Patient-Centered Management of Metastatic Renal Cell Carcinoma

Brian I. Rini, MD

Treatment Strategies

James J. Hsieh, MD, PhD, on the Frontline Treatment of Kidney Cancer

Hsieh is a medical oncologist at Memorial Sloan-Kettering Cancer Center.

The development of drugs that target angiogenesis and signal transduction pathways in the treatment of metastatic renal cell carcinoma (RCC) has led to improved survival rates for patients. Although these drugs are more effective and better tolerated than the older cytokine therapies, they are still associated with considerable toxicity that can severely affect patient quality of life. Effective management of treatment-related side effects is therefore paramount to effective disease management and patient quality of life.There are eight FDA-approved drugs for metastatic RCC, with most of them being approved in the last five to seven years, noted Brian I. Rini, MD, Department of Solid Tumor Oncology, Cleveland Clinic, Taussig Cancer Institute in Ohio. “Kidney cancer is a rare disease,” he said, “so the average practitioner doesn’t see that many patients per year. Therefore, he or she most likely doesn’t have the opportunity to get to know all of the drugs really well from a risk-benefit ratio and how to best give them. So, one of the important principles in patient management is to gain expertise with a particular drug and become comfortable using it, know how to dose it, when to hold dose, when to reduce dose, how to monitor/recognize side effects, and supportive care strategies to reduce toxicity.”

The COMPARZ phase III noninferiority trial, recently published inThe New England Journal of Medicine, is a case in point. In this trial, sunitinib and pazopanib, two tyrosine kinase inhibitors (TKIs), were compared as a treatment in 1110 previously untreated patients with metastatic RCC. Both treatments were shown to have similar efficacy.

Patients in the sunitinib treatment group versus those in the pazopanib arm had a higher incidence of fatigue (63% vs 55%), hand-foot syndrome (50% vs 29%), and thrombocytopenia (78% vs 41%). Patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60% vs 43% with sunitinib).

“Each drug has a somewhat unique toxicity profile" said Rini. This factor, among others, has important consequences for treatment. “For example, panzopanib would not be a treatment choice for patients with liver dysfunction. But pazopanib is a good choice when more common sunitinib toxicities such as fatigue and hand-foot syndrome would be particularly troubling to an individual patient,” he said.

Dosing Strategies: Intermittent and Alternate Schedules

This is why, Rini said, it’s better to become completely familiar with a given therapy and be reassured that efficacy is similar. Overall, there is probably more to be gained by developing a greater expertise with a smaller number of drugs rather than knowing a little bit about each of them. Patients are better served that way because none of the current drugs are considered curative, he said. Rini believes that in the long run, it is likely more optimal for a patient to receive two or three drugs that are given for the maximal duration rather than to get five or six drugs, where none of them is optimized.Avoiding unnecessary side effects is an important part of any treatment strategy. This makes managing a toxicity profile and side effects a major objective because treatment therapies are continuous. However, emerging data are challenging traditional dosing strategies, and offering new possibilities. These new strategies appear to maintain both dose intensity and patient quality of life.

“We have reported a retrospective experience demonstrating that extended treatment breaks are feasible without a reduction in efficacy. We also recently presented data at the 2013 ASCO meeting on a phase III prospective study of intermittent sunitinib. This was a trial that enrolled 36 treatment-naïve patients with metastatic RCC to look at longer break periods. Patients with 10% or greater reduction in tumor burden following 4 cycles had sunitinib held, with CT scans approximately every 10 weeks. Sunitinib was re-started for 2 cycles in those patients who had an increase in tumor burden of 10% or greater and again held if a 10% or greater tumor burden reduction was achieved. The results of the trial showed that sunitinib dosing with periodic extended time off drug is feasible and also associated with resolution of toxicity during the off periods. For some study patients, that amounted to as much as 12 months off treatment. So, for a select group of patients, some time off drug is possible. We are still trying to understand for which patients this might be the right approach,” said Rini.

Decision to Switch Therapies: Progression

There are also emerging data suggesting that an alternate strategy for sunitinib is possible. “There are data from MD Anderson, from Sunnybrook in Toronto, and from our center,” Rini said. “The data suggest that the standard 4 weeks on/ 2 weeks off schedule may not suit all patients. It might be reasonable to explore other dosing schemas—for instance, 2 weeks on/1 week off to maintain dose intensity and preserve quality of life. Of course, these are all retrospective data. A prospective study of the alternative schedule of sunitinib is in the works for the near future and should help resolve this.”Treatment for RCC is maintained with a given drug for as long as it works. “Some patients will have some response to a drug; the tumors will get smaller after they start taking it, sometimes by a little, sometimes by a lot. Often patients experience reductions in their tumor burden for a while, and then the burden slowly starts to increase. Often, a patient may meet the defined threshold for progression before we think the benefit of the drug has been exhausted, or a radiology report indicates that there’s progression,” Rini said.

But, in all actuality, Rini noted, it is not that much worse, not in an absolute sense. “It’s hard to define it in words, exactly what that looks like—but there’s progression and then there’sprogression. There’s a little bit worse and then there’s something that’s obviously a red flag: new organ sites of disease, a new disease-related problem or symptom. That’s the indication that the patient very likely needs a change in therapy.”

The Right Drug for the Right Patient

Familiarity with the disease and how it changes over time is imperative, Rini said. “Looking at your own scans can be really helpful.” The bottom line is to know the drug well enough in order to get the most out of it as opposed to a “rapid fire” trial of five different drugs. “This is where knowledge about the drug, where understanding of nuance and detail, comes into its own.”