ASCO In a randomized phase III study from the
Cancer and Leukemia Group B (CALGB), weekly paclitaxel proved superior to
conventional every-3-week paclitaxel in women with metastatic breast cancer.
The initial findings showed both response rate and time to disease progression
to be significantly better in women receiving the weekly regimen, principal
investigator Andrew D. Seidman, MD, said at the 40th Annual Meeting of the
American Society of Clinical Oncology (abstract 512).
"These data clearly demonstrate the advantage of weekly
paclitaxel over every-third-week dosing, whether with trastuzumab [Herceptin]
for patients with HER-2-positive breast cancer or without it for HER-2-negative
breast cancer," said Dr. Seidman, associate attending physician, Breast Cancer
Medicine, Memorial Sloan-Kettering Cancer Center. He maintained that the weekly
paclitaxel schedule should be adopted as a new standard of practice when
taxanes are used in the metastatic setting.
CALGB 9840 involved 738 patients, including 580 treated on
this study and an additional 158 patients treated with every-3-week paclitaxel
at 176 mg/m2 in the prior CALGB 9342 trial (Winer et al: J Clin
Oncol 22:2061-2068, 2004). Patients could have received one prior
chemotherapy regimen for metastatic or locally advanced disease or as adjuvant
or neoadjuvant therapy. Prior taxane was allowed only if more than 12 months
had passed since the last administration, and no prior trastuzumab was allowed.
The 580 new patients were randomized 40:60 to receive
paclitaxel 175 mg/m2 every 3 weeks or weekly paclitaxel 80 mg/m2.
Patients were assessed for HER-2 status, and those with overexpression received
trastuzumab, while those with normal HER-2 status (HER-2 negative) were
randomized to trastuzumab or no trastuzumab.
Weekly paclitaxel produced a significantly greater tumor
response, with or without trastuzumab, compared with the every-3-week regimen:
40% vs 28% (P = .017). Time to disease progression was also
significantly improved with the weekly therapy: 9 months vs 5 months (P
= .0008). There was a trend toward longer survival among patients on weekly
paclitaxel: 24 vs 16 months (P = .17).
When the results were analyzed for only those patients
recruited to CALGB 9840 (eliminating those borrowed from the previous CALGB
study), the results were still significant. Dr. Seidman explained that the
populations were combined in order to reach the target number of patients and
have statistical power while "conserving resources."
The side effect profiles differed slightly, with less grade
3-4 granulocytopenia on the weekly arm (5% vs 15%; P = .013), but more
grade 3-4 sensory neuropathy (23% vs 12%, P = .001) and motor neuropathy
(8% vs 4%, P = .04).
"CALGB 9840 should be a practice-changing study for those
physicians who have not been using weekly paclitaxel," Dr. Seidman commented.
"The improvement in terms of time to progression, in particularwhere we saw an
almost doubling with weekly paclitaxelis very meaningful, and provides
important benefits to patients."
The study also aimed to determine to what degree women with
normal HER-2 status might benefit from trastuzumab therapy. CALGB 9840 found no
significant improvement with the addition of trastuzumab in the HER-2-normal
group, Dr. Seidman said. Response rates were 35% in the trastuzumab arm vs 29%
without trastuzumab; time to progression was 7 months vs 6 month; and overall
survival was 22 months vs 20 months. The investigators concluded that
trastuzumab does not contribute to the efficacy of paclitaxel in the absence of
The study also provided some contribution to the ongoing question of dose
intensity vs dose density (frequency). Dr. Seidman noted, "When considered
together with the results of CALGB 9342, where an increase in paclitaxel dose
did not improve outcome, the present results are consistent with the concept
that the frequency of drug administration, or density, may account for the
improved efficacy that was observed."