Less than 20 years ago, an individual with stage IV kidney cancer had few options: interferon or IL-2 immunotherapy with or without upfront cytoreductive nephrectomy (CRN).

Outcomes with either treatment were poor, with a median overall survival of 8 months for immunotherapy alone and 14 months when combined with surgery.1

Around 2006, the field underwent its first major breakthrough with the introduction of multitargeted tyrosine kinase inhibitors (TKIs). Suddenly, the median overall survival rates doubled to between 24 and 30 months depending on other risk factors.

On October 1, 2018, the Nobel Prize in Physiology or Medicine was jointly awarded to Drs James Allison (USA) and Tasuku Honjo (Japan) for their discoveries of immune checkpoint inhibitors. Sentinel work performed by Dr Allison on the T-cell protein CTLA-4 and separately by Dr Honjo on PD-1 expressed on the surface of T cells led to their discovery of effective cancer therapies by inhibition of negative immune regulation: in other words, reinvigorating an antitumor immune response. Just 6 months earlier, the results of the Checkmate 214 trial were published. The study showed that in a population of primarily intermediate- to poor-risk metastatic renal cell carcinoma (RCC), treatment with the combination of ipilimumab (a CTLA-4 inhibitor) and nivolumab (a PD-1 inhibitor) was associated with a nearly 10% complete response rate and a median overall survival that had not been reached at the time of publication!

In just over a decade, overall survival for metastatic RCC has increased 3- to 4-fold, forcing physicians to reassess the role of extirpative surgery for stage IV disease. Importantly, the recently published CARMENA trial noted that upfront systemic therapy with an oral TKI was noninferior to CRN followed by systemic therapy in selected intermediate- to poor-risk patients.2 While caveats exist, the trial demonstrates that refinements in surgical thinking must occur in parallel with improvements in systemic therapies.

The speed of the evolving science and therapeutics in RCC is staggering. Most physicians do not see such incremental benefits and new treatment paradigms in their entire career, but in kidney cancer, we are seeing incredible progress in only a fraction of our own careers, and this progress is expected to keep accelerating.

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Robert G. Uzzo, MD, FACS is G.Willing “Wing” Pepper Chair in Cancer ResearchProfessor and Chairman, Department of SurgeryFox Chase Cancer CenterTemple University School of Medicine, Philadelphia 

Reference

1. Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastaticrenal cancer: a combined analysis. J Urol. 2004;171:1071-1076.2. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cellcarcinoma. N Engl J Med. 2018;379:417-27.