Kidney Cancer Journal 15
blocks FGFR in addition to VEGF receptors. Unfortunately,
this study was closed after six patients were enrolled
as the toxicity stopping rule was met, mainly
because of the development of rash. No responses were
observed and this agent was not considered for further
development in this indication.
Pazopanib
Efforts to avoid unnecessary surgery for asymptomatic
cerebellar hemangioblastomas have also focused on the
use of pazopanib. Three case reports have helped provide
an avenue for further investigation of this TKI in this setting.
The first report from MD Anderson by Kim et al12
provided evidence demonstrating clinical and radiological
anti-tumor response using pazopanib in a patient with
treatment-refractory VHL-associated CNS hemangioblastoma.
Treatment with 800mg/day of pazopanib resulted
in significant neurologic improvement and radiologic
tumor volume reduction in a 47-year-old African-American
male. This case report represented the first time any
agent had demonstrated clinical benefit for CNS hemangioblastomas.
With the exception of neutropenia, the patient
experienced only mild adverse events (grade 1 and
2.)
In a second case report, Swiss authors17 reported on
pazopanib treatment in a 37-year-old female patient with
recurrent and rapidly progressive VHL-associated hemangioblastomas
that caused severe disability. A 24-
month treatment with pazopanib achieved progressive
improvement in her condition. Radiological findings did
not show significant changes in the size of target lesions
and did not reveal any new lesion in contrast to the continuous
multifocal progression prior to therapy. The report
offers further evidence supporting the use of a TKI in
this setting and underscoring the rationale of such treatment
because RCC harbors the same molecular abnormalities
as CNS hemangioblastoma. A third, more recent
case report demonstrated heterogeneous response in a patient
with multiple CNS hemangioblastomas.18
We presented a phase II study testing pazopanib in
VHL patients (NCT01436227) at the 2017 ASCO meeting.
19 In this trial, 31 VHL patients were treated with pazopanib.
The objective response rate was 42%, with a
greater than 50% response rate in RCCs and in pancreatic
lesions. Hemangioblastomas demonstrated a response
rate of 4%, but disease stabilization was noted in
a number of patients. Two cases of bleeding were reported
in hemangioblastomas. This study represents the largest
prospective study using an antiangiogenic agent in VHL
patients, with a number of individuals remaining on
study for several years.
Treatment of Retinal Hemangioblastoma
Treatment of retinal hemangioblastomas with intravitreal
Tracing the Origins of VHL Disease
to the Work of Two Physicians
The investigative work of two physicians began more
than 100 years ago, each working independently and
unaware of the other’s research. Today, the condition
they observed bears both of their names, reflecting the
discoveries of these two pioneers. They were Eugen
von Hippel and Arvid Lindau. When their revelations
were further validated, the disease became known as
von Hippel-Lindau (VHL) disease.
In 1904, Eugen von Hippel , a German ophthalmologist,
described a rare disorder of the retina, and in 1911
discovered the anatomical basis of this disease, which
he named "angiomatosis retinae". However, it was not
until 1926 that Swedish pathologist Arvid Lindau recognized
an association between angiomatosis of the
retina with hemangioblastomas of the cerebellum and
other parts of the central nervous system. Thus the
condition is known today as VHL disease.
Lindau was the first to describe a coherent link between
the retinal, cerebellar and visceral components
of a disease he called "angiomatosis of the central
nervous system". This disease is characterized by tumors
of the retina and the brain, along with cysts and
tumors of several visceral organs such as the kidneys,
pancreas and adrenal glands. Lindau's research soon
attracted the attention of famed neurosurgeon Harvey
Cushing, who named the disorder, "Lindau's disease".
By 1964 the medical community had become more
aware of early 20th century research on retinal angiomata
conducted by von Hippel, and both men were
recognized for their contribution in describing the condition.
Eugene von Hippel Arvid Lindau