Agarwal Stresses Importance of Risk Stratification in Kidney Cancer Case Study

Samantha Hitchcock

Neeraj Agarwal, MD, recently discussed the treatment considerations and decisions he makes when treating patients with renal cell carcinoma. Agarwal, director of the Genitourinary Oncology Program, University of Utah School of Medicine, explained his treatment decisions based on a case scenario during a <em>Targeted Oncology </em>live case-based peer perspectives presentation.

Neeraj Agarwal, MD

Neeraj Agarwal, MD, recently discussed the treatment considerations and decisions he makes when treating patients with renal cell carcinoma (RCC). Agarwal, director of the Genitourinary Oncology Program, University of Utah School of Medicine, explained his treatment decisions based on a case scenario during aTargeted Oncologylive case-based peer perspectives presentation.

Case

February 2018

A 52-year-old Caucasian man presented to his physician complaining of severe left-sided back pain. The patient works full-time and travels frequently. Laboratory findings showed mild anemia, but he was otherwise within normal limits. A CT of the abdomen and pelvis shows a large left renal mass and several small lytic lesions in the lumbar and thoracic vertebrae. The patient underwent cytoreductive nephrectomy. He was diagnosed with stage IV clear-cell RCC and considered intermediate risk.

TARGETED ONCOLOGY: What are your impressions of this patient?

Agarwal:This is a 52-year-old man, otherwise very healthy, who is working full time. He has an aggressive advanced kidney cancer with bone metastases. When you see a large kidney renal mass, it usually needs to come out as the first step. Cytoreductive nephrectomy, or tumor debulking or debulking of the primary kidney mass, has been shown to improve survival in randomizes trial conducted in 1990s.

More importantly, he has symptomatic kidney masses, because it was reported that he has severe left-sided back pain. The back pain could be because of multiple metastases, but in patients such as this who have big kidney masses, those masses can cause a lot of symptoms, such as back pain, hematuria, blood clots, urinary obstruction, and others. Those are the reasons in which I would take the kidney mass out first and have this patient undergo cytoreductive nephrectomy.

This patient belongs to the intermediate-risk category. This is because he has anemia and metastatic disease at the time of initial presentation.

TARGETED ONCOLOGY: What are the criteria for risk stratification in a patient with metastatic RCC?

Agarwal:More than ever before, it is important to remember the risk criteria. Just 2 years ago, there was no need to remember risk criteria for the clinical decision making because the commonly used treatments available to our patients were not approved based on trials that risk-stratified the patients. Now, new trials and many of the drugs are going to be based on risk stratification to provide personalized medicine and individualized care.

The risk stratification includes consideration of these 6 factors (known as IMDC risk factors developed based on seminal studies done by Dr Heng and Dr Choueiri): any anemia, high neutrophil count, high platelet count, poor performance status, metastatic disease present at the time of initial presentation or less than 1 year between nephrectomy and onset of systemic therapy, and high calcium. If a patient has none of the 6, they belong to the good-risk category. If a patient has 1 or 2 of these, they belong to the intermediate-risk category, and patients with 3 or more of these belong to the poor-risk category.

This patient belongs to the intermediate-risk category because he has mild anemia and metastatic disease at the time of initial presentation, or less than 1 year between the time of nephrectomy and onset of systemic therapy.

TARGETED ONCOLOGY: Are there patients who can safely undergo active surveillance versus initiating therapy?

Agarwal:We do not have any high-level data or randomized, controlled trials to show that active surveillance is a good option versus initiating therapy immediately. In absence of that, there has been a single-center trial published in theJournal of Clinical Oncology,by Dr. Brian Rini and colleagues, suggesting that some patients could undergo active surveillance.1However, this trial was done in a high-volume and one of the top cancer centers with doctors specializing in kidney cancer.

In the community setting, if you tried to make someone undergo active surveillance they would require very close monitoring, a high level of patient education to recognize symptoms early on, and a close follow-up by a person who specializes in kidney cancer treatment. If you do not have those resources or means available, I would not recommend active surveillance on a routine basis.

There will always be some patients who have 1 lung lesion that cannot be biopsied, where you do not know 100% if this is metastatic disease. They are completely asymptomatic, but they have a lot of comorbidities and they are older. In those very small number of patients, who have negligent metastatic disease, I would favor or be agreeable to active surveillance. But this is a very small number of patients, and the vast majority of patients do not have active therapy surveillance as an option at the community level.

TARGETED ONCOLOGY: Which factors affect your decision making for therapy?

Agarwal:The factors which drive my decision making do not deal with age. Instead, risk stratification is something that I look at very carefully, especially now because it has become very important. Definitely, performance status is something I take into consideration; other than risk stratification, it drives my decision making.

Other than risk factors and performance status, I also look at the site of metastases. If somebody has liver and/or bone metastases, I know they are going to have a more aggressive disease compared with a patient who has a small number of lung metastases. If they have brain metastasis, these patients have a more aggressive disease as well.

That is my clinical perspective, but I also ask my patients about their lifestyle and how often they are willing to come into the hospital. For example, this patient is working full-time. How convenient will it be for him to come to the hospital for infusions? The patient’s preference is a big deal for me. I educate them, but I also ask them for their preference, specifically regarding oral versus intravenous (IV) therapy. Most younger patients who are working full-time or even part-time or who are living more than an hour of drive away from the cancer center tend to prefer oral therapies. On the other side, older patients who are retired or who have difficulty with the co-pays, or who do not mind coming to the hospital for infusions, may prefer IV therapy. However, even those patients like to minimize the number of doctor visits. The majority of my patients prefer oral over IV therapy.

TARGETED ONCOLOGY: What would the therapy options be for a patient who had a nephrectomy >1 year prior to onset of bone metastatic disease and belonged to good risk category? How would these options differ for this patient based on his characteristics?

Agarwal:Bevacizumab (Avastin) with interferon (IFN)-alpha is not used, mainly because of the combined toxicities of the 2 agents. IFN is difficult to tolerate, so we abandoned using this combination long ago. Additionally, the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) is not approved yet. Even if it were approved, I would not use it for good-risk patients because it was clearly inferior to sunitinib in the good-risk patient population, looking at the response rates and progression-free survival.

Cabozantinib, on the other hand, has shown to be superior to sunitinib (Sutent) in a randomized, controlled trial, which only included patients with intermediate- or poor-risk disease. Because it was [shown] to be superior to sunitinib with equivalent adverse events (AEs), my take is that all 3 tyrosine kinase inhibitors (TKIs) are acceptable for good-risk category patients: pazopanib (Votrient), cabozantinib, and sunitinib. Pazopanib is preferred for patients who are older, frail, have poor performance status, and who cannot tolerate too many AEs. As I said before, the type of metastases or the metastatic site drives my decision making regarding whether I use cabozantinib or sunitinib. If I see liver metastases or bone metastases in a good-risk patient, I tend to pick up cabozantinib. If I see only lung metastases in patients within the good-risk category, I tend to pick up sunitinib. But both are my preferred treatments over the other therapeutic options.

TARGETED ONCOLOGY: Is there still a role for interleukin (IL)-2?

Agarwal:I would say IL-2 has been used for 25 years, but the expertise [in its use] is no longer available at the most community level. Even in those few high-volume centers, the use of IL-2 is quickly disappearing. So, I do not see a role for IL-2 at the community level, particularly in light of so many new agents coming up.

He was started on cabozantinib (Cabometyx) 60 mg daily. After 1 month, he developed grade 1 hypertension, requiring medical treatment, and grade 2diarrhea, requiring dose modification. The first follow-up scan showed a significant decrease in the size of the renal mass.

TARGETED ONCOLOGY: What are your impressions of this patient at this point?

Agarwal:This patient was started on cabozantinib based on his performance status and his preference of oral therapy. Because he was working full-time, he did not want to go to the hospital for IV therapy. Additionally, he has bone metastases, and we know cabozantinib is unusually effective in patients with bone metastases. He was started on a dose of 60 mg, which is the standard initial dose. He later developed some expected AEs for cabozantinib, but, according to the scans 2 months after, he had a great response.

TARGETED ONCOLOGY: What is the toxicity management with cabozantinib?

Agarwal:Cabozantinib has a toxicity profile which is very similar to that of other VEGF TKI therapies currently approved. In fact, in the randomized, controlled trial comparing cabozantinib with sunitinib, AEs were very similar. We have to manage these patients for the typical AEs associated with VEGF TKI therapies, such as hand/foot syndrome, mucositis, hypertension, and fatigue.

We all know that these AEs respond very quickly and improve with timely dose reduction of the TKI. That is why it is important to recognize these AEs early on with proper patient education. A timely reduction, or a temporary dose hold before dose reduction, along with expedited symptomatic management may have a dramatic effect on these AEs and on the quality of life of these patients. The key is to educate patients so they can recognize these AEs early on, instead of having to wait for the next appointment with their oncologist weeks or months after. There are usually no permanent long-term AEs with these drugs.

TARGETED ONCOLOGY: What is important to know about drug interactions?

Agarwal:Most of the oral therapies in cancer have the potential to interact with multiple drugs patients may be on. It is important to establish drug interactions before starting therapy with any of these choices.

TARGETED ONCOLOGY: What is important to know about the half-life of cabozantinib?

Agarwal:Cabozantinib has a relatively long half-life of approximately 14 days. Hence, early detection of AEs and timely intervention with symptomatic management is the key. For grade 3 AEs, temporary discontinuation of the drug, followed by a restart of the drug at a lower dose, is critical. Given the long half-life of cabozantinib, that strategy of temporary breaks from the cabozantinib therapy might not be effective if you recognize those effects too late. That is why earlier recognition of those AEs are important, before they become grade 2/3, so that early institution of symptomatic management and dose reduction will have the potential to manage those effects.

References:

  1. Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial.Lancet Oncol. 2016;17(9):1317-1324. doi: 10.1016/S1470-2045(16)30196-6.
  2. Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomized trial): progression-free survival by independent review and overall survival update.Eur J Cancer. 2018;94:115-125. doi: 10.1016/j.ejca.2018.02.012.