Uzzo Shares Insight on Sequencing Surgery in RCC

Robert G. Uzzo, MD, MBA, FACS

The renal cell carcinoma space (RCC) has witnessed a shift in the role of surgery with the introduction of immunotherapy, combination regimens, and novel agents; however, it is still an important modality to consider, explained Robert G. Uzzo, MD, MBA, FACS. 

"Twenty years ago when the Von Hippel-Lindau gene was identified, nobody would have realized the monumental shift in patient care, which benefits not only longevity of life but quality of life," explained Uzzo. "Before that, it was interferon and/or clinical trials. Now we have so many therapies for patients with advanced kidney cancer."

Even with the addition of these systemic regimens, surgery continues to have an integral role, and a growing one for patients with metastatic disease, he added.

In an interview with  OncLive  during the 2019 Kidney Cancer Research Summit, Uzzo,  professor of surgery, Temple University Health System, chair of the Department of Surgical Oncology, senior vice-president, Physician Services, Fox Chase Cancer Center, discussed the evolving yet relevant role of surgery in RCC. 

OncLive: What do you see coming down the pipeline in RCC?

Uzzo: I'm a surgeon, so I spend much of my time thinking about the biology of the tumor and whether or not surgery can intervene for a therapeutic benefit. In the past, when we did not have a lot of systemic therapy, surgery usually was the answer. It may be uncommon for a surgeon to talk about a diminishing role in the management of kidney cancer; however, there is a growing role [for surgery] in patients with metastatic disease. 

A lot of new data, mostly from the CARMENA and SURTIME trials, has emerged regarding whether surgery should be upfront for patients with metastatic disease. There is recognition now that patients may be served by having upfront systemic therapy. These patients get upfront systemic therapy and then become good responders and prolonged, durable complete responses or partial responses. The question then becomes, “How do you consolidate the results of the systemic therapies with surgery?”

We are talking about the idea of lifelong therapies for people who are not cured. If we could get them to a point where they have got a significant partial response from dual therapy or from combinations, and then we could take them to the operating room and excise them, can we now give them a period of time where they are off of therapy? 

Yes, we could discuss the mechanistic aspects of new therapies that are coming down, the HIF inhibitors and other combinations and sequential therapies, but surgery is evolving. The role of surgery in patients with metastatic disease may look a lot different 3 to 5 years from now.

What factors determine whether a patient should receive neoadjuvant therapy, adjuvant therapy, or upfront surgery?

The question about adjuvant therapy and neoadjuvant therapy is something that is still not settled. There are a lot of clinical trials and level 1 evidence to suggest that we haven't hit on the right combination, certainly for adjuvant therapy. 

Right now, in the immunotherapy era, a lot of studies are asking questions, such as, “Do you need to use immunotherapy before surgery or after?” We haven't gotten to the point where we have multiple agents being used in the adjuvant setting, though there are existing trials. 

The jury is out, and it is a hard conversation to have with a person. From a surgical perspective, you bring a patient to the operating room, you remove their stage III kidney cancer—essentially rendering them surgically NED or R0. However, the risk of recurrence is high. You want to give the patient good news, but you have to temper that enthusiasm with the risk of recurrence. 

In terms of the neoadjuvant setting, most people think that based on CARMENA and SURTIME, that patients with metastatic, high-risk disease ought to have systemic therapy first. The real question surrounds the favorable-risk, young patient with lung-only metastatic disease. Most likely, there is a portion of patients who would benefit from surgery upfront followed by a potential period of time off of systemic therapy. The goal isn't just longevity but quality of life, which is impacted both by surgery and systemic therapies. 

Is there a rationale to try the combinations that are approved in the metastatic setting either before or after surgery?

Certainly, the idea is that if it works for stage IV disease, it probably works in the adjuvant setting—or it should work. The question is, “How robust of a signal can we get?” Those data take a long time to mature. I suspect that the earliest read out that we will see for immunotherapy in the adjuvant setting is going to be another 2 to 3 years. 

What other research are you a part of that you want to highlight?

One of the sessions I co-chaired at the [2019 Kidney Cancer Research Summit] was on novel delivery mechanisms. We discussed about whether there are ways to focally deliver novel systemic therapies, such as immunotherapies or nanoparticles directly injected into the tumor. Those delivery mechanisms and the engineering of them is the next frontier. 

Would you like to add anything about the Kidney Cancer Research Summit for those who could not attend this year?

The most important thing that clinicians should know about—and we do intuitively know about—the science drives the cure. This was a discussion about how the science today may look for the cure not just 10 years from now, but perhaps with a compressed time frame. We live in the year where the big data are allowing us to deliver [cures] much quicker. Clinical trials take a long time, but discovery to therapeutic benefit is compressed. That's an important point.