ASCOAlthough evidence-based medicine tends to
support the use of single-agent chemotherapy for metastatic breast cancer,
trials are beginning to document a benefit from combination chemotherapy. One
study, reported at the 39th Annual Meeting of the American Society of Clinical
Oncology (abstract 25), showed a statistically significant improvement in time
to disease progression and objective response when the combination of
gemcitabine (Gem-zar) and paclitaxel was compared with paclitaxel alone.
"Because of the favorable risk benefit profile reported
in this clinical trial, gemcitabine/paclitaxel is a new treatment option for
metastatic breast cancer patients who may benefit from combi-nation
chemotherapy," said Joyce O’Shaughnessy, MD, codirector of the Breast
Cancer Prevention Program, Baylor-Sammons Cancer Center, Dallas.
Dr. O’Shaughnessy presented interim results from a global
phase III trial of combination therapy and monotherapy in 529 patients with
unresectable, locally recurrent or metastatic breast cancer and a generally
significant tumor burden.
A total of 73% of patients had visceral disease, and more
than 40% of patients had three or more sites of metastasis.
Although patients in the study had not received chemotherapy
for metastatic disease, more than 95% had been treated with anthracycline-based
adjuvant or neoadjuvant therapy, and 50% had undergone previous hormonal
The regimens were 175 mg/m2 pac-litaxel for 3
hours on day 1 alone or paclitaxel at the same dose followed by 1,250 mg/m2
gemcitabine on day 1 for 30 minutes and then alone on day 8 at the same dose,
repeated every 21 days.
At the time of the interim analysis, with a total of 424
events, the median time to disease progression was 5.4 months for women who
received both gemcitabine and paclitaxel, compared with 3.5 months for women on
paclitaxel monotherapy. Forty-four percent of patients on gemcitabine/paclitaxel
were progression-free at 6 months vs 30% of patients on paclitaxel alone. The
hazard ratio for progression with gemcitabine/paclitaxel was 0.73, which is
statistically significant with a two-sided P value of .0013, Dr. O’Shaughnessy
The objective response rate with gem-citabine/paclitaxel was
39.3% vs 25.6% for paclitaxel (P = .0007); the median duration of
response (8.8 months vs 7.2 months, respectively) was not statistically
There was a nonsignificant trend toward improvement in mean
pain inventory scores over time among symptomatic patients who received gem-citabine/paclitaxel.
Improvement in pain scores was associated with 25% of patients being able to
reduce their level of analgesic use.
There was no difference in overall mean quality-of-life
scores per cycle, measured by the Rotterdam symptom checklist. However,
quality-of-life scores in cycles 5 and 6 were statistically significantly
higher than at baseline for patients in the gemcitabine/paclitaxel arm of the
study, Dr. O’Shaughnessy said.
Hematologic toxicities were relatively mild in both
treatment arms: 17% of combination patients and 7% of mono-therapy patients
developed grade 4 neutropenia. Febrile neutropenia or sepsis occurred in 5% of
combination and 2% of monotherapy patients. Although grade 3/4 anemias were
uncommon, red blood cells were transfused in 10% of combination patients and 4%
of monotherapy patients.
‘The Big Picture’
The results of this trial and others by Dr. O’Shaughnessy
involving taxanes in combination with capecitabine (Xeloda) or gemcitabine have
led to a randomized clinical trial that is comparing the effects of docetaxel (Taxotere)/gemcitabine
with docetaxel/capecitabine, said the discussant for the paper Andrew Seidman,
MD, associate attending physician, Memorial Sloan-Kettering Cancer Center.
Patients who progress on one combination therapy will cross over to the other.
"The examination of these two lines of treatment for
metastatic breast cancer in this trial should allow for a more meaningful and
robust look at the big picture," Dr. Seidman commented.
He pointed out that the appropriate use of combination
chemotherapy and single-agent chemotherapy for metastatic breast cancer remains
Dr. Seidman, along with many other clinicians, starts these
patients on a single chemotherapeutic agent and then switches to another single
agent when the disease progresses or the patient develops an intolerable
toxicity. He noted that other clinicians use combination chemotherapy
throughout the management of the disease, and still others pick and choose
between single and combination chemotherapeutic regimens on the basis of the
latest promising findings from clinical trials.
When to Use Combinations?
Clinical trials have not defined the features that mandate
the use of combination chemotherapy for advanced breast cancer, he said.
Dr. Seidman posed a number of relevant questions concerning
selection of patients for combination chemotherapy: "Should combination
therapy be reserved for younger patients who might tolerate the inherent
toxicity of this approach better? Or should combination therapy be routinely
employed for patients with visceral- as opposed to soft-tissue-dominant
disease? Or should it perhaps be used in those with an aggressive molecular
phenotype or those whose cancer demonstrates a rapid volumetric tempo of
In clinical practice today, he said, "the choice remains more the art
rather than the science of medicine."