Role of LND in patients undergoing radical nephroureterectomy

Upper tract urothelial carcinoma (UTUC) is a relatively rare urologic malignancy, making up at most 10% of all urothelial carcinomas in the United States (Eur Urol 2015; 68:868-79). Yet, it is essential to recognize that surgery with radical nephroureterectomy (RNU) and bladder cuff represents the primary form of curative therapy among patients diagnosed with localized tumors from UTUC, in particular those with high-grade or multifocal tumors, based on current clinical practice guidelines (Eur Urol 2015; 68:868-79; J Natl Compr Canc Netw 2016; 14:1213-24).

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One area of increasing controversy is the role of concomitant regional lymph node dissection (LND) at the time of RNU. While it has been established as the standard of care to have pelvic LND at the time of radical cystectomy for bladder cancer based on the observational studies suggesting a staging and therapeutic benefit, there is some discordance in agreement about regional LND with RNU (Eur Urol 2014; 66:1065-77). For example, the National Comprehensive Cancer Network endorses the role of RNU and regional LND, while the European Association of Urology does not recommend routine LND and acknowledges the limited high-quality evidence suggesting a survival benefit (Eur Urol 2015; 68:868-79; J Natl Compr Canc Netw 2016; 14:1213-24).

This article examines several factors behind this lack of consensus and whether robotic surgery may increase the use of regional LND for UTUC.

Why the lack of consensus?

Several factors likely explain the lack of consensus and uniform adoption of regional LND for patients diagnosed with UTUC and surgically treated with RNU.

Tumor location adds to uncertainty. The location of the upper tract tumor does contribute to the uncertainty of regional LND, especially considering a lack of agreed-upon anatomic template and tumor aggressiveness. In a retrospective multi-institution study, Matin et al examined the spread of lymph node metastasis and proposed regional LND templates based on location among patients with clinical lymphadenopathy who underwent RNU and LND (figure) (J Urol 2015; 194:1567-74). Patients with right renal pelvis tumors for UTUC had a majority of lymph nodes positive in the paracaval (44%) and hilar region (22%), but one-third had lymph nodes in the interaortocaval (20%) and retrocaval region (10%). For patients with distal ureteral tumors, approximately half of the lymph node metastases were located in the ipsilateral pelvic LND (iliac vessels), but half were located on the ipsilateral paracaval or para-aortic lymph node regions.

Tumor location correlates with prognosis. Another consideration regarding the implications of regional LND is that the UTUC tumor location also correlates with oncologic outcomes in patients diagnosed with ureteral tumors having poorer prognosis relative to those with renal pelvis tumors. A recent population-based study of Medicare beneficiaries showed that when compared to surgically treated patients with renal pelvis UTUC by RNU with/without LND, patients with ureteral UTUC had higher cancer-specific mortality (HR: 1.29; p=.008) and all-cause mortality (HR: 1.18; p=.02) on multivariable analysis (Urol Oncol Jul 27, 2016 [Epub ahead of print]).

This finding is likely attributable to some degree to the difficulty of accurately ascertaining tumor aggressiveness by clinical T stage and grade from the primary tumor by endoscopic biopsy and risk of stricture if the primary management will involve renal preservation. As a result, urologic surgeons and patients are often confronted making clinical treatment decisions about UTUC surgical management in the absence of accurate staging for the clinical T stage and rely more on grade. Therefore, appropriately selecting patients who would benefit from RNU and regional LND is highly challenging, in particular for patients with ureteral tumors.

Next: Surgical challenges

Surgical challenges. A key factor in the feasibility of regional LND is the surgical approach. With most patients undergoing laparoscopic RNU for localized UTUC without lymph node or distant metastasis, performing a regional LND based on anatomic landmarks is technically challenging even among experienced laparoscopic surgeons (Int J Urol 2012; 19:1060-6). The rapid dissemination of robotic surgery technology, however, may increase the use of regional LND for UTUC.

Also see: Researchers validate robotic cystectomy quality tool

For instance, patients with testis cancer have been shown to safely undergo robotic retroperitoneal lymph node dissections with similar yields for lymph node counts (Eur Urol 2011; 60:1299-302). However, it remains uncertain the degree to which robotic surgery will supplant laparoscopy for UTUC patients undergoing RNU, as was the case for robotic radical prostatectomy. Nonetheless, robotic surgery may offer a platform for urologic surgeons to more routinely perform regional LND at the time of RNU for all patients irrespective of UTUC tumor location.

Most importantly, it is essential to recognize that regional LND has been shown to confer a survival advantage for patients treated with RNU for localized UTUC similar to the radical cystectomy for bladder cancer. In several series of retrospective multi-institutional or population-based patients, there have been universal findings that regional lymph node metastasis is associated with adverse prognosis, and UTUC patients who underwent LND fared better than those who underwent RNU alone (J Urol 2015; 194:1567-74; Urol Oncol Jul 27, 2016 [Epub ahead of print]). Moreover, the yield from regional LND, as measured by the number of lymph nodes retrieved, also correlated nicely with better survival (Urol Oncol Jul 27, 2016 [Epub ahead of print]).

These inferences may be confounded by selection bias and latent variables that may better explain the possible survival benefits attributable to LND due to the low quality of evidence. Although this question of clinical benefit from LND in RNU for UTUC is best answered by performing a randomized clinical trial, it is unlikely this will happen due the rarity of this genitourinary malignancy.

Summary

In summary, consideration of regional LND is needed for patients with high-grade or large renal pelvis or ureteral UTUC tumors, if we are to extrapolate from the existing evidence, albeit low-quality studies, from urothelial carcinoma of the bladder. Indeed, the National Comprehensive Cancer Network clinical practice guidelines currently recommend RNU and regional LND for patients diagnosed with UTUC. Future studies are needed to better risk stratify patients to identify which patients need RNU and regional LND rather than RNU alone. However, robotic surgery may offer a surgical approach where regional LND can be easily implemented in patients diagnosed with UTUC.

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