBBP, CDKN2A and NRAS; 93.5–98.3% of UBCs of all grades and stages harboured ≥1 SM (mean: 2.5 SMs/tumour). RAS mutations were associated with better overall survival (P = 0.04). Mutations in RXRA, RHOB and TERT (promoter) were associated with shorter time to recurrence (P < 0.05). MAFs in urinary cfDNA and cpDNA were highly correlated; using a capture‐based approach, >94% of tumour SMs were detected in both cpDNA and cfDNA.

Conclusions

SMs are reliably detected in urinary cpDNA and cfDNA. The technical capability to identify very low MAFs is essential to reliably detect UBC, regardless of the use of cpDNA or cfDNA. This 23‐gene panel shows promise for the non‐invasive diagnosis and risk stratification of UBC.

Read more Articles of the week

 

Editorial: Non‐invasive diagnosis and monitoring of urothelial bladder cancer: are we there yet?

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In this issue of BJUI, Ward et al. [1] describe the development of DNA‐based urinary biomarkers for urothelial carcinoma (UC). The genomics of UC have been well characterized through interrogation of tumour issues in institutional series (e.g. the Memorial Sloan Kettering Cancer Center [MSKCC] experience), multi‐institutional collaborations (e.g. The Cancer Genome Atlas [TCGA]) and commercial platforms (e.g. the Foundation Medicine experience) [2]. Until recently, these have been largely academic pursuits, with possible impact on prognostication but limited clinical applicability and utility for therapy selection and monitoring of response; however, with the US Food and Drug Administration approval of erdafitinib several weeks ago, patients with advanced UC will routinely receive genomic assessment for FGFR2/3 mutation or fusion, the targets for this therapy [3]. In due time, it is anticipated that multiple other putative targets with associated therapies (e.g. ERBB2, CDKN2A), as well as potential predictive biomarkers, may also warrant testing.

The evolving landscape in advanced UC makes a non‐invasive biomarker particularly attractive. The authors of the present commentary have previously reported results from a series of 369 patients with advanced UC, demonstrating that genomic alterations in ctDNA could be identified in 91% of patients using a commercially available 73-gene panel [4]. More recently, Christensen et al. [5] assessed a cohort of 68 patients receiving neoadjuvant chemotherapy for muscle‐invasive disease, demonstrating 100% sensitivity and 98% specificity for the detection of relapsed disease with a patient‐specific ctDNA assessment (sequenced to a median target coverage of 105 000×) after cystectomy. Impressively, the data also showed that the dynamics of ctDNA appeared to be more useful than pathological downstaging in predicting relapse.

In contrast to these studies, Ward et al. have developed a 23‐gene panel based on frequently expressed genes in a cohort of 916 UC tissue specimens, largely derived from patients with non‐muscle‐invasive disease. Ultimately, with a cohort of 314 patients with DNA derived from a urinary cell pellet, sequencing identified 645 (71.4%) of 903 mutations detected in tumour. Using urinary supernatant, 353 (80.7%) of 437 mutations were detected. These relatively high sensitivities, if they can be interpreted as such, are promising but do not rise to the level of replacing existing strategies for UC detection, staging and monitoring. Notably, another study demonstrated that urinary ctDNA can be detected with high sensitivity and specificity in patients with localized early‐stage bladder cancer and for after‐treatment surveillance, providing the foundation for further studies evaluating the role of ctDNA in non‐invasive detection, genotyping and monitoring [6].

Beyond its use as a diagnostic tool, it is hoped that urinary ctDNA may also find applications in the selection of therapeutics. To this end, Ward et al. identified FGFR3, PIK3CA, ERCC2 and ERBB2 mutations in 45%, 32%, 14% and 7% of patients, respectively. The frequency of FGFR3 alteration decreased with increasing stage and grade, ranging from 72% in pTaG1 disease to just 13% in ≥pT2 disease, consistent with other reports [7]. These results may guide forthcoming studies evaluating FGFR inhibitors in non‐muscle‐invasive, muscle‐invasive and metastatic disease, where studies are ongoing. In reviewing the potential link between genomic alterations and clinical outcomes, perhaps the most curious finding is that between RAS mutations and improved overall survival (P = 0.04), the only such association found in multivariate analysis. These results stand in sharp contrast to reports in lung cancer, colorectal cancer and multiple other tumour types [8]. A closer look at the deleterious nature and functional impact of NRAS and KRAS mutations seen in this series is certainly warranted, along with further external validation in a more homogenous and larger patient population. There is also the potential application of monitoring treatment response by assessing eradication of urinary ctDNA, a hypothesis that is being evaluated in ongoing studies [9].

How will the results of this and other emerging urinary biomarker studies eventually make their way to the clinic? The answer is simple: incorporation of these biomarkers in prospective therapeutic trials. As the bladder cancer investigative community formulates novel trials for non‐muscle‐invasive and muscle‐invasive disease using targeted therapies, an excellent opportunity exists to correlate urinary, blood and tissue‐based biomarkers and to assess their relative predictive capabilities and clinical utility. Furthermore, with clinical surrogate endpoints likely to drive regulatory approval (e.g. landmark complete response rates for non‐muscle‐invasive disease, or pT0N0 rate for muscle‐invasive disease), a validated urinary biomarker could ultimately offer an alternative biological surrogate endpoint [10]. In an era of genomic revolution, prospective validation can help establish the potential clinical utility of promising biomarkers and help realize the dream of ‘precision oncology’.

by Rohit K. Jain, Petros Grivas and Sumanta K. Pal

References

  1. Ward DG, Gordon NS, Boucher RH et al. Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23‐gene panel with utility for non‐invasive diagnosis and risk stratification. BJU Int 2019
  2. Schiff JP, Barata PC, Yu EY, Grivas P. Precision therapy in advanced urothelial cancer. Expert Rev Precis Med Drug Dev 2019; 4: 81– 93
  3. FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma [press release] 2019.
  4. Agarwal N, Pal SK, Hahn AW et al. Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA. Cancer 2018; 124: 2115– 24
  5. Christensen E, Birkenkamp‐Demtroder K, Sethi H et al. Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra‐deep sequencing of plasma cell‐free DNA in patients with urothelial bladder carcinoma. J Clin Oncol 2019; 37: 1547– 57
  6. Dudley JC, Schroers‐Martin J, Lazzareschi DV et al. Detection and surveillance of bladder cancer using urine tumor DNA. Cancer Discov 2019; 9: 500– 9
  7. Tomlinson DC, Baldo O, Harnden P, Knowles MA. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol 2007; 213: 91– 8
  8. Zhuang R, Li S, Li Q et al. The prognostic value of KRAS mutation by cell‐free DNA in cancer patients: a systematic review and meta‐analysis. PLoS One 2017; 12: e0182562
  9. Abbosh PH, Plimack ER. Molecular and clinical insights into the role and significance of mutated DNA repair genes in bladder cancer. Bladder Cancer 2018; 4: 9– 18
  10. Jarow JP, Lerner SP, Kluetz PG et al. Clinical trial design for the development of new therapies for nonmuscle‐invasive bladder cancer: report of a Food and Drug Administration and American Urological Association public workshop. Urology 2014; 83: 262– 4

 

 

Video: Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA

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Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23‐gene panel with utility for non‐invasive diagnosis and risk stratification

Read the full article

Abstract

Objectives

To develop a focused panel of somatic mutations (SMs) present in the majority of urothelial bladder cancers (UBCs), to investigate the diagnostic and prognostic utility of this panel, and to compare the identification of SMs in urinary cell‐pellet (cp) DNA and cell‐free (cf) DNA as part of the development of a non‐invasive clinical assay.

Patients and Methods

A panel of SMs was validated by targeted deep‐sequencing of tumour DNA from 956 patients with UBC. In addition, amplicon and capture‐based targeted sequencing measured mutant allele frequencies (MAFs) of SMs in 314 urine cpDNAs and 153 urine cfDNAs. The association of SMs with grade, stage and clinical outcomes was investigated by univariate and multivariate Cox models. Concordance between SMs detected in tumour tissue and cpDNA and cfDNA was assessed.

Results

The panel comprised SMs in 23 genes: TERT (promoter), FGFR3, PIK3CA, TP53, ERCC2, RHOB, ERBB2, HRAS, RXRA, ELF3, CDKN1A, KRAS, KDM6A, AKT1, FBXW7, ERBB3, SF3B1, CTNNB1, BRAF, C3orf70, CREBBP, CDKN2A and NRAS; 93.5–98.3% of UBCs of all grades and stages harboured ≥1 SM (mean: 2.5 SMs/tumour). RAS mutations were associated with better overall survival (P = 0.04). Mutations in RXRA, RHOB and TERT (promoter) were associated with shorter time to recurrence (P < 0.05). MAFs in urinary cfDNA and cpDNA were highly correlated; using a capture‐based approach, >94% of tumour SMs were detected in both cpDNA and cfDNA.

Conclusions

SMs are reliably detected in urinary cpDNA and cfDNA. The technical capability to identify very low MAFs is essential to reliably detect UBC, regardless of the use of cpDNA or cfDNA. This 23‐gene panel shows promise for the non‐invasive diagnosis and risk stratification of UBC.

 

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Making real change where it is needed! The HSIB investigation into a case of testicular torsion

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This week saw the first Health Service Investigation Branch (HSIB) investigation into a urological condition. The HSIB is the health services version of the Air Investigation Branch, which investigate air crashes, and the case that it was investigating was one of testicular loss from torsion.

The investigation followed the best principles of human factors theory and causal analysis. It was not looking to assign blame but instead to constructively implement better process and systems that do not relay solely on one individual, as humans are notoriously fallible. The outcome of any investigation is to make it easier for medical teams and administrators to perform well and to mitigate the risk of errors, in an inherently complex area such as medicine.

Only a small number of HSIB investigations have taken place so far so we are fortunate that a Urology case was chosen. The report concentrated on the community aspects of the testicular pain pathway, and the investigating team had fruitful meetings with NHS 111 that led to changes in the questions and prompts that were asked of callers with testicular pain who dialled in. The Royal College of GPs, as a result of the investigation, has convened a group to review the communication standards between practices running telephone services and emergency departments; and NICE has agreed to improve the on-line guidance on testicular torsion and scrotal pain to make it more accessible to clinicians, patients and their carers.

The fact that this came about after an investigation of a single case shows the power of this investigative process and the rigour with which it was carried out.

I would encourage others who may want to be involved with this type of work. I was lucky enough to be approached by the HSIB to be the subject matter expert (SME) on this case as I have a known interest in both Quality Improvement (QI) and Torsion. Anyone approached to help with investigations of this type should be reassured of the professionalism under which a case is undertaken: no individuals or organisations are named; no fingers are pointed but instead the HSIB are able to open a lot of doors and instigate change by negotiating agreements from departments and institutions that most clinicians involved in QI could only dream of getting.

Maybe we need a few more investigations of this type in Urology; retained stents spring immediately to mind as a strong candidate as the HSIB is also experienced in talking to industry. Wouldn’t retained stents be so much easier to avoid if each stent had an individualised barcode that could be scanned and tracked? The companies making stents could perhaps be encouraged to be more involved in making sure that they were easier to track across the whole of the UK (or the world) so patients wouldn’t have so many problems with stents in the future.  Every component of a jet is tracked in a similar way so why shouldn’t we look for the same standard in Urology Healthcare!

by Tony Tien & James Green

Twitter: @greenxmedical

 

James S. A. Green is a Urological Surgeon, Network Lead for Urology at Barts Health NHS Trust, Quality Improvement Director at Whipps Cross University Hospital and visiting Professor in Health Services Research at Kings College, London. His interest in medical education and improvement started when developing medical support for the British Army and he has published extensively on team-working and improving clinical care. He was SME for the HSIB investigation into a case of delayed testicular torsion.

Mr Tony Tien MRCS is a clinical fellow in Urology at Whipps Cross Hospital and a champion for Quality Improvement.

 

Article of the week: A longitudinal analysis of urological chronic pelvic pain syndrome flares in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network

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Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urological community. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

A longitudinal analysis of urological chronic pelvic pain syndrome flares in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network

Siobhan Sutcliffe*, Robert Gallop†, Hing Hung Henry Lai‡§, Gerald L. Andriole‡, Catherine S. Bradley**††, Gisela Chelimsky‡‡, Thomas Chelimsky§§, James Quentin Clemens¶¶, Graham A. Colditz*, Bradley Erickson††, James W. Griffith***, Jayoung Kim†††, John N. Krieger‡‡‡, Jennifer Labus§§§, Bruce D. Naliboff§§§, Larissa V. Rodriguez¶¶¶, Suzette E. Sutherland‡‡‡, Bayley J. Taple*** and John Richard Landis†

 

*Division of Public Health Sciences, Department of Surgery and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, †Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, ‡Division of Urologic Surgery, Department of Surgery, §Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, Department of Obstetrics and Gynecology, Carver College of Medicine University of Iowa, **Department of Epidemiology, College of Public Health, ††Department of Urology, Carver College of Medicine, University of Iowa, Iowa City, IA, ‡‡Department of Pediatrics, Division of Pediatric Gastroenterology, §§Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, ¶¶Division of Neurourology and Pelvic Reconstructive Surgery, Department of Urology, University of Michigan, Ann Arbor, MI, ***Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, †††Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, ‡‡‡Department of Urology, University of Washington, Seattle, WA, §§§Oppenheimer Center for Neurobiology of Stress and Resilience and Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, and ¶¶¶Institute of Urology, University of Southern California, Beverly Hills, CA, USA

Read the full article

Abstract

Objective

To describe the frequency, intensity and duration of urological chronic pelvic pain syndrome symptom exacerbations (‘flares’), as well as risk factors for these features, in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Epidemiology and Phenotyping longitudinal study.

Participants and Methods

Current flare status (‘urological or pelvic pain symptoms that are much worse than usual’) was ascertained at each bi‐weekly assessment. Flare characteristics, including start date, and current intensity of pelvic pain, urgency and frequency (scales of 0–10), were assessed for participants’ first three flares and at three randomly selected times when they did not report a flare. Generalized linear and mixed effects models were used to investigate flare risk factors.

Results

Of the 385 eligible participants, 24.2% reported no flares, 22.9% reported one flare, 28.3% reported 2–3 flares, and 24.6% reported ≥4 flares, up to a maximum of 18 during the 11‐month follow‐up (median incidence rate = 0.13/bi‐weekly assessment, range = 0.00–1.00). Pelvic pain (mean = 2.63‐point increase) and urological symptoms (mean = 1.72) were both significantly worse during most flares (60.6%), with considerable within‐participant variability (26.2–37.8%). Flare duration varied from 1 to 150 days (94.3% within‐participant variability). In adjusted analyses, flares were more common, symptomatic, and/or longer‐lasting in women and in those with worse non‐flare symptoms, bladder hypersensitivity, and chronic overlapping pain conditions.

Conclusion

In this foundational flare study, we found that pelvic pain and urological symptom flares were common, but variable in frequency and manifestation. We also identified subgroups of participants with more frequent, symptomatic, and/or longer‐lasting flares for targeted flare management/prevention and further study.

Read more Articles of the week

Article of the week: Global, regional and national burden of testicular cancer, 1990–2016: results from the Global Burden of Disease Study 2016

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Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urological community, and a video prepared by the authors. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

Global, regional and national burden of testicular cancer, 1990–2016: results from the Global Burden of Disease Study 2016

Farhad Pishgar*†, Arvin Haj-Mirzaian†, Hedyeh Ebrahimi*, Sahar Saeedi Moghaddam*‡, Bahram Mohajer*, Mohammad Reza Nowroozi†, Mohsen Ayati†,  Farshad Farzadfar*, Christina Fitzmaurice§¶ and Erfan Amini†

*Non-Communicable Diseases Research Centre, Endocrinology and Metabolism Population Sciences Institute, †Uro-Oncology Research Centre, ‡Endocrinology and Metabolism Research Centre, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran, §Institute for Health Metrics and Evaluation, andDivision of Haematology, Department of Medicine, University of Washington, Seattle, WA, USA

Read the full article

Abstract

Objective

To provide estimates of the global incidence, mortality and disability‐adjusted life‐years (DALYs) associated with testicular cancer (TCa) between 1990 and 2016, using findings from the Global Burden of Disease (GBD) 2016 study.

Materials and Methods

For the GBD 2016 study, cancer registry data and a vital registration system were used to estimate TCa mortality. Mortality to incidence ratios were used to transform mortality estimates to incidence, and to estimate survival, which was then used to estimate 10‐year prevalence. Prevalence was weighted using disability weights to estimate years lived with disability (YLDs). Age‐specific mortality and a reference life expectancy were used to estimate years of life lost (YLLs). DALYs are the sum of YLDs and YLLs.

Fig.1. Testicular cancer incidence, mortality and DALYs globally, and in the five socio‐demographic index (SDI) quintiles. (A) Incident cases. (B) Age‐standardized incidence rate (ASIR). (C) Deaths. (D) ASDR. (E) Disability‐adjusted life‐year (DALYs). (F) Age‐standardized DALY rate.

Results

Global incidence of TCa showed a 1.80‐fold increase from 37 231 (95% uncertainty interval [ UI] 36 116–38 515) in 1990 to 66 833 (95% UI 64 487–69 736) new cases in 2016. The age‐standardized incidence rate also increased from 1.5 (95% UI 1.45–1.55) to 1.75 (95% UI 1.69–1.83) cases per 100 000. Deaths from TCa remained stable between 1990 and 2016 [1990: 8394 (95% UI 7980–8904), 2016: 8651 (95% UI 8292–9027)]. The TCa age‐standardized death rate decreased between 1990 and 2016, from 0.39 (95% UI 0.37–0.41) to 0.25 (95% UI 0.24–0.26) per 100 000; however, the decreasing trend was not similar in all regions. Global TCa DALYs decreased by 2% and reached 391 816 (95% UI 372 360–412 031) DALYs in 2016. The age‐standardized DALY rate also decreased globally between 1990 and 2016 (10.31 [95% UI 9.82–10.84]) per 100 000 in 2016).

Conclusion

Although the mortality rate for TCa has decreased over recent decades, large disparities still exist in TCa mortality, probably as a result of lack of access to healthcare and oncological treatment. Timely diagnosis of this cancer, by improving general awareness, should be prioritized. In addition, improving access to effective therapies and trained healthcare workforces in developing and under‐developed areas could be the next milestones.

Read more Articles of the week

Editorial: Testicular cancer outcome inequality: a curable disease?

/1 Comment/by

Inequalities in cancer survival exist across cities, countries and global regions [1]. Testicular cancer provides a particularly stark example. It has extremely high survival rates, but cure is strongly dependent upon prompt diagnosis. In turn, that depends on reliable access to high‐quality healthcare [2, 3].

In this issue of BJUI, Pishgar et al. [4] report a richly detailed analysis of international variations in testicular cancer mortality. Using data from the 2016 Global Burden of Disease study (GBD), they examine variation in incidence and outcomes from testicular cancer, including impact on disability‐adjusted life years (DALYs) and mortality, across 21 regions and 195 countries, since the GBD started in 1990.

Testicular cancer incidence increased globally between 1990 and 2016. This may reflect underlying, environmentally determined birth cohort effects, improving identification of underlying disease burden, or both [5]. Notably, increases do not appear to have been shared evenly between countries, or across different social sociodemographic index (SDI) quintiles; the age‐standardised incidence rate actually decreased in the low and low–middle SDI quintiles, but increased in high, high–middle and middle SDI quintiles. However, evidence of a link between access to healthcare and incidence of testicular cancer is lacking.

More strikingly, the authors conclude that although testicular cancer survival globally is improving, disparities between countries remain entrenched. In fact, a countervailing increase in mortality in some developing countries over the study period suggests a major task ahead for those healthcare systems.

Testicular cancer does not have a screening test. Early diagnosis and optimal outcome generally relies upon self‐examination; prompt referral to a urology service for initial surgical management; and early involvement of a wider multidisciplinary team, including a specialist oncologist; in accordance with international guidelines. Accordingly, disparities in testicular cancer outcomes may be attributable to variations in one or more of the following:

  • Education and health literacy
  • Health insurance cover, equivalent ability to pay ‘out of pocket’ (OOP) charges. With the health insurance coverage, cover your family to protect them from costly final expenses by getting a final expense insurance or burial insurance from insuranceforfinalexpense.com.
  • Access to both primary care and specialty services
  • Availability of key resources (e.g., platinum‐based chemotherapy)
  • Adherence to best practice guidelines

Access to healthcare and protection of individuals from OOP costs may predominate amongst all of these factors. In countries with partial or total OOP funding, the early diagnosis of cancer risks being seen, not as an opportunity to avert the development of life‐threatening disease, but as a financial decision with significant personal and family implications [6]. Encouraging proactive health‐seeking behaviours is challenging in the setting of universal health coverage; much more so in the context of such basic conflicts. The likely effects of these conflicts are observable in developed and developing countries alike, as long as OOP costs remain a fact of life for significant numbers of citizens [2, 3].

The Pishgar et al. [4] study, and the GBD more widely, are subject to some basic methodological limitations inherent in any international registry‐based analysis. Unmeasured and uncontrolled confounding is inevitable. Variation in outcomes between countries and over time may reflect true variation, or variation in coding practice, quality assurance and accuracy.

More fundamentally, quantitative analysis is limited to identifying, rather than explaining international trends in cancer outcomes. Such trends can then be used to generate hypotheses. Qualitative methods can then be incorporated, generating meaningful insights into different healthcare systems’ relative performances, and testing those hypotheses.

Building on the data reported here, Medicare Advantage 2020 qualitative analysis incorporate insights into better‐performing countries’ strategies for promoting self‐examination, and providing high‐quality, evidence‐based multidisciplinary care, through an appropriately trained specialist workforce, could provide a basis for developing countries to develop their own contextually tailored strategies. Across many developing world contexts, access to platinum‐based chemotherapy remains an essential priority [7].

It is notable that DALYs are incorporated into this high‐level international comparison and encouraging that they are falling globally [4]. Again, combining qualitative analysis with the insights provided by these international and temporal analyses of DALYs could enrich our understanding of the interaction between approaches to testicular cancer care and patient experience. For example, Pishgar et al. [4] report that Kiribati, Chile, and Argentina had the highest testicular cancer‐specific age‐standardised DALY rates. Focussed qualitative research in these countries, possibly incorporating comparisons with higher performing settings, could facilitate targeted improvements to patient care and experience. As more countries achieve the highest cure rates for testicular cancer, patient experience will assume increasing importance as a measure of care quality in this disease.

Analyses like this have the potential to provoke important conversations and to generate hypotheses in specialist clinical and health policy research. As clinicians, researchers and policy‐makers, this study should encourage us to think critically about the policy context in which we see testicular cancer, the reasons patients might present late, and how equity of outcome might be achieved both within and beyond our own immediate surroundings. Pishgar et al. [4] invaluably remind us that we remain some way off being able to call testicular cancer a curable disease for all patients, in all settings.

References

  1. Global Cancer Observatory (GLOBOCAN). Available at: https://gco.iarc.fr. Accessed June 2019.
  2. Markt SC, Lago‐Hernandez CA, Miller RE et al. Insurance status and disparities in disease presentation, treatment, and outcomes for men with germ cell tumors. Cancer 2016; 122: 3127– 35
  3. Withington J, Cole AP, Meyer CP et al. Comparison of testis cancer‐specific survival: an analysis of national cancer registry data from the USA, UK and Germany. BJU Int 2019; 123: 385– 7
  4. Pishgar F, Haj‐Mirzaian A, Ebrahimi H et al. Global, regional, and national burden of testicular cancer, 1990–2016: results from the global burden of disease study 2016. BJU Int 2019; 124: 386– 94
  5. Shanmugalingam T, Soultati A, Chowdhury S, Rudman S, Van Hemelrijck M. Global incidence and outcome of testicular cancer. Clin Epidemiol 2013; 5: 417– 27
  6. Rajpal S, Kumar A, Joe W. Economic burden of cancer in India: evidence from cross‐sectional nationally representative household survey, 2014. PLoS One 2018; 13: e0193320.
  7. Lancet Global Health. Lifting the veil on cancer treatment. Lancet 2019; 7: PE281. DOI: 10.1016/ S2214‐109X(19)30014‐2

Video: Global, regional and national burden of testicular cancer

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Global, regional and national burden of testicular cancer, 1990–2016: results from the Global Burden of Disease Study 2016

Read the full article

Abstract

Objective

To provide estimates of the global incidence, mortality and disability‐adjusted life‐years (DALYs) associated with testicular cancer (TCa) between 1990 and 2016, using findings from the Global Burden of Disease (GBD) 2016 study.

Materials and Methods

For the GBD 2016 study, cancer registry data and a vital registration system were used to estimate TCa mortality. Mortality to incidence ratios were used to transform mortality estimates to incidence, and to estimate survival, which was then used to estimate 10‐year prevalence. Prevalence was weighted using disability weights to estimate years lived with disability (YLDs). Age‐specific mortality and a reference life expectancy were used to estimate years of life lost (YLLs). DALYs are the sum of YLDs and YLLs.

Results

Global incidence of TCa showed a 1.80‐fold increase from 37 231 (95% uncertainty interval [ UI] 36 116–38 515) in 1990 to 66 833 (95% UI 64 487–69 736) new cases in 2016. The age‐standardized incidence rate also increased from 1.5 (95% UI 1.45–1.55) to 1.75 (95% UI 1.69–1.83) cases per 100 000. Deaths from TCa remained stable between 1990 and 2016 [1990: 8394 (95% UI 7980–8904), 2016: 8651 (95% UI 8292–9027)]. The TCa age‐standardized death rate decreased between 1990 and 2016, from 0.39 (95% UI 0.37–0.41) to 0.25 (95% UI 0.24–0.26) per 100 000; however, the decreasing trend was not similar in all regions. Global TCa DALYs decreased by 2% and reached 391 816 (95% UI 372 360–412 031) DALYs in 2016. The age‐standardized DALY rate also decreased globally between 1990 and 2016 (10.31 [95% UI 9.82–10.84]) per 100 000 in 2016).

Conclusion

Although the mortality rate for TCa has decreased over recent decades, large disparities still exist in TCa mortality, probably as a result of lack of access to healthcare and oncological treatment. Timely diagnosis of this cancer, by improving general awareness, should be prioritized. In addition, improving access to effective therapies and trained healthcare workforces in developing and under‐developed areas could be the next milestones.

by @ErfanAmini and @FarhadPishgar

 

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