EAU 2019: Surgery for Non Seminoma Clinical Stage 1 High Risk

Barcelona, Spain (UroToday.com) In the debate for the testis cancer (TCa) session, the focus was the role of surgery for men with clinical stage 1 high-risk nonseminomatous germ cell tumor (NSGCT). Dr. Daneshmand argued for Retroperitoneal lymph node dissection (RPLND), while Dr. Nichols argued against. As a caveat up front, these arguments don’t necessarily reflect their practice – Dr. Daneshmand offers surveillance to many of these men, and Dr. Nichols is a high volume surgeon who does complete primary RPLND for some of these patients.

Men with clinical stage 1 NSGCT have 3 main treatment options at this time: surveillance (AS), RPLND, or adjuvant chemotherapy (AC). The main point made by both individuals is that, regardless of treatment choice, overall survival for these patients exceeds 99%. So, for the most part, these patients do really well. As Dr. Nichols nicely put it, “while the destination is the same for all these men, it’s the pathway to get there that changes.”

Much of what was presented by both speakers overlapped, particularly their premise on the need for treatment over AS. First, they both highlighted the definition of “high-risk” CS1 NSGCT. The two main risk factors for higher rates of relapse in men with CS1 NSGCT are the presence of lymphovascular invasion (LVI) and presence/percentage of embryonal histology on the primary tumor. Both agreed that LVI is the primary driver, while percentage embryonal histology is a not as clear (conflicting reports). Dr. Sheinfeld (MSKCC, USA) later commented that it is probably more a reflection of the volume of embryonal rather than a percentage.
  • Without either feature, the recurrence rates are ~20%
  • With both features, recurrence rates are about ~50%
As a result, high-risk CS1 may warrant upfront treatment rather than AS. Additionally, AS requires the following: patient acceptance, patient compliance, availability of cross-sectional imaging.
  • Daneshmand highlighted the anxiety that men have on AS prior to each appointment and scan, as reported by Thompson et al. (Annals of Oncology 2010)
  • He also mentioned a few times that, while we talk about “compliance,” we have no good way of accurately identifying who will be compliant and who will not – so this is a tough thing to document/measure, and should not be used in the decision-making process easily
PRO:

Dr. Daneshmand’s focus was on the toxic effects of chemotherapy, much of which is known and well documented. Avoiding chemotherapy is a primary driver of the reason to move forward with RPLND.

First, he highlighted the fact that modern RPLND is not nearly as morbid as it used to be. He has previously presented on his experience with a smaller incision open extraperitoneal RPLND (Kim et al. Surgical Techniques in Urology). Many of his patients go home now POD #1, are tolerating a diet the day of surgery and do very well. In general, modern day primary RPLND is associated with 1-2 day hospital stay and no real long-term complications (<2% ejaculatory dysfunction, small bowel obstruction, etc).

In contrast, chemotherapy has significant short and long-term toxicity, that has been well documented.

  • Short term toxicity with chemotherapy: >30% have grade 3-4 toxicity
  • Toxicity is dose-related
  • Long-term toxicity for 3 cycles BEP (treatment of recurrence and metastatic disease) is now well documents and includes: increased cardiovascular disease, secondary malignancy (Travis et al. JNCI 2005), Raynaud's phenomenon, impaired hearing, among others
  • He does concede that single-dose or 2-dose adjuvant chemotherapy doesn’t have as much long-term data – but presumably would still carry increased risk compared to no chemotherapy
He then used the following flowchart to highlight the potential breakdown of how 100 high-risk CS1 patients undergoing primary RPLND may fare:

EAU2019 UroToday RPLND


50% will be upstaged to Stage 2. 50% will stay CS1. Following this flowsheet out, of 100 patients, 26 patients will likely require chemotherapy subsequent to RPLND – most requiring 3 cycles BEP, a few requiring just 2 cycles.

Using known estimates of recurrence, he noted the following:

  • If all these men undergo RPLND, 25% will require dual treatment, and 50% were probably overtreated
  • If all underwent surveillance, 50% will require chemo (all 3 cycles BEP), ~10% will get both chemo+RPLND, and there will be no overtreatment
  • If all receive 2 cycles BEP adjuvant therapy, 100% get chemo (but only 2 cycles), ~2% will also need an RPLND, and 50% will be overtreated
So, either choosing RPLND or AC, there will be 50% overtreatment – but, in his mind, the relatively less morbid RPLND with no long term side effects is the better choice.

CON:

Dr. Nchols first started by addressing the concept of AC. There is increasing evidence that BEPx1 may be just as effective as BEP x2, potentially reducing both short and long-term complications. Unfortunately, long-term data is not yet available. SWENOTECA (Sweden/Norway) and 111 Study (UK) both address this question, and at least preliminarily, there is a low recurrence rate of 2% with single-dose BEP.

Next, he highlighted the fact that the RPLND outcomes cited by Dr. Daneshmad represent the outcomes of high volume centers with significant expertise – and this likely doesn’t reflect true general practice. He noted that ~50% of RPLNDs in the US are done by surgeons who do <1 RPLND/year – and they are likely not achieving the same cleanout as expert centers. In which case, their retroperitoneal relapse rate is likely to be much higher than reported – and those patients will require BEPx3.

He made a distinction to separate BEP x 3 from adjuvant chemotherapy (BEP x 1 or 2), as he feels the associated complications are much higher for BEP x 3. As such, he repeated the 100 patient scenario that Dr. Daneshmand presented – 100 men with high risk CS1 NSGCT.

  • Men on AS - ~50% will eventually need BEP x 3
  • Men receiving RPLND - ~18-25% will eventually need BEP x 3
  • Men all receiving adjuvant chemotherapy – only ~2-3% will need BEP x 3
An important distinction is he is looking at specifically BEPx3 as an outcome, while Dr. Daneshmand looked at any chemo usage.

Ultimately, as both mentioned, it is a discussion with the patient and weighing patient risk/concern for recurrence, clinical and histological features. Both states that only men with both LVI and embryonal would warrant early treatment – and that men with just one or the other, they would probably lean towards AS.

Presented by: 
PRO: Siamak Daneshmand, MD, Associate Professor of Urology (Clinical Scholar); Director of Clinical Research, Keck School of Medicine of University of Southern California
CON: D. Nichols (United Kingdom)

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 34th European Association of Urology (EAU 2019) #EAU19 conference in Barcelona, Spain, March 15-19, 2019.

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