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Editorial: Do all patients with renal cell carcinoma need a chest computed tomography?

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While all patients with RCC need chest imaging for staging evaluation, the answer to the question in the title is ‘No’, and, in fact, many patients would be adequately staged with a chest X-ray, albeit with reduced accuracy. Evidence to support this assertion is provided by Larcher et al. [1] in this issue of BJUI, who retrospectively evaluated 1946 patients with a solitary and sporadic RCC mass. While excluding patients who did not have surgery and those with visceral metastases seen on abdominal imaging, the authors observed pulmonary metastases in 6% (119 patients) of their population. In a multivariable analysis, features associated with a positive chest CT included cT1b+, cN1, systemic symptoms, anaemia, and thrombocytosis. Incorporating these features into a predictive model, the authors report a robust concordance index of 0.88, with the effect of each feature demonstrated in a nomogram. Further, the authors report that if a chest CT is only performed when the risk of a positive result is >1%, 37% of their population could have been spared a chest CT while missing a positive result in only 0.2% (four patients). Patient factors that predict for a <1% risk of a positive chest CT essentially include those with cT1aN0 RCC without systemic symptoms, anaemia, or thrombocytosis. Thus, the authors conclude that in these low-risk patients, a chest CT can be omitted, while any patient that is cT1b+, cN1, or with systemic symptoms, anaemia, or thrombocytosis warrants a dedicated chest CT at diagnosis.

The finding that patients with RCC with smaller tumours (cT1a or ≤4 cm) were unlikely to harbour pulmonary metastases is consistent with prior literature. Observations from the Memorial Sloan-Kettering Cancer Center (MSKCC) [2], and subsequently validated by our group at Mayo Clinic [3], suggested that among surgically treated patients with RCC, risk of M1 disease (at any location) at diagnosis was non-existent for tumours of <2 cm, was <1% for tumours of 2–3 cm, and was only 1–2% for tumours of 3-4 cm in size. Given that it is rare for patients with small renal masses to endorse systemic symptoms or have paraneoplastic symptoms related to the tumour, these prior observations suggest a lack of utility for chest CT for patients with small renal masses supporting the findings from Larcher et al. [1].

In patients with RCC with synchronous metastases, lung is the most common site of spread and guidelines uniformly recommend chest imaging at diagnosis. However, a ‘select-all’ strategy for chest CT in patients with renal masses leads to unnecessary findings in those with a benign primary tumour, increased use of healthcare resources, and relatively frequent findings of indeterminate lesions. In fact, contemporary observations from the MSKCC found that about half of patients with RCC undergoing surgery had indeterminate pulmonary nodules on chest CT that required either additional evaluation or subsequent chest CT to document stability [4]. Further, the presence of indeterminate pulmonary nodules was not associated with distant metastases or death from RCC after surgery unless they were >1 cm, which only represented a small portion (4%) of the entire cohort [4]. Thus, the analysis from Larcher et al. [1] in this issue of BJUI has meaningful clinical relevance; that is, patients with cT1aN0 RCC without symptoms or laboratory abnormalities do not require a chest CT for screening of their lungs.

R. Houston Thompson
Department of Urology, Mayo Clinic, Rochester, MN, USA

 

 

References

 

1 Larcher A, Dell’Oglio P, Fossati N et al. When to perform preoperative chest computed tomography for renal cancer staging. BJU Int 2017; 120: 490–6

 

2 Thompson RH, Hill JR, Babayev Y et al. Metastatic renal cell carcinoma risk according to tumor size. J Urol 2009; 182: 41–5

 

3 Umbreit EC, Shimko MS, Childs MA et al. Metastatic potential of a renal mass according to original tumour size at presentation. BJU Int 2011; 109: 190–4

 

4 Mano R, Vertosick E, Sankin AI et al. Subcentimeter pulmonary nodules are not associated with disease progression in patients with renal cell carcinoma. J Urol 2015; 193: 776–8

 

Article of the Month: Immortal-Time Bias in Urological Research

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Every Month the Editor-in-Chief selects an Article of the Month 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 accompanying editorial written by a prominent member of the urological community. This blog is 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.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video discussing the paper.

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

Estimating the effect of immortal-time bias in urological research: a case example of testosterone-replacement therapy

 

Christopher J.D. Wallis*†, Refik Saskin†‡, Steven A. Narod§, Calvin Law†, Girish S. Kulkarni† **, Arun Seth†† and Robert K. Nam*†

 

*Division of Urology, Sunnybrook Health Sciences Centre, †Institute for Health Policy, Management and Evaluation, University of Toronto, ‡Institute of Clinical Evaluative Sciences, Sunnybrook Health Sciences Centre, §Department of Public Health Sciences, University of Toronto, Division of General Surgery, Sunnybrook Health Sciences Centre, **Division of Urology, University Health Network, University of Toronto, and ††Department of Anatomic Pathology, Platform Biological Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

 

Read the full article

Abstract

Objective

To quantify the effect of immortal-time bias in an observational study examining the effect of cumulative testosterone exposure on mortality.

Patients and Methods

We used a population-based matched cohort study of men aged ≥66 years, newly treated with testosterone-replacement therapy (TRT), and matched-controls from 2007 to 2012 in Ontario, Canada to quantify the effects of immortal-time bias. We used generalised estimating equations to determine the association between cumulative TRT exposure and mortality. Results produced by models using time-fixed and time-varying exposures were compared. Further, we undertook a systematic review of PubMed to identify studies addressing immortal-time bias or time-varying exposures in the urological literature and qualitatively summated these.

Results

Among 10 311 TRT-exposed men and 28 029 controls, the use of a time-varying exposure resulted in the attenuation of treatment effects compared with an analysis that did not account for immortal-time bias. While both analyses showed a decreased risk of death for patients in the highest tertile of TRT exposure, the effect was overestimated when using a time-fixed analysis (adjusted hazard ratio [aHR] 0.56, 95% confidence interval [CI]: 0.52–0.61) when compared to a time-varying analysis (aHR 0.67, 95% CI: 0.62–0.73). Of the 1 241 studies employing survival analysis identified in the literature, nine manuscripts met criteria for inclusion. Of these, five used a time-varying analytical method. Each of these was a large, population-based retrospective cohort study assessing potential harms of pharmacological agents.

Conclusions

Where exposures vary over time, a time-varying exposure is necessary to draw meaningful conclusions. Failure to use a time-varying analysis will result in overestimation of a beneficial effect. However, time-varying exposures are uncommonly utilised among manuscripts published in prominent urological journals.

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Editorial: Immortal-Time Bias – A Crucial Yet Overlooked Confounder in Urological Research

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The measurement of treatment effect through observational studies has become commonplace in the medical literature. These cohort studies provide valuable data on outcomes that can be difficult to assess in randomized controlled trials, such as long-term mortality. Accurate interpretation of observational data, however, requires accounting for potential confounders of study design, including the immortal-time bias. In this issue of BJUI, Wallis et al. [1] show how accounting for this bias can influence the measured effect of cumulative testosterone exposure on mortality. The implications of their findings extend to several other studies, whose designs may also be subject to immortal-time bias.

‘Immortal time’ refers to the portion of a follow-up period during which an outcome could not have occurred (e.g. subjects in the ‘exposure group’ cannot die before they receive the exposure); thus, potentially allowing the artificial magnification of an effect on the study outcome [2]. As the authors point out, this concept is not new. It was first identified several decades ago to highlight how a study’s finding of a survival advantage for patients undergoing heart transplant was nullified once immortal time was properly accounted for [3]. Despite its long existence in epidemiological teachings, the authors cite several studies both within and outside of the urological literature that have failed to appropriately account for this bias. Many of these studies employ binary exposure variables, but Wallis et al. delve into relatively uncharted territory by examining the effect of immortal-time bias on multi-level categorical exposures.

The relationship between testosterone replacement therapy (TRT) and mortality, the focus of the accompanying study, is apt because it is a controversial topic that weighs heavily on an accurate assessment of the therapy’s risks and benefits. The authors, using data from their own prior study, show that this delicate balance can be easily tipped when immortal-time bias is not properly accounted for. In their analysis, the overall result was the same regardless of controlling for this bias; men in the lowest tertile of TRT exposure had a higher risk of mortality, and those in the highest tertile had a lower risk of mortality; however, use of a time-fixed as opposed to the more appropriate time-varying analysis led to a substantial magnification of the effect size in each direction. While the overall result may have been the same in this example, the authors cite other instances of high-impact research whose published conclusions were shown to be completely different once accounting for immortal-time bias [4]. One can easily imagine how this type of erroneous data analysis could have deleterious consequences in the clinical setting. Healthcare providers rely on research to make decisions that have far-reaching impacts on patients’ lives. This study highlights the importance of ensuring that such analyses are carried out properly so that patients can receive the high-quality, evidence-based care they deserve.

The authors should be commended for taking the time to deconstruct and evaluate an analytical concept that is pertinent to study designs across several disciplines. Much of the research published today seeks to find answers to important clinical questions, but not nearly enough investigation is devoted to verifying that the analyses to obtain these answers are conducted properly. Urology in particular is a field that is still maturing with respect to the use of secondary data analytical techniques, such as propensity score models and instrumental variables [5]. To sustain our improvement in investigative skills alongside our fellow medical disciplines, we must pay special attention to studies that hold a magnifying glass to commonly used methodologies in the urological literature. In a similar vein, there have been increasing efforts recently to improve the process and transparency of corroborating the results of scientific studies, and these authors’ findings reinforce why these efforts are so crucial. If we expect to continue pushing forward the boundaries of medical research, it is our duty to ensure that our analytical methods are as rigorous and accurate as possible.

Sean A. Fletcher, Philipp Gild and Quoc-Dien Trinh
Division of Urological Surgery and Center for Surgery and Public Health, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA

 

Read the full article

 

References

 

1 Wallis CJD, Saskin R, Narod SA et al. Estimating the effect of immortal-time bias in urological research: a case example of testosterone-replacement therapy. BJU Int 2017; 120: 584–90

 

2 Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 2008; 167: 492–9

 

3 Gail MH. Does cardiac transplantation prolong life? A reassessment Ann Intern Med 1972; 76: 815–7

 

4 van Walraven C, Davis D, Forster AJ et al. Time-dependent bias was common in survival analyses published in leading clinical journals. J Clin Epidemiol 2004; 57: 672–82

 

5 Cole AP, Trinh QD. Secondary data analysis: techniques for comparing interventions and their limitations. Curr Opin Urol 2017; 27: 354–9

 

Video: Immortal-Time Bias in Urological Research

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Estimating the effect of immortal-time bias in urological research: a case example of testosterone-replacement therapy

 

Read the full article

Abstract

Objective

To quantify the effect of immortal-time bias in an observational study examining the effect of cumulative testosterone exposure on mortality.

Patients and Methods

We used a population-based matched cohort study of men aged ≥66 years, newly treated with testosterone-replacement therapy (TRT), and matched-controls from 2007 to 2012 in Ontario, Canada to quantify the effects of immortal-time bias. We used generalised estimating equations to determine the association between cumulative TRT exposure and mortality. Results produced by models using time-fixed and time-varying exposures were compared. Further, we undertook a systematic review of PubMed to identify studies addressing immortal-time bias or time-varying exposures in the urological literature and qualitatively summated these.

Results

Among 10 311 TRT-exposed men and 28 029 controls, the use of a time-varying exposure resulted in the attenuation of treatment effects compared with an analysis that did not account for immortal-time bias. While both analyses showed a decreased risk of death for patients in the highest tertile of TRT exposure, the effect was overestimated when using a time-fixed analysis (adjusted hazard ratio [aHR] 0.56, 95% confidence interval [CI]: 0.52–0.61) when compared to a time-varying analysis (aHR 0.67, 95% CI: 0.62–0.73). Of the 1 241 studies employing survival analysis identified in the literature, nine manuscripts met criteria for inclusion. Of these, five used a time-varying analytical method. Each of these was a large, population-based retrospective cohort study assessing potential harms of pharmacological agents.

Conclusions

Where exposures vary over time, a time-varying exposure is necessary to draw meaningful conclusions. Failure to use a time-varying analysis will result in overestimation of a beneficial effect. However, time-varying exposures are uncommonly utilised among manuscripts published in prominent urological journals.

View more videos

Article of the Week: Profiling microRNA from nephrectomy and biopsy specimens

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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 accompanying editorial written by a prominent member of the urological community. This blog is 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.

Profiling microRNA from nephrectomy and biopsy specimens: predictors of progression and survival in clear cell renal cell carcinoma

 

Casey G. Kowalik*, Drew A. Palmer*, Travis B. Sullivan†, Patrick A. Teebagy†, John M. Dugan‡, John A. Libertino*, Eric J. Burks‡, David Canes* and Kimberly M. Rieger-Christ* †

 

Departments of *Urology, †Translational Research – Ian C. Summerhayes Cell and Molecular Biology Laboratory, and ‡Pathology, Lahey Hospital and Medical Center, Burlington, MA, USA

 

Read the full article

Abstract

Objective

To identify microRNA (miRNA) characteristic of metastatic clear cell renal cell carcinoma (ccRCC) and those indicative of cancer-specific survival (CSS) in nephrectomy and biopsy specimens. We also sought to determine if a miRNA panel could differentiate benign from ccRCC tissue.

Materials and Methods

RNA was isolated from nephrectomy and kidney biopsy specimens (n = 156 and n = 46, respectively). Samples were grouped: benign, non-progressive, and progressive ccRCC. MiRNAs were profiled by microarray and validated by quantitative reverse transcription-polymerase chain reaction. Biomarker signatures were developed to predict cancer status in nephrectomy and biopsy specimens. CSS was examined using Kaplan–Meier and Cox proportional hazards analyses.

Results

Microarray analysis revealed 20 differentially expressed miRNAs comparing non-progressive with progressive tumours. A biomarker signature validated in nephrectomy specimens had a sensitivity of 86.7% and a specificity of 92.9% for differentiating benign and ccRCC specimens. A second signature differentiated non-progressive vs progressive ccRCC with a sensitivity of 93.8% and a specificity of 83.3%. These biomarkers also discriminated cancer status in biopsy specimens. Levels of miR-10a-5p, -10b-5p, and -223-3p were associated with CSS.

Conclusion

This study identified miRNAs differentially expressed in ccRCC samples; as well as those correlating with CSS. Biomarkers identified in this study have the potential to identify patients who are likely to have progressive ccRCC, and although preliminary, these results may aid in differentiating aggressive and indolent ccRCC based on biopsy specimens.

Read more articles of the week

Editorial: The utility of microRNAs as biomarkers in predicting progression and survival in patients with clear-cell renal cell carcinoma

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RCC constitutes a diverse group of malignancies, yet the clear-cell subtype comprises ~80% of all diagnosed RCC cases [1]. The widespread use of abdominal imaging and subsequent stage migration has resulted in improved RCC 5-year cancer-specific survival. However, the overall mortality of RCC remains largely unchanged [2] and one-third of the patients have metastatic disease at the time of presentation [3]. Accordingly, the ability to precisely predict patient outcome has become an increasingly significant question in the management of these patients with RCC.

Accruing evidence suggests that changes in various biomarkers and their consequent downstream pathways affect cancer initiation and progression. Therefore, accurate prediction of the outcome and prognosis after treatment is necessary [4]. MicroRNAs (miRNAs) are small non-coding RNA molecules that can have significant functions in tumorigenesis [5]. Because of their ability in post-transcriptional regulation of gene expression, tumour-specific genetic defects in miRNA biogenesis and production correlate with development of human cancers. Thus, the differential expression of specific miRNA signatures in different tumours might become an important tool to help in directing cancer diagnosis and treatment [5].

As such, Kowalik et al. [6] report on profiling miRNA to identify biomarker signatures predictive of clear-cell RCC (ccRCC) progression and survival. The authors used 202 formalin-fixed paraffin-embedded samples to isolate RNA from nephrectomy and biopsy specimens (n = 156 and n = 46, respectively) (Fig. 1).

Figure 1. Schematic diagram of miRNA-based biomarkers and potential utility in clinical decision-making approach for targeted therapy and RCC personalised treatment.

The primary analysis of their study [6] focused on the identification of miRNA signatures capable of differentiating between benign and ccRCC, as well as discerning those patients with a non-progressive ccRCC from a progressive clear-cell subtype. The secondary outcome examined the association of miRNA profiles discovered on cancer-specific survival.

In their initial microarray screening 20 differentially expressed miRNAs, comparing non-progressive with progressive tumours, were identified. The authors found four miRNA panels (10a-5p, 10b-5p, 106a-5p, and 142-5p) as a potential biomarker signature. This model was validated in nephrectomy specimens and resulted in a sensitivity of 86.7%, a specificity of 92.9%, and an area under the curve (AUC) of 0.930 for detecting ccRCC. Further analysis revealed a second signature of two biomarkers (miR-10a-5p and -223-3p) with 93.8% sensitivity, 83.3% specificity, and an AUC of 0.932 when validated for detecting progressive ccRCC. Similarly, the differential expression of these biomarkers could delineate cancer status in biopsy specimens. For correlation of miRNA expression levels with cancer-specific survival, higher expression levels of (miR-10a-5p and miR-10b-5p) and a lower expression level of (miR-223-3p) were significantly associated with survival (P< 0.001), and the median survival times were not reached.

In conclusion, the lack of precise prediction tools has led the authors to explore the potential utility of miRNAs as biomarkers to detect disease presence, biological aggressiveness, and prognosis in ccRCC. However, until future multicentre large prospective studies validate the results of the present work, the transition of miRNA from bench to bedside is emerging on the horizon and has encouraged urologists and scientists to pursue intense translational research in the field. The ability to use miRNAs as biomarkers might be promising for diagnostic and prognostic purposes. These biomarkers may exemplify different aspects of RCC pathogenesis and may potentially have important therapeutic implications to help in a clinical decision-making approach for targeted therapy and RCC personalised treatment.

Firas G. Petros* and Christopher J.D. Wallis†‡
*Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, †Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada and ‡Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

 

Read the full article

 

References

 

1 Reuter VE, Presti JC Jr. Contemporary approach to the classification of renal epithelial tumors. Semin Oncol 2000; 27: 124–37

 

2 Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK. Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst 2006; 98: 1331–4

 

3 Gupta K, Miller JD , Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev 2008; 34: 193–205

 

4 Sorbellini M, Kattan MW, Snyder ME et al. A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma. J Urol 2005; 173: 48–51

 

5 Esquela-Kerscher A, Slack FJ. Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 2006; 6: 259–69

 

6 Kowalik CG, Palmer DA, Sullivan TB et al. Profiling microRNA from nephrectomy and biopsy specimens: predictors of progression and survival in clear cell renal cell carcinoma. BJU Int 2017; 120: 428–40

 

Video: Profiling microRNA from nephrectomy and biopsy specimens

/by

Profiling microRNA from nephrectomy and biopsy specimens: predictors of progression and survival in clear cell renal cell carcinoma

 

Read the full article

Abstract

Objective

To identify microRNA (miRNA) characteristic of metastatic clear cell renal cell carcinoma (ccRCC) and those indicative of cancer-specific survival (CSS) in nephrectomy and biopsy specimens. We also sought to determine if a miRNA panel could differentiate benign from ccRCC tissue.

Materials and Methods

RNA was isolated from nephrectomy and kidney biopsy specimens (n = 156 and n = 46, respectively). Samples were grouped: benign, non-progressive, and progressive ccRCC. MiRNAs were profiled by microarray and validated by quantitative reverse transcription-polymerase chain reaction. Biomarker signatures were developed to predict cancer status in nephrectomy and biopsy specimens. CSS was examined using Kaplan–Meier and Cox proportional hazards analyses.

Results

Microarray analysis revealed 20 differentially expressed miRNAs comparing non-progressive with progressive tumours. A biomarker signature validated in nephrectomy specimens had a sensitivity of 86.7% and a specificity of 92.9% for differentiating benign and ccRCC specimens. A second signature differentiated non-progressive vs progressive ccRCC with a sensitivity of 93.8% and a specificity of 83.3%. These biomarkers also discriminated cancer status in biopsy specimens. Levels of miR-10a-5p, -10b-5p, and -223-3p were associated with CSS.

Conclusion

This study identified miRNAs differentially expressed in ccRCC samples; as well as those correlating with CSS. Biomarkers identified in this study have the potential to identify patients who are likely to have progressive ccRCC, and although preliminary, these results may aid in differentiating aggressive and indolent ccRCC based on biopsy specimens.

View more videos

Article of the Week: 11C-acetate PET/CT imaging for detection of recurrent disease after RP or RT in patients with PCa

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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 accompanying editorial written by a prominent member of the urological community. This blog is 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.

11C-acetate positron-emission tomography/computed tomography imaging for detection of recurrent disease after radical prostatectomy or radiotherapy in patients with prostate cancer

Lukas Hendrik Esch*, Melanie Fahlbusch†, Peter Albers‡, Hubertus Hautzel§ and Volker Muller-Mattheis‡

 

*Department of Urology, St Antonius Hospital, Gronau, †Department of Gynaecology, Bethesda Hospital, Duisburg, Departments of‡ Urology, and §Nuclear Medicine, Medical Faculty, Heinrich-Heine University, Dusseldorf, Germany

 

Read the full article

Abstract

Objectives

To evaluate, in a prospective study, the effectiveness of computed tomography (CT)-matched 11C-acetate (AC) positron-emission tomography (PET) in patients with prostate cancer (PCa) who had prostate-specific antigen (PSA) relapse after radical prostatectomy (RP) or radiotherapy (RT).

Patients and Methods

In 103 relapsing patients after RP (n = 97) or RT (n = 6) AC-PET images and CT scans were obtained. In patients with AC-PET-positive results with localized PCa recurrence, detected lesions were resected and histologically verified or, after local RT, followed-up by PSA testing. Patients with distant disease on AC-PET were treated with androgen deprivation/chemotherapy.

Results

Of 103 patients, 42 were AC-PET-positive. PSA levels were <1.0, <2.0 and <4.0 ng/mL in six, 16 and 20 patients, respectively. In 25/42 patients AC-PET suggested lymph node metastases: 16/25 patients underwent surgery (10/16 metastasis, 6/16 inflammation); 9/25 patients underwent RT of lymph node metastases, which was followed by decreasing PSA level. In 17/42 patients who had distant disease, systemic treatment was commenced. Combining patients who underwent surgery and those who underwent RT, 19/25 patients were true-positive in terms of AC-PET (positive predictive value 76%). In 5/19 patients, PSA level was <2.0 ng/mL, in 2/19 patients it was <1.0 ng/mL and in 14/19 patients it was 5.4–23.1 ng/mL. In AC-PET-positive patients after surgery or RT (without androgen deprivation), median (range) time to renewed PSA increase was 6 (5–9) months.

Conclusions

Only a minority of patients with relapsing PCa appear to benefit from AC-PET for guiding potential local treatment. False-positive results show that factors other than tumour metabolism induce increased AC uptake. The time free of recurrence after local treatment was shorter than expected.

Read more articles of the week

Editorial: Is choline-based PET imaging still relevant in recurrent prostate cancer?

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The search for the ideal imaging method to detect small metastatic deposits has largely remained elusive in the field of prostate cancer. However, functional positron emission tomography (PET)/CT is now guiding us in different directions. 11C-acetate PET/CT imaging was one of the first molecular imaging probes showing promise in clinical studies, along with 11C-choline, and more recently challenged by 68Ga-prostate-specific membrane antigen (PSMA) PET/CT [1-3]. So against this background, what does this new study by Esch et al. [4] presented here offer us?

Let us rewind and focus on where molecular imaging may have an impact in prostate cancer. In primary staging, the potential to accurately identify oligometastatic disease or even widespread metastatic disease before primary gland treatment is clearly advantageous. It can allow for wider treatment fields (extended lymphadenectomy or radiation fields), directed treatment of oligometastatic disease, placement into appropriate cytoreductive trials, and in some instances consideration of the use of earlier chemo-hormonal therapy. This study did not address this important clinical scenario [4]. Nor did it focus on primary diagnosis, another ‘holy grail’ for imaging more recently dominated by MRI [5].

The clinical question addressed in this study was whether 11C-acetate PET is able to detect distant metastatic disease in men with PSA relapse after having undergone radical prostatectomy or prostate bed radiotherapy [4]. In other words, if distant metastatic disease is found then prostate bed radiation may be futile, although this assumption has not been subjected to high quality trials, but would seem logical. Also, in the era of oligometastatic disease, treatment (surgery and/or radiation) may be directed at nodal and other deposits to prolong time of systemic therapy such as androgen-deprivation therapy. So what is the ‘sweet spot’? Some would state for men having undergone surgery a PSA level of 0.2 ng/mL places the patient at risk of recurrence, although in clinical practice the level at which investigations are warranted can be as high as 1.0 ng/mL. This study found 11C-acetate PET had few positive results below a PSA level of 1.0 ng/mL. This is in contrast to a recent meta-analysis of 68Ga-PSMA PET/CT reporting positive studies at PSA levels of ≤0.2 ng/mL in 42% of patients [6].

The other group studied the detection of recurrent disease in men having undergone primary radiotherapy, although the numbers were low (six patients). We know this group of men are often undertreated for salvage treatment, and frequently placed on hormonal therapy. Again, early knowledge of locoregional or distant recurrence is required to allow best case selection and thus avoid futile salvage surgery, and also to know who may benefit from salvage lymphadenectomy and treatment of distant oligometastatic disease, if required.

The false-positive rate result for 11C-acetate PET/CT of 24% is notable and concerning. This may lead to unnecessary intervention, or even withholding prostate bed radiation that may have been of benefit. In contrast the false-positive rate for 11C-choline and 68Ga-PSMA PET/CT is far lower, although false-positive PSMA studies may occur in benign conditions and non-prostate cancer tumours.

It should be acknowledged that a strength of this study was comparative histology in a proportion of patients, allowing true sensitivity and specificity to be determined [4]. This is important information, as it guides correct decision-making, and such information is lacking for many other prostate cancer imaging probes, including 68Ga-PSMA, where these data are urgently required.

Overall, this study is important and adds to the rich milieu of available molecular imaging data on staging of possible recurrent or metastatic prostate cancer to date [4]. Current prospective trials exploring 11C-choline, 18F-FACBC (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid), 18F-choline and 68Ga-PSMA with MRI and clinical outcomes should provide further insight into the most appropriate molecular imaging technique for staging prostate cancer.

Nathan Lawrentschuk, BJUI USANZ Editor*,†,, Julia M. Corfield* and Andrew Scott‡,§,¶
*Department of Surgery, University of Melbourne and Olivia Newton-John Cancer Research Institute, Austin Hospital , †Peter MacCallum Cancer Centre, La Trobe University, Departments of

 

‡Medicine, § Molecular Imaging and Therapy
Read the full article

 

References

 

1 Afshar-Oromieh A, Zechmann CM, Malcher A et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline- based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2014; 41: 11–20

 

2 Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate- specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 1997; 3: 81–5

 

3 Meredith G, Wong D, Yaxley J et al. The use of 68 Ga-PSMA PET CT in men with biochemical recurrence after definitive treatment of acinar prostate cancer. BJU Int 2016; 118 (Suppl. 3): 49–55
4 Esch LH, Fahlbusch M, Albers P, Hautzel H, Muller-Mattheis V. 11C-acetate positron-emission tomography/computed tomography imaging for detection of recurrent disease after radical prostatectomy or radiotherapy in patients with prostate cancer. BJU Int 2017; 120: 337–42

 

5 Johnson LM, Turkbey B, Figg WD, Choyke PL. Multiparametric MRI in prostate cancer management. Nat Rev Clin Oncol 2014; 11: 346–53

 

6 Perera M, Papa N, Christidis D et al. Sensitivity, specificity, and predictors of positive 68ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. Eur Urol 2016; 70: 926–37

 

Residents’ Podcast: sRPLND+PLND for ‘node-only’ recurrent PCa

/1 Comment/by

Jesse Ory, Kyle Lehmann and Jeff Himmelman

Department of Urology, Dalhousie University
Halifax, NS, Canada

Read the full article

Abstract

Objectives

To describe the technique of robot-assisted high-extended salvage retroperitoneal and pelvic lymphadenectomy (sRPLND+PLND) for ‘node-only’ recurrent prostate cancer.

Patients and Methods

In all, 10 patients underwent robot-assisted sRPLND+PLND (09/2015–03/2016) for ‘node-only’ recurrent prostate cancer, as identified by 11C-acetate positron emission tomography/computed tomography imaging. Our anatomical template extends from bilateral renal artery/vein cranially up to Cloquet’s node caudally, completely excising lymphatic-fatty tissue from aorto-caval and iliac vascular trees; RPLND precedes PLND. Meticulous node-mapping assessed nodes at four prospectively assigned anatomical zones.

Results

The median operative time was 4.8 h, estimated blood loss 100 mL and hospital stay 1 day. No patient had an intraoperative complication, open conversion or blood transfusion. Three patients had spontaneously resolving Clavien–Dindo grade II postoperative complications. The mean (range) number of nodes excised per patient was 83 (41–132) and mean (range) number of positive nodes per patient was 23 (0–109). Seven patients (70%) had positive nodes on final pathology. Node-positive rates per anatomical level I, II, III and IV were 28%, 32%, 33% and 33%, respectively. In patients with positive nodes, the median PSA level had decreased by 83% at the 2-month follow-up.

Conclusion

The initial series of robot-assisted sRPLND+PLND is presented, wherein we duplicate open surgery with superior nodal counts and decreased morbidity. Robot-assisted technical details for an anatomical LND template up to the renal vessels are presented. Longer follow-up is necessary to assess oncological outcomes.

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