TREATMENT OF METASTATIC RENAL CELL
CARCINOMA
Nephrectomy
Approximately one third of patients with RCC have metastatic disease at
the time of initial diagnosis (synchronous metastatic disease), and 40% to
50% will develop distant metastases after initial diagnosis. The value of
nephrectomy has been examined retrospectively in patients with
synchronous metastases. Prospective controlled trials have also examined
the value of nephrectomy. Initially, the rationale for nephrectomy
included palliation for severe bleeding, pain, and paraneoplastic
symptoms. In addition, there have been occasional patients who
demonstrate regression of metastases after nephrectomy; the frequency of
this finding has been estimated as 1% to 2%). These responses have been
predominantly in pulmonary nodules, with a median duration of
approximately 6 months. Several retrospective studies suggested that
prior nephrectomy was a good prognostic factor for patients with
metastatic RCC, but concerns about selection bias predominated. About
10% to 30% of patients undergoing cytoreductive nephrectomy were
unable to receive systemic therapy because of postoperative medical
complications or rapid cancer progression
Selection of patients for nephrectomy followed by cytokine therapy in the
setting of advanced disease must be careful—this is not a pathway that
should be used indiscriminately. Individuals with advanced symptoms
(performance status ≥ 2), metastases in critical areas (central nervous
system, spinal cord compression), major organ dysfunction, and
significant comorbid illnesses are not candidates for such approaches.
The role of this approach in patients with non–clear cell carcinoma is not
well defined.
Hormonal Therapy
The use of hormonal therapy for patients with metastatic RCC has
minimal value. It was originally thought that progestational agents would
be useful since they inhibit the growth of diethylstilbestrol-induced renal
tumors in Syrian hamsters. Unfortunately, the collective experience with
medroxyprogesterone acetate, androgens, and antiestrogens has shown
that such preclinical models of renal cancer do not correlate with human
RCC. Although the initial clinical trials using progestins for patients with
advanced RCC looked promising, studies using modern objective
response criteria have demonstrated only limited activity.
Two multicenter randomized trials tested oral medroxyprogesterone
acetate as initial therapy for patients with metastatic RCC. Response rates
to medroxyprogesterone acetate were uniformly low (2.0% and 2.5%,
respectively), and overall median survival of the patients varied from 6.0
months to more than 15.0 months. The difference in survival probably
reflects patient entry criteria used in the two studies rather than a true
difference in biologic responsiveness. Therefore, whereas progestational
agents may be useful for symptom palliation, they do not appear to have
any significant value in the treatment of patients with metastatic RCC.
Chemotherapy
Multiple clinical trials performed during the 1980s established RCC as a
prototype of a chemotherapy-resistant tumor.. The overall response rate
in this review was 18.5%, but protocols incorporated immunotherapy in
combination with chemotherapy, and this probably accounts for the
marginal increase in activity. In the past, it has been suggested that the
fluoropyrimidines or vinblastine might have antitumor activity in patients
with metastatic RCC. However, when vinblastine was tested in a
randomized prospective setting, the response rate was 2.5% in 81 patients
receiving chemotherapy alone, and overall survival was inferior to the
combination of vinblastine and interferon alfa. Virtually every other
cytotoxic agent has been tested for this disease, either alone or in
combination with other chemotherapeutic approaches, almost uniformly
with discouraging results.
Radiation Therapy
Radiation therapy has been used primarily as adjuvant treatment after
radical nephrectomy and for palliation of metastatic lesions. Most studies
have failed to demonstrate improvement in survival or a reduction in
local recurrence rates after postoperative radiation therapy. At present,
the main role of radiation therapy for patients with metastatic RCC is for
the palliation of symptomatic osseous metastases. Radiation therapy has
also been combined with surgery for the treatment of vertebral body
metastases with spinal cord compression, allowing substantially reduced
blood loss. Standard radiation therapy may also be employed for
palliation of brain metastases. Stereotactic radiosurgery has shown
promise for the treatment of select patients with brain metastases, thereby
avoiding the risks associated with craniotomy.
Cytokines and Immunologic Therapy
The therapeutic potential of cytokines and immunotherapy has been
investigated for the last 30 years in patients with metastatic RCC and has
shown real but limited efficacy. The demonstration of T-cell infiltrates
the development of T-cell lines (CD8+) with specificity for autologous
tumor and the finding of tumor-associated antigens on renal tumors that
are MHC restricted provide laboratory evidence for a specific antitumor
immune response. Coincident with these observations, a series of clinical
trials demonstrated the antitumor activity of cytokines such as interferon
alfa and IL-2 in patients with advanced disease.
Targeted Agents
The VHL gene has been cloned, functions of the protein have been
elucidated, and a high frequency of mutations or epigenetic silencing of
this gene in sporadic clear cell carcinoma has been recognized. These
findings led to a series of studies identifying the VEGF and PDGF
pathways as molecular targets in this tumor. These growth factors bind to
receptor tyrosine kinases that regulate cell proliferation and survival and
can promote tumor-associated angiogenesis and growth. Inhibition of the
VEGF and PDGF signaling pathways may therefore inhibit angiogenesis
and tumor progression. A series of agents inhibiting VEGF or tyrosine
kinase receptors such as VEGFR types 1 to 3 and PDGFR are now under
investigation and appear to have antitumor effects in renal cancer
patients.