According to our results, we cannot postulate any benefit of salvage ePLND because of the limitation of the study, in particular its’ small retrospective character and heavily selected cohort of patients. Despite of that, the results have showed, that in the majority of patients BCRF were achieved, even in those with no histologically proven LN metastases. Moreover, CSS and OS data compared with acceptable complications rate makes this procedure feasible for selected patients. Similar results were found in previous studies on salvage ePLND. Thus, the data collected in different centers demonstrate comparable results [15] The most important two parameters are (1) complete biochemical response within 40 d after surgery (range: 46 %; 48.9 % up to 56.9 %) and (2) achievement of BCR-freedom after salvage ePLND with rates of up to 71.8 %. The role of ADT after salvage surgery remains a critical and unresolved issue, however.
The retrospective character of the study does not provide us with the opportunity to divide the patients into different groups with and without ADT. Moreover, the concept of recurrent PCa salvage treatment makes it impossible to split salvage ePLND and ADT; both treatments can and should be used in a combined approach. This approach has allowed us and other centers to achieve similarly high rates of CSS ranging between 75 % and 80.6 % [15].
We believe that the aim of any further research is to demonstrate that patients benefit from salvage ePLND. The selection of patients, taking into consideration the above-shown absence of reliable LN recurrence imaging tools, remains a matter of dispute.
13 (68.4 %) of 19 node-negative patients showed a BR immediately after salvage ePLND. 16 (84.2 %) reached BCRF during postoperative follow-up with a mean duration of 33 ± 22 months, median 28.5 (min 6 – max 81) months. However, 17 (89.5 %) undergone ADT after salvage ePLND in follow-up.
Again, 84.2 % patients with stage N0 after salvage surgery were BCR free. We discussed possible explanations for this with our pathologist and during various international meetings. For a better understanding, we also need to consider the method of pathological examination.
Pathological examination of removed LNs may miss micrometastases, which are defined in different ways depending on the cancer entity. In malignant melanoma, for example, one isolated tumor cell is already considered a micrometastasis according to the American Joint Committee on Cancer, although it can only be detected by means of immunohistochemistry. In breast cancer, micrometastases are defined as >200 μm (and/or >200 tumor cells) and <2 mm in diameter. Such micrometastases can be detected by light microscopy. In penile cancer, a micrometastasis is defined as being <2 mm [16].
There is no clear definition of micrometastasis with respect to PCa or cancer of other parenchymal organs. The International Society of Urological Pathology has no consensus on the definition of micrometastasis in PCa [17]. The problem is that something that is not clearly defined cannot be found.
However, we believe that we did remove LNs carrying micrometastases or even true metastases that were missed using the applied pathological method. We systematically removed all potentially positive LNs from various areas following the Kiel surgical template of salvage ePLND [14]. Most of the positive LNs were found in the area of the common iliac artery (37.5 %), paraaortal area (20 %), sacral area (12.5 %), and in the area of the triangle of Marcille (5 %). This is an important argument in favor of template-oriented surgery rather than selective or limited LN removal.
The small number of studies [15] shows the outcome of salvage ePLND, but it is more difficult to assess the difference in survival of patients after salvage ePLND alone versus patients after salvage ePLND and adjuvant ADT. In addition, it is difficult to assess the independent impact of these two therapeutic measures on progression-free survival. We observed an interesting phenomenon: in patients with CRPC and BCR, ADT can be effective again after salvage ePLND. We reported this side effect of salvage surgery at the 2014 meetings of the German Society of Urology, EAU and American Urological Association. This effect was detected after analysing all data and is a largely unexpected result of our study. We describe this effect with caution and as a preliminary statement. Moreover, we still lack an adequate explanation for this effect. However, we believe that this finding will have a major impact on the role of salvage ePLND if our data are confirmed by other study groups, ideally in a prospective setup with larger patient cohorts and in multicenter trials.
Our hypothesis so far is based on the tumor biology of PCa. The PCa tumor architecture is heterogeneous and probably depends on the different c-types and their mutation characteristics. There are a few theories about this heterogeneity, which can have an impact on the aggressiveness and speed of metastatic spread. In breast cancer, for example, the BRCA-1 and BRCA-2 genes indicate a strong dependency between BRCA-gene types and lymphatic and hematogeneous metastatic spread [18]. These two genes are found in LN or organ metastases of PCa. However, we believe that heterogeneity in PCa metastasis is even more complex. Based on the described facts, we see the potential reason for the renewed ADT response as the removal of aggressive tumor cells, which are probably chiefly responsible for metastatic spread of the tumor.
The interest in lesion-targeted salvage therapies has increased recently [19]. The outcome of salvage surgery and other diagnostic methods for positive LN detection compared to pathological examination needs to be evaluated further. Moreover, salvage surgery needs to be included in PCa guidelines. Lesion-targeted or selective salvage PLND can only be enhanced with development of new diagnostic imaging. Some recent studies have shown promising results with Ga-PSMA (68Gallium- Prostate-specific membrane antigen) PET/magnetic resonance imaging (MRI) and Ga-PSMA PET/CT [20, 21].
Most of the studies describing the clinical outcome of salvage ePLND are based on the findings of 18F choline PET/CT findings. Application of the tracer 18F-2-fluoro-2-deoxyglucose in PET/CT is successfully used in many tumor types. However, a benefit in PCa diagnosis has been questioned by several authors [22, 23].
There have been divergent results on choline-PET/CT regarding PCa recurrence. In several studies the detection rates were analyzed in relation to the PSA level. These studies have shown the sensitivity of choline-PET/CT for detection of LN metastases to be as low as 41.1 % [24]. Therefore, extensive salvage treatment is needed to maximize the chance of cure [19]. However, these results are insufficient to standardize the indications for salvage ePLND.
Data from our own department show a low specificity of 18.2 % with a relatively satisfactory sensitivity of 85.2 %. Most importantly, the positive predictive value and negative predictive value were 56.1 % and 50.0 %, respectively [25]. Therefore, we conclude that the reliability of PET/CT imaging for detection of LN metastases is limited by a high false-positive rate, and the findings in patients with low PSA values were associated with a high ratio of errors. In this situation, there is still no alternative to the template-based salvage ePLND to remove all LNs and thus to detect all metastatic LNs, including those that were false negative by PET/CT.
Here, as well as in the validation of the method mentioned above, a prospective study design should be set up for a full analysis of false-positive and false-negative results regarding LN metastasis. This will only be possible if histological verification is done after template-based ePLND.
Looking at the largest studies in this field, the CSS results in patients who underwent salvage ePLND seem to be similar despite the different cohorts analyzed by different workgroups. Thus, Jilg et al. reported 5-years CSS of 77.7 %, Rigatti et.al – 75 %, and our current data show 80.6 % [9, 10].
In the absence of evidence-based guidelines regarding salvage ePLND, our study and the publications listed in Table 1 allow us to conclude that salvage ePLND is effective and useful in selected patients. The only statistically significant finding in this study is that bone metastasis is associated with more rapid mortality. This is an important point which can help us define the indication criteria for salvage ePLND, but it should not be used to question the clinical significance of salvage surgery.
The requirements placed on the surgeon are high, however. The current situation remains unsatisfactory due to the lack of prospective multicenter randomized studies. We concede that our study was only a retrospective analysis. However, there are two good reasons for publishing these data. First, we needed to evaluate our own patient data in order to decide whether we can go further with salvage ePLND as a treatment option. Second, this analysis will serve as a basis for a prospective trial, for example, by joining in the SALPRO study of our colleagues from Freiburg, Germany. Finally, the low rate of complications that we found justifies further pursuit of this strategy.
