Bone Marrow Transplantation (2004) 33, 1219–1224
& 2004 Nature Publishing Group All rights reserved 0268-3369/04 $30.00
www.nature.com/bmt
Ovarian cancer
Analysis of 96 patients with advanced ovarian carcinoma treated with
high-dose chemotherapy and autologous stem cell transplantation
ML Donato1, A Aleman1, RE Champlin1, RM Saliba1, JT Wharton2, TW Burke2, DC Bodurka2,
MW Bevers2, CF Levenback2, JK Wolf2, RC Bast Jr2, RS Freedman2, C Ippoliti1, M Brewer2,
JL Gajewski1 and DM Gershenson2
1
Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA;
and 2Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
Summary:
The purpose of this study was to identify characteristics
significant to survival and progression-free survival in
patients with advanced ovarian cancer receiving high-dose
chemotherapy. In all, 96 patients received autologous stem
cell transplantation. Regimens included paclitaxel with
carboplatin (PC), topotecan, melphalan, cyclophosphamide (TMC) and cyclophosphamide, BCNU, thiotepa
(CBT). At the time of transplantation, 43% of patients
were in clinical CR, 34% were in clinical PR, 18% had
progressive disease and 5% had stable disease. There were
no treatment-related deaths. The 6-year survival by
Kaplan–Meier was 38%. For patients who received
transplantation for remission consolidation, the 6-year
survival was 53% with a PFS of 29%. On univariate
analysis, the CBT regimen, clear cell histology and
disease status other than CR prior to treatment were
statistically significant adverse prognostic factors. This
analysis has demonstrated that patients in clinical
remission are most likely to benefit from autologous
transplantation, with the exception of patients with clear
cell histology. The TMC combination appeared to be
superior to the PC and CBT combinations. Comparative
studies of different consolidation approaches will be
necessary to determine if autologous transplantation is
the preferred treatment for this patient population.
Bone Marrow Transplantation (2004) 33, 1219–1224.
doi:10.1038/sj.bmt.1704473
Published online 3 May 2004
Keywords: ovarian cancer; high-dose chemotherapy;
stem cell transplantation
Although some advances have been made in first-line and
salvage treatment, epithelial ovarian carcinoma remains a
Correspondence: Dr ML Donato, Department of Blood and Marrow
Transplantation, The University of Texas M.D. Anderson Cancer
Center, Box 423, 1515 Holcombe Blvd, Houston, TX 77030-4095,
USA; E-mail: [email protected]
Received 15 April 2003; accepted 10 January 2004
Published online 3 May 2004
leading cause of gynecological cancer deaths.1–3 Numerous
studies have focused on dose intensification, based on the
in vivo observation that there is a dose–response correlation
for certain tumors. Modest nonmyeloablative dose increases have been evaluated in a randomized manner with
the general conclusion that this approach is unlikely to
yield a survival advantage.4 A much higher dose intensity
can be achieved with hematopoietic stem cell support and
this technology has greatly evolved over the past decade.
The use of peripheral blood as the source of hematopoietic
progenitors along with improvement in supportive care has
reduced transplant mortality and morbidity. Progress has
also been made in the understanding that not all patients
are likely to benefit from such an approach. To try to
further elucidate this point, we have looked at 96 patients
treated with high-dose chemotherapy and autologous stem
cell transplantation. We have analyzed patient and disease
characteristics along with transplant regimens, with the
objective of defining survival and disease-free survival in
different clinical settings.
Patients and methods
Patients
Between February 1994 and June 2000, 96 patients with
epithelial ovarian cancer received high-dose chemotherapy
with peripheral blood stem cell transplantation. Patients
provided written informed consent in accordance with our
institutional review board. Patients’ demographics and
tumor characteristics are summarized in Table 1.
Patients were eligible for transplantation if they were
physiological age p60 years, had histologically proven
invasive epithelial ovarian cancer stage III–IV in first
clinical CR, clinically persistent or progressive disease with
initial induction chemotherapy or if they had recurrent
disease. Patients with fallopian tube or primary peritoneal
carcinoma were also treated. Patients had to have undergone prior tumor reductive surgery, total abdominal
hysterectomy, bilateral salpingo-oophorectomy and staging
laparotomy.
Other criteria for transplantation included: an estimated
creatinine clearance greater than 50 or 60 ml/min depending
on the regimen, adequate liver function with an ALT, AST
Autologous transplantation in ovarian cancer
ML Donato et al
1220
Table 1
Patient and tumor characteristics (N ¼ 96)
Characteristics
Median age
Histological type (no. of patients)
Papillary/serous
Clear cell
Other
49 (range 22–67)
81
4
11
Histological grade (no. of patients)
Intermediate/high
Low
84
12
Median number of prior regimens
2 (range 1–6)
and bilirubin less than twice the upper normal limit; normal
cardiac ejection fraction; pulmonary diffusion capacity
greater than 50% of predicted; and platelet count greater
than 100 109/l.
Relapsed patients were considered platinum-refractory
or resistant if they had failed to achieve at least a partial
remission to a platinum-containing regimen or had relapsed
within 6 months of completing a platinum-containing
regimen.
Treatment plan
Blood stem cell mobilization and collection. For peripheral
blood stem cell mobilization and collection, 17 patients
received cyclophosphamide 4 g/m2 by intravenous infusion
over 2 h. Mesna 1 g/m2 was given intravenously over 30 min
prior to the cyclophosphamide and 3 g/m2 was given by
continuous infusion over 24 h after the cyclophosphamide.
In all, 12 patients received cyclophosphamide 3 g/m2 by
intravenous infusion with mesna as previously described
(day 1) and paclitaxel 200 mg/m2 by intravenous infusion
over 3 h (day 1). A total of 67 patients received ifosfamide
3.33 g/m2/day administered by continuous infusion over
24 h for three doses (days 1–3), and etoposide 150 mg/m2
administered intravenously over 2 h every 12 h for six doses
(days 1–3). Mesna was given at 2 g/m2 by intravenous
infusion before and at the completion of the ifosfamide.
Mesna was also given at a total dose of 8 g/m2 by
continuous infusion concomitantly with the ifosfamide
infusion. All patients received filgrastim 5–6 mg/kg rounded
to the nearest vial size (300 or 480 mg), subcutaneously twice
per day until completion of stem cell collection. Details of
the mobilization and collection of these patients have been
previously described.5
High-dose chemotherapy regimens. Patients received one
of three high-dose chemotherapy regimens. In all, 24
patients received a regimen of four cycles of high-dose
paclitaxel with carboplatin (PC). The first 12 patients were
on a dose escalation study, three patients were treated at
one of four dose levels and the remainder were treated at
the maximum tolerated dose, which is the highest dose
described below. Paclitaxel at a dose of 175–250 mg/m2 was
administered on day 3 as a single 24 h intravenous
infusion after premedication with dexamethasone 20 mg
orally given 14 and 7 h prior, and cimetidine 300 mg
Bone Marrow Transplantation
intravenously and diphenhydramine 50 mg intravenously
both given 1 h prior. At the completion of the paclitaxel,
carboplatin was administered at a dose determined by the
Calvert equation.6 The desired AUC ranged from 10 to
16.6. This combination was administered monthly for a
total of four cycles.
In all, 73 patients received the high-dose combination of
topotecan, melphalan and cyclophosphamide (TMC). Of
these patients, 53 were treated as part of a topotecan dose
escalating study and have been previously reported.7 The
other 15 patients were treated at the described maximal
tolerated dose, which is 4 mg/m2/day. Cyclophosphamide
1 g/m2/day was given intravenously over 2 h on days 6,
5, 4; melphalan 70 mg/m2/day was given intravenously
over 30 min on days 3 and 2. Both agents were
administered immediately before the topotecan. Topotecan
was given intravenously over 30 min daily for five total
doses on days 6 to 2. The topotecan dose ranged from
1.25 to 4 mg/m2/day.
Five patients received a combination of high-dose
cyclophosphamide, carmustine and thiotepa (CBT). Cyclophosphamide 2 g/m2/day was given intravenously over 2 h
on days 7, 6, 5 with mesna 500 mg/m2 intravenously
30 min before the first dose, than 2 g/m2/day by continuous
infusion for 3 days. Carmustine 150 mg/m2/day was given
intravenously over 2 h on days 7, 6 and 5. Thiotepa
240 mg/m2 was given intravenously over 4 h on days 7, 6
and 5. For all regimens, peripheral blood hematopoietic
stem cells were infused on day 0.
Supportive care. All patients received filgrastim 5 mg/kg/
day rounded to the nearest vial size, subcutaneously from
day 0 until the absolute neutrophil count reached at least
1.5 109/l. Prophylactic antibiotics with ciprofloxacin,
noroxin or levaquin, fluconazole, acyclovir or valacyclovir
were given. Transfusion of blood products was administered to maintain a hemoglobin level above 8.0 g/dl and
platelets above 15 109/l.
Definition of relapse and response
Patients had disease evaluation within 30 days prior to
enrollment, 30 days after transplantation and every 3
months for the following 2 years. Evaluation was carried
out with a complete physical examination, CT scan or MRI
of the abdomen and pelvis and serum CA-125. After the
second year, patients were evaluated every 4 months with a
physical examination and a CA-125. Patients were considered to have measurable disease if they had a tumor that
could be measured in two dimensions by imaging studies or
physical examination. Patients were considered to have
evaluable disease if they had no measurable disease on
scans or physical examination but had an elevated serum
CA-125 level (435 U/ml) in two samples. For patients with
measurable disease, a complete response was defined as the
complete disappearance of clinical evidence of tumor and a
normalization of the serum CA-125 level. A partial
response was defined as a 50% or greater decrease in the
sum of the products of the longest perpendicular diameters
of all measurable disease and, if elevated, a 50% or greater
decrease or normalization of the CA-125 level. For patients
Autologous transplantation in ovarian cancer
ML Donato et al
1221
with evaluable disease only, response was determined by
using the CA-125 serum levels as described by Rustin et al:8
(1) A 50% response is considered to have occurred if there
is a 50% decrease in CA-125 serum levels. There must be
two initial samples, and the sample showing the 50%
decrease must be confirmed by a fourth sample. (2) A 75%
response is considered to have occurred if there has been a
decrease in serum CA-125 levels of more than 75% over
three samples.
For establishing disease progression, elevation of the
CA-125 above 35 U/ml measured on two separate occasions was considered an independent indicator of relapse.
Patients with a previously elevated CA-125 level as a
disease marker and who presented with a new abnormality
on their CT scan or physical examination required a biopsy
to confirm the relapse only if their CA-125 level was within
the normal range. Patients who never presented with an
elevated CA-125 as a disease marker were considered to
have relapsed if a new lesion clinically consistent with
recurrence was detected radiologically or on physical
examination without requiring a biopsy.
phosphamide regimen for treatment of persistent or
recurrent disease. Follow-up since the first transplant was
considered in this analysis (N ¼ 96), except for the
comparison of outcomes according to the preparative
regimen where data from both transplants were included
(N ¼ 102). The pretransplant characteristics of patients
treated with each preparative regimen are summarized in
Tables 2 and 3. The median number of prior chemotherapy
regimens was 2 (range: 1–6). The median age was 49 years
(range: 22–67). In total, 71 patients (74%) were platinumsensitive, and 25 (26%) were platinum-refractory or
resistant.
Survival and PFS
There were no treatment-related deaths. The 6-year
survival by Kaplan–Meier was 38% (95% CI 15–60) with
a PFS of 13% (95% CI 4–25). For the 41 patients who
received transplantation for remission consolidation, the 6year survival was 53% (95% CI 18–79) with a PFS of 29%
(95% CI 10–50). The survival and PFS is shown in Figures
1 and 2.
Statistical analysis
Analysis of progression-free survival (PFS) and overall
survival was carried out from the time of registration,
which was immediately prior to the start of the mobilization or high-dose chemotherapy. All surviving patients
were followed up to October 2000, with the exception of
one patient, who was lost to follow-up 18 months post
transplantation. The median follow-up among surviving
patients is 18 months (range: 3.5–68). The cumulative
proportion for survival and PFS was estimated by the
Kaplan–Meier method. Prognostic factors for survival and
PFS at median follow-up were evaluated on univariate
analysis using the log rank test. Statistical significance was
determined at the 0.05 level. The analysis was performed
using STATA 7.0 (STATA Corporation, College Station,
TX, USA).
Prognostic factors for survival and PFS
Histology, tumor grade, response prior to transplantation,
transplant regimen, platinum-sensitivity, age, initial stage
and tumor debulking were analyzed. The results are
summarized in Table 4. The disease status prior to
transplantation was the most significant prognostic
factor for both overall survival (Figure 3) and PFS. As
expected, this factor was highly correlated with platinum
sensitivity (all patients in clinical CR were platinumsensitive), which was also associated with improved
overall survival and PFS. The CBT regimen was associated
with a significantly worse survival, and there was a
trend for better survival beyond 18 months for TMC
compared to the paclitaxel and carboplatin combination
Results
Table 2
Percentage of patients with platinum-sensitive or
platinum-resistant/refractory disease in each treatment group
Patients
Preparative
regimen
A total of 96 patients were treated and a total of 102
transplantations were performed. Six patients received two
transplant regimens, five patients who had previously
received high-dose cyclophosphamide, carmustine, thiotepa, and one patient who had received paclitaxel and
carboplatin went on to the topotecan, melphalan, cyclo-
Table 3
PC (N ¼ 24)
TMC (N ¼ 73)
CBT (N ¼ 5)
Platinum
sensitive (%)
Platinum resistant/
refractory (%)
87.5
72.6
60
12.5
27.4
40
PC ¼ paclitaxel, carboplatin; TMC ¼ topotecan, melphalan, cyclophosphamide; CBT ¼ cyclophosphamide, carmustine, thiotepa.
Disease status prior to transplantation in each treatment group
Preparative
regimen
Newly
diagnosed
No initial
clinical CR
Positive
2nd look
Relapsed,
untreated
Second
clinical CR
Second
clinical PR
Relapsed
SD/PD
PC (N ¼ 24)
TMC (N ¼ 73)
CBT (N ¼ 5)
46% (11)
0
0
13% (3)
18% (13)
20% (1)
0
33% (24)
20% (1)
25% (6)
5% (4)
20% (1)
13% (3)
16% (12)
0
4% (1)
15% (11)
20% (1)
0
12% (9)
20% (1)
PC ¼ paclitaxel, carboplatin; TMC ¼ topotecan, melphalan, cyclophosphamide; CBT ¼ cyclophosphamide, carmustine, thiotepa.
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ML Donato et al
1222
Table 4
follow-up
Univariate analysis of prognostic factors at median
N
Survival
(%)
Log rank
P-value
PFS
(%)
Log rank
P-value
81
4
11
79
0
65
0.001
35
0
14
o0.000
Disease status pretransplant
Clinical CR
41
PD/SD/PR
55
84
66
Preparative regimen
PC
TMC
CBT
24
73
5
78
83
20
0.5
0.0001
39
37
20
0.3
0.2
71
25
79
61
0.05
35
20
0.04
Age
p50
450
51
45
70
79
0.5
33
27
0.6
Stage at diagnosis
III
IV
77
11
76
81
0.9
28
51
0.3
Tumor grade
Intermediate/high
Low
84
12
72
90
0.2
30
38
0.1
Initial tumor debulking
Optimal
Suboptimal
61
35
74
76
0.8
33
27
Histology
Papillary/serous
Clear cell
Other
Figure 1
Overall survival and PFS for all patients treated.
Platinum sensitivity
Platinum-sensitive
Platinum-resistant or
refractory
Figure 2
Overall and PFS for patients who received transplantation for
X1st remission consolidation.
(Figure 4). The clear cell histology did significantly
worse than all other histologies for both survival and
PFS.
Since four of the five patients receiving the CBT regimen
and all the patients with clear cell histology were not in a
clinical CR at the time of transplantation, a multivariate
analysis to account for the independent effect of each
factor could not be made. However, when excluding
the CBT regimen and clear cell histology, disease status
before transplantation remained the only significant
predictor of PFS (P ¼ 0.01). Similarly, the CBT regimen
and clear cell histology remained significant adverse
factors for both survival and PFS (Po0.05) when restricting the analysis to patients not in clinical CR at the time of
transplantation. This suggests that these three factors,
CBT regimen, clear cell histology and clinical CR at the
time of transplantation, affect prognosis independently.
Owing to the high correlation between diseases status and
platinum-sensitivity, the independent effect of these factors
could not be evaluated in a multivariate analysis. Platinum
sensitivity, however, had no significant impact on survival
or PFSs for patients not in clinical CR at the time of
transplantation.
Bone Marrow Transplantation
0.02
53
14
0.0005
0.3
Figure 3 Overall survival by response prior to transplantation.
Discussion
In this analysis, we have again demonstrated that patients
with low volume disease are more likely to benefit from
high-dose treatment. We have also observed that there are
differences in efficacy for different transplant regimens, and
that clear cell histology is a significant adverse prognostic
factor.
Autologous transplantation in ovarian cancer
ML Donato et al
1223
Figure 4 Overall survival by preparative regimen. TMC ¼ topotecan,
melphelan, cyclophosphamide; PC ¼ paclitaxel, carboplatin; CBT ¼ cyclophosphamide, BCNU, thiotepa.
Clear cell ovarian carcinoma has been previously
described as a subset of epithelial ovarian carcinomas
presenting with somewhat unique clinical features.
Although some controversy still exists, most specifically
for endometriosis-associated clear cell carcinomas, it is
usually recognized that these patients have an overall worse
prognosis in the context of standard therapy.9–12 Although
we only treated a small number of patients with this
histology, based on our analysis it is unlikely that patients
with clear cell ovarian carcinoma will benefit from intensive
chemotherapy regimens such as the ones described here.
The Autologous Blood and Marrow Transplant Registry
also reported on the unfavorable prognosis of clear cell
histology.13
This analysis demonstrates that transplantation may be
most beneficial for remission consolidation. Several
different consolidative approaches have been explored over
the past few years. Barakat et al14 reported on 433 patients
with stage I–IV ovarian carcinoma, who received
intraperitoneal (IP) platinum-based chemotherapy for
consolidation of a clinical remission. Most of these
patients received IP therapy following induction chemotherapy and a second-look operation. The median
survival from initiation of IP therapy ranged from 1.2
years for patients with greater than 1 cm of disease, to
8.7 years for patients with a negative second-look
operation. Patients with microscopically and macroscopically positive second-look had a median survival of 4.8
and 3.3 years, respectively. Similarly, Tournigand et al15
administered IP cisplatin, etoposide and mitoxanthrone to
61 patients with less than 2 cm of residual disease at the
time of second-look surgery. The median survival was 71
months, approximately 81 months and 32 months, respectively, for patients with a negative or a positive second-look
surgery.
Another approach with somewhat more limited data has
been radiation therapy. In a study by MacGibbon et al,16
51 patients with o2 cm of residual disease at the time of
second-look surgery were treated with whole abdominal
radiotherapy. The median dose delivered was 2244 cGY in
a median of 22 fractions; 86% of patients also received a
pelvic boost. The 5-year survival was 27%. Other studies
have shown 5-year survivals in the ranges of 40–49% for
patients consolidated with whole abdominal radiotherapy.17,18 A commonly used consolidation method in clinical
practice is standard-dose chemotherapy continued beyond
remission. There have been trials comparing shorter vs
longer chemotherapy treatments; overall, there is little
scientific evidence that prolonging standard induction
chemotherapy offers a survival advantage.19,20 Newer
approaches have included IP interferon-alpha, which has
shown activity in patients with low volume chemosensitive
disease.21 Clinical trials are underway to determine the
role of other therapies, including interleukins and gene
therapy.22
High-dose chemotherapy has been studied in the
consolidation setting. Recently, the European Blood
and Marrow Transplant (EBMT) Registry reported
on 254 patients with ovarian carcinoma treated with
hematopoietic transplantation. The patients treated in
remission had a median overall survival of 32 months.
Patients with stage III disease transplanted in first
complete or partial remission had a median survival of
59 months.23 The French study by Legros et al24
reported a median survival of 66 months in a
similar consolidation group treated after second-look
surgery.
The availability of only phase II data makes it difficult to
conclude that one of these approaches to consolidation
therapy is superior. Our series, which includes patients in
first and in greater than first remission, had a 6-year overall
survival and PFS of 53 and 29%. This appears to be at least
equal to other consolidation strategies. A concern with
high-dose treatment has been the mortality risk and
quality-of-life issues. Current high-dose chemotherapy
treatments have very low mortality risks (0% in this
cohort) and with single intensification regimens, the
therapy is usually completed in under 2 months.
Quality of life trials will be necessary to assess patients
undergoing transplantation consolidation, compared to
other therapies.
This analysis has also demonstrated that the TMC
regimen may be superior to the paclitaxel/carboplatin
combination and is superior to the cyclophosphamide/
carmustine and thiotepa regimen. Previous comparisons of
different transplant regimens had failed to demonstrate the
superiority of a single combination.24,25 It is possible that
using non-cross-resistant drugs for consolidation of mostly
platinum-treated patients is the preferable approach. The
importance of combining drugs that have significant singleagent activity is also demonstrated by our results. Longer
follow-up will be needed to confirm the advantage of TMC
in our series.
Numerous strategies have been studied for remission
consolidation of ovarian carcinoma. Fairly extensive
phase II data are available for the use of high-dose
chemotherapy in this setting. However, because of
patient selection biases, it is impossible to compare
reliably these different modalities. Since there is no
standard or clearly superior treatment of patients in
clinical remission, continued participation in clinical trials
is recommended. Phase III trials of high-dose chemotherapy in patients with low volume disease are currently
underway.
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ML Donato et al
1224
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