Risk Stratification in Renal Cell Carcinoma


A historical overview regarding the development of parameters used to help stratify risk in patients with renal cell carcinoma and the relevance of current models in the context of selecting systemic therapy to treat appropriate patients.

Robert Alter, MD: When a patient presents to the office and you are given the luxury of having some laboratory analysis, you should already try to risk-categorize your patients. Think about how we have done it in the past, going by a gut feeling, or whether we think the patient can tolerate it. But many of these risk categorizations are important to not only define the patients’ risk but also our treatments.

Dating back to the initial immunotherapy clinical trials, the MSKCC [Memorial Sloan–Kettering Cancer Center] risk categorization first presented by Robert Motzer, [MD,] utilizes parameters including patient’s functional performance status, time from initial diagnosis to first therapy, and other parameters including hemoglobin, LDH [lactate dehydrogenase], as well as calcium level. When the patients come to your office, you already have seen the patient’s functional performance status.

You already know the time of diagnosis to when you first see the patient in therapy, and you have a CBC [complete blood count]. Automatically, you have 3 of the 5 parameters to define the patients’ risk. Favorable risk patients are those who have no risk factors. I define risk factors as elevated calcium levels, hemoglobin that’s less than 12 [g/dL], and LDH greater than the upper limit of normal. If you have 1 to 2 risk factors, you are at intermediate risk, and if you have 3 or more, then you are at a high risk.

More recently, Daniel Heng [MD, MPH] has formed the International Metastatic Renal Cell Carcinoma Database Consortium criteria, or the IMDC, which utilizes most of those same factors. It utilizes the patients’ functional performance status, time from diagnosis to initial therapy, hemoglobin level, as well as calcium level. But they removed the LDH, and they are now utilizing the number of white blood cells and platelets as a measurement. They consider both an elevated white blood cell count and an elevated platelet count. Usually, those conditions are signs of inflammatory processes, most likely due to the tumor.

Under their categorization, if you have no risk factors, you’re considered to be of favorable risk. If you have 1 to 2 risk factors, then you are of intermediate risk. If you have 3 or more risk factors, you are considered to be at poor risk. This is important because the new NCCN [National Comprehensive Cancer Network] guidelines have incorporated the risk categorization of patients and have determined whether their therapies may be beneficial to these patients. 

After analyzing the data to define the risk categorization and looking at more recent clinical trials like CheckMate 214 and the KEYNOTE-426, we have been given more insight into and recommendations on how to treat these patients. It is a simple task, since there is a nominal amount of effort, but it is quite important for patient care.

Robert Motzer, MD: Risk models have been described for advanced RCC [renal cell carcinoma], primarily in first-line treatment, and are important tools for the clinician. They aid the clinician in assessing prognosis, assessing outcome to clinical trial, and now, directing treatment. The first model was a model that I developed with my colleagues at Memorial Sloan Kettering, called the MSKCC model. It was developed in the cytokine era. Most of the patients had treatment with interferon, interleukin-2, or clinical trials with those drugs. We developed that because people were making comparisons between outcomes at various centers with interferon or interleukin- 2, and they were noticing that this trial is reporting much better results than a trial done at a different center. 

There really was no language that could be used to assess the relative prognosis in that group. That was one of the driving factors behind the creation of the MSKCC model. The other was to utilize it for stratification factors in phase 3 trials. We initially developed the MSKCC risk group. It was based on 5 preclinical factors that all predicted a short survival. They included anemia, high calcium, low performance status, and a high lactate dehydrogenase level. We also considered prior nephrectomy at first, but that was changed to diagnosis from treatment to start of therapy of less than a year. 

That was the first system that we were able to categorize patients by 0, 1, 2, or 3 or more risk factors into favorable, intermediate, and poor risk groups. That was revisited in the targeted therapy era by Dr Heng and Toni Choueiri, [MD]. They developed the international criteria that we use. It was a modification of the MSKCC, whereby the lactate dehydrogenase came out of the model, and instead they consider high platelet and neutrophil counts. That fits patients in the targeted therapy era much better, and that system has been used in studies to evaluate the new IO [immune oncology] combinations. It has proved predictive in that setting. Based on those criteria, there has been some differential outcomes for IO therapy versus TKI [tyrosine kinase inhibitor] therapy, which is now used to direct and drive treatment.

Transcript edited for clarity.

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