SIU Virtual Congress 2020: Renal Cell Cancer: Does Lymphadenectomy Make a Difference? And When?

Dr. Bex highlighted that there are several unanswered questions regarding lymphadenectomy for patients with RCC:

• For cN0 patients, does early potentially curable occult pN disease exist in cN0 patients? If yes, how frequent is this event and can we identify these patients to resect these lesions?
• For cN1 patients, does resection of clinically evident locoregional lymph node metastases lead to a benefit in terms of disease-free or overall survival?
• If the adjuvant immune checkpoint inhibitor trials are positive, will we be more inclined to perform lymph node dissection to provide prognostication and risk assessment?

Starting the discussion with cN0 disease patients, Dr. Bex discussed the important EORTC 30881, which assessed radical nephrectomy with and without lymph node dissection.¹ In this trial, there were 383 patients randomly selected to receive a complete lymph node dissection together with a radical nephrectomy, and 389 patients were randomly selected to undergo a radical nephrectomy alone. Complete lymph node dissections in 346 patients revealed an absence of lymph node metastases in 332 patients (96.0%), with no significant differences in overall survival, time to progression of disease, or progression-free survival (PFS) between the two study groups. Importantly, in the control arm that did not have a lymphadenectomy, only 0.5% (2/385) developed local lymph node recurrence during follow-up 16 years.

With regards to pN1 disease and whether they can be cured is somewhat theoretical according to Dr. Bex. The biggest issue with lymph node metastatic disease is that if the disease is very early on, it is a rare event and patients are likely to have a local problem (ie. M0), whereas if more lymph nodes are involved (particularly if they are cN1 disease), there is a higher likelihood that they will have distant metastatic disease. Dr. Bex provided the following diagram to summarize these points:

Dr. Bex and his group were involved in the sentinel node study assessing lymphatic drainage of renal tumors using SPECT/CT imaging.² In this Phase II, prospective, single-arm study, 68 patients with cT1-3c (<10 cm) cN0M0 kidney tumors had an intratumor ultrasound-guided injection of 0.4 ml ^99mTc-nanocolloid followed by preoperative imaging of sentinel nodes with lymphoscintigraphy and single-photon emission/computerized tomography. Of the 68 patients, 40 underwent preoperative single-photon emission/computerized tomography of sentinel nodes and were included in primary endpoint analysis. Lymphatic drainage outside the locoregional retroperitoneal templates was observed in 14 patients (35%) and 8 patients (20%) had supradiaphragmatic sentinel nodes. According to Dr. Bex, this is likely secondary to direct drainage through the thoracic duct leading to supraclavicular nodal disease.

Regarding cN1 disease, imaging is unreliable in predicting pN+ disease. The following table summarizes the available evidence for cN1 to pN1 disease:

As such, this makes it difficult to ascertain whether lymph nodes seen on imaging are actually true metastatic disease.

Whether resection of isolated lymph node metastases cures patients has been looked at in two studies. Russell et al. looked at 50 patients who underwent resection of isolated retroperitoneal lymph node recurrence of RCC at four institutions after nephrectomy for pTany Nany M0 disease.³ The median time to retroperitoneal lymph node recurrence after nephrectomy was 12.6 (IQR 6.9-39.5) months. The median PFS after retroperitoneal lymph node recurrence resection was 19.5 months, with a 3- and 5-year PFS rate of 40.5% and 35.4%, respectively. Furthermore, the 3- and 5-year CSS rates were 75.8% and 73.6%, respectively. Gershman et al. assessed 138 patients with isolated pN1M0 RCC that underwent partial or radical nephrectomy and lymph node dissection from 1980 to 2010.⁴ Over a median follow-up of 8.5 years, the 5-year and 10-year metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) rates were 16% and 15%, 26% and 21%, and 25% and 15%, respectively. Additionally, the median time to development of metastases was only 4.2 months. Dr. Bex notes that lymph node metastasectomy does come at a price, with a reported 25% major complication rate in this setting.

Adjuvant studies with immune checkpoint inhibitors is an exciting and busy disease space, as highlighted by the following table provided by Dr. Bex:

If we assume these adjuvant studies, does it mean that we will change our attitude towards looking for lymph node metastases in cN0 patients to provide better prognostication? Based on the sentinel node study,² we know that 65% of these nodes are inside lymph node dissection templates, however, 35% are outside of typical drainage basins of which 20% are in the thoracic area:

Dr. Bex concluded his presentation of lymphadenectomy for patients with kidney cancer with the following take-home messages:

• Routine lymph node dissection in cN0 patients has not been shown to improve survival and is not recommended by guidelines
• The likelihood of occult lymph node involvement in cN0 patients is low (2% -- ? in higher risk) and does not justify lymph node dissection despite reported long-term survival
• Between 58-95% of patients with lymph node involvement harbor distant metastatic disease
• Metastasectomy of isolate lymph node metastases is unlikely to cure patients but may provide limited disease- or recurrence-free survival
• The attitude towards lymph node dissection in cN0M0 and cN1M0 patients may change if adjuvant immune checkpoint inhibitor trials demonstrate positive results

Presented by: Axel Bex, MD, Ph.D., Urologic Surgeon at the Netherlands Cancer Institute, Amsterdam, The Netherlands