Abstract and Introduction

Abstract
Traditional chemotherapy regimens for advanced breast cancer have produced complete response
(CR) rates of 5%-25% and remissions of 5-13 months. Autologous stem cell transplantation
(ASCT), however, permits a 5- to 10-fold escalation of chemotherapy, which results in a
substantial increase in tumor-cell killing relative to standard therapy. This technique involves
protecting hematopoietic function by collecting stem cells from bone marrow or peripheral blood
before subjecting the patient to high-dose chemotherapy. These stem cells are then reinfused in
an autologous bone marrow transplant (ABMT) or autologous blood stem cell transplant
(ABSCT) to quickly repopulate the patient's marrow and blood. The largest and most mature of
phase II trials of ASCT for metastatic breast cancer reports rates of 35%-68% and 4-year
survival rates of 19%-27%. Although most patients develop recurrent disease 6-12 months post-
ASCT, it is encouraging that a few patients survive, disease-free, beyond 5 years. The
Autologous Blood and Marrow Transplant Registry analyzed data on more than 800 patients
with metastatic breast cancer who underwent ASCT. The Registry reported a 3-year progression-
free survival rate of 20% and an overall survival rate of 37%, which compares favorably with an
expected 17%-25% 3-year survival rate after conventional chemotherapy. Whether similar
success can be achieved with ASCT in ovarian cancer is uncertain because few ovarian cancer
patients are presently entered in high-dose studies using ASCT support.
Introduction
Autologous stem cell transplantation (ASCT) involves removing hematopoietic stem cells from a
cancer patient's bone marrow or peripheral blood, administering high-dose chemotherapy, and
then reinfusing the stem cells. After the autologous bone marrow transplant (ABMT) or
autologous blood stem cell transplant (ABSCT), the stem cells repopulate the patient's bone
marrow, which otherwise would be irreversibly damaged by the intensive chemotherapy. This
technique permits raising the dose of chemotherapy 5- to 10-fold to substantially increase tumor
cell killing relative to standard therapy. Because of the ease of collection and more rapid patient
recovery, many centers now collect the stem cells from blood instead of bone marrow.
[1]

Although ASCT has become standard therapy for selected patients with lymphoma, acute
myelogenous leukemia, and multiple myeloma, its application to breast and ovarian carcinomas
is experimental.

Epithelial Ovarian Cancer: Prognosis With Conventional Therapy
Ovarian cancer presents a significant health problem with increasing incidence and mortality
rates. Ovarian cancer is the fourth most common cause of cancer death in women in the U.S. and
Canada.
[49]
In approximately 60% of patients, the cancer has already spread to peritoneal or
distant sites by the time it is detected (stages III and IV). Five-year survival rates are under
20%.
[50,51]

Epithelial ovarian cancer is a chemosensitive malignancy and the majority of advanced-stage
patients achieve complete remissions in response to surgical debulking and postoperative
chemotherapy.
[51]
Unfortunately, only 50% of these patients have a complete response--that is,
no evidence of residual disease on second-look laparotomy.
[52,53]
Even those patients with a
complete response according to the pathology report still have a 50% chance of relapse.
[54,55]

There are currently no curative forms of salvage therapy for patients with persistent or relapsed
ovarian cancer.
[51]
Responses to standard-dose salvage therapy occur in only 20%-30% of
patients with relapsed ovarian cancer.
[56,57]
Median PFS is under 6 months, and 2-year PFS rates
are under 5% with standard-dose salvage chemotherapy.
[56]
Thus, the treatment picture with
standard therapy is bleak.
Dose-Response Relationship in Ovarian Cancer
In a retrospective analysis, both the clinical response and survival rates of patients with ovarian
cancer correlated with the dose intensity of the chemotherapy delivered.
[58]
Several studies have
demonstrated the antitumor activity of high-dose cisplatin in patients with ovarian cancer that
had failed to respond to lower doses of the drug.
[59-61]
Several randomized trials have been
performed evaluating the value of increasing the dose or dose intensity of cisplatin for ovarian
cancer.
[62-66]
One study in which cisplatin was given for a total of 6 cycles, either at a dose of
100mg/m
2
or 50mg/m
2
showed that the high dose improved response rates--61% vs 34%--and
18-month survival--73% vs 48%.
[62]
A similar study
[63]
demonstrated a 3-year survival rate of
60% for 6 cycles of cisplatin at a dose of 120mg/m
2
vs 30% for 6 cycles at 60mg/m
2
. Other
studies, which showed no survival benefit of increased cisplatin dose intensity, had similar total
cisplatin doses in both the experimental and control arms.
[64-66]
These studies suggest that the
total cisplatin dose is important in determining the outcome of the ovarian cancer treatment.
Also, in none of these studies did patients receive a truly high dose of platinum. In vitro models
suggest that a 5-fold or greater increase in platinum dose may be required to overcome
mechanisms of relative platinum resistance.

High-Dose Chemotherapy With ASCT to Treat Ovarian Cancer
Unlike breast cancer, very few ovarian cancer patients worldwide have been treated with true
high-dose chemotherapy requiring hematopoietic stem cell support. This is unfortunate, because
ovarian is suitable to such treatment for several reasons: First, it is a chemosensitive malignancy
with low but consistent rates of long-term, disease-free survival following standard
chemotherapy. Second, dose-response relationships have been identified for agents such as
platinum and alkylators; the response could be significantly escalated with higher doses using
stem cell support.
[68]
Finally, ovarian cancer rarely involves peripheral blood; therefore,
autologous blood stem cell products are unlikely to have been contaminated by tumor cells.
[69]
A
few promising results of high-dose therapy have been reported, but the number of patients
involved is small, and their characteristics and high-dose regimens are mixed.
Salvage therapy. Stiff and coworkers
[70]
reported the results of combination therapy with high-
dose cyclophosphamide, mitoxantrone, and carboplatin using ASCT in 30 patients with relapsed
ovarian cancer. Twenty of these were platinum-resistant, and most had relatively bulky disease.
Overall, 89% of patients responded to the treatment. Complete remissions occurred in 88% of
platinum-sensitive disease versus 47% of platinum-resistant disease. The median overall survival
posttransplant for all 30 patients was 29 months. At 3 years, 7 (23%) of the 30 patients were
alive without evidence of disease. These results are superior to those with conventional-dose
salvage therapy, particularly for those with platinum-sensitive disease.
Many other investigators have reported similar high response rates, often with encouraging
response durations for patients with refractory ovarian cancer.
[71-85]
Table I summarizes results
from some of these studies. The optimal high-dose chemotherapy regimen is unknown.
Currently, the Southwest Oncology Group is performing a randomized trial for stage III to IV
ovarian cancer with residual disease following one cisplatin- or carboplatin-based induction
regimen. Patients in this study are given cyclophosphamide and are randomly assigned to receive
either high-dose cyclophosphamide, cisplatin, thiotepa, or cyclophosphamide, carboplatin,
mitoxantrone; both regimens were supported with ASCT.
Because there have been no randomized studies comparing high-dose versus conventional-dose
salvage therapy, definitive proof of overall survival benefit is lacking. Nevertheless, some
patients are alive and disease-free more than 5 years following high-dose therapy with ASCT for
persistent or relapsed disease. For example, 4 out of 18 patients who had ASCT performed and
reported by Mulder and associates
[77]
and 2 out of 5 patients transplanted in Vancouver (M.
Barnett, personal communication, 1995) for persistent or relapsed ovarian cancer remained
relapse-free 6 to 12 years after ASCT. Therefore, long-term relapse-free survival is possible
following high-dose salvage therapy.
Stiff and coworkers
[82]
reported a survey of 153 ovarian cancer patients who had ASCTs at one
of 11 centers in the US. Only 5% of these patients had received high-dose therapy during their
first remission. The remaining 95% had relapsed or refractory disease. Although 20 different
high-dose regimens were used, the overall response rate was 71%, with a complete remission
rate of 43% (73% for platinum-sensitive vs 34% for platinum-resistant disease). Despite these
high initial response rates, the median time to progression of the disease after ASCT was only 6
months. High-dose therapy, therefore, seems to be more effective than standard-dose therapy in
terms of response rates, but a single high-dose treatment is unlikely to cure ovarian cancer if it is
reserved for patients with relapsed or refractory disease. Moreover, it is clear that current high-
dose regimens offer no long-term benefit to patients with platinum-resistant disease or bulky
disease (>1cm at second-look laparotomy) and should not be used for these patients.
Front line high-dose therapy. Logically, high-dose chemotherapy should be compared with
conventional therapy as front-line treatment for stage III or IV disease in large randomized trials.
The few front-line ASCT pilot studies are promising, but they are difficult to interpret because of
differences in patient and regimen. (See Table II.) The high-dose regimens were not particularly
aggressive and were used following at least 6 cycles of standard-dose therapy in all but 1 trial.
Benedetti-Panici
[86]
reported the most uniformly treated group of patients. In this study, patients
were treated with 2 cycles of standard-dose cyclophosphamide/cisplatin followed by a single
course of high-dose carboplatin combined with standard-dose etoposide, cisplatin, and ASCT.
Despite the relatively nonaggressive high-dose regimen and a total of only 3 chemotherapy
courses, this group of patients with poor prognosis (85% stage IIIc or IV, 85% high grade) had
an excellent 4-year progression-free survival rate of 57%. Trials such as this justify large
randomized studies to fully explore the potential survival benefit of front-line high-dose therapy.
It may be that optimal results require high-dose therapy to be given as initial treatment rather
than reserving it for remission consolidation. Investigators at Memorial Sloan Kettering and
elsewhere are piloting studies of repetitive cycles of moderately intensive chemotherapy in
which several cycles are supported by autologous blood stem cells.
[87,88]
After it is shown to be
feasible, this approach will also need to be compared with standard therapy in randomized trials.
Conclusion: A Place for ASCT in Treating Breast and Ovarian Cancer
Because of the lack of randomized controlled studies, high-dose chemotherapy with ASCT must
still be considered experimental for breast and ovarian cancer. However, based on phase II and
III trials of ASCT for hematologic malignancies and the phase II trials of ASCT for breast and
ovarian cancer, it is likely that high-dose therapy will find a place in the treatment of selected
patients with these diseases.
Well-designed phase II and III studies are under way for breast cancer stages II-IV. The role of
ASCT for breast cancer should become clearer by the end of the decade. In contrast, few ovarian
cancer patients are presently entered in high-dose studies. It is imperative that ASCT be
adequately evaluated in ovarian cancer before it is prematurely judged as ineffective or too toxic.
Randomized studies comparing front-line conventional dose therapy to front-line high-dose
therapy will soon be undertaken in patients who have stages III and IV ovarian cancer.
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