AMELIA ISLAND, Fla--Do the available data support the use of
high-dose chemotherapy with peripheral blood stem cell support
(HDC/PBSC) in advanced breast cancer? That was the question for
debate at a session of the Southern Association for Oncology (SAO)
Providing the case for HDC/PBSC was C. Dean Buckner, MD, of Response
Oncology, Inc., Seattle. He presented background data from a large
study by Greenberg at M.D. Anderson (J Clin Oncol 14:2197,
1996) showing that approximately 20% of patients with metastatic
breast cancer who achieved a complete remission with conventional
doxorubicin-based chemotherapy were disease-free at between 5 and 10
years. "These data document the potential curability of patients
with metastatic breast cancer who achieve complete remission,"
he said, "but with the relatively low complete remission rate in
these patients (20% or less), the overall percentage of patients with
newly diagnosed metastatic breast cancer who are alive and
disease-free at 5 years following conventional chemotherapy is 5% or less."
Dr. Buckner reviewed data from the International Bone Marrow
Transplant Registry and studies performed by Response Oncology Inc.
These findings suggest that at least 30% to 35% of patients with
metastatic breast cancer who received HDC/PBSC while in complete
remission would be disease-free at 5 years, an approximately 10% to
15% increase, compared with chemotherapy without HDC/PBSC consolidation.
He also cited data from a published intent-to-treat trial from
Response Oncology in which patients agreed to HDC/PBSC at the time of
diagnosis. In this trial, approximately one-quarter of 114 patients
achieved a complete response to doxorubicin-based induction therapy
(AFM), and approximately one-half were in remission after HDC/PBSC,
ie, a doubling of the complete remission rate.
"Conversion of patients to complete remission who had failed AFM
induction is the best evidence that HDC/PBSC is effective in
metastatic breast cancer," Dr. Buckner said. He noted that 15%
of patients who were converted to a complete remission with HDC/PBSC
were disease free at 4 to 5 years. "None of these patients would
be expected to be salvaged with conventional-dose therapies," he
said, adding that there were no treatment-related deaths in this trial.
One Randomized Trial
There has been only one randomized phase III trial comparing HDC/PBSC
with conventional-dose chemotherapy in patients with newly diagnosed
metastatic breast cancer (conducted by Bezwoda and colleagues in
South Africa), he said. In this trial, disease-free survival for
HDC/PBSC was 20% vs 0% for the control group, with a minimum
follow-up of more than 5 years. The control arm had only a 5%
complete response rate, which was worse than historical controls.
Dr. Buckner pointed out that there have been no studies of
conventional-dose therapies resulting in a 20% 5-year disease-free
survival. He also noted that the South African investigators recently
reported that patients in this study who had HER2-positive tumors did
as well following HDC/PBSC as patients with tumors that were HER2
negative, which was not true for the control group.
"No studies have ever suggested that conventional-dose therapies
are superior to HDC/PBSC, and the only arguments against HDC/PBSC
therapies relate to cost and the perception of increased
toxicities," he said, adding that mortality is 1% or less in
Response Oncology breast cancer studies, and costs are decreasing
with increasing utilization.
He noted, however, that both conventional-dose chemotherapy and
HDC/PBSC are relatively ineffective treatments for patients with
newly diagnosed metastatic breast cancer. At most, he said, 20% of
these patients will be long-term disease-free survivors. To improve
patient outcomes, he urged the development of newer strategies that
would improve remission induction, enhance the effectiveness of HDC
regimens, or deliver effective treatment after HDC/PBSC.
Dr. Buckner suggested that meaningful comparisons between HDC/PBSC
and lower-dose therapies will take large numbers of patients followed
for at least 5 years. "It is currently more important to improve
overall outcomes of high-risk patients with metastatic breast cancer
than to make these comparisons," he said.
Dr. Buckner also discussed the ongoing trials of HDC/PBSC as adjuvant
therapy begun in 1989 by Dr. William Peters. The original comparisons
suggested a 30% to 40% difference in event-free survival between
HDC/PBSC and conventional adjuvant therapy for patients with 10 or
more positive axillary nodes.
Several ongoing national and international breast trials are
comparing adjuvant HDC/PBSC with adjuvant chemotherapy without PBSC,
he said. In all these studies, the intensity of treatment in the
control arm has been increased over that administered in the 1980s,
which reinforces the general concept that higher-dose therapies are
thought to be superior to lower-dose therapies.
"PBSC transplantation is readily available and should be used
more widely to evaluate treatment strategies to improve outcomes of
patients with breast cancer in the metastatic and adjuvant settings,
" Dr. Buckner said. He predicted that, in the future, PBSC will
be more widely used to abrogate the hematologic toxicity of HDC and
will become a more cost-effective means of supportive care. He
suggested that all patients with high-risk breast cancer should have
PBSC cryo-preserved at diagnosis.
Why the Enthusiasm?
Frankie Ann Holmes, MD, of Texas Oncology, Houston, subtitled her
rebuttal "Why would any (sane) person consider HDC for breast
cancer?" She proposed several fanciful reasons for the recent
enthusiasm for HDC/PBSC. The first she called the "Mount Everest
Principle" (because its there), which may lead people to
see things that arent there (ie, the Emperors New Clothes
Some advocates of HDC/PBSC subscribe to the "Star Wars
Principle" of using the most aggressive, modern therapy
available, she said. And also there is the "Texas Principle"
that "Bigger is Better." However, Dr. Holmes said, "we
have learned that there is no clinical benefit to higher doses of
chemotherapeutic agents; in fact, for cyclophosphamide, doses of 600
mg/m² are optimal. Lesser doses lead to lesser antineoplastic
efficacy, while higher doses lead to more toxicity."
In addition, she said, inducible resistance to cyclophosphamide can
develop after previous treatment with standard cyclophosphamide
doses. Finally, combining cyclophosphamide with other alkylators
actually may dilute the efficacy of the multiple alkylator regimen.
A perhaps more plausible reason for the enthusiasm for high-dose
chemotherapy with transplantation is the dissemination of
"promising data" from phase II trials, Dr. Holmes
continued. "Phase II trials provide important data about new
therapeutic strategies by defining efficacy," she said, "but
these trials are, at best, hypothesis-generating,
defining the ranges of efficacy." Also, she said, most phase II
trials are quite small, and vary in terms of schedules, doses, and
"I view the phase II trials of bone marrow transplants with
optimistic skepticism," she added, citing unsuspecting bias that
eliminated many of the biologically unfavorable tumors in some trials
and assured a favorable population in others, resulting in the
"cherry picking" of included patients.
Dr. Holmes noted that the early results of the phase III trials,
which are comparative trials of high-dose therapy vs no high-dose
therapy, "have either not shown any significant improvement in
outcome--that is, a 30% or greater increase in disease-free
survival--or had too few patients enrolled to make any statistically
significant conclusion at all."
A Dutch Randomized Trial
She cited in particular a phase III study from the Netherlands Cancer
Institute, Amsterdam, presented at the 1998 American Society of
Clinical Oncology (ASCO) meeting (abstract 470). This trial enrolled
97 patients below age 60 who had breast cancer with extensive
axillary node metastases. All patients received three courses of
upfront conventional chemotherapy consisting of 3-weekly
administrations of cyclophosphamide, 500 mg/m², epidoxorubicin,
120 mg/m², and fluorouracil, 500 mg/m².
After surgery, stable and responding patients were randomized to
either a fourth course of conventional chemotherapy followed by
radiation therapy and 2 years of tamoxifen (Nolvadex) or identical
treatment plus HDC/PBSC after the fourth course of conventional
chemotherapy. The high-dose regimen incorporated cyclophosphamide, 6
g/m², thiotepa, 480 mg/m², and carboplatin (Paraplatin),
After surgery, 81 patients were randomized. With a median follow-up
of 49 months, there was no significant difference between the
high-dose and conventional dose groups with respect to overall
survival (79% vs 72% at 4 years) or relapse-free survival (45% vs
56%). The power of the study to detect a 30% difference in
relapse-free survival was 80%.
Dr. Holmes noted that newer agents such as taxanes and capecitabine
(Xeloda) and new ways to use old and new agents, including modulation
of drug schedules, offer incremental strategies that, when combined,
may benefit patients.
"Despite overuse of the B (for breakthrough) word,
we are standing at the brink of some exciting new therapies for
breast and all cancers," Dr. Holmes said. "These are the
result of our improved understanding of tumor biology and include,
for example, some of the more recently discussed molecules that allow
tumors to recruit and retain a blood supply (angiostatin and
endostatin) or to penetrate and invade surrounding tissues (the
One interesting aspect of these therapies is that they offer the
paradoxical promise of improved or even normal survival but without
cure, she said. "These agents may someday allow us to think
about cancer as a normal consequence of aging. Imagine treating our
tumors the way we treat liver spots!" she said.