Breast cancer has been the most common indication for
high-dose therapy and hematopoietic stem cell rescue in
North America between 1993 and 1998 . Despite this, out-
comes of large series of breast cancer patients treated with
high-dose chemotherapy (HDCT) and autologous hemato-
poietic stem cell rescue are lacking. The largest publication of
outcomes to date was from the North American Autologous
Bone Marrow Transplant Registry (ABMTR) . Although
providing some insight into outcomes of HDCT for breast
cancer, the North American ABMTR data are constrained by
reporting bias and lack of subgroup analysis, such as stage
II/IIIA patients with 10 or more involved axillary lymph
nodes. This information has not resolved the controversies
underlying HDCT for breast cancer [2-4]. Furthermore, the
recent presentation of prospective, randomized trials compar-
ing HDCT to conventional treatment has contributed to
more confusion about the role of this treatment modality for
breast cancer, owing in part to early reporting of the data [5-
8]. We reasoned that the compilation and reporting of out-
comes from a large series of breast cancer patients consecu-
tively undergoing HDCT with long-lead follow-up times at 5
California bone marrow transplant centers would be of value
in understanding the expected results of HDCT for breast
cancer and would provide a basis to assess the HDCT arms of
the prospective, randomized trials.
MATERIALS AND METHODS
We compiled raw data on 1111 consecutive breast can-
cer patients who underwent HDCT with autologous
High-Dose Chemotherapy and Hematopoietic Stem Cell
Rescue for Breast Cancer: Experience in California
Lloyd E. Damon,1Wendy W. Hu,2Keith E. Stockerl-Goldstein,2Karl G. Blume,2Jeffrey L. Wolf,3
Eric Gold,3Gary R. Cecchi,3David Irwin,3John Glaspy,4Mary Territo,4William Miller,5
James R. Mason,5Charles A. Linker1
1School of Medicine, University of California, San Francisco; 2Stanford University Medical Center, Stanford;
3Alta Bates Comprehensive Cancer Center, Berkeley; 4School of Medicine, University of California, Los Angeles;
5Scripps Clinic, La Jolla, California
Correspondence and reprint requests: Lloyd E. Damon, MD, A502, University of California, San Francisco,
San Francisco, CA 94143-0324.
(Received January 28, 200; accepted May 30, 2000)
The role of high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell rescue in breast cancer is
still controversial. We analyzed the outcomes of 1111 consecutive patients with histologically proven breast cancer
who underwent HDCT at 5 major California medical centers. The overall treatment-related mortality (TRM) was
2.3%. TRM was not influenced by disease stage or the HDCT regimen delivered, but it was influenced by hemato-
poietic graft source. The TRM was 6.1% when bone marrow with or without blood stem cells was used, but only
1.4% when blood stem cells alone were used (P < .001). With a median follow-up of 2.8 years (range, 0.1-8.2 years)
after HDCT and autologous hematopoietic stem cell rescue, the estimated 5-year event-free survival (EFS) and
overall survival (OS) for stage II/IIIA patients with ≥10 involved axillary lymph nodes were 67% and 76%, respec-
tively. Patients with metastatic breast cancer (MBC) (median follow-up, 1.9 years [range, 0.03-8.3 years]) achieving a
complete response (CR) to conventional-dose chemotherapy or rendered to a “no evidence of disease” status before
HDCT had significantly better estimated 5-year EFS and OS (28% and 57%, respectively) than those achieving a
partial response before HDCT (19% and 27%, respectively; P ≤ .0001). Our data suggest that HDCT with hemato-
poietic stem cell rescue is safe and can be beneficial to patients with high-risk primary breast cancer and for those
with MBC achieving CR/no evidence of disease.
Biology of Blood and Marrow Transplantation 6:496-505 (2000)
© 2000 American Society for Blood and Marrow Transplantation
High-Dose Chemotherapy for Breast Cancer
hematopoietic stem cell rescue (bone marrow or peripheral
blood) at 5 California bone marrow transplant centers
(Table 1). The contributing institutions were Alta Bates
Comprehensive Cancer Center (Berkeley), Scripps Clinic
(La Jolla), Stanford University Medical Center (Stanford),
University of California, Los Angeles School of Medicine
(UCLA), and University of California, San Francisco
(UCSF). These patients were all enrolled in phase 2 HDCT
protocols approved by each center’s Institutional Review
Board, and each patient gave written, informed consent for
their protocol treatment.
All patients had a histological diagnosis of breast cancer
and were staged by the criteria of the American Joint Com-
mittee on Cancer . All patients underwent standard rec-
ommended staging procedures  as well as radionuclide
bone scintigraphy. Computer tomographic or magnetic res-
onance scans were done on areas of suspected or known
metastases. There was no uniform practice for staging with
bone marrow biopsies.
Eligibility for HDCT varied at each transplant center
but uniformly included histological confirmation of breast
cancer; written, informed consent; age <70 years; ambulatory
performance status; adequate organ function (serum liver
tests <3? that of each institution’s upper limit, total bilirubin
<2 mg/dL, serum creatinine <2 mg/dL, carbon monoxide
diffusing capacity (DLCO) on pulmonary function testing
≥50% of predicted, and normal left ventricular ejection frac-
tion by nuclear wall motion study or echocardiogram); lack
of known bone marrow involvement with breast cancer; lack
of significant comorbid medical or psychiatric illness; and
insurance authorization. Eligibility was also stage-dependent
(Table 1): (1) stage II with ≥10 involved axillary lymph nodes
(LN); (2) stage IIIA; (3) stage IIIB (pre- or postmastectomy,
with or without inflammatory changes); and (4) recurrent or
metastatic breast cancer (MBC). MBC patients were eligible
if they demonstrated a complete response (CR) or partial
response (PR) to conventional-dose chemotherapy  or if
they were rendered to a “no evidence of disease” (NED) sta-
tus by surgery or radiation therapy. Previous treatment for
MBC was not an exclusion.
Response criteria were fulfilled if the documented
response lasted at least 4 weeks. For analysis purposes, NED
patients were combined with CR patients. MBC patients
with bone-only metastases were eligible if they demon-
strated correction of hypercalcemia (if present), improve-
ment in bone pain, and a reduction or stabilization in the
size and/or number of bony lesions on radionuclide bone
scintigraphy after conventional-dose chemotherapy.
Except for some NED MBC patients, all patients
received conventional-dose induction chemotherapy before
HDCT. The conventional-dose regimen used and the num-
ber of cycles given varied depending on each institution’s
protocol(s). The source of autologous hematopoietic stem
cells was pelvic bone marrow in 71 patients (6.3%), periph-
eral blood in 909 (81.7%), both in 44 (4.0%), and not
reported in 90 (8.0%). Peripheral blood stem cells were
mobilized according to each institution’s protocol(s) using
growth factors alone or in combination with chemotherapy.
All institutions required a minimum of 2 ? 106/kg CD34+
cells or a minimum of 5 ? 108/kg mononuclear cells to pro-
ceed to HDCT.
The HDCT regimen used varied at each transplant center
(Table 2). STAMP I (CBP: cyclophosphamide, carmustine,
cisplatin)  was the regimen of choice at both Stanford Uni-
Table 1. Patient Accrual by Transplant Center*
II/IIIA, ≥10 LNTransplant Center IIIIIAIIIB MBC
*LN indicates involved axillary lymph nodes; MBC, metastatic breast cancer; UCLA, University of California, Los Angeles; UCSF,
University of California, San Francisco.
Table 2. High-Dose Chemotherapy Regimens by Transplant Center*
Transplant CenterCBP CTMCTCbCT Other
*CBP indicates cyclophosphamide, carmustine, cisplatin; CTM, cyclophosphamide, thiotepa, mitoxantrone; CTCb, cyclophosphamide, thiotepa,
carboplatin; CT, cyclophosphamide, thiotepa; UCLA, University of California, Los Angeles; UCSF, University of California, San Francisco.
L.E. Damon et al.
versity and UCLA and accounted for 44.3% of all patients.
CTM (cyclophosphamide, thiotepa, mioxantrone)  was the
regimen of choice at Alta Bates and UCSF and accounted for
31.9% of all patients. STAMP V (CTCb: cyclophosphamide,
thiotepa, carboplatin)  was the regimen of choice at
Scripps and accounted for 12.2% of all patients. The CT regi-
men (cyclophosphamide, thiotepa)  (5.0%) and other regi-
mens (6.6%) accounted for the remainder.
Patients with primary breast cancer received standard
chest wall and axillary radiation therapy (including mastec-
tomy patients) approximately 2 months after HDCT
[16,17]. Some stage IIIB patients had mastectomy per-
formed post-HDCT followed by radiation therapy. Primary
breast cancer patients known to be positive for estrogen
and/or progesterone receptor (or whose receptor status was
unknown) received 5 years of tamoxifen (or other hormonal
agent). Post-HDCT therapy for MBC patients was subject
to the discretion of each transplant center and included no
therapy, hormonal therapy, involved-field radiation therapy,
and/or trastuzumab (Herceptin) therapy.
The outcomes evaluated included: treatment-related
mortality (TRM), event-free survival (EFS), and overall sur-
vival (OS). TRM was defined as any death related to HDCT
but not due to breast cancer. There was no time limit as to
when TRM could occur. TRM differences based on source
of hematopoietic stem cells, stage of disease, and HDCT reg-
imen were analyzed by the ?2contingency table method. The
Kaplan-Meier estimates for EFS and OS were determined
from the date of hematopoietic stem cell infusion using Surv-
Macro2 software (Dan Moore, Calico Computing) . For
EFS analysis, events included any deaths, relapse of breast
cancer (local or distant), or first progression of breast cancer
. For OS analysis, events included death due to any cause
. All survival data were censored for patients without
events at the date of last contact. Survival data were analyzed
as of July 1, 1998, and presented as probabilities and 95%
confidence intervals (CIs). Survival differences were analyzed
by the Cox-Mantel log-rank method.
A total of 1111 breast cancer patients were treated with
HDCT between November 20, 1978, and June 30, 1998. A
total of 13 different HDCT regimens were used, but 1 of
3 regimens (CBP, CTM, and CTCb) was delivered to the vast
majority of patients (87.4%) (Table 2). The overall TRM was
2.3% (Table 3). The TRM was significantly greater when
bone marrow (with or without blood stem cells) was used
(6.1%) than when blood stem cells alone were used (1.4%) as
hematopoietic stem cell graft source (Table 3) (P < .001).
There was no significant difference in TRM by patient stage
or HDCT regimen (Table 3) (P > .05). When blood stem cells
alone were used, there was no difference in TRM between
stage II/III patients (1.2%) and MBC patients (1.8%) (P > .25).
With a median follow-up of 2.8 years (range, 0.1-
8.2 years), the estimated 5-year EFS and OS for stage II/IIIA
patients with ≥10 LN were 67% (95% CI, 60%-73%) and
76% (95% CI, 70%-81%), respectively (Table 4, Figure 1).
There was no significant difference in EFS (P = .59) or OS
(P = .11) for patients with ≥10 LN in stage II versus stage IIIA
(Table 4; Figure 2). Stage IIIA patients with <10 LN (median
follow-up 2.7 years [range, 0.1-7.2 years]) had survivals simi-
lar to those of stage IIIA patients with ≥10 LN (median
follow-up, 2.0 years [range, 0.3-7.1 years]). The estimated
5-year EFS was 74% (95% CI, 61%-87%) versus 68% (95%
CI, 57%-79%) (P = .09), respectively, and OS was 84% (95%
CI, 76%-92%) versus 69% (95% CI, 55%-82%) (P = .06),
respectively (Table 4). The median EFS has not been reached
in the stage II and IIIA patients. The median OS is 8.1 years
in both stage II and stage II/IIIA patients with ≥10 LN.
Stage IIIB patients, with a median follow-up of 1.9 years
(range, 0.5-6.5 years), had an estimated 5-year EFS of 55%
(95% CI, 41%-68%) and OS of 59% (95% CI, 4%2-75%),
respectively (Table 4; Figure 1). The median EFS was
5.1 years, and OS was 5.9 years.
All patients with MBC (median follow-up, 1.9 years
[range, 0.1-8.3 years]) had an estimated 5-year EFS of 29%
(95% CI, 23%-35%) and OS of 40% (95% CI, 33%-46%)
(Table 4; Figure 1). The median EFS for MBC patients was
1.4 years, and OS was 2.8 years. MBC patients entering
Table 3. Treatment-Related Mortality Following High-Dose Chemotherapy*
TRM, nTotal, n TRM, %
Bone marrow and blood
*TRM indicates treatment-related mortality; MBC, metastatic breast cancer; HDCT, high-dose chemotherapy; CBP, cyclophosphamide, carmus-
tine, cisplatin; CTM, cyclophosphamide, thiotepa, mitoxantrone; CTCb, cyclophosphamide, thiotepa, carboplatin; CT, cyclophosphamide, thiotepa.
†Excludes 87 patients (5 TRM) for whom the graft source was not reported.
High-Dose Chemotherapy for Breast Cancer
HDCT in CR/NED (median follow-up 1.9 years [range,
0.1-7.1 years]) had significantly better outcomes than those
entering HDCT in PR (median follow-up, 1.3 years [range,
0.1-6.4 years]), with median EFS of 2.2 and 1.0 years (P =
.0001) and median OS of 6.0 and 2.0 years (P < .0001),
respectively (Table 4; Figure 3).
A survival analysis was done on subgroups by stage
according to the 3 most commonly used HDCT regimens,
CBP, CTM, and CTCb (Table 5). Survival was estimated at
4 years rather than 5 because many subgroups of patients
receiving CBP or CTCb had lead follow-ups of <5 years. In
stage II/IIIA patients with ≥10 LN, EFS (P = .45) and OS
(P = .19) were not significantly different among the
3 HDCT regimens (Table 5; Figures 4A and 5A). In no
other stage II and IIIA subgroup was there a significant dif-
ference in EFS or OS among the 3 HDCT regimens exam-
ined (Table 5). Stage IIIB patients receiving CBP have EFS
(P = .96) and OS (P = .08) rates similar to those of patients
receiving CTM (Table 5; Figures 4B and 5B). Too few IIIB
patients received CTCb for an adequate comparison.
In MBC patients as a whole, the EFS (P = .29) and OS
(P = .053) were similar when the 3 regimens were analyzed
by 3-way comparison (Table 5; Figures 4C and 5C). By pair-
wise comparison, CTCb appeared to be better than CBP
(P = .02) and CTM (P = .02) in OS (Figure 5C) but was not
statistically different than CBP or CTM in EFS (Figure 4C).
The data in this study represent one of the largest series
of HDCT for breast cancer published to date, second only to
that of the North American ABMTR . Our series differs
from that of the North American ABMTR by virtue of con-
secutive patients being analyzed, more uniform therapy given
in a small number of institutions, longer lead follow-up, and
more detailed analysis of TRM and subgroup outcomes.
Our overall TRM (2.3%) was lower than that reported
by the North American ABMTR (7.7%) . This is likely
because a greater proportion of our patients (88.8%)
received blood stem cell grafts rather than bone marrow
grafts (with or without blood stem cells) compared with the
North American ABMTR (42.6%). We were able to
demonstrate that the source of hematopoietic stem cells
influenced TRM (significantly less TRM when blood stem
Table 4. Survival After High-Dose Chemotherapy With Hematopoietic Stem Cell Rescue*
5-Year Probability, % (95% CI) Median, y
Disease StagenEFS OS EFS OSFollow-Up, y
II/IIIA, ≥10 LN
II, ≥10 LN
*CI indicates confidence interval; EFS, event-free survival; OS, overall survival; LN, involved axillary lymph nodes; NR, not reached; MBC,
metastatic breast cancer; CR/NED, complete response/no evidence of disease before HDCT; PR, partial response before HDCT.
†Includes 145 patients for whom no pre-HDCT disease status was reported.
Figure 1. Survival of breast cancer patients undergoing high-dose chemotherapy (HDCT). Event-free survival (A) and overall survival (B) are
shown according to breast cancer stage. LN indicates lymph nodes; MBC, metastatic breast cancer.
Years from HDCT
Years from HDCT
L.E. Damon et al.
cells were used alone), whereas patient disease stage and
HDCT regimen did not. A significantly lower TRM when
blood rather than bone marrow is used as hematopoietic
stem cell grafts after HDCT has been previously demon-
strated in lymphoma  and has been the primary explana-
tion for a trend in decreasing TRM in HDCT for breast
cancer in North America. Unlike our series, primary breast
cancer patients had a lower TRM (3%) than metastatic
patients (10%) in the North American AMBTR report.
Blood stem cell rescue after HDCT is thought to reduce
TRM by shortening the period of neutropenia, facilitating
the recovery of mucosal damage, and decreasing the inci-
dence of veno-occlusive disease of the liver . One might
expect the same benefit, however, when blood stem cells are
added to bone marrow grafts. In our series, the combination
of bone marrow and blood stem cells had a TRM similar to
bone marrow alone. The most likely explanation is that in
our study the combining of stem cell grafts was not done as a
deliberate procedure but rather that bone marrow was added
to blood stem cells in patients who failed to mobilize ade-
quate numbers of stem cells alone for HDCT rescue. Such
patients demonstrate engraftment kinetics more resembling
bone marrow rescue than blood stem cell rescue . When
bone marrow is deliberately combined with blood stem cells,
hematopoietic recovery is fast and resembles blood stem
cell–only engraftment . Paradoxically, rapid hemato-
poietic engraftment following deliberately combined bone
marrow and blood stem cell rescue did not reduce the TRM
in the recent Cancer and Leukemia Group B (CALGB)-led
Intergroup trial (CALGB 9082/SWOG 9114/NCIC MA-
13) comparing CBP with hematopoietic stem cell rescue to
intermediate-dose CBP in primary breast cancer patients
with ≥10 LN . The TRM following CBP was 7.3% and
thought to be a consequence of treatment-induced intersti-
tial pneumonitis and hemolytic-uremic syndrome [12,22].
The TRM with CBP was lower (2.0%) in our 492 patients
who received CBP. In California, CBP was the HDCT regi-
men of choice at 2 centers and was the most common
HDCT regimen delivered in our series. The experience with
CBP at these 2 centers produced a low TRM. The Inter-
group trial  showed a trend toward reduced TRM at cen-
ters performing >50 transplantations during the course of the
study, which likely explains the low TRM in our series. The
Intergroup trial involved many more transplantation sites with
Figure 3. Survival of metastatic breast cancer (MBC) patients undergoing high-dose chemotherapy (HDCT). The event-free survival (EFS) (A) and
overall survival (OS) (B) of patients with MBC are shown according to disease status at time of HDCT (complete response/no evidence of disease
[CR/NED] vs. partial response [PR]). CR/NED patients had better EFS (P = .0001) and OS (P < .0001) than did PR patients by log-rank analysis.
Figure 2. Survival of primary breast cancer patients with ≥10 axillary lymph nodes (LN) undergoing high-dose chemotherapy (HDCT). The
event-free survival (EFS) (A) and overall survival (OS) (B) of stage II/IIIA breast cancer patients with ≥10 LN are shown according to stage of dis-
ease. There was no difference in EFS (P = .59) or OS (P = .11) between the 2 stages by log-rank analysis.
Years from HDCT
Years from HDCT
Years From HDCT
Years From HDCT
High-Dose Chemotherapy for Breast Cancer
less CBP experience and hence a higher TRM than expected
(1-3%) . A surprising finding in our study was that the
HDCT regimen used did not impact TRM. Our observations
suggest that centers experienced with CBP will generate TRM
rates no different from those of other HDCT regimens.
Of particular interest over the past decade has been the
use of HDCT for primary breast cancer with ≥10 LN. The
survival analysis of such patients was lacking in the North
American ABMTR report . Experience at several centers
involving 18 to 85 patients each has been published, with
estimated 5-year EFS ranging from 50% to 64% (follow-up
range, 2.7-5.0 years) [7,13,23-25]. The previously men-
tioned Intergroup trial randomized 394 patients to CBP, had
a median follow-up of 3 years, and did not report 5-year
EFS or OS . The analysis of the Intergroup trial is con-
sidered to be preliminary. Our series of patients with ≥10
Table 5. Survival After High-Dose Chemotherapy With Hematopoietic Stem Cell Rescue by Regimen*
4-Year Probabilities, % (95% CI)
CBP CTM CTCb
Stagen EFSOSn EFSOSn EFSOS
II/IIIA, ≥10 LN
II, ≥10 LN
67 (51-83) 148
*CI indicates confidence interval; CBP, cyclophosphamide, carmustine, cisplatin; CTM, cyclophosphamide, thiotepa, mitoxantrone; CTCb, cyclophos-
phamide, thiotepa, carboplatin; EFS, event-free survival; OS, overall survival; LN, involved axillary lymph nodes; MBC, metastatic breast cancer.
Figure 4. Event-free survival (EFS) of breast cancer patients undergoing high-dose chemotherapy (HDCT) according to regimen. The EFS of breast
cancer patients is shown according to the following 3 HDCT regimens: CTCb (cyclophosphamide, thiotepa, carboplatin), CBP (cyclophosphamide,
carmustine, cisplatin), and CTM (cyclophosphamide, thiotepa, mioxantrone). A, Stage II/IIA with ≥10 involved axillary lymph nodes. B, Stage IIIB.
C, Metastatic breast cancer. There was no difference in EFS in any stage by log-rank analysis done by 3-way comparison or by pair-wise comparisons.
Years from HDCT
Years from HDCT
Years from HDCT
L.E. Damon et al.
LN is virtually identical to the Intergroup study experimen-
tal arm in number (397) and median follow-up (2.8 years).
With a range of follow-up from 0.1 to 8.2 years and 42
patients more than 5 years from hematopoietic stem cell
rescue, the estimated 5-year EFS and OS in our stage
II/IIIA patients with ≥10 LN are 67% and 76%, respec-
tively. This result compares favorably to 5-year relapse-free
survivals of 17% to 56% (weighted mean, 38%) in such
patients receiving conventional-dose adjuvant chemotherapy
with follow-ups ranging from 3.3 to 10.3 years [4,7,23,26-
37]. Comparisons of outcomes with HDCT to historical
outcomes with conventional-dose chemotherapy must be
interpreted with caution. Factors such as patient selection,
differences in supportive care, and length of follow-up pre-
clude our ability to draw definitive conclusions. Neverthe-
less, reported survivals for HDCT are consistently higher
than conventional-dose chemotherapy in high-risk primary
breast cancer patients.
In this study, we were able to support previous observa-
tions that stage IIIA patients (with or without ≥10 LN) did
as well as stage II patients after HDCT [1,25]. We did not
have the primary data to confirm or refute other previously
described prognostic variables in primary breast cancer
patients undergoing HDCT, including hormone receptor
status, primary tumor size, and the ratio of number of
involved axillary LN to the total number of LN sampled
[13,25,38]. Our data suggest a benefit of HDCT over con-
ventional chemotherapy in primary breast cancer patients
with ≥10 LN. Encouraging results in the ≥10 LN patients
have led to the exploration of HDCT in stage II/IIIA
patients with 4 to 9 LN .
Our stage-IIIB patients included a mixture of those with
clinical inflammatory breast cancer and those without clini-
cal inflammatory breast cancer but who met pathologic cri-
teria for stage IIIB disease. With a range of follow-up of 0.5
to 6.5 years (median, 1.9 years) and 6 patients more than 5
years from hematopoietic stem cell rescue, the 5-year esti-
mated EFS and OS were 55% and 59%, respectively. This
outcome is similar to that of 30 IIIB patients undergoing
HDCT at the University of Colorado (estimated 4-year
EFS 62% and OS 83%)  and appears to be better than
that observed from “inflammatory” patients reported to the
North American ABMTR whose 4-year progression-free
survival (PFS) and OS were approximately 40% and 46%,
respectively . Overall, the HDCT survival data from
these analyses, including ours, appear better than those for
“inflammatory” patients receiving conventional-dose
chemotherapy (weighted average 5-year PFS 34%, range
Figure 5. Overall survival (OS) of breast cancer patients undergoing high-dose chemotherapy (HDCT) according to regimen. The OS of breast
cancer patients is shown according to the following 3 HDCT regimens: CBP (cyclophosphamide, carmustine, cisplatin), CTCb (cyclophosphamide,
thiotepa, carboplatin), and CTM (cyclophosphamide, thiotepa, mioxantrone). A, Stage II/IIIA with ≥10 involved axillary lymph nodes (LNs).
B, Stage IIIB. C, Metastatic breast cancer (MBC). There was no difference in OS in stage II/IIIA with ≥10 LNs or in stage IIIB patients by log-rank
analysis done by 3-way or by pair-wise comparisons. There was no difference in OS in MBC patients by log-rank 3-way comparison (P = .053), but
CTCb was better than CBP (P = .02) and CTM (P = .02) by log-rank pair-wise comparisons.
Years from HDCT
Years from HDCT
Years from HDCT
High-Dose Chemotherapy for Breast Cancer
10-54%) . Whether all “inflammatory” patients
reported to the North American ABMTR were truly
“inflammatory” or a mixture including both inflammatory
and noninflammatory stage IIIB patients is unclear. This
distinction is important because a series of inflammatory-
only stage IIIB patients would be expected to do worse than
a series of mixed-stage IIIB patients.
Patients with MBC undergoing HDCT are notable for
having heterogeneous disease. Although some clinical trials
of HDCT have reduced heterogeneity by restricting inclu-
sion only to those individuals responding to their first
course of chemotherapy for metastatic disease [5,42,43] or
to those receiving no prior chemotherapy for metastatic dis-
ease [44,45], others (including this California series) have
not [1,14]. Presumably, patients responding to their first
course of chemotherapy for metastatic disease will fare bet-
ter than those failing their first course . Other variables
known to predict survival outcomes following HDCT for
MBC include age, performance status, tumor grade, hor-
mone receptor status, her2/neu overexpression, use of
tamoxifen in the adjuvant setting, number of metastatic
organ sites, organ distribution of metastasis, time from ini-
tial breast cancer diagnosis, whether previous adjuvant
chemotherapy was administered, use of post-HDCT radio-
therapy, and the degree of response to conventional-dose
chemotherapy before HDCT [47-54]. The large number of
prognostic variables reflects the heterogeneity of MBC and
makes comparisons between phase 2 trials problematic.
In our series, we were able to confirm that disease status
before HDCT is prognostic for outcome, as previously
shown [1,14,42,49]. Our patients achieving CR/NED before
HDCT did particularly well, with an estimated 5-year EFS
and OS of 28% and 57%, respectively. Their median EFS
and OS were 2.2 and 6.0 years, respectively (Table 4). Two
other studies of HDCT in patients with minimal disease
(NED by surgery or radiation, <5% bone marrow involve-
ment as the only site of metastatic disease, or stage IV by
virtue of only supraclavicular LN involvement) have shown
median EFSs of 2.6 and 3.6 years and median OSs of 3.0
and 6.4 years [52,55]. These outcomes appear to be better
than those reported for 263 patients with MBC at the M.D.
Anderson Cancer Center who achieved CR with conven-
tional-dose chemotherapy but did not receive HDCT inten-
sification. Their median EFS and OS were 1.8 and 3.5 years,
respectively . Again, comparison must be interpreted
with caution because the median follow-up in our series (1.9
years) is much shorter than in the M.D. Anderson series
(median follow-up, 6.3 years). On the other hand, the M.D.
Anderson patients had previously untreated MBC and
therefore were more likely to have responsive disease and
more favorable survivals. Many of our MBC patients had
been previously treated and therefore had more unfavorable
prognoses. Furthermore, survival for conventionally treated
MBC patients is determined from the date of commence-
ment of first therapy, whereas survival for MBC patients
undergoing HDCT is determined from the date of stem cell
transplantation, skewing survival in favor of conventionally
The observation of more favorable outcomes with
HDCT in CR/NED patients may be important. A recent
large (n = 199), prospective, randomized trial of HDCT
using CTCb versus conventional-dose maintenance chemo-
therapy in patients with MBC responding to conventional-
dose induction chemotherapy found no difference in OS
between randomized groups . However, this study had
insufficient numbers of CR patients before randomization
(n = 56) to exclude the possibility of benefit from HDCT
for MBC patients with minimal disease . Whether
HDCT for MBC patients with minimal disease is superior
to conventional-dose treatment remains uncertain.
An unanswered question is whether a particular HDCT
regimen influences outcome. A multivariate analysis from
the North American ABMTR found that HDCT regimens
had no influence on treatment failure for women with MBC
. HDCT regimens for breast cancer have not been com-
pared in a controlled fashion to date. Our uncontrolled
comparison of outcomes with CBP, CTM, and CTCb found
no difference in TRM based on the HDCT regimen deliv-
ered (Table 3). Further, we could not find any significant
differences in EFS or OS in any stage subgroups comparing
the 3 regimens. Because of the relatively small numbers
within the subgroups analyzed, we had the power to detect
only large differences in outcomes. In addition, because
each center used predominantly 1 HDCT regimen, differ-
ences in patients’ prognostic characteristics between centers
could have inherently biased outcomes. Thus, our analysis is
insufficient to exclude possible differences in outcome
related to the HDCT regimen. If outcome differences exist
between HDCT regimens, they will likely be small and may
depend on other factors, such as type of prior conventional-
dose therapy. Only large, prospective randomized trials will
be able to definitively determine whether the HDCT regi-
men administered influences survival outcomes.
In conclusion, our analysis of a large number of consecu-
tive breast cancer patients who underwent HDCT supports
the contention that the role of HDCT in treating this dis-
ease is far from settled. Outcomes in stage II/IIIA disease
with ≥10 LN appear to be better than those in historical
patients who received conventional-dose adjuvant chemo-
therapy in this setting. The use of peripheral blood stem cells
is associated with a low TRM, making this therapy routinely
applicable in the high-risk primary breast cancer setting.
Furthermore, based on comparison with historical controls,
our outcome data cannot exclude the possibility of benefit
from HDCT intensification in patients with MBC achieving
a minimal disease status.
The authors wish to thank Danielle Moss for her expert
assistance in the preparation of this manuscript.
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