Site of Metastasis Is Significant in Renal Cell Carcinoma, Dr Daniel George Explains

Kidney cancer has a wide range of presentations and spread, and each site of metastasis has varying prognostic significance, explained Daniel J. George, MD, professor of Medicine, member of the Duke Cancer Institute, Duke University School of Medicine.

As a result, it’s important to educate patients on their risk of disease spread and the likelihood of recurrence, he added.

During an interview with The American Journal of Managed Care^® (AJMC^®), George discussed emerging therapies for renal cell carcinoma (RCC), the balance of treatment efficacy and quality of life, and the role of complimentary therapies for patients with advanced RCC.

AJMC: What are some of the most common sites of metastasis in renal cell carcinoma, and how does the location of metastatic disease impact prognosis and treatment options?

George: Kidney cancer has a wide range of presentations and spread. The most common area for kidney cancer, or renal cell carcinoma, to spread is to the lungs. Probably over 50% of our patients have lung metastasis; that's followed by lymph node, liver, and bone—round 20 to 30% for those sites of disease. Then, less commonly, we'll see metastasis to the brain, in about 10% of patients, and then, interestingly, to endocrine organs like the thyroid or the pancreas.

These different sites carry prognostic significance. Patients with liver, bone and brain metastasis have the worst prognosis. Patients with lung and lymph node and endocrine organs tend to have better prognosis; particularly, the endocrine organs tend to be associated with the longest natural history. Some of these patients living, on average, 10 years or more. This affects how we treat patients in terms of our local control sites, particularly, for brain and bone we’ll think of focal therapies to radiate and surgically remove these areas when possible. For other areas like liver, where may or may not be possible, we'll think about more aggressive treatment options including combination immunotherapies.

AJMC: What are some promising emerging therapies for treating metastatic RCC, and how do these compare to existing treatment options in terms of efficacy and safety?

George: Over the last 6 years, we've seen a revolutionary change in how we treat metastatic renal cell carcinoma, particularly in what we termed the first-line or previously untreated setting. And that's really been led by combinations of immunotherapies or immunotherapies and targeted therapies, really demonstrating significant survival benefit, particularly in patients with intermediate or poor risk features. And it's really become our standard of care.

I think new research now is looking at 2 strategies in this field. One is to combine with these regimens in order to get even greater responses, including potentially greater partial and incomplete responses, which tend to be really durable and beneficial for patients. A second approach is looking at an adaptive approach of starting with a regimen and then adding to it additional therapies. Perhaps as some treatment therapies drop off, others can come on board—there are clinical trials looking at this type of sequencing, not waiting for progression. And then lastly, there's a lot of activity in developing new targets and therapies in what we call the refractory or previously treated metastatic renal cell carcinoma setting. It's probably where most of our newest agents are being developed—agents that are targeting the vascular supply to tumors by directly blocking the hypoxia-inducible factor that, at least in clear-cell carcinoma, tends upregulated.

In addition, there's number of novel immunotherapy approaches that are being developed, recognizing that once patients have progressed on a checkpoint inhibitor, it's not clear that additional checkpoint inhibitors are beneficial. So, there's room for new immunotherapies in that setting, including other checkpoints like LAG-3 or other mechanisms of targeting the tumor immunity, whether it be bispecific antibody approaches or chimeric antigen receptor T cell, or other novel strategies. So, there’s a lot of activity in kidney cancer, particularly in that refractory disease setting.

AJMC: How do you approach patient education and communication when discussing the risk of metastasis and treatment options for patients with RCC? What resources do you recommend for patients and their families to help them understand and manage metastatic RCC?

George: Understanding a patient's risk—in terms of disease spread and metastasis—is really critical for decision making and really shared decision making with patients. So, to me, it's a critical time for patients newly diagnosed with kidney cancer, perhaps having undergone a surgical resection to meet with them and to explain the factors that we use to predict the likelihood of the cancer coming back or spreading. And those tend to be factors that involve the pathology from the surgery—the size of the tumor, the extent of the tumor. These are what we call the stage factors. And stage III criteria are really critical in addition grade. How aggressive this cancer looks under the microscope is a really important independent and additional factor to stage. And we primarily focus on those 2 factors and helping patients understand, based on those, the likelihood of this disease recurring.

And if they're stage III and particularly high grade or have some nodal involvement or other high-risk features, these are the patients we're going to talk to about adjuvant therapy, using treatment to help prevent the recurrence of disease or spread of disease. There's a proven, FDA-approved in this setting called pembrolizumab, or Keytruda, that's been beneficial. It does have side effects, and we talk about those, but the vast majority of patients are able to tolerate the therapy. And the vast majority of side effects when we saw them were low-grade. So we feel that there is a risk-benefit associated with this, that it's favorable for these patients with high likelihood of disease recurrence. And we'll talk with them about that.

I'll also refer patients to a number of advocacy sites, including the Kidney Cancer Association, which has a toolkit online that's free for patients newly diagnosed with kidney cancer. And I think it explains a lot in layman's terms of the issues we'll discuss and it also gives them resources to tap into if they have questions from either other patients or other services that could be helpful to them. I'll frequently refer them to kidneycancer.org for those resources.

AJMC: How do you balance treatment efficacy with the potential impact on quality of life when making treatment decisions for patients with advanced renal cell carcinoma?

George: When we talk with patients with advanced renal cell carcinoma about treatment, we start by focusing on goals of care. It really depends on both the patients’ goals and realistic expectations based upon their disease. And based upon that, we'll decide if this is the patient that we think we can get to a complete response. And that is a goal. We will be aggressive in treating with combination therapy with the hopes of getting the greatest response and perhaps consolidation with other treatments. We'll balance that with the side effects, but since the goals are lofty, patients are willing to tolerate side effects a little bit more.

If on the other hand, we have a patient that is particularly symptomatic from disease and has poor risk features, our goals are more around disease control in response as well as quality of life. And here we’ll also, because the patients are symptomatic, talk about an aggressive treatment approach, but we’ll tailor that to what they can tolerate and recognize the limitations both their disease and their physical conditioning put on our treatments, but we'll still want to be able to manage those toxicities.

When we get into the settings of second-, third-, or fourth-line settings of patients, our treatment goals change. We're less likely to be able to offer patients durable responses and complete remissions, and more likely our goals are around stable disease and preventing further deterioration. Their quality of life is really important, and a lot of our therapies become sort of single agent and dosed in a way that they can still tolerate and maintain their quality of life while achieving that more modest goal of disease control.

So, it does change over time, but thankfully, for many of our front-line patients, we're able to offer some real hope that these therapies can change the trajectory of their disease for potentially years to come.

AJMC: What role do complimentary therapies, such as nutrition counseling and psychosocial support, play in optimizing quality of life for patients with advanced renal cell carcinoma?

George: Advanced renal cell carcinoma is a journey. It is an up-and-down long course, and I really try to prepare my patients upfront for the highs and lows that will follow, and making sure that they have the support services they need to manage those, and it's important to have that ahead of time rather than be reactive. So kind of setting patients up with whatever counseling and support they may need. And to recognize that, some of that will change. And nutrition's a big part of this. A lot of the treatments we have will affect the gastrointestinal tract causing diarrhea and nausea. It's so important for patients to be able to maintain their nutritional status and to recognize they may have to change that in the course of things. And having that sort of partner on board is key.

I also think, having some kind of an exercise routine, however modest it may need to be during times of treatment, is important. It really creates some normalcy to their life, and it's really helpful for their physiologic blood flow and organ function and preservation of muscle and skeleton to have some regular exercise. And even very modest, mild exercise has been shown to be beneficial over no exercise. So it's another really critical part.

And then the sort of the psychological aspects to this. Some patients may have that support at home with others, some caregivers may need support. It's really helpful to have a third party that people can have a relationship with so that even if they're doing well, they may not need it, but later it's somebody they know and trust to be able to work with. So, those are all really critical aspects to the journey of kidney cancer.