Contemporary Role of Lymph Node Dissection in Genitourinary Cancers: Where Are We in 2023? - Amanda Myers

January 10, 2024

Amanda Myers presents a comprehensive review on lymph node dissection in GU cancers as of 2023. She emphasizes its critical role in surgical urologic care for accurate staging and detecting micrometastases. The review, based on systematic research from 2014 to 2023, covers bladder, upper tract, kidney, prostate, and penile cancers. Key findings include the recommendation of standard pelvic lymph node dissection for bladder cancer, the necessity of dissection in high-grade upper tract urothelial carcinoma, a case-by-case approach for high-risk renal cell carcinoma, and extended lymph node dissection for prostate cancer based on risk stratification. In penile cancer, radical inguinal lymph node dissection is essential, especially in high-risk, clinically node-negative patients. Dr. Myers concludes that lymph node dissection remains vital for staging in GU cancers, with ongoing research aimed at refining patient selection and improving outcomes.

Biographies:

Amanda Myers, MD, MD Anderson Cancer Center, Houston, TX

Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX


Read the Full Video Transcript

Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of urologic oncology at MD Anderson Cancer Center, and it's a pleasure today to welcome one of our fellows from MD Anderson, Amanda Myers. Amanda has done a truly phenomenal job here in collating all the data that's current until just last year 2023, when it comes to lymph node dissection in GU cancers. And it's a very important topic because over the past few years, a lot has changed as far as the thought process and the understanding and, of course, the recommendations for lymph node dissection in GU cancers. So Amanda, thanks for taking the time and putting this presentation together. It's sort of taking us beyond the abstract, beyond the article, and our audience would clearly like to hear what you have to say in summarizing your article, so take it away.

Amanda Myers: Thank you, Dr. Kamat. I'm thrilled to be here today to really discuss lymph node dissection in GU cancers. As you had said, many things have changed. Before we do begin, I just wanted to express my gratitude to my co-authors for their contributions and expertise in the development of this work. Today we will be discussing some of the highlights from our review article available at European Urology Oncology, The Contemporary Role of Lymph Node Dissection: Where Are We in 2023?

We'll start with an introduction, our evidence acquisition strategy, and then dive into each of the following: bladder cancer, upper tract, kidney cancer, prostate, and penile cancer.

Lymph node dissection is an integral component of surgical urologic care, primarily for accurate lymph node staging and detecting micrometastases. Yet the challenge has always been striking a delicate balance, maximizing the therapeutic benefit while minimizing the potential morbidity. Despite the progress in recent years, the interpretation of the role remains complex and evolving. Evidence for our review was obtained by a systematic search from 2014 to 2023. Over 1300 studies were screened and we prioritized high-level evidence such as randomized control trials, meta-analyses, and we used a collaborative method with final inclusion approved by all our co-authors and our narrative synthesis concentrated on the extent of dissection refining patient selection criteria.

First, I'd like to talk about bladder cancer. Lymph node dissection is a must at the time of cystectomy due to the propensity for lymph node metastasis and the limitations in clinical staging. Three different dissection templates have been used over time. First, the super-extended template goes all the way up to the IMA. Moving to the extended lymph node template, it really goes to the level of the aortic bifurcation. And then the standard lymph node template includes the pelvic lymph nodes, the obturator, internal, and external iliac nodes.

Two pivotal clinical trials have really compared dissection templates. First, the LEA trial aimed to demonstrate a 15% five-year recurrence-free survival benefit with a super-extended compared to a limited dissection of the internal and external iliac as well as the anterior obturator nodes in patients with clinically T1 to T4a disease who did not have neoadjuvant chemo.

Next, the SWOG trial randomized patients to an extended template, at least to the level of the aortic bifurcation, compared to a standard lymph node dissection of the external, internal iliacs, and anterior and posterior obturator nodes targeting a 10 to 12% disease-free survival benefit in clinically T2 to T4a with or without neoadjuvant chemo. Both studies have failed to show an outcome benefit with the extended dissection but did report higher nodal yields along with an increased risk of adverse events and mortality, challenging previous retrospective data suggesting a benefit with extended dissection.

Thus, in 2023, a standard pelvic lymph node dissection is the standard of care for urothelial carcinoma based on the SWOG and LEA trials. This does not detract from the need for a meticulous dissection. Both of these trials emphasize surgeon selection, ensuring accuracy and completeness of the dissection. Lymph node yield is actually a marker of dissection quality. For example, in the limited arm of the LEA trial, 19 nodes were dissected on average and a thorough dissection is likely necessary to achieve similar outcomes to these trials.

For upper tract urothelial carcinoma, the support for dissection really comes from meta-analysis of retrospective data. The AUA and EAU guideline committees found that template-based lymph node dissection was associated with an improved recurrence-free survival and cancer-specific survival in certain patient groups. Lymph node dissection is recommended during radical nephroureterectomy and distal ureterectomy for patients with high-grade upper tract cancer based on clinical and biological rationale. Pathologic node staging is crucial for both prognosis and can determine the need for adjuvant therapy. Templates have been based on lymph node mapping studies. Both evidence for this rare cancer remains limited, particularly for distal ureter tumors. There is actually an ongoing randomized control trial further evaluating the efficacy of lymph node dissection here.

For kidney cancer, lymph node dissection is not recommended for low-stage disease as evidence from the EORTC trial shows only a 4% node-positive rate and really no clear survival advantage, which is supported by contemporary retrospective data. In high-risk RCC, you really need to have a case-by-case approach in the absence of prospective studies. Lymph node involvement portends a poorer prognosis and may identify patients who could benefit from adjuvant treatment. Risk factors for nodal involvement include nuclear grade three or four, a sarcomatoid component, a tumor greater than 10 centimeters, stage T3 to T4, and tumor necrosis. A template-based dissection has been proposed, but it's not included in the guidelines. The rationale for an extended template arises from studies that actually showed in patients with clinically suspicious nodes, 50% of the node-positive patients had disease outside of the radiographic suspicious area, underscoring the need for a meticulous dissection again.

So moving on to prostate cancer. The current guidelines from the EAU, AUA, and NCCN are relatively similar. Nomograms and risk stratification are recommended. Notably, these guidelines advise against omitting an extended node dissection solely based on PSMA-PET imaging findings. Nomograms that are used are based on clinical parameters from Briganti and the MSKCC nomogram as well as the Briganti 2019, which incorporates MRI and MRI fusion diagnosis as well as the most recent Briganti 2023, which uses PSMA-PET and is awaiting external validation. Guidelines all agree that an extended template for lymph node dissection is necessary and that includes the external iliac, internal iliac, and obturator lymph nodes. Notably, the extended template for prostate cancer is the same as the standard template for bladder cancer. Limited dissections along just the obturator fossa and iliac vein only really remove less than half of the nodes receiving drainage from the prostate.

Despite these guidelines, the extent remains controversial as no prospective trial has confirmed a therapeutic benefit. Two randomized control trials found no advantage in lowering biochemical recurrence rates. However, we really need to carefully interpret these findings. On the left, we have the study led by Touijer published in 2021, in men with clinically localized prostate cancer, comparing an extended dissection to a control group of only the external iliac nodes, and they found the median number of nodes removed between these groups was similar, suggesting the templates were executed in a similar fashion and the node-positive rate was 13%.

On the right, this study led by Lestingi, also published in 2021, looked at intermediate or high-risk patients and extended a broader template that included up to the presacral and common iliac nodes to the ureteral crossing versus a control group of obturator nodes only. Here the median nodes removed were significantly different, 3 vs. 17, and the positive node rate was 10%. Both trials did not find a significant benefit in biochemical recurrence. However, neither trial was really designed to evaluate that benefit. In high-risk patients, they both accrued predominantly grade group one to grade group 2, 62% and 76% respectively, and the negative results allude to the fact that not all patients will benefit from a pelvic lymph node dissection.

There are multiple ongoing trials hoping to clarify this. First, there are two de-escalation trials evaluating pelvic lymph node dissection versus no pelvic lymph node dissection. The PREDICT trial will look at intermediate-risk patients and the MSK trial will involve patients with negative imaging results. There are also two trials ongoing looking at no dissection in the setting of PSMA-PET imaging. The first will examine patients with a negative PSMA-PET extended versus no pelvic lymph node dissection. And the second will look at patients stratified by PSMA-PET versus an extended pelvic lymph node dissection as the control.

And finally, we have penile cancer. Radical inguinal lymph node dissection is essential in this disease process for staging, prognosis, determining the need for adjuvant, and may have a therapeutic benefit in patients with low-volume disease.

First, in high-risk clinically node-negative patients with grade three or greater than T1b tumors, up to 24% will have occult lymph node metastasis, and lymph node dissection can be curative here. Importantly, an early dissection is critical as a delayed dissection beyond three months leads to significantly worse five-year disease-specific survival, 46% vs. 79%. Dynamic sentinel lymph node biopsy is increasingly used as an alternative; if the results come back positive, then you proceed with an inguinal lymph node dissection. Although dynamic sentinel lymph node biopsy is not widely available and timely referrals are really essential for these patients. In patients with clinically N1 disease, a single palpable node, the pathway is direct. We go straight to a dissection which may be curative. Fascial sparing is frequently employed here to reduce the morbidity for these patients.

In clinically N2 disease with multiple palpable or bilateral nodes, there are a few different options. In bulkier fixed nodes, those patients will get neoadjuvant chemo. In low-volume disease, they may go directly to resection. The InPACT trial is ongoing with the hope to identify an optimal treatment pathway for these patients, including two parts, looking at various combinations of node dissection, chemotherapy, and radiation, as well as looking into pelvic lymph node dissection, which really has limited data. Currently, pelvic lymph node dissection is done based on 2+ nodes positive or extra nodal extension.

In conclusion, lymph node dissection is the gold standard for lymph node staging, and we really need to focus on patient selection and anatomic-based templates to leverage the potential benefits and ongoing efforts to refine our patient selection will lead to improved ability to optimize our outcomes and mitigate unnecessary risks.

Thank you.

Ashish Kamat: Great. Thanks, Amanda. That was a nice summary of the entire article. Just to recapitulate and summarize what you said, if you look at bladder cancer, of course, there's been a pendulum swing going back all the way to nothing then too much, and it looks like finally there is consensus for the most part that for the routine patient undergoing a radical cystectomy, a standard pelvic lymph node dissection should be offered with meticulous lymph node resection, right? There's still patients who, based on certain nuances, you might need to do more, but for the most part, at least a standard lymph node dissection with a good template dissection is required.

With upper tract disease, as you mentioned, we should use anatomic templates and do lymph node dissection, especially in those patients that are at high risk for metastatic disease based on several nomograms that are available. Now, if we stop and talk about urothelial, for example, in the bladder and the upper tract, not to put you on the spot because we all know you're still in training, but what was your sense going through all the literature as to what the evolution of lymph node dissection has been?

Amanda Myers: It's interesting because in bladder cancer we have gone from these super-extended dissections to kind of refining it to a more standard dissection that is the standard of care now. Whereas in upper tract, whether or not to do a lymph node dissection was really unknown, and it seems that now the guidelines are supporting a lymph node dissection and have kind of gone through and looked through the limited evidence to say, this is also urothelial cancer and has a high propensity for lymph node metastasis and we should be doing those.

Ashish Kamat: Right. Yeah, that's a good summary because in many patients, the lymph node dissection and the positive nodes might purely be a staging modality, but there's a preponderance of evidence to suggest that in some patients it can actually be curative. So ignoring or not doing a lymph node dissection at all is not something that people should consider in 2023 for most patients with urothelial cancer. Now moving to kidney cancer, again, things have evolved over the years. In low-stage and low-grade patients, currently the recommendation is to not offer lymph node dissection unless there are extenuating circumstances. Clearly, the lymph nodes don't correlate with what you find on pathologic examination, but in patients who are either cN1 or high-risk, it really is again, a nuanced decision and a case-by-case decision. But if you do a lymph node dissection, the recommendation is really to use anatomic templates and resect everything that can be done safely and feasibly. Any comments on the kidney cancer conclusions?

Amanda Myers: Yeah, I think for kidney cancer, more and more patients are having biopsies done before these cases are undertaken. And looking at patients who have non-clear cell histology may have a higher risk of lymph node involvement. That's kind of unknown at this point. Also, patients are having more and more imaging done, so seeing a suspicious node, it may or may not be positive, and really the template-based dissection is necessary.

Ashish Kamat: Right. And then again, you can correlate this with histology on biopsy and of course, many patients are on protocol and all of that factors in as well. Prostate cancer, again, you summarized it pretty well, but that's an area where there's still a lot of discussion, a lot of discourse, people pushing for PSMA-PET, people talking about nomograms, folks still saying, well, we don't believe that a lymph node dissection should not be offered to patients, some people saying yes. So there's still a lot of discussion, but I think your summary for those prostate cancer patients is right spot on.

Today in 2024, your paper is 2023, but even in 2024, we should not omit a lymph node dissection just based on PSMA-PET with the current data that we have. And a lymph node dissection that is thorough should be offered, keeping in mind that when we recommend extended pelvic lymph node dissection for prostate cancer patients, we're talking about external iliac, internal iliac, and obturator. Not going up to the common, not going to the presacrals, not doing this big dissection that can lead to extended morbidity and mortality. Any comments on the prostate cancer literature based on your review?

Amanda Myers: I think that based on the drainage of the prostate and new imaging modalities being used, I think there's part one which is deciding if you're going to do a dissection, which is still unclear, but I think part two is if you're going to do it, you need to do a complete dissection.

Ashish Kamat: Correct. And again, lastly, penile, I think things have evolved and it's pretty well-defined now. And of course, we didn't talk about testis cancer because the role of lymph node dissection is fairly standard and it's mentioned briefly in your manuscript. So Amanda, thanks again for taking the time, putting this presentation together. Really great effort on your part and a good lecture for our UroToday viewers and audience to listen to. Thanks again.

Amanda Myers: Thank you.