Q. If a patient has been identified with VHL disease, how would you characterize their risk for developing renal cell carcinoma (RCC)?
Dr Jonasch: More than 50% of these cases will develop multifocal, bilateral RCC.
Q. What are the implications when a germline mutation in VHL is identified?
Dr Jonasch: The mutation results in a number of manifestations, including hemangioblastomas, pheochromocytomas, pancreatic neuroendocrine tumors and RCC. Patients endure a lifetime of surveillance and invasive procedures.
Q. What are some of the guidelines with respect to intervention?
Dr Jonasch: The standard of care is still surgical intervention, including ablations. Patients with retinal lesions are candidates for laser and other types of ablation. Among the patients with a hemangioblastoma, there are a number of treatment considerations, including the option of surgery for RCC. With regard to management, there is the 3 cm rule. We have found that if RCC are less than 3 cm, they do not have metastatic potential. However, once they have reached 3 cm, we either recommend surgery, cryoablation or radiofrequency ablation to minimize the risk of metastases. Patients may need multiple surgeries throughout their lifetime to keep them out of trouble.
Q. Please describe the noninvasive approaches to management.
Dr Jonasch: Our knowledge of the VHL gene and its effect on biology has spurred development of antiangiogenic therapy. Bill Kaelin at Dana Farber, for example, and others have unraveled the biology of the VHL protein and led to the knowledge that this is a regulator of hypoxia-inducible factor (HIF) which, in turn, regulates VEGF (vascular endothelial growth factor). And VEGF regulates angiogenesis. So the angiogenesis blocking agents like sunitinib and bevacizumab in this setting basically arose out of the understanding of VHL biology.
Q. Do we have a favorable outlook with these agents?
Dr Jonasch: None of these agents has been FDA-approved for VHL disease. So what we’re trying to do is create a path forward for these agents. There are only a handful of centers in the world that are able to do the research, ours at M.D. Anderson being one of them. We’ve published a number papers on the medical treatment of VHL disease. And yet, it is all investigational. The big question for the future is can we validate an antiangiogenic agent? Sunitinib is too toxic. Pazopanib is better but it has its own issues. A new clinical trial has just been launched testing a novel HIF-blocking agent, PT2977.
Q. How would you encapsulate your goal in this disease?
Dr Jonasch: The bottom line or goal is to use these agents to decrease the number of surgical interventions. But using therapies that are not so toxic that that the prospects are worse than surgery. For example, after 6 months of receiving sunitinib, most patients preferred surgery. I still have close to 10 patients on a trial receiving pazopanib. They like pazopanib because it is better tolerated. And yet, I remain optimistic when I consider some of the patients on study who excellent quality of life while preventing tumor growth. We’ve really changed the lives of several of these people. KCJ