From OncoLog, December 2003, Vol. 48, No. 12
On the Move: Efforts Under Way to Improve Outcomes for Patients with Renal Cancer
by Dawn Chalaire
Renal cell carcinoma (RCC) has long been a challenge for researchers and clinicians alike, but the prospect of an uphill battle to improve outcomes for patients has not dampened the enthusiasm of faculty at The University of Texas M. D. Anderson Cancer Center. They have instead responded with an all-out assault against the disease: less-invasive treatments for localized tumors, studies of promising adjuvant agents, innovative therapies for patients with metastatic disease, genetic and epigenetic research to find new treatment targets, and data acquisition technology that integrates tissue collection and storage with patient information and data from laboratory studies and clinical trials.
Less-invasive treatments
for localized tumors
For small, incidental tumors, the trend of late has been toward procedures that are less invasive and that spare more of the kidney. For the past 15 years or so, partial nephrectomy, in which the tumor and a margin of surrounding tissue are removed but the remainder of the kidney is left intact, has been offered at M. D. Anderson and elsewhere. Partial nephrectomy is used primarily in cases of small peripheral or exophytic tumors; it also can enable patients who have poor renal function or only one kidney to undergo surgery. Surena Matin, M.D., an assistant professor in the Department of Urology, is developing a technique for performing partial nephrectomy laparoscopically in selected patients.
Kamran Ahrar, M.D., an assistant professor in the Department of Diagnostic
Radiology, is examining the role of percutaneous radiofrequency ablation
to treat small renal tumors. Researchers are also looking at ways to perform
cryoablation percutaneously using magnetic resonance imaging for guidance.
Laparoscopic renal cryoablation is already being performed on tumors that
are not accessible percutaneously.
For localized tumors that are not amenable to partial nephrectomy, radiofrequency
ablation, or cryoablation, laparoscopic radical nephrectomy may still
be appropriate. The primary advantage of a laparoscopic procedure over
open surgery is a decrease in morbidity, according to Christopher Wood,
M.D., an assistant professor in the Department of Urology and one of the
busiest renal surgeons in the country.
“Laparoscopic nephrectomy is rapidly becoming the gold standard
in the country,” Dr. Wood said, “but it’s not an easy
operation to learn, and clearly, experience matters.”
Studies of adjuvant therapies
After years of multi-institutional trials investigating the role of agents
such as interferon and interleukin-2 in the adjuvant setting, there is
no standard adjuvant therapy for RCC. However, two ongoing clinical trials
are investigating promising alternatives.
In one randomized, multicenter trial of patients at high risk for recurrence,
heat shock protein peptide complex 96 (HSPPC-96) vaccine, made from each
patient’s own tumor, is being administered postoperatively. The
other trial looks at the role of thalidomide in the adjuvant setting.
Both HSPPC-96 and thalidomide have shown activity in metastatic RCC and
have acceptable toxicity profiles.
Innovative therapies for metastatic disease
For patients with metastatic renal cancer, the emphasis is on developing
novel therapies. Response rates to immunotherapy with interleukin-2 or
interferon—the standard of care in metastatic RCC—vary from
5% to 25%; but durable responses are rare, and the median survival duration
is only 12 to 16 months.
Laboratory studies suggest that in the case of interferon for RCC, lowering
the dose may actually improve response. In a recently closed clinical
study, investigators in the Department of Genitourinary Medical Oncology
are testing this hypothesis by comparing the efficacy
of a continuous, low-dose infusion of interferon with that of the standard
intermediate dose in patients with metastatic disease.
Other studies include an assessment of the efficacy of capecitabine combined
with gemcitabine in patients with advanced RCC who have been previously
treated with immunotherapy and an investigation of the effects of interleukin-2
and thalidomide on bone metastases. Several additional clinical trials
are on the horizon, according to Eric Jonasch, M.D., an assistant professor
in the Department of Genitourinary Medical Oncology.
Another issue for patients
with metastatic disease is the integration of surgery with systemic therapy.
One way to ensure that patients who undergo surgery for their metastatic
disease are able to receive systemic therapy is to administer the chemotherapy
neo-adjuvantly.
According to Dr. Jonasch, giving patients chemotherapy before surgery
has several advantages. First, it gives the oncologists time to identify
patients with rapidly progressing disease who will not benefit from surgery.
Second, it allows for an assessment of the chemotherapy regimen. If the
type of chemotherapy administered prior to surgery is effective, it is
continued postoperatively; if it is not effective, a different agent is
used. Last, neoadjuvant therapy enables researchers to collect valuable
clinical data by observing patients before and after nephrectomy and by
collecting tumor tissue that has been treated with various agents.
“So it ends up being a win-win situation for the patient and the
investigator,” Dr. Jonasch said.
Laboratory investigations In addition to clinical investigations, researchers
are conducting animal studies and translational research to identify new
targets and treatment agents for RCC.
Cheryl Walker, Ph.D., a professor in the Department of Carcinogenesis
at M. D. Anderson’s Science Park-Research Division, is studying
the only two existing animal models for RCC: a rat model and a mouse model.
“The challenge in developing animal models in renal cell carcinoma
is that the major gene, the von Hippel-Lindau (VHL) tumor suppressor gene,
in humans is not involved in RCC in rats or mice,” Dr. Walker said.
Instead, defects in the tuberous sclerosis complex-2 (TSC-2) gene are
the major cause of RCC in rats and mice. The TSC gene is also found, infrequently,
in humans, where it leads to tuberous sclerosis (benign lesions) and a
higher risk for RCC.
Dr. Walker, who has been studying VHL and TSC-2 for the past several years,
has found that the two pathways controlled by these genes converge very
early on and that the downstream effects of the loss of either gene are
the same.
“RCC is a vascular tumor that is very good at recruiting blood vessels,”
Dr. Walker said. “In humans, the VHL gene keeps the process in check
through suppressing angiogenesis, but loss of the VHL gene sends out VEGF
[vascular endothelial growth factor] to recruit blood vessels. The same
thing happens in rodent tumors when TSC-2 is lost.”
This is an important finding because it means that the efficacy of antiangio-genesis
agents in RCC can be studied in animal models before the agents are tested
in humans.
Dr. Wood and his colleagues are using genomic hybridization and DNA array
analysis to identify other genes that are altered as a consequence of
carcinogenesis and progression and to develop therapies to target those
genes. Specifically, Dr. Wood is comparing alterations in gene and protein
expression in RNA and protein samples from tumor cells and normal cells.
So far, several novel molecular pathways have been identified that may
be involved in RCC carcinogenesis and progression and serve as targets
for therapy.
“Currently, my laboratory is looking at the role of the TGF [transforming
growth factor]-b signaling pathway in RCC,
which was altered in our gene array data, and we’ve identified specific
receptors for TGF-b that are deleted during
the course of kidney cancer carcinogenesis and progression,” Dr.
Wood said.
Although VHL is the most common gene linked to the development of RCC
in humans, it is probably not sufficient for the generation of metastatic
disease, according to Dr. Jonasch. In collaboration with Tim McDonnell,
M.D., Ph.D., a professor in the Department of Molecular Pathology, Dr.
Jonasch is looking at candidate genes and proteins generated from tissue
microarrays of archival specimens from primary and metastatic tumors to
determine the similarities and differences in the genetic makeup of the
tissues and to begin to understand which genetic abnormalities drive metastasis
in kidney cancer.
Along with Amado Zurita-Saavedra, M.D., a postdoctoral fellow in the Department
of Genitourinary Medical Oncology, Dr. Jonasch also is investigating the
possibility that high levels
of circulating stem cells after RCC surgery may enable the spread of metastatic
disease in patients with a poor prognosis.
“The stem cells act as sort of Trojan horses to enable circulating
tumor cells to set up shop at distant sites. So we want to evaluate levels
of circulating stem cells, endothelial precursor cells, and tumor cells
to see whether or not there is a relationship between the levels and ratio
of these cells and the prevalence of metastatic disease,” Dr. Jonasch
said.
Integration of collected tissue, patient information, and study
data
Studies such as these are made possible in part by the researchers’
efforts to learn as much as they can from each and every patient with
RCC at M. D. Anderson. Currently, every kidney tumor removed from a patient
is saved (after pathologic study) and preserved for laboratory analysis.
Dr. Jonasch and his colleagues are taking that one step further by developing
an integrated tissue collection system whereby every piece of renal tissue
will be processed in a systematized manner, and the data will be stored
in a computerized tissue library.
The data collection software needed to make this possible was developed
for the Department of Genitourinary Medical Oncology by Randall Millikan,
M.D., Ph.D., an associate professor in the department. Genitourinary Research
Unlimited, or GURU, is a data repository for both clinical and research
data points. The GURU system is being used for all of the genitourinary
tumors —renal, prostate, bladder, testicular, penile—and is
a model for an institution-wide data collection system.
“There really aren’t any good informatic systems that can
capture data in a modular, searchable, robust manner. A lot of it ends
up on data sheets, which someone has to laboriously, manually search through.
To have a system that allows one to look at all of these endpoints plus
link that to some sort of a pure research database—so essentially
you can go from start to finish in one particular patient and then across
patients—it’s an incredibly powerful tool,” said Dr.
Jonasch.
For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.
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