LONDON-A combination regimen
of gemcitabine (Gemzar) and capecitabine
(Xeloda) shows modest activity in
patients with metastatic renal cell carcinoma
refractory to immunotherapy. A
recent phase II trial suggests that the combination
is associated with manageable
toxicity, and that it is easily administered.
Justin Waters, MD, Royal Marsden Hospital,
London, England, reported these
findings (ASCO abstract 1549).
"The response rate is similar to that
produced by the combination of infused
5-FU and gemcitabine, but without the
need for an indwelling intravenous catheter,"
Dr. Waters said. "The regimen is
reasonably tolerated, the major grade 3/4
toxicity being myelosuppression. However
mild nonhematologic toxicity was
common and dose reductions and delays
were frequently required."
Two-thirds of patients with renal cell
carcinoma develop metastatic disease,
with a median survival time from the development
of metastases of less than 1
year. "Standard first-line therapy for metastatic
disease is immunotherapy with interferon-
alpha 2a or interleukin-2, producing
response rates of 10% to 20%," Dr.
"Chemoimmunotherapy with combinations
of fluorouracil (5-FU), interfer-
on-alpha 2a (IFN-α) and interleukin-2
(IL-2) appears to increase response rates
to between 20% and 39%. Single-agent
chemotherapy has generally produced response
rates below 10%, and there is currently
no standard second-line therapy
following failure of immunotherapy," he
One combination that has been tested
following immunotherapy failure is gemcitabine
plus 5-FU. This combination has
achieved a 17% response in patients with
metastatic renal cell carcinoma. Administration
of this regimen, however, requires
an indwelling IV catheter and ambulatory
Gemcitabine is a fluorine-substituted
cytarabine analogue with broad experimental
antitumor activity. Phase II trials
of single-agent gemcitabine have produced
response rates of 6% to 9% in
metastatic renal cell carcinoma. A phase
II trial of the combination of continuous
infusion 5-FU and gemcitabine demonstrated
a response rate of 17%.
In testing an alternative combination,
Dr. Waters considered the potential advantages
of substituting capecitabine for
5-FU. "Preclinical models have demonstrated
a synergistic activity of gemcitabine
and capecitabine in breast and colon
cancer cell lines," he said. "In addition, in
phase I trials, full single-agent doses of
the two drugs appear to be tolerated in
combination, with myelosuppression and
mucositis reported as dose-limiting toxicities,"
Substitution Does Not
"Capecitabine has been substituted for
5-FU in a chemoimmunotherapy regimen
incorporating IFN-α, IL-2, and 13-
cis-retinoic acid without compromising
activity (overall response rate 34%)," Dr.
Twenty-one patients with metastatic
renal cell carcinoma (median age, 57 years)
received gemcitabine 1,200 mg/m2 on days
1 and 8 plus capecitabine 1,300 mg/m2 po
bid for 14 days every 3 weeks. The study is
designed as a single-center, open-label,
phase II trial. A two-stage Gehan design
was used with the aim of rejecting a response
rate lower than 20%.
The primary objective of the study
was to determine the response rate to
gemcitabine and capecitabine in patients
with metastatic renal cell carcinoma who
have progressed following immunotherapy
or are unsuitable for immunotherapy.
The secondary objectives were to characterize
the adverse effects of this
chemotherapy combination in this patient
population, and to determine the
time to disease progression, overall survival
duration, and duration of response.
Eligible patients must have: histologically
confirmed metastatic renal cell carcinoma;
measurable disease outside previously
irradiated areas; performance
status 0 to 2; adequate bone marrow, renal
and hepatic function; and no prior
treatment with gemcitabine, capecitabine,
or 5-FU infusion.
Responses and Toxicities
The overall response rate was 20%.
No patients experienced complete response,
but four patients (20%) had partial
responses and 10 patients (50%) had
stable disease. Progressive disease occurred
in six patients (30%). The median
overall survival was 12 months, and median
progression-free survival was 6.7
Grade 3/4 toxicity included lethargy
(9.5% patients), vomiting (4.8%), diarrhea
(14.3%), hand-foot syndrome
(19.0%), rash (9.5%), anemia (9.5%),
neutropenia (52.4%), thrombocytopenia
(23.8%), and infection (33.3%). Three
patients had thromboembolic events during
therapy. Dose reductions/delays were
required in 49 (29%) of cycles.
"The combination of gemcitabine and
capecitabine proved reasonably well tolerated
and demonstrated activity in metastatic
renal cancer," Dr. Waters concluded.
"Potential future directions might
include combination with targeted agents,
or further exploration of the concept of
intratumoral chemotherapy activation."