"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 therapy.
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 said.
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 significant.
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(Drug information on capecitabine) (Xeloda) or gemcitabine have led to a randomized clinical trial that is comparing the effects of docetaxel(Drug information on 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 unclear.
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 disease progression?"
In clinical practice today, he said, "the choice remains more the art rather than the science of medicine."