Drs. Wolchok and Motzer provide a succinct, timely review of the
diagnosis and management of renal carcinoma. The article leads us to
ask a number of questions: What factors account for the major
increase in the incidence of renal carcinoma? How has surgical
management evolved with the advent of newer operative techniques?
What role, if any, does chemotherapy play in the treatment of this
disease? What is the current status of and future outlook for
Risk Factors for Renal Carcinoma
The etiologic factors responsible for renal carcinoma have not been
as well defined as have factors in other malignancies. A recent
report by Yuan et al found a significant increase in the risk of
developing renal carcinoma with tobacco use (odds ratio, 1.35; 95%
confidence interval [CI], 1.14 to 1.60). The risk correlated with
current use and with an increasing number of cigarettes smoked per
day. This study helps confirm the role of tobacco in the development
of renal carcinoma.
Mutations of the von Hippel-Lindau (VHL) gene have also been
implicated in the development of clear cell and granular histologic
subtypes. The mechanism by which these mutations lead to such tumors
has been further defined recently. The normal VHL gene product,
pVHL, suppresses the synthesis of carbonic anhydrase IX, also known
as G250. The mutated pVHL no longer suppresses G250, which leads (by
still obscure means) to vascular endothelial growth factor expression
and resultant hypervascularity. Although the mechanisms remain to be
defined, it is becoming clear that specific types of VHL mutations
influence tumor biology, as seen in the acute leukemias, where
specific cytogenetic abnormalities lead to characteristic clinical
syndromes. Hopefully, further studies will lead to more targeted
therapies, such as with all-trans-retinoic acid (ATRA
[Vesanoid]) for acute promyelocytic leukemia.
Furthermore, recent evidence implicates occupational
trichloroethylene exposure in the development of renal carcinoma with
specific VHL gene defects. However, the validity of this exposure
risk is questioned by some. Thus, as more becomes known about the
environmental and genetic influences on the pathogenesis of renal
carcinoma, the disturbing trend of an increase in incidence can
hopefully be reversed with more efficient prevention and detection
efforts, perhaps by molecular screening of high-risk, targeted populations.
Surgerya mainstay of therapy for localized renal
carcinomaremains the only curative modality. Recently, several
centers have explored the role of nephron-sparing surgery (partial
nephrectomy) in selected patients.
In general, the local recurrence rate after nephron-sparing surgery
for T1 renal carcinoma is in the range of 2.7% to 5.8%, with a 90%
disease-free survival rate at 5 and 10 years.These results are
comparable to those obtained in similar patients treated with radical
nephrectomy. The favorable results of nephron-sparing surgery do not
extend to patients with > T1 lesions. Thus, patients with a
solitary functioning kidney or other conditions that may affect
future renal function can benefit from this procedure.
Furthermore, the newer techniques of laparoscopic nephrectomy and
cryoablation may offer similar surgical results with less blood loss,
fewer days of hospitalization, and reduced narcotic requirements;
these techniques are also an attractive alternative to open surgery
for low-stage tumors.
We agree with the authors recommendation against routine
nephrectomy in the setting of metastatic disease in the absence of
symptoms. Although there is evidence that soluble tumor products,
including interleukin-6, macrophage colony-stimulating factor,
interleukin-10, transforming growth factor-beta, and vascular
endothelial growth factor, have negative effects on dendritic cells,
elimination of the primary tumor has not conclusively been shown to
reverse these deficits in a clinically meaningful way.
Certainly, nephrectomy following response to immune or other
therapies, especially combined with resection of a solitary
metastasis, can prolong disease-free survival in selected patients
and should be considered. An ongoing Southwest Oncology Group study
that is randomizing patients to nephrectomy or no surgery followed by
interferon therapy will help further define the role of surgery in
patients with metastatic renal carcinoma.
As noted by the authors, chemotherapy for metastatic renal carcinoma
has been disappointing. This does not mean, however, that newer
chemotherapeutic agents and other nonimmunologic approaches should be
forever abandoned in cytokine-refractory patients.
Our recently completed phase II trial of gemcitabine (Gemzar) and
continuous-infusion fluorouracil (5-FU) demonstrated a 17% response
rate in a heavily pretreated cohort of metastatic renal carcinoma
patients.[Rini BI, Vogelzang NJ, Dumas M, et al, unpublished data]
Other trials using monotherapy with 5-FU or gemcitabine have produced
response rates in the range of 5% to 10%, suggesting additive or
synergistic effects of the combination.[5,6]
Clearly, new chemotherapeutic agents must continue to be developed.
In addition, the hypervascularity that is typical of renal cancer may
make the disease the ideal proving ground for the newer
generation of angiogenesis inhibitors.
The authors review the major issues surrounding cytokine treatment
for metastatic renal carcinoma. Interleukin-2 (IL-2 [Proleukin]) and
interferon-alfa (Intron A, Roferon-A) are the mainstays of treatment,
achieving responses rates ranging from 15% to 20%.
A recent Finnish trial demonstrated a survival advantage of
interferon-alfa plus vinblastine over vinblastine alone. Since
only 2 of the 81 patients responded to vinblastine, while 16.5%
responded to interferon, the trial provides strong evidence that
cytokine treatment can improve overall survival compared to
essentially no treatment.
Ritchie et al reported a similar survival advantage when treatment
with 12 weeks of interferon-alfa was compared to 300 mg of daily
medroxyprogesterone acetate in 335 patients with metastatic renal
carcinoma. Median survival was increased by 2.5 months in the
The debate over high- vs low-dose IL-2 is ongoing. Current National
Institutes of Health studies may demonstrate that high-dose IL-2
provides an advantage by increasing the percentage of durable
complete responders. However, low-dose, subcutaneous, outpatient IL-2
regimens are an accepted option.
In an attempt to build on the partial success of cytokine therapy,
investigators have studied many other immunologic approaches,
including antibody and vaccine therapies (as outlined by the
authors). Identification of renal carcinomaspecific antigens,
as in melanoma, will facilitate the development of targeted
approaches, including cluster of differentiation 8 (CD8+)
T-cellbased therapy. A further understanding of dendritic cell
function, T-cell activation, and costimulatory cytokines is also
needed to develop effective approaches.
Finally, a novel immunologic approach to renal cell carcinoma has
been developed involving the use of nonmyeloablative peripheral blood
stem-cell transplantation. Immunosuppressive chemotherapy is followed
by peripheral blood stem-cell infusion from a human lymphocyte
antigenmatched sibling to induce a graft-vs-tumor effect. This
approach has shown early promising results at the National Cancer Institute.
The treatment of renal carcinoma often involves a coordinated effort
by the surgeon, pathologist, and oncologist. The issues reviewed here
highlight the current knowledge base and some promising new
approaches. This challenging disease affords limitless research
opportunities, and every avenue of antitumor therapy needs to be explored.
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2. Ivanov SV, Kuzmin I, Wei MH, et al: Down-regulation of
transmembrane carbonic anhydrase in renal cell carcinoma cell lines
by wild-type von Hippel-Lindau transgenes. Proc Natl Acad Sci USA
3. Brauch H, Weirich G, Hornauer MA, et al: Trichloroethylene
exposure and specific somatic mutations in patients with renal cell
carcinoma. J Natl Cancer Inst 91:854-861, 1999.
4. Novick AC: Nephron-sparing surgery for renal carcinoma. Presented
at First International Kidney Cancer Symposium, October 1, 1999.
5. Kish JA, Wolf M, Crawford ED, et al: Evaluation of low-dose
continuous infusion 5-fluorouracil in patients with advanced and
recurrent renal carcinoma: A Southwest Oncology Group Study. Cancer
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7. Pyrhonen S, Salminen E, Ruutu M, et al: Prospective randomized
trial of interferon alfa-2a plus vinblastine versus vinblastine alone
in patients with advanced renal cell cancer. J Clin Oncol
8. Ritchie AWS, Griffiths G, Cook P, et al: Alpha interferon improves
survival in patients with metastatic renal carcinomapreliminary
results of an MRC randomised, controlled trial (abstract). Proc Am
Soc Clin Oncol 17:310a, 1998.
9. Childs R, Clave E, Bahceci E, et al: Non-myeloablative allogeneic
peripheral blood stem cell transplantation (N-PBSCT) as adoptive
allogeneic immunotherapy for metastatic melanoma (MM) and renal cell
carcinoma (RCC) (abstract). Proc Am Soc Clin Oncol 18:52a, 1999.
© 2000 by PRR, Inc. All rights reserved.