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Research Correspondence: Extended pelvic lymph‐node dissection is independently associated with improved overall survival in patients with PCa at high‐risk of lymph‐node invasion

Dear Editor,

It is generally agreed upon that an extended pelvic lymph‐node dissection (ePLND) provides valuable staging information and helps guide adjuvant therapy, and thus should be undertaken in prostate cancer patients with aggressive preoperative disease features at the time of radical prostatectomy [1,2]. However, whether it has a ‘direct’ therapeutic benefit in the aforesaid patients has remained difficult to demonstrate [3]. The only patients that seem to derive a survival advantage from an ePLND are patients with pN1 disease [4] – this cited study suggested a direct therapeutic effect of an ePLND, with a 7% incremental benefit in 10‐year cancer‐specific survival per every additional LN removed ( = 0.02). However, it did not identify these patients preoperatively.

Given the significant side‐effects associated with an ePLND [3], it is worth asking the questions: which patients, identified preoperatively, may derive a direct therapeutic benefit from an ePLND, and who benefit indirectly only (i.e. via optimal utilisation of adjuvant therapies). The latter question has been answered [5,6]. Here, we try to answer the former.

We relied on the National Cancer Database (NCDB) to answer our question. The NCDB, a joint programme of the Commission on Cancer and the American Cancer Society, is a nationwide cancer database that contains information on ~70% of newly diagnosed tumours in the USA. We identified all patients with prostate cancer undergoing radical prostatectomy between the years 2004 and 2015. After excluding patients with clinical LN/metastatic disease ( = 2568), neoadjuvant radiotherapy, chemotherapy or hormonal therapy ( = 10 931), missing information on biopsy Gleason score, cT stage or preoperative PSA value ( = 166 696), and missing information regarding PLND ( = 95 348), a final sample of 311 061 patients was achieved. All available baseline patient/tumour characteristics and overall survival (OS) data (outcome) were noted. Preoperative LN invasion (LNI) risk was calculated using the Godoy nomogram. We used this nomogram as it was developed using the PLND data from North American men, and has been validated in them [6]. The cut‐off of ≥10 LNs to define an ePLND was based on prior studies [5,6,7,8]. To analyse the impact of ePLND (≥10 LNs) vs none/limited PLND (0–9 LNs) on 10‐year OS, interaction between Godoy nomogram predicted LNI probability, which is based on the preoperative PSA value, clinical stage and biopsy Gleason grade, and ePLND/PLND was plotted using locally weighted methods controlling for age, comorbidities and adjuvant radiation therapy (aRT). This was called model 1 (M1). In a second model (M2), in addition to controlling for age, comorbidities and aRT, we also adjusted for receipt of adjuvant hormonal therapy (aHT). We performed this analysis as we reasoned that a survival benefit in patients undergoing an ePLND may be due to better staging and receipt of aHT. All analyses were performed with the Statistical Analysis System (SAS), version 9.4 (SAS Institute, Cary, NC, USA), with a two‐sided  < 0.05 considered as statistically significant. An Institutional Review Board waiver was obtained prior to conducting this study, in accordance with institutional regulations on dealing with de‐identified administrative data.

Table S1 provides baseline characteristics. Of the 311 061 patients, 49 470 (15.9%) patients underwent an ePLND. The median number of LNs removed in patients undergoing none/limited PLND vs ePLND were 2 and 14, respectively ( < 0.001). The median age and preoperative PSA values for the groups were 61 and 62 years (P  < 0.001) and 5.5 and 6 ng/mL ( < 0.001), respectively. Patients undergoing an ePLND had more aggressive disease on pathological analysis: Gleason ≥8 disease (17.3% vs 10.0%), pT3+ stage (37.4% vs 21.9%) and pN1 disease (8.6% vs 1.5%;  < 0.001 for all). These patients also received aRT (3.9% vs 3.1%) and aHT (4.3% vs 1.9%) more frequently than patients undergoing none/limited PLND ( < 0.001 for both).

The median (interquartile range) follow‐up for the ePLND and none/limited PLND groups was 54.0 (31.3–79.9) and 57.5 (35.1–82.0) months, respectively. In interaction analyses, the lines for ePLND and none/limited PLND separated at Godoy nomogram predicted LNI risk of 20% in model M1 (Fig. 1a), indicating that patients with a preoperative LNI risk >20% derived an OS benefit from an ePLND. This finding remained preserved in model M2, which adjusted for receipt of aHT, in addition to age, comorbidities and aRT, thus indicating a ‘direct’ independent benefit of an ePLND on OS in patients with a LNI risk of >20% (Fig. 1b).

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Fig. 1. The 10‐year OS rates plotted against preoperative Godoy nomogram predicted LNI risk, stratified by ePLND vs none/limited PLND (red line indicates ePLND and blue line indicates none/limited PLND); () represents model M1 (adjusting for age, comorbidities, and aRT), () represents model M2 (adjusting for age, comorbidities, aRT, and aHT).

In Cox regression analyses, the first model (M1) demonstrated that patients undergoing an ePLND (hazard ratio [HR] 1.20, 95% CI 1.17–1.24) had a 9% incrementally lower hazard of 10‐year mortality than patients undergoing none/limited PLND (HR 1.29, 95% CI 1.26–1.31) for every 10% increment in Godoy nomogram predicted LNI risk, beyond the 20% cut‐off ( < 0.001). Similarly, the second model (M2) demonstrated that patients undergoing an ePLND (HR 1.18, 95% CI 1.14–1.21) had a 6% incrementally lower hazard of 10‐year mortality than patients undergoing none/limited PLND (HR 1.24, 95% CI 1.23–1.26) for every 10% increment in Godoy nomogram predicted LNI risk, beyond the 20% cut‐off ( < 0.001). This lower but preserved incremental improvement in OS after adjustment for aHT (model M2) supports our hypothesis that an ePLND is in itself a ‘direct’ independent factor in OS in patients at high‐risk of LNI.

The current American and European urological societal guidelines recommend performing an ePLND in high‐risk and unfavourable intermediate‐risk patients, especially when the estimated risk for LNI is >5% [12]. However, at this cut‐off, the benefit is mainly that of accurate staging and subsequent optimal adjuvant treatment (indirect benefit). This must be balanced against the morbidity of an ePLND. In line with this, a recent exhaustive systematic review by Fossati et al. [3] found that ePLND, as it is currently utilised, is associated with increased risk of postoperative complications without an oncological benefit. The findings of our present study are thus timely and important. We for the first time identify patients preoperatively that may derive both direct and indirect therapeutic benefits of an ePLND. In the present study 4.5% of the 311 061 patients had a LNI risk of >20%. This constitutes a substantial number of patients. These patients should be strongly advised to receive an ePLND. For patients constituting the LNI risk group between 5% and 20%, they should still be encouraged to undergo an ePLND after discussing the risks and benefits of it, as accurate staging may improve their survival by receipt of aHT.

Our present study is not devoid of limitations. First, it is limited by its retrospective nature, an inherent drawback of all observational studies based on administrative data. Therefore, our findings should be interpreted with caution. However, randomised data on this subject are currently scarce. The two randomised trials (NCT01812902 and NCT01555086) comparing ePLND vs limited PLND have not yet matured to provide clinically meaningful information. While we await results from these trials, our present study provides an avenue to have an informed discussion with the patients with high‐risk prostate cancer about the risks/benefits of undergoing an ePLND. Second, no centralised pathological review was available in our study. While this might be considered a limitation, it is also a strength, as it implies that our results are applicable to clinical practice, regardless of pathology review variation. Lastly, the definition of our ePLND was based on number of LNs removed rather than the anatomical zones dissected [7]. The information regarding LN zonal anatomy is not available within NCDB; however, several prior studies of anatomical ePLND have shown median LN counts between 10 and 20 [5,6,7,8], and it was 14 in our series for patients undergoing an ePLND (vs a median of two LNs for none/limited PLND), thus suggesting that the patients were likely classified appropriately into ePLND and none/limited PLND groups.

Limitations notwithstanding, our present study is the first to preoperatively identify patients in whom an ePLND may confer a direct survival advantage, in addition to superior prognostication (indirect benefit). As we identify these patients preoperatively, this may facilitate patient counselling and optimal utilisation of ePLND.

References

  1. Sanda MG, Cadeddu JA, Kirkby E et al. Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Part II: recommended approaches and details of specific care options. J Urol 2018; 199: 990– 7
  2. Mottet N, Bellmunt J, Bolla M et al. Guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol 2017; 71: 618– 29
  3. Fossati N, Willemse PM, Van den Broeck T et al. The benefits and harms of different extents of lymph node dissection during radical prostatectomy for prostate cancer: a systematic review. Eur Urol 2017; 72: 84– 109
  4. Abdollah F, Gandaglia G, Suardi N et al. More extensive pelvic lymph node dissection improves survival in patients with node‐positive prostate cancer. Eur Urol 2015; 67: 212– 9
  5. Briganti A, Larcher A, Abdollah F et al. Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores. Eur Urol 2012; 61: 480–7
  6. Godoy G, Chong KT, Cronin A et al. Extent of pelvic lymph node dissection and the impact of standard template dissection on nomogram prediction of lymph node involvement. Eur Urol 2011; 60: 195– 201
  7. Weingartner K, Ramaswamy A, Bittinger A, Gerharz EW, Voge D, Riedmiller H. Anatomical basis for pelvic lymphadenectomy in prostate cancer: results of an autopsy study and implications for the clinic. J Urol 1996; 156: 1969– 71
  8. Abdollah F, Sun M, Thuret R et al. Lymph node count threshold for optimal pelvic lymph node staging in prostate cancer. Int J Urol 2012; 19: 645– 51

Article of the week: Use of 68Ga-PSMA/PET for detecting lymph node metastases in primary and recurrent PCa and location of recurrence after radical prostatectomy: an overview of the current literature

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.

If you only have time to read one article this week, we recommend this one. 

Use of gallium‐68 prostate‐specific membrane antigen positron‐emission tomography for detecting lymph node metastases in primary and recurrent prostate cancer and location of recurrence after radical prostatectomy: an overview of the current literature

Henk B. Luiting*, Pim J. van Leeuwen, Martijn B. Busstra*, Tessa Brabander, Henk G. van der Poel, Maarten L. Donswijk§, André N. Vis, Louise Emmett**††, Phillip D. Stricker‡‡§§¶¶ and Monique J. Roobol*

*Department of Urology, Erasmus University Medical Centre, Rotterdam, Department of Urology, Netherlands Cancer Institute, Amsterdam, Department of Radiology and Nuclear Medicine, Erasmus University Medical Centre, Rotterdam, §Department of Nuclear Medicine, Netherlands Cancer Institute, Department of Urology, Amsterdam UMC, Location VUmc, Amsterdam, The Netherlands, **Department of Nuclear Medicine, St Vincent’s Hospital, ††University of New South Wales, Sydney, ‡‡St. Vincent’s Prostate Cancer Centre, §§Garvan Institute of Medical Research, Kinghorn Cancer Centre, Darlinghurst and ¶¶St Vincent’s Clinical School, UNSW, Sydney, NSW, Australia

Abstract

Objectives

To review the literature to determine the sensitivity and specificity of gallium‐68 prostate‐specific membrane antigen (68Ga‐PSMA) positron‐emission tomography (PET) for detecting pelvic lymph node metastases in patients with primary prostate cancer (PCa), and the positive predictive value in patients with biochemical recurrence (BCR) after initial curative treatment, and, in addition, to determine the detection rate and management impact of 68Ga‐PSMA PET in patients with BCR after radical prostatectomy (RP).

Materials and Methods

We performed a comprehensive literature search. Search terms used in MEDLINE, EMBASE and Science Direct were ‘(PSMA, 68Ga‐PSMA, 68Gallium‐PSMA, Ga‐68‐PSMA or prostate‐specific membrane antigen)’ and ‘(histology, lymph node, staging, sensitivity, specificity, positive predictive value, recurrence, recurrent or detection)’. Relevant abstracts were reviewed and full‐text articles obtained where possible. References to and from obtained articles were searched to identify further relevant articles.

Fig. 1. Axial and sagittal plane gallium‐68 prostate‐specific membrane antigen positron‐emission tomography /CT images of two patients with locoregional lymph node recurrence after initial curative treatment. The metastasis in patient A is located in the obturator area and the metastasis in patient B is located in the presacral area.

Results

Nine retrospective and two prospective studies described the sensitivity and specificity of 68Ga‐PSMA PET for detecting pelvic lymph node metastases before initial treatment, which ranged from 33.3% to 100% and 80% to 100%, respectively. In eight retrospective studies, the positive predictive value of 68Ga‐PSMA PET in patients with BCR before salvage lymph node dissection ranged from 70% to 100%. The detection rate of 68Ga‐PSMA PET in patients with BCR after RP in the PSA subgroups <0.2 ng/mL, 0.2–0.49 ng/mL and 0.5 to <1.0 ng/mL ranged from 11.3% to 50.0%, 20.0% to 72.7% and 25.0% to 87.5%, respectively.

Conclusion

The review results showed that 68Ga‐PSMA PET had a high specificity for the detection of pelvic lymph node metastases in primary PCa. Furthermore, 68Ga‐PSMA PET had a very high positive predictive value in detecting lymph node metastases in patients with BCR. By contrast, sensitivity was only moderate; therefore, based on the currently available literature, 68Ga‐PSMA PET cannot yet replace pelvic lymph node dissection to exclude lymph node metastases. In the salvage phase, 68Ga‐PSMA PET had both a high detection rate and impact on radiotherapy planning in early BCR after RP.

Article of the Month: 68Ga-PSMA PET/CT for LN staging in PCa

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.

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

Prospective evaluation of 68Gallium-prostate-specific membrane antigen positron emission tomography/computed tomography for preoperative lymph node staging in prostate cancer

Pim J. van Leeuwen*, Louise Emmett,§, Bao Ho, Warick Delprado, Francis Ting*Quoc Nguyen† and Phillip D. Stricker*

 

*St Vincents Prostate Cancer Centre, St Vincents Clinic, Australian Prostate Cancer Research Centre, New South Wales, The Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Department of Diagnostic Imaging, St Vincents Public Hospital, §University of New South Wales, Sydney, and University of Notre Dame, Darlinghurst, NSW, Australia

 

Abstract

Objectives

To assess the accuracy of 68Gallium-prostate-specific membrane antigen (68Ga-PSMA) positron emission tomography/computed tomography (PET/CT) for lymph node (LN) staging in intermediate- and high-risk prostate cancer (PCa).

Materials and Methods

From April to October 2015, 30 patients with intermediate- (n = 3) or high-risk (n = 27) PCa were prospectively enrolled. Patients underwent preoperative 68Ga-PSMA PET/CT. Both visual and semi-quantitative analyses were undertaken. Subsequently, all patients underwent radical prostatectomy (RP) with an extended pelvic lymph node dissection. The sensitivity, specificity, and positive (PPV) and negative predictive value (NPV) for LN status of 68Ga-PSMA were calculated using histopathology as reference.

aotmfeb2017-results

Results

Eleven patients (37%) had lymph node metastases (LNMs); 26 LNMs were identified in the 11 patients. Patient analysis showed that 68Ga-PSMA PET/CT had a sensitivity of 64% for the detection of LNMs, its specificity was 95%, the PPV was 88%, and the NPV was 82%. In total, 180 LN fields were analysed. In the LN-region-based analysis, the sensitivity of 68Ga-PSMA PET/CT for detection of LNMs was 56%, the specificity was 98%, the PPV was 90% and the NPV was 94%. The mean size of missed LNMs was 2.7 mm. Receiver-operating characteristic curve analysis showed a high accuracy of maximum standardized uptake value (SUVmax) for the detection of LNMs, with an area under the curve of 0.915 (95% confidence interval 0.847–0.983); the optimum SUVmax was 2.0.

Conclusions

In patients with intermediate- to high-risk PCa, 68Ga-PSMA PET/CT had a high specificity and a moderate sensitivity for LNM detection. 68Ga-PSMA PET/CT had the potential to replace current imaging for LN staging of patients with PCa scheduled for RP.

info-feb-2017

Click on image for full infographic

 

Editorial: Bringing clarity or confusion? The role of prostate-specific membrane antigen positron-emission/computed tomography for primary staging in prostate cancer

The use of 68Ga-labelled prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/CT for staging prostate cancer in Australia has reached almost plague-like proportions. Despite what must be admitted is little high-level evidence to guide us in the accuracy or appropriateness of this imaging technique for either primary staging or prostate cancer recurrence, hundreds of these scans are being performed every week around Australia, and in many cases we simply do not know what to do with the results. We performed the first such scan at our centre in Melbourne in August 2014, and were soon receiving 10 requests per day, with patients waiting up to 3 months to be scanned. Fast-forward 2 years, and there are now eight centres offering PSMA PET/CT in Melbourne, a city of 4.5 million people. Scans can be obtained within 24 h of referral and costs have dropped to €500. A similar situation exists in Germany where this imaging method was pioneered [1], and interest is also growing in Belgium, Italy, India and a number of other countries (the USA being a notable exception). But do we really understand the impact of the decision to perform PSMA/PET scanning, and do we have enough evidence to guide us on the most appropriate setting for its use?

The current interest in PSMA PET/CT has been triggered by the development of small molecule ligands which bind to the extracellular domain of the PSMA molecule, leading to increased sensitivity and specificity when compared with conventional imaging [2]. Previously, the use of PET imaging for prostate cancer detection was greatly limited by the relatively poor performance characteristics of choline-based PET/CT, and limited availability and high costs associated with this type of imaging. The introduction of 68Ga-labelled PSMA PET/CT has addressed many of these concerns, although high-quality evidence is still lacking to help guide its most appropriate utility. The best data exist for identification of prostate recurrence in patients with biochemical recurrence (BCR) after previous definitive therapy. In our recent systematic review and meta-analysis of this topic, we reported pooled data on 1309 men with BCR undergoing PSMA PET/CT [3]. When stratified by PSA level post-radical prostatectomy, positive scans are reported in 42, 58, 76 and 95% of patients with PSA levels of 0–0.2, 0.2–1, 1–2, and >2 ng/mL, respectively. Fewer data exist for the role of PSMA PET/CT in the primary staging setting.

In this interesting paper from some of our Australian colleagues, van Leeuwen et al. [4] report their experience of PSMA PET/CT in the primary staging setting, in particular to evaluate the performance of PSMA PET/CT to evaluate lymph node positivity in patients with intermediate- and high-risk disease, scheduled for radical prostatectomy. A total of 30 patients underwent preoperative PSMA PET/CT, of which 27 were stratified as high risk, and all subsequently underwent radical prostatectomy and pelvic lymph node dissection. In total, 11 patients (37%) had histologically proven lymph node metastases. On a per-patient basis, PSMA PET had a sensitivity of 64%, specificity of 95%, positive predictive value of 88%, and negative predictive value of 82%. The average size of positive lymph nodes not detected by PSMA PET/CT was 2.7 mm; therefore, in this population of patients with predominately high-risk prostate cancer, PSMA PET/CT had very high specificity and moderate sensitivity for lymph node metastasis detection.

In a larger experience from Munich, Maurer et al. [5] compared pathology findings of 130 patients with intermediate- and high-risk disease who underwent radical prostatectomy and pelvic lymph node dissection, with preoperative PSMA PET/CT or PET/MRI findings. They reported similar sensitivity, specificity and accuracy of 65.9, 98.9 and 88.5%, respectively. On receiver-operating characteristic analysis, PSMA-PET performed significantly better than conventional imaging alone on patient and template-based analyses (P = 0.002 and <0.001, respectively).

Just as there appears to be some clarity, however, in the role of PSMA PET/CT in patients with BCR, and in improving the detection of lymph node metastases preoperatively, there are many instances in which the high specificity of this scanning method leaves us in a decision-making quandary. As van Leeuwen et al. identified in their paper, and as we have frequently observed ourselves, PSMA PET/CT may identify prostate cancer in hitherto unidentified and unusual locations such as the mesorectum (Fig. 1). Disease may also be identified in quite distant locations despite relatively low PSA levels, thereby disrupting traditional management algorithms including the use of postoperative radiotherapy [6]. Should we alter patients’ management based on novel imaging, or should we assess the decision impact more formally in prospective studies? The answer should obviously be the latter, but the current plague of PSMA PET imaging means such decisions are already being taken in the absence of high-quality evidence.

image

Figure 1. 68Ga-labelled prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/CT in a 72-year-old man with biochemical recurrence after previous radical prostatectomy. His PSA level was 0.21 ng/mL and conventional staging including CT and bone scan showed no evidence of disease. PSMA PET/CT demonstrates intense avidity in an 11-mm mesorectal node near the recto-sigmoid junction on the left side. (a) CT demonstrates non-specific findings in area of subsequent avidity; (b) PSMA PET raw data demonstrating avidity in mesorectal node; (c) fused PSMA PET/CT image provides anatomical correlation; (d) coronal fused PET/CT image.

Nonetheless, PSMA PET imaging is here to stay, and will doubtless have a positive impact in improving decision-making in prostate cancer management as a result of the more accurate staging which it heralds. We must await more formal evaluation of the decision impact before defining the patient population who will benefit the most from this exciting imaging method.

Declan G. Murphy, Urologist*,, Michael Hofman, Nuclear Medicine Physician, Nathan Lawrentschuk, Urologist*,§ and Tobias Maurer, Urologist

 

*Division of Cance r Surgery, Peter MacCallum Cancer Centre, University of Melbourne, Epworth Prostate Centre, Epworth Hospital, Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, §Department of Surgery, The Austin Hospital, University of Melbourne, Heidelberg, Vic.Australia and Department of Urology, Technische Universitat Munchen, Klinikum rechts der Isar, Munich, Germany

 

References

 

 

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