velopment of screening guidelines to identify patients
with germline mutations in the absence of secondary
clinical manifestations that are at highest risk for potentially
lethal disease manifestations. As we learn which elements
are necessary to engender early-onset RCC in
syndromic patients, it could help identify persons who
have an increased risk of developing sporadic RCC.
12 Kidney Cancer Journal
Understanding VHL Disease, its Genetic
Underpinnings, and Pathophysiology
Clear cell RCC can be sporadic (>96%) or familial (<4%).
Almost all familial clear cell RCCs arise from an inherited
mutation in the VHL tumor suppressor gene located on
chromosome 3p.3 Patients with VHL disease develop kidney
cysts and multiple bilateral clear cell RCC at an average
37 years of age.4 The second VHL allele has been
shown to be inactivated by deletion and less commonly
Encapsulating VHL Disease and
Seeking to Optimize Outcomes
In this brief interview, Eric Jonasch, MD, offers a perspective
on some of the key issues related to von Hippel-Lindau (VHL)
disease and the prospects for noninvasive approaches to
treatment.
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 inter ventions. But using
therapies that are not so toxic that that the prospects are
worse than surger y. For example, after 6 months of receiving
sunitinib, most patients preferred surger y. 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.
I N T ERVIEW