Answer: The optimal first-line therapy for kidney cancer is still up for debate. What's described here is a relatively typical patient with kidney cancer, with what sounds like bone-only metastases. This presentation is relatively uncommon, but we certainly see it.

There is general consensus in the US that sunitinib,^1-3 pazopanib,⁴ and bevacizumab/interferon^5-7 are all reasonable front-line standards of care, based on the most robust clinical data and their side effect profiles (Table 1).⁸ We're waiting for a trial of sunitinib versus pazopanib that may inform that decision a little more, but, of course, there are not trials of every drug versus every other drug, so we really don't have definitive comparative data.

The issue of bone metastases is an interesting one. It seems that when patients with RCC fail their front-line therapy, they tend to do so preferentially in bone and brain. This observation comes from retrospective studies and isn’t definitive, but it suggests that the activity of these agents is perhaps less in those organ sites.

At this point, we do not have any bone-targeted therapy for patients with RCC. Radiation is most often used for alleviating pain and other problems caused by symptomatic bone metastases. The use of bisphosphonates in these patients has been explored, with mixed results.^9-11 Unfortunately, the large trials of pamidronate, zoledronate, and now with denosumab haven't really included many kidney cancer patients; so, we don't know whether there really is an effect in these patients. My general practice is to use those drugs in patients with more extensive bone disease but not necessarily a single bone metastasis. But, that remains an unanswered question.

This patient has a number of options. If he is not eligible for a clinical trial—which he may not be because bone metastases are not measurable— then I think that sunitinib, pazopanib, or bevacizumab/interferon would be reasonable choices. We treat people with metastatic disease until they fail to respond or have toxicity. In someone with bone-only disease, that becomes difficult to judge. If all their disease is controlled and they have one new area that flares, is that really progression or not? That can be very hard to determine. The important thing is to not give up on any individual drug too soon. With our patients who have bone metastases and metastases to other organ sites, we will treat any worsening areas with radiation or other means but continue their systemic therapy.

Although there are many drugs available to treat RCC, the list is not unlimited. Our general practice is to drag our feet in changing therapy if we think there is still benefit with the existing drug. Many side effects, such as hypertension, mucositis, blood count problems, skin toxicity, and diarrhea can be managed without dose reduction. There are drugs to approach each of those toxicities; they are not always successful, but we can make the attempt. Once the severity reaches grade 3 or higher, though, dose reduction may be necessary. Fatigue and hand-foot syndrome do require dose reduction when they get severe enough. We really don't have great ways to manage them.

Back to top

Answer: The issue of treatment-refractory kidney cancer is even less certain than front-line kidney cancer. Temsirolimus is certainly the most data-supported treatment of choice for poor-prognosis patients.^12,13

Having said that, I think a lot of poor-prognosis patients are probably also getting tyrosine kinase inhibitors like sunitinib. So, I think the initial sequence in this patient was very rational.

There is no obvious next step here, and by that I mean there are no data that would necessarily support one drug over another drug (Table 2). The only phase 3 data currently available in the refractory setting are with everolimus.¹⁴ Those patients had not gotten prior temsirolimus, as you can imagine, and that was only compared with placebo; so, I'm not sure those data help us here. Nor would I give another m-TOR inhibitor to someone with pneumonitis. So, I think the options are the available VEGF inhibitors, which would be sorafenib,¹⁵ pazopanib,⁴ or bevacizumab/interferon.¹⁶

Choosing among those three therapies is more a question of practical considerations than science. Pazopanib and sorafenib are available orally, while bevacizumab is administered intravenously. Pazopanib and sorafenib have comparable toxicity profiles. Pazopanib may be associated with more liver toxicity and sorafenib with more hand-foot syndrome, alopecia, or diarrhea. Depending on what toxicity or comorbid conditions this patient has experienced, we might select one versus another, but it's an empiric decision. The reality is that this patient is likely to get more than one of the remaining therapies depending on the bulk and pace of disease; so, it's really a matter of choosing which one you'd go to first.

Even in this poor-prognosis patient, we are going to treat to toxicity or progression. He is going to need constant treatment. In a patient with very good prognosis who has indolent disease, we've stopped therapy when patients have had great responses and observed them, but that’s strictly investigational and not at all a standard way to do things.

Back to top

Answer: Certainly, that's the next big question in kidney cancer: can we use targeted therapies earlier in disease? The short answer to this question is: no, targeted therapy does not have a role in this setting at this time. It’s understandable that we want to do something, since this patient has an extremely high risk of progression. But, there are no data whatsoever to support giving him targeted therapy—or any therapy—in this setting at this time. There would be nothing to monitor to know if the patient is benefiting from the treatment. These drugs can have life-threatening side effects; so, we would never treat a patient without evidence that the benefits outweighed the risks.

Targeted therapy with sorafenib or sunitinib in the adjuvant setting, after nephrectomy, is being explored in clinical trials.^17-19 These trials are still recruiting, and thousands of patients in total will be randomized. We're all interested in these results, but it's going to be at least 3 years before we have them.

There are no clinical trials of targeted therapy before surgery in patients with resectable disease, although there has been discussion. So, for this patient the best course is nephrectomy, surgery, or radiation on L3, and then monitoring. After nephrectomy, all we can do is observe this patient, realizing, of course, that he is likely to have a recurrence within several months. Depending on the nature of and time to recurrence, we continue with this sort of localized “cherry picking” approach to treating disease.

Back to top