SILVER SPRING, MdThe Oncologic Drugs Advisory Committee (ODAC)
unanimously recommended that the FDA approve Taxol (paclitaxel for
injection, Bristol-Myers Squibb) for use in the adjuvant treatment of
node-positive breast cancer administered sequentially to standard
doxorubicin-based combination therapy.
The major issue in the panels debate centered on whether to
exclude estrogen- and progesterone-receptor-positive patients from
the indication. Such women gained no benefit from Taxol in the large,
single study presented by Bristol-Myers Squibb to support its
Taxol was first approved in the United States in late 1992 for the
second-line treatment of ovarian cancer. It has since won approval
for use in breast cancer after failure of combination chemotherapy
for metastatic disease; for the first-line treatment of ovarian
cancer in combination with cisplatin (Platinol); for the second-line
treatment of AIDS-related Kaposis sarcoma; and in combination
with cisplatin for the first-line treatment of non-small-cell lung
To support its new application, Bristol-Myers Squibb presented data
from a randomized phase III study involving 3,170 women enrolled
between May 1, 1994, and April 15, 1997. The study was coordinated by
the Cancer and Leukemia Group B, with participation by the Eastern
Cooperative Oncology Group, the North Central Cancer Treatment Group,
and the Southwest Oncology Group.
The company called the study the largest adjuvant breast cancer
study ever conducted and said the results constitute a
major advance similar to that seen nearly 30 years ago when it was
discovered that combination chemotherapy after surgery improved
breast cancer survival compared to surgery alone.
The studys aim was to assess the effects of three doxorubicin
doses (60, 75, and 90 mg/m²) in combination with a fixed dose of
cyclophosphamide (600 mg/m²) and to assess the effects of the
sequential addition of Taxol (4 courses at 175 mg/m² over 3
Women were randomized to one of the three doxorubicin doses and then
either to Taxol therapy (1,570) or no Taxol (1,551). All women with
hormone-receptor-positive tumors were to receive 5 years of tamoxifen
(Nolvadex) therapy after completing chemotherapy.
The studys primary endpoint was disease-free survival. The
separate analyses presented by the company and by an FDA review team
were in close agreement regarding the results. The FDA review found
that 624 relapses occurred within 3 years among the 3,121 women
included in the trial results.
At 3 years, 76.6% of the Taxol-treated women were disease-free,
compared with 73.0% of the control group, a statistically significant
difference of 3.6%. Among receptor-negative women, 67.3% of the Taxol
group were disease free, compared with 56.8% in control group, a
statistically significant difference of 10.5%.
However, among receptor-positive women, 81.2% of the Taxol group and
81.6% of controls were disease free at 3 years, and among
receptor-positive women who received tamoxifen, 81.9% of Taxol
patients and 82.7% of controls were disease free at 3 years. Neither
of these two findings regarding receptor-positive women was
These data provide little justification for believing that
Taxol sequential [to doxorubicin and cyclophosphamide] confers added
benefit to patients with ER-positive and/or PR-positive tumors,
said FDA reviewer James OLeary, MD.
In its analysis of receptor-positive women, the company presented
disease-free survival at 3 yearly intervals. At 1 year, 97.7% of the
Taxol group and 94.5% of the control group were disease free. At 2
years, the Taxol group still had an advantage, 89.6% vs 87.7%, but at
3 years, 81.5% of both groups were disease free.
Six percent of the women in the study were age 65 or older, and
there was no difference in results between patients over age 65 and
those under age 65, said Renzo Canetta, MD, vice president for
clinical oncology at Bristol-Myers Squibb.
Although the company said the study revealed no toxicity problems
that had not been observed in previous Taxol trials, the FDA
emphasized that Taxol therapy poses a risk of serious toxicity.
At least two deaths [in the study] were attributed to
Taxol, the FDA noted. During Taxol treatment, 15% of patients
experienced grade 4 neutropenia, 15% grade 2-3 neurosensory toxicity,
23% grade 2-3 myalgias, and 46% alopecia.
Much of the ODAC discussion focused on whether, given the efficacy
findings and the safety risks associated with Taxol use, women with
hormone-receptor-positive tumors should be excluded from the
indication. Members debated the details of the data on the
receptor-positive women and the reliability of using subset analyses
in making their decision.
At one point, Larry Norton, MD, of Memorial Sloan-Kettering, serving
as a sponsor consultant, said: I think there is a danger that
people who could potentially benefit from Taxol may end up not
getting it, depending on what the committee does. It would be a very
bad thing if that happens. The company said that about 40% of
the 180,000 women diagnosed annually with breast cancer would be
candidates for the adjuvant therapy.
In the end, the committee decided against excluding women with
receptor-positive tumors. Derek Raghavan, MD, PhD, of the University
of Southern California, said the discussion had persuaded him that
the damage we would do by withholding the drug with the
knowledge base we have is more than the damage we would do by letting
The panel did, however, advise the FDA that, if it approved the new
indication, it should highlight the findings regarding
receptor-negative and receptor-positive tumors in the clinical
studies section of the package labeling and specifically refer
physicians to that data in the indications section.