ASCO 2019: Case Closed: CARMENA Puts an End to Unnecessary Surgery

Chicago, IL (UroToday.com) In this talk, Robert Uzzo, MD, discussed the role of cytoreductive nephrectomy in the post-CARMENA era. He admits that, even in his center, with excellent medical oncologists and surgeons who know their literature, there is still uncertainty on a case-by-case basis on the need for CNx. 

When you see a patient with a new diagnosis of metastatic renal cell carcinoma (mRCC), there are a couple of options in front of you and the patient:
ASCO 2019 options for new mRCC diagnosis
But, he states the obvious – sometimes it is the type of specialist the patient sees first that determines what therapy they get, unfortunately. Realistically, that should not be the case.

Surgeons and pro-CNx advocates cite the following as reasons to do CNx:
  1. Clonal deletion – by removing the primary tumor, you remove most of the clones. You decrease the source of new metastases from the primary tumor. And, in oligometastatic disease, you have the potential for complete resection.
  2. Improved pharmacokinetics – primary tumors are often not treated by systemic therapy, especially if there is central necrosis
  3. Primary tumors are immunosuppressive and pro-angiogenic – occasionally, removing them can result in spontaneous regression
  4. Symptomatic relief
Ultimately though, CNx is aggressive therapy – it's what surgeons want and its what surgeons do.

However, the field has changed. Prior to 2006, there weren’t good systemic therapy options – so it was a choice between incompletely effective surgery vs. completely ineffective systemic therapies; so CNx made sense:
ASCO 2019 past state 2006
But, now there are incompletely effective (some would argue pretty effective) systemic therapy – so the playing field has changed:
ASCO 2019 present state
As Dr. Uzzo puts it, in the patient’s mind, surgery is like playing offense (attack the tumor, remove the tumor, active treatment), while systemic therapy is like playing defense (treat and monitor, conservative management). Hence, there is an inherent need to take the offensive. But, it is important that patient education plays an important part in this decision-making process – sometimes defensive strategies can win!

He then highlighted some important findings with regards to the novel therapies currently in the first line, including ipi/nivo and axinitib/pembrolizumab – they have objective response rates exceeding 50%, and nearing 10% durable responses! More importantly, they have <2-3% treatment-related deaths – which cannot be said for CNx. Response to these agents is common, early and ongoing; survival benefits are indisputable. However, for various reasons, >50% of patients undergoing CNx don’t make it to systemic therapy. This drop-off and lack of receipt of potentially life-saving therapy are inappropriate.

He then took a step back and took a broader view. Ultimately, from Dr. Blake Cady’s “Basic Principles in Surgical Oncology,” he notes that “Tumor Biology is King.” He continues this analogy later, so remember that! We are slowly increasing our understanding of RCC tumor biology, but we still don’t understand it clearly. We know that RCC aggressiveness is somewhere in the middle of the spectrum of tumors (not as aggressive as metastatic bladder or pancreas, but not as indolent as metastatic prostate or breast). Ultimately, even within mRCC, tumor biology is a spectrum – with some patients who are rapid progressors and others who are slow progressors.

There are 2 tumor progression algorithms – Halsted and Fisher. Halstedian model would suggest a linear progression from primary to nodes to metastases (T→ N →M):
ASCO 2019 surgery then systemic RxIn this model, CNx would make sense.

However, RCC is likely more along the lines of the Fisher model, which isn’t as linear:
ASCO 2019 surgery neoadjuvant Rx

In this setting, systemic therapy would make more sense.

He does accept though that in some patients, cytoreduction and active surveillance may be appropriate, as demonstrated by Rini et al. (Lancet Oncology 2018). Yet, this leads to his next point – case selection is key.

In that prior analogy, while tumor biology is king, case selection is queen. In the original SWOG study,1 the benefit of CNx was primarily in patients with ECOG 0 performance status. Similarly, in the Heng et al2 data, patients with good risk disease had >20% survival at 5 years. In the CARMENA study, as Dr. Psutka mentioned in the first talk, 40% of the patients were poor risk and the rest were intermediate risk – hence, they were selected to probably fail.

He then spent some time talking about the series of papers by Turajlic et al. in Cell3, utilizing the TracerX Renal dataset. They assessed 575 primary and 335 metastatic biopsies, and found the following:
  1. There were few de novo mutational drivers found in metastatic sites (most came from primary) → supports CNx
  2. More rapid progression noted in cases with low primary clonal heterogeneity → argues against CNx
  3. There were tissue-specific patterns of mRCC
Ultimately, he was able to distill it into the following: patients with low clonal heterogeneity and low genomic instability were slow progressors. Those with low clonal heterogeneity, but high genomic instability were the rapid progressors.

Then, going back to clinical trials, he notes that they address the known knowns – but have no way of addressing the unknowns and remove the uncertainty completely. Therefore, in the absence of certainty, he looks to prospect theory:4
  1. Distill and simplify choices
  2. Frame the decision
  3. Estimate probability
To finish off the original analogy: biology is king, selection is queen, while unbiased judgment and surgical excellence are prince and princess – they are always looking to take over from the king and queen, but often fail to overcome the powerful forces of the king and queen.

Dr. Uzzo's final take-home slide:
ASCO 2019 CARMENA endslide
CNx isn’t dead yet – but it is probably just marginally needed, in select cases.

Presented by: Robert Uzzo, MD, BS, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References: 
  1. Flanigan et al. Nephrectomy Followed by Interferon Alfa-2b Compared with Interferon Alfa-2b Alone for Metastatic Renal-Cell Cancer. NEJM 2001
  2. Heng et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium Eur Urol. 2014 Jun 13. pii: S0302-2838(14)00494-1.
  3. Turajlic et al. Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal. Cell. 2018 Apr 19;173(3):595-610.e11.
  4. Verma et al. JAMA 2014
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