Kuzel Discusses Treatment Options for Metastatic RCC Based on Risk Stratification

Timothy M. Kuzel, MD, recently spoke on the treatment decisions and consideration he makes when treating patients with renal cell carcinoma. Kuzel, chief of the Division of Hematology/Oncology, deputy director of Rush Cancer Center, Rush University Medical Center, explained his treatment decisions based on 2 case scenarios during a <em>Targeted Oncology </em>live case-based peer perspectives presentation.

Timothy M. Kuzel, MD

Timothy M. Kuzel, MD, recently spoke on the treatment decisions and consideration he makes when treating patients with renal cell carcinoma (RCC). Kuzel, chief of the Division of Hematology/Oncology, deputy director of Rush Cancer Center, Rush University Medical Center, explained his treatment decisions based on 2 case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.

Case 1

February 2018

A 52-year-old Caucasian man presented to his primary care physician complaining of severe left-sided back pain. The patient worked full-time and traveled frequently. His laboratory findings are within normal limits, but a CT of the abdomen and pelvis showed a large left renal mass. The patient underwent nephrectomy.

More than 1 year after nephrectomy, he developed several small lytic lesions in the lumbar and thoracic vertebrae and a 3-cm lung lesion. He was later diagnosed with stage IV clear-cell RCC, favorable-risk disease.

Targeted Oncology: What are the criteria for risk stratification in a patient with metastatic RCC?

Kuzel:Generally, in my practice, I use one of the 2 current risk stratification models. For every new patient I see with metastatic clear-cell RCC, I use either the criteria that Robert J. Motzer, MD, developed for Memorial Sloan Kettering, which look at 5 clinical features: poor performance status, over 1 year from nephrectomy to systemic treatment, hypercalcemia, anemia, and high lactic acid dehydrogenase; or I use the criteria that Daniel Heng, MD, developed for the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. There are 6 features: poor performance status, over 1 year from nephrectomy to systemic treatment, hypercalcemia, anemia, neutrophilia, and thrombocytosis. I use those 2.

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

I do consider following patients with close observation for select patients with metastatic newly diagnosed clear-cell RCC. Brian Rini, MD, at the Cleveland Clinic, has published a fairly large series demonstrating that this is a reasonable approach for some patients.1

The criteria I tend to use [for active surveillance] would be a patient with favorable-risk metastatic disease and, generally, a very limited burden of disease. Several to multiple small pulmonary nodules or several borderline enlarged lymph nodes would be characteristics of a patient that I might consider. Probably an older patient, with multiple comorbidities, might be a good patient to consider for observation as well.

This patient developed lytic lesions in his bones more than 1 year after his nephrectomy. So I would not consider this [patient for] active surveillance because of this presence of multifocal bone lesions. That would be the biggest reason I would not suggest it.

What treatment therapies would you consider for this patient with newly diagnosed intermediate-risk metastatic RCC?

In this case, I would advocate for active treatment. I would certainly have a discussion about all the different options for patients. However, with the recent randomized clinical trial showing a favorable survival benefit for patients receiving combination immuno-oncology (IO) therapy compared with sunitinib (Sutent),2I think that for a younger patient without any prior autoimmune history, that would be a very reasonable option for this patient who would be intermediate risk based on his presentation.

The IO combination is intravenous. If for some reason the patient had a strong bias against receiving intravenous therapy, or the patient had a preexisting autoimmune disease for which I didn’t feel the risk benefit was the same, then certainly an oral agent would be a reasonable alternative.

In reality, cabozantinib, in terms of the oral tyrosine kinase inhibitors (TKIs), has a [progression]-free survival benefit over sunitinib and, by extension, pazopanib (Votrient). The cabozantinib (Cabometyx) trial included only intermediate- and poor-risk patients but does have a broad label. So it could be considered for favorable-risk patients. Sunitinib and pazopanib could similarly be considered for favorable-risk with category 1 National Comprehensive Cancer Network designations. I, personally, do not use the bevacizumab (Avastin)/interferon (IFN)—α combination because the IFN-α toxicities really affect quality of life. And if we are going to choose an IO combination, nivolumab (Opdivo)/ipilimumab (Yervoy) would be the one to go with.

Is there still a role for high-dose IL-2?

A third option would be the consideration for high dose IL-2 as another immunotherapy option. There are no randomized data supporting that, but it does appear that high-dose IL-2, if it is going to be administered, may be reasonable to administer prior to any other therapies.

The patient was started on cabozantinib at 60 mg daily. After 1 month, he developed grade 1 hypertension, requiring medical treatment, and grade 2 diarrhea, requiring dose modification. His first follow-up scan showed stable bone lesions and reduction in size of the lung lesion to 2 cm.

What should oncologists know about toxicity management with cabozantinib in RCC?

The [toxicity management for] patients with cabozantinib is similar to [that for] all patients on a TKI. Fatigue is a significant issue with many of the drugs, including cabozantinib. Loose bowel movements or diarrhea can be an issue for many patients. Similarly, some patients will develop clinical or lab manifestations of hypothyroidism. Certainly, in the early trials, there were some concerns regarding cardiac toxicity with declining ejection fractions. So some attention to cardiac function is probably important. Also, issues around discomfort on the palms, soles, and pressure points can be an issue with all the TKIs.

Most of those adverse effects (AEs) will be improved with dose reduction. That should be considered for appropriate patients, especially adults who are having antitumor benefits. Dose interruption should be considered for anyone who is experiencing intolerable AEs or anybody with grade 3 or 4 toxicities.

What is important to know about drug interactions?

They are plentiful. All these drugs have drug interactions, and ideally, you would identify one of these agents that you feel very comfortable with and use it whenever possible so that you can learn the spectrum of drug interactions that exist and be aware of them when you are prescribing these agents.

Case 2

March 2017

A 73-year-old woman was diagnosed with clear-cell RCC, hyperlipidemia, and type 2 diabetes, which are both managed medically. Her baseline patient and disease characteristics were: ECOG performance status of 1; Karnofsky performance status of 90; 5-cm left kidney tumor mass with extension into the left renal vein; pT3bNxM0 (AJCC stage III disease). She underwent radical nephrectomy within 1 month of diagnosis.

December 2017

Nine months later, the patient reported loss of appetite and weight loss. CT imaging later showed multiple liver lesions, 2 small nodules in the right lung upper lobe, and mediastinal lymphadenopathy. Her laboratory findings were notable for: hemoglobin, 11.5 g/dL; calcium, 14.8 mg/dL. She had a PD-L1 expression, 2%. It was found that she had RCC disease recurrence, IMDC intermediate-risk.

What are your general impressions of this patient?

This is an older patient with intermediate-risk clear-cell RCC. Within 1 year of her nephrectomy, she develops weight loss, loss of appetite, and insomnia. There is new metastatic disease in her liver and lung, as well as lymphadenopathy, and she is hyperglycemic. So this is certainly a much more aggressive disease. The disease is intermediate risk in terms of the stratification. This is not a patient whom you would consider giving IL-2 to.

What are the treatment options for this patient?

Probably, the first step would be to control her hypercalcemia. That may change her performance status and may significantly improve the way she feels as you’re deciding on a definitive treatment strategy. At that point, for intermediate-risk patients, there are several different options.

The randomized clinical trial data with the nivolumab/ipilimumab combination has shown a survival benefit compared with sunitinib. And in a randomized phase II trial, cabozantinib has shown a relapse-free survival benefit over sunitinib.3In general, for someone like this, I am going to talk about the relative benefits and tolerability of an oral versus intravenous approach. I think this woman has aggressive disease. If her performance status looks good after correcting her hypercalcemia, I would probably encourage her to consider the IO combination up front to try to give her both median and long-term survival.

The patient was started on nivolumab/ipilimumab, but she developed grade 2 diarrhea.

What type of monitoring will be required for this patient?

The patient clearly needs to be monitored for the AEs that are associated with any of the immune-mediated therapies, any AEs that would be consistent with a new autoimmune problem including endocrinopathies, pneumonitis, hepatitis, and colitis.

This patient develops grade 2 diarrhea, which can be awfully hard to sort out, between mild and intolerable, because of true autoimmune colitis. So you have to keep a high threshold for suspicion and think about evaluating the patient either with a colonoscopy and definitely with the usual diarrhea evaluation to assess for the severity of that problem.

Are you using nivolumab/ipilimumab in your practice?

I do use the combination. You have to have a healthy respect for the potential of AEs if you are going to use this regimen in practice and be ready to manage them 24/7 when you administer these agents.


  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. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.N Engl J Med. 2018;378(14):1277-1290. doi: 10.1056/NEJMoa1712126.
  3. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial.J Clin Oncol. 2017;35(6):591-597. doi: 10.1200/JCO.2016.70.7398.