Stem Cells, Vol. 19, No. 2, 151-160,
March 2001
© 2001 AlphaMed Press
Comparison of Double and Triple High-Dose Chemotherapy with Autologous Blood Stem Cell Transplantation in Patients with Metastatic Breast Cancer
A. Schneeweissa,
M. Henselb,
R. Goernera,
T. Khbeisa,
S. Hohausb,
G. Egererb,
E. Solomayera,
R. Haasc,
E.-M. Grischkea,
G. Basterta,
A.D. Hob
a Department of Gynecology and Obstetrics, and
b Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany;
c Department of Hematology and Oncology, University of Düsseldorf, Düsseldorf, Germany
Key Words. Metastatic breast cancer • High-dose chemotherapy • Multiple cycle • Blood stem cell transplantation
Andreas Schneeweiss, M.D., University of Heidelberg, Department of Gynecology and Obstetrics, Vossstrasse 9, D-69115 Heidelberg, Germany. Telephone: 49-6221-567856; Fax: 49-6221-565233; e-mail: andreas_schneeweiss{at}med.uni-heidelberg.de
 |
ABSTRACT
|
|---|
In patients with metastatic breast cancer (MBC), early dose intensification with multiple cycles of peripheral blood stem cell-supported high-dose chemotherapy (HDCT) seems superior to a late dose-intensification strategy. We compared the progression-free survival (PFS) and overall survival (OS) of 20 patients treated with a double (D)-HDCT regimen to 20 patients who received a triple (T)-HDCT, matched by age, estrogen receptor (ER) status, adjuvant chemotherapy, initial disease-free interval, predominant metastatic site, and number of metastatic sites. At a median follow-up of 41.5 months (range, 14-88 months) an intent-to-treat analysis showed no difference in PFS (p = 0.72) and OS (p = 0.93) between the matched patients. For all 76 patients treated within the D- or T-HDCT trial, median PFS and OS was 13 months (range, 2-78 months) and 24.5 months (range, 7-78 months), respectively. In multivariate analysis independent predictors of shorter OS included negative ER (relative risk [RR] = 3.0 [95% confidence interval (CI) 1.5-5.9]; p = 0.002), more than two metastatic sites (RR = 2.4 [95% CI 1.0-5.7]; p = 0.049) and failure to achieve complete remission/no evidence of disease (CR/NED) after HDCT (RR = 4.5 [95% CI 2.0-10.1]; p < 0.0001). These data show that early dose intensification with T-HDCT is not superior to a D-HDCT regimen in patients with MBC. ER-negative tumors, more than two metastatic sites and no CR/NED after HDCT, are associated with inferior outcome.
|
INTRODUCTION
|
|---|
Unlike early-stage breast cancer, metastatic breast cancer (MBC) is probably incurable [1]. Initially some 60%-70% of patients might respond to conventional chemotherapy and hormonal therapy, but the median survival is about two years [2, 3]. Most patients ultimately succumb to their disease [4]. A number of in vitro, preclinical and clinical trials support the concept that dose-intense therapy has a greater antitumor effect in a number of tumors including breast cancer [5-10]. Several nonrandomized studies with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) have indicated that a higher rate of objective responses and a longer response duration might be achieved compared to conventional dose chemotherapy [11]. Results of randomized trials comparing standard- and high-dose chemotherapy with ASCT are still controversial [12-14]. There was no survival benefit when HDCT was administered as a consolidation treatment after remission induction with several cycles of standard-dose chemotherapy. One hypothesis is that early HDCT might be necessary to eliminate a small volume of resistant tumor cells that could already be present initially and therefore has survival benefit compared to standard-dose chemotherapy. Another reason for early HDCT is the theoretical development of multidrug resistance with repeated exposure to cycles of chemotherapy.
From September 1992 to December 1995, we enrolled patients with newly diagnosed MBC in a trial using double (D)-HDCT. They received two conventional cycles followed by two cycles of HDCT with autologous blood stem cell transplantation (ABSCT). To shorten the induction period and further increase the dose intensity, we adopted another study design using three cycles of HDCT after only one cycle of induction chemotherapy. We have retrospectively analyzed the data to compare the toxicity and outcome of the two strategies and identify prognostic factors that might allow selection of patients who might benefit from HDCT.
|
PATIENTS AND METHODS
|
|---|
Patients
Between September 1992 and October 1998, 76 female patients with MBC were enrolled onto a first-line chemotherapy trial with D-HDCT (25 patients) or triple (T)-HDCT (51 patients). Inclusion criteria were: age between 18 and 60 years, Karnofsky performance score 
90%, normal hematological, cardiac, renal, and hepatic function and no relevant concomitant disease. Patients with only bone metastases or central nervous system (CNS) involvement were excluded from the clinical trials.
Twenty out of the 51 patients in the T-HDCT protocol were matched for age (
45 years, >45 years), hormone receptor status (estrogen receptor [ER]-negative, ER-positive, or unknown), prior adjuvant chemotherapy (yes, no), initial disease-free survival interval after adjuvant chemotherapy (18 months, >18 months), predominant metastatic site (viscera, soft tissue), and number of metastatic sites (2, >2) to 20 patients treated within the D-HDCT trial.
Patients' characteristics in detail including age, menopausal status at initial diagnosis, estrogen hormone receptor status, HER-2/neu receptor status, prior adjuvant chemotherapy, initial disease-free survival interval after adjuvant chemotherapy, predominant metastatic site, number of metastatic sites, and the prognostic index "Possinger score" are given in Table 1
. The "Possinger score" comprised hormone receptor status, initial disease-free survival, and predominant metastatic site and was calculated as described by Possinger et al. [15]. HER-2/neu status was measured by immunohistochemistry staining on primary tumor sections using the monoclonal antibody 3B5.
The study was conducted under the guidelines of the Joint Ethical Committee of the University of Heidelberg. Each patient gave her informed consent to participate in the study.
Cytotoxic Chemotherapy
For the D-HDCT trial, conventional induction chemotherapy consisted of two cycles of ifosfamide, 2,500 mg/m–2 as 20-hour i.v. infusion on days 1-3 (total dose 7,500 mg/m–2), and epirubicin, 40 mg/m–2 as a 4-hour i.v. infusion on days 1-3 (total dose 120 mg/m–2) repeated on day 22 (Fig. 1). For the T-HDCT trial, induction chemotherapy consisted of only one cycle of paclitaxel, 45 mg/m–2 as a 1-hour i.v. infusion on days 1-3 (total dose 135 mg/m–2), ifosfamide, 2,000 mg/m–2 as a 4-hour i.v. infusion on days 1-3 (total dose 6,000 mg/m–2), and epirubicin 30 mg/m–2 as a 1-hour i.v. infusion on days 1-3 (total dose 90 mg/m–2) (Fig. 2). Mesna was given at the same dose as ifosfamide on 3.5 days. All cycles were supported with recombinant methionyl human granulocyte colony-stimulating factor (filgrastim, 300 µg day 1 s.c.; Neupogen®, Amgen Inc.; Thousand Oaks, CA). The growth factor was administered to accelerate leukocyte recovery and mobilize progenitor cells into circulating blood.
View larger version (16K):
[in this window]
[in a new window]
|
Figure 1. Treatment plan double high-dose protocol. anumber of patients; bno carboplatin in five patients.
|
|
Peripheral blood stem cell (PBSC) collection began after the last cycle of induction chemotherapy when a distinct population of CD34+ cells was measurable in the PB. The leukaphereses were performed using a Fenwal CS3000 (Baxter Deutschland GmbH; Munich, Germany) or a Spectra (Cobe Laboratories; Lakewood, CA). Between 10 l and 20 l were processed at flow rates of 70-150 ml min–1. For PBSC collection, the patients received large-bore catheters in the jugular vein as previously described [16].
The first stem cell-supported HDCT followed approximately four weeks after the last induction chemotherapy. In case of D-HDCT the cytotoxic therapy was continued with two cycles of PBSC-supported high-dose ifosfamide (total dose 12,000 mg/m–2), epirubicin (total dose 180 mg/m–2), and carboplatin (total dose 900 mg/m–2) (Fig. 1
). The dose of all drugs was delivered over a period of five days. Carboplatin was not included for the first five patients. In case of T-HDCT two cycles of high-dose ifosfamide, epirubicin, and carboplatin were followed by one cycle of PBSC-supported high-dose paclitaxel (total dose 180 mg/m–2), etoposide (total dose 1,500 mg/m–2), and thiotepa (total dose 600 mg/m–2) split over three days (Fig. 2). Ifosfamide was given as 24-hour continuous i.v. infusion, epirubicin was administered over four hours i.v., etoposide over three hours i.v. (days 1 and 2) or 1.5 hours i.v. (day 3), carboplatin and paclitaxel over two hours i.v., and thiotepa over one hour i.v. Mesna was given at the same dose as ifosfamide, on days 1-5, followed by an additional administration of 50% of the dose on day 6. If there was no response after one cycle of T-HDCT, the second and third cycle consisted of high-dose paclitaxel, etoposide, and thiotepa. The scheduled intervals between the three HDCT cycles were five to seven weeks.
If the disease progressed after two or more cycles of chemotherapy or there was no remission after two cycles of T-HDCT, patients were excluded from the trials.
PBSC were reinfused 48 hours after the end of HDCT, and no cytokines were given following transplantation. The patients received prophylactic antimicrobial therapy with ciprofloxacin (1,000 mg day 1) and fluconazole (400 mg day 1).
Endocrine Therapy
Irrespective of receptor status, premenopausal patients received goserelin 3.6 mg s.c. once a month starting from the first induction chemotherapy for two years or until the disease progressed. In case of hormone receptor-positive tumor, postmenopausal patients received tamoxifen 20-30 mg day–1 peroral (po) or, if the metastases occurred during tamoxifen, anastrozole 1 mg day–1 po, starting at least 6 weeks following the last PBSC-supported high-dose therapy until the disease progressed.
Statistical Analysis
The comparability of patient and tumor characteristics of the matched patients treated within the D- and T-HDCT protocol was tested by chi-square tests. Progression-free survival (PFS) and overall survival (OS) were examined as clinical outcome variables. PFS was defined as the time from first induction chemotherapy to progress or death. OS was defined as the time from first induction chemotherapy to death. Survival curves were estimated using the Kaplan-Meier product limit method [17]. The univariate and multivariate analyses were performed to identify risk factors associated with PFS and OS. Differences between the survival curves were compared using the log-rank test [18]. Multivariate analysis was performed using the Cox regression model with stepwise analysis (p values for entry = 0.15 and for removal = 0.05) [19]. In the subgroup of 40 matched patients the trial protocol (D- versus T-HDCT) was examined as a risk factor for survival. In all 76 patients the following risk factors were examined in a univariate analysis using the log-rank test: age (45 years versus >45 years), menopausal status at initial diagnosis (pre- versus postmenopausal), ER status (positive/unknown versus negative), HER-2/neu receptor status (0-2+ versus 3+), adjuvant chemotherapy (yes versus no), initial disease-free survival interval after adjuvant treatment (18 months versus >18 months), predominant metastatic site (soft tissue versus viscera), number of metastatic sites (2 versus >2), the prognostic index "Possinger score" (<7 versus 7-10 versus >10), and the status after HDCT (complete remission [CR] including no evidence of disease [NED] versus no CR/NED). In a second step, variables that were significant in the univariate analysis were included in a multivariate analysis as stated above.
|
RESULTS
|
|---|
HDCT with ABSCT
Twenty-five patients with newly diagnosed MBC were enrolled into the first trial with two cycles of induction chemotherapy followed by two cycles PBSC-supported HDCT. The treatment was completed as scheduled in 23 patients. Two patients were withdrawn from the study. The reasons for discontinuation were progressive disease (PD) after induction chemotherapy in one patient, and development of allo-reactive antibodies against platelets without availability of appropriate cross-matched donors after the first cycle of HDCT in one patient. The median time interval between the two cycles of high-dose therapy was seven weeks (range, 5-12 weeks). In seven patients response was not evaluable because of surgical treatment of the measurable lesions before chemotherapy. These patients were classified as showing NED. Three CR, 11 partial remissions (PR), three stable diseases (SD), and one case of PD were achieved following induction chemotherapy before the administration of HDCT. After two cycles of HDCT, we achieved 10 CR and 7 PR for an overall response rate in the D-HDCT trial of 94% (17/18) (Table 2).
Fifty-one patients were enrolled to receive three cycles of PBSC-supported HDCT after one preceding cycle of induction chemotherapy. Thirty-nine patients completed the treatment as scheduled; 12 patients were withdrawn from the study. The reasons for withdrawal were refusal to proceed with HDCT in one patient, PD after the first cycle of HDCT in one patient, severe renal insufficiency after the first cycle of HDCT in two patients, PD after the second cycle of HDCT in two patients, SD after the second cycle of HDCT in two patients, missing further insurance coverage after the second cycle of HDCT in two patients, severe neurotoxicity with suspected myocardial infarction, and sino-atrial exit block after the second cycle of HDCT, each in one patient (Table 3). The median time intervals between the first and second, and second and third cycles of high-dose therapy were six weeks (range, 4-12 weeks) and six weeks (range 4-10 weeks), respectively. Seven patients were not evaluable for response because of NED before chemotherapy. With one cycle of induction chemotherapy we achieved 1 CR, 8 PR, and 20 SD. Three patients had PD; the status of 12 patients was not evaluated. After three cycles of HDCT, 10 patients were in CR and 20 in PR for an overall response rate following T-HDCT of 68% (30/44) (Table 2).
HDCT was supported with a median number of 3.7 x 106 CD34+ cells kg–1 (range, 0.8-38 x 106), which were collected following the last cycle of induction chemotherapy. Considering a threshold number of 2.5 x 106 CD34+ cells kg–1 as an adequate amount for sustained engraftment, in 52/74 (70%) patients the high-dose therapy could be supported with portions of up to three leukaphereses products.
Both D-HDCT and T-HDCT regimens were well tolerated. There was no difference in hematological reconstitution and transfusion requirements between the three cycles of HDCT except a slightly increased reconstitution time for platelets after the third cycle. Only one patient had a very slow hematological recovery after the third cycle of HDCT because of reinfusion of only 0.8 x 106 viable CD34+ cells kg–1. Except for this patient, a leukocyte count of 1.0 x 109 l–1 was observed at a median time of 12 days (range, 5-22 days), a neutrophil count of 0.5 x 109 l–1 was reached after a median time of 13 days (range, 5-23 days) and an unsupported platelet count of 20 x 109 l–1 between 9 and 10 days (range, 0-34 days). Following each cycle of HDCT, a median number of two platelet concentrations and two packed red cell concentrations had to be transfused (Table 4).
The nonhematological toxicity was generally moderate. Again we observed no remarkable difference between the three cycles of HDCT. No treatment-related deaths were observed within 100 days of transplantation. The most frequent grade 3 and 4 nonhematological toxicity was stomatitis, which developed in 26%-29% of patients requiring total parenteral nutrition for a maximum of 14 days. Other grade 3 and 4 nonhematological toxicity occurring in 7%-14% of patients comprised renal insufficiency in three patients, vomitus, diarrhea, and neurotoxicity, each in two patients, and arterial hypertension, atrioventricular block, epistaxis, and septicemia with disseminated intravascular coagulation, each in one patient. The median number of days with fever 38.5°C was 1.5 days (range, 0-6 days). As a result, the number of days of i.v. antibiotic therapy amounted to a median of 6.5 days (range, 0-22 days). Patients were hospitalized for a median of 20 days (range, 0-50 days) (Table 5).
|
OUTCOME
|
|---|
At a median follow-up of 41.5 months (range, 14-88 months), the median PFS and median OS of the 76 patients was 13 months (range, 2-78 months) and 24.5 months (range, 7-78 months), respectively (Fig. 3). Twenty patients from the D- and T-HDCT trial were then matched for age, estrogen hormone receptor status, prior adjuvant chemotherapy, initial disease-free survival interval, predominant metastatic site, and number of metastatic sites. No difference in PFS (p = 0.72) and OS (p = 0.93) between the two study groups could be found in an intent-to-treat analysis (Fig. 4). Furthermore a comparison of the 35 patients, who actually received the scheduled two (19 patients) or three (16 patients) PBSC-supported cycles of HDCT also showed no difference in PFS (p = 0.81) and OS (p = 0.93) (Fig. 5).
View larger version (12K):
[in this window]
[in a new window]
|
Figure 4. PFS (A) and OS (B) of matched patients after the first cycle of induction chemotherapy according to the trial protocol.
|
|
View larger version (12K):
[in this window]
[in a new window]
|
Figure 5. PFS (A) and OS (B) of matched patients after the first cycle of induction chemotherapy, who actually received the scheduled cycles of HDCT. sD-HDCT = scheduled D-HDCT; sT-HDCT = scheduled T-HDCT.
|
|
Considering only the 31 patients who were staged after each cycle of chemotherapy, with conventional chemotherapy we achieved a CR in 13% (4/31), a PR in 26% (8/31), an SD in 48% (15/31), and a PD in 13% (4/31) of patients. After one, two, and three cycles of HDCT, the remission rates were CR 19% (6/31), 19% (6/31), and 13% (3/23), PR 39% (12/31), 39% (12/31), and 35% (8/23), and SD 36% (11/31), 32% (10/31), and 30% (7/23), respectively (Table 2).
With a median follow-up period of 41.5 months relapses occured in 57 patients (75%). Forty-five out of 57 patients (79%) relapsed in previous metastatic sites. Twelve patients relapsed in previously uninvolved organs. Four had a relapse in the CNS, three developed bone metastases, two soft tissue metastases, and one patient each developed metastases in liver, lungs, and ovaries.
|
PROGNOSTIC FACTORS
|
|---|
For all 76 patients treated within both HDCT trials in univariate analysis negative ER (p = 0.022), visceral disease (p = 0.013), more than two metastatic sites (p = 0.006), "Possinger score" >10 (p = 0.0006), and failure to achieve CR/NED after HDCT (p < 0.0001) were associated with a poorer PFS. Predictors of shorter OS were negative ER (p = 0.004), more than two metastatic sites (p = 0.009), "Possinger score" >10 (p = 0.014), and failure to achieve CR/NED after HDCT (p < 0.0001). In the subgroup of 43 patients with known HER-2/neu receptor status, HER-2/neu overexpression (3+) was not associated with inferior PFS (p = 0.27) or OS (p = 0.46).
In multivariate analysis independent predictors of shorter PFS included negative ER (relative risk [RR] = 2.5 [95% confidence interval (CI) 1.3-4.9]; p = 0.007) and failure to achieve CR/NED after HDCT (RR = 4.8 [95% CI 2.2-10.4]; p < 0.0001). Independent predictors of a shorter OS were negative ER (RR = 3.0 [95% CI 1.5-5.9]; p = 0.002), more than two metastatic sites (RR = 2.4 [95% CI 1.0-5.7]; p = 0.049) and failure to achieve CR/NED after HDCT (RR = 4.5 [95% CI 2.0-10.1]; p < 0.0001). As a consequence, patients with ER-negative primary tumors had a Kaplan-Meier estimate of OS at three years of 27%, in comparison to 67% for patients with ER-positive tumors (32/76 patients) or tumors with unknown ER status (4/76 patients) (Fig. 6A). Along the same line, the probability of OS was significantly worse for patients with more than two metastatic sites in comparison to those with a maximum of two (23% versus 48% at three years) (Fig. 6B) and for patients with no complete remission after HDCT in comparison with patients who had NED before chemotherapy or achieved a CR (26% versus 73% at three years) (Fig. 6C).
|
DISCUSSION
|
|---|
The treatment outcome of MBC with conventional chemotherapy leaves much room for improvement. Achievement of a CR has been a prerequisite for long-term survival [4]. As HDCT has been demonstrated to increase the initial CR rate, this treatment strategy might improve long-term survival. Thus far a definitive role of HDCT in long-term survival has yet to be confirmed [2]. Extrapolating the initial encouraging data from phase II trials, many authors have conducted clinical trials exploring the role of double, triple, or quadruple sequential high-dose regimens with ASCT in patients with MBC [20-23]. Moreover, administration of HDCT with ASCT early on might overcome the likelihood of resistance development and might eradicate minimal residual disease (MRD).
Considering the patients who were evaluated after each cycle of HDCT, we were not able to convert any patient with PR or SD after the first HDCT to CR or any better remission status upon the second or third cycles of HDCT. This observation indicates that the maximum effect was achieved with the first cycle of HDCT and further treatment was not able to induce any better remission status. It has been proposed that double, triple, or sequential HDCT might induce a longer remission duration than a single HDCT. In the present matched-pair analysis, we have demonstrated that there was no difference in PFS and OS between patients receiving two or three cycles. These results are consistent with the reports by Hu et al. and Bashey et al. [24, 25].
Hu et al. retrospectively compared PFS and OS of 55 patients with MBC after four cycles of HDCT with ASCT with the outcome of 55 patients after only one single-cycle of HDCT. Within the constraints of their patient population, they also found no significant differences in PFS and OS. The median PFS and OS after four cycles of PBSC-supported HDCT were 12 months and 19 months, and after a single high-dose therapy 8 months and 26 months, respectively. Features predicting more favorable outcome included metastatic disease at one or two sites and the achievement of CR or "very good" PR prior to HDCT [24]. Bashey et al. compared the CR rate and PFS of 16 patients with MBC who received one cycle of stem cell-supported HDCT to 13 patients receiving two cycles. Despite a higher CR rate after two cycles of HDCT (33% versus 54%), the PFS two years after HDCT was not statistically different [25].
In a recent analysis of the North American Autologous Blood and Marrow Transplantation Registry, factors associated with poorer progression-free survival after HDCT for MBC were age older than 45 years, Karnofsky performance score less than 90%, absence of hormone receptors, prior adjuvant chemotherapy, initial disease-free survival interval after adjuvant treatment of no more than 18 months, metastases in the liver or CNS, and more than two sites of metastatic disease [26]. According to these risk factors, the patient characteristics were well balanced in the present matched-pair analysis. Therefore the equally bad PFS and OS after both HDCT regimens do not justify and argue against the use of early dose intensification with PBSC-supported HDCT after only one cycle of induction chemotherapy in patients with MBC.
It is still controversial whether the higher remission rates induced with HDCT and stem cell support will lead to a significantly better survival compared to conventional treatment. With HDCT we achieved a CR in 32% (20/62) and a PR in 44% (27/62) of patients for an overall response rate of 76%. When the 14 patients with no measurable lesions were included in the analysis, we achieved a status of CR/NED in 45% of patients (34/76). The median PFS and OS was 13 months and 24.5 months, respectively. These data are comparable to those reported in two recent reviews for patients with MBC treated with tandem or sequential autotransplant regimens [11, 27]. So far only one randomized study with an upfront tandem high-dose strategy without conventional induction chemotherapy showed a significant benefit in survival in the HDCT arm. The validity of this trial and other trials from this group has recently been challenged [14]. In two other randomized studies, which used only one cycle of HDCT as late consolidation after remission induction with conventional treatment, HDCT was not superior to the conventional approach [12, 13].
Except for a slightly increased reconstitution time for platelets after the third cycle, the hematological and nonhematological toxicity was not different between the first, second, and third cycles of HDCT. No treatment-related toxic death occurred. All patients have tolerated the treatment well without undue toxicity, and the spectrum of adverse events was not different from any other conventional chemotherapy regimen. However, each further cycle of HDCT, which led to an additional World Health Organization °3-°4 toxicity in about 40% of patients and a further hospital stay of about three weeks, should not be administered without any improvement in response or survival.
Our data indicated that independent risk factors for progression included negative ER and no CR/NED after HDCT. Risk factors for poor survival included negative ER, no CR/NED after HDCT and more than two metastatic sites. These are similar to the findings of Greenberg et al. and Rowlings et al. [4, 26]. In accordance with our results, Greenberg et al. described the achievement of CR or NED as the strongest predictor and maybe a prerequisite for long-term survival. The fact that we were not able to improve the remission status in any patient after the second or third HDCT indicated that one or single HDCT after conventional chemotherapy might be the most efficient strategy to achieve an MRD status. Further chemotherapy, high-dose or conventional dose, might have no impact and other treatment paradigms, such as active immunotherapy through vaccination or passive immunotherapy such as monoclonal antibodies, might be another option.
As the majority of relapses occurred in prior rather than new sites of disease, this observation also suggests that insufficient eradication rather than possible reinfusion of tumor cells by PBSC transplantation is responsible for progress and ultimately death on breast cancer and that immunotherapy might play a role [28, 29].
Probably due to the small subgroup of patients with known HER-2/neu receptor status (43 patients), we were not able to detect an association between expression of HER-2/neu and survival as reported by others [30].
|
CONCLUSION
|
|---|
Early dose intensification with T-HDCT is feasible with a tolerable toxicity, but it is not superior to a D-HDCT regimen in patients with MBC. A new paradigm of PBSC-supported HDCT followed by novel immunological treatment modalities including the use of antibodies (for example, trastuzumab, Herceptin®, Genentech Inc.; San Francisco CA; http://www.gene.com) or vaccines (for example, sialyl Tn-KLH, Theratope®, Biomira Inc.; Edmonton, Canada; http://www.biomira.com) to further control occult tumor should be considered in the context of clinical trials.
|
REFERENCES
|
|---|
-
Henderson IC, Harris JR, Kinne DW et al. Cancer of the breast. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer-Principles & Practice of Oncology (ed 3). Philadelphia: Lippincott, 1989:1197-1268.
-
Hortobagyi GN. Overview of new treatments for breast cancer. Breast Cancer Res Treat 1992;21:3-13.[CrossRef][Medline]
-
Gregory WM, Smith P, Richards MA et al. Chemotherapy of advanced breast cancer: outcome and prognostic factors. Br J Cancer 1993;68:988-995.[Medline]
-
Greenberg PAC, Hortobagyi GN, Smith TL et al. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 1996;14:2197-2205.[Abstract]
-
Hryniuk WM, Bush H. The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 1984;2:1281-1288.[Medline]
-
Hryniuk WM. The importance of dose-intensity in the outcome of chemotherapy. In: DeVita VT, Hellman S, Rosenberg SA, eds. Advances in Oncology. Philadelphia: Lippincott, 1988:121-141.
-
Frei E III, Cucchi C, Rosowsky A et al. Alkylating agent resistance: in vitro studies with human cell lines. Proc Natl Acad Sci USA 1985;82:2158-2162.[Abstract/Free Full Text]
-
Frei E III, Teicher BA, Holden SA et al. Effect of alkylating agent dose: studies and possible clinical correlation. Cancer Res 1988;48:6417-6432.[Abstract/Free Full Text]
-
Cheson BD, Lacerna L, Leyland-Jones B et al. Review: autologous bone marrow transplantation: current status and future directions. Ann Intern Med 1989;110:51-65.
-
Stewart THM, Retsky MW, Tsai SCJ et al. Dose response in the treatment of breast cancer. Lancet 1994,343:402-404.[CrossRef][Medline]
-
Lazarus HM. Hematopoietic progenitor cell transplantation in breast cancer: current status and future directions. Cancer Invest 1998;16:102-126.[Medline]
-
Stadtmauer EA, O'Neill A, Goldstein LJ et al. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med 2000;325:1371-1372.[Medline]
-
Lotz JP, Curé H, Janvier M et al. High-dose chemotherapy (HD-CT) with hematopoietic stem cell transplantation (HSCT) for metastatic breast cancer (MBC): results of the French protocol PEGASE 04. Proc Am Soc Clin Oncol 1999;18:43a.
-
Weiss RB, Rifkin RM, Stewart FM et al. High-dose chemotherapy for high-risk primary breast cancer: an on-site review of the Bezwoda study. Lancet 2000;355:999-1003.[CrossRef][Medline]
-
Possinger K, Williams W. Palliative Therapieführung zur Hemmung der Tumorprogression bei Patientinnen mit metastasiertem Mammakarzinom. Internist 1993;34:340-350.[Medline]
-
Hahn U, Goldschmidt H, Salwender H et al. Large-bore central venous catheters for the collection of peripheral blood stem cells. J Clin Apheresis 1995;10:12-16.[Medline]
-
Kaplan EL, Meier P. Non-parametric estimation from incomplete observation. J Am Stat Assoc 1958;47:457-481.
-
Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc (A) 1972;135:185-210.
-
Cox DR. Regression models and life tables. J R Stat Soc (B) 1972;34:187-220.
-
Crown J, Kritz A, Vahdat L et al. Rapid administration of multiple cycles of high-dose myelosuppressive chemotherapy in patients with metastatic breast cancer. J Clin Oncol 1993;11:1144-1149.[Abstract/Free Full Text]
-
Ghalie R, Williams SF, Valentino LA et al. Tandem peripheral blood progenitor cell transplants as initial therapy for metastatic breast cancer. Biol Blood Marrow Transplant 1995;1:40-46.[Medline]
-
Bitran JD, Samuels B, Klein L et al. Tandem high-dose chemotherapy supported by hematopoietic progenitor cells yields prolonged survival in stage IV breast cancer. Bone Marrow Transplant 1996;17:157-162.[Medline]
-
Honkoop AH, van der Wall E, Feller N et al. Multiple cycles of high-dose doxorubicin and cyclophosphamide with G-CSF mobilized peripheral blood progenitor cell support in patients with metastatic breast cancer. Ann Oncol 1997;8:957-962.[Abstract/Free Full Text]
-
Hu WW, Negrin RS, Stockerl-Goldstein K et al. Four-cycle high-dose therapy with hematopoietic support for metastatic breast cancer: no improvement in outcomes compared with single-course high-dose therapy. Biol Blood Marrow Transplant 2000;6:58-69.[CrossRef][Medline]
-
Bashey A, Corringham S, Garrett J et al. A phase II study of two cycles of high-dose chemotherapy with autologous stem cell support in patients with metastatic breast cancer who meet eligibility criteria for a single cycle. Bone Marrow Transplant 2000;25:519-524.[CrossRef][Medline]
-
Rowlings PA, Williams SF, Antman KH et al. Factors correlated with progression-free survival after high-dose chemotherapy and hematopoietic stem cell transplantation for metastatic breast cancer. JAMA 1999;282:1335-1343.[Abstract/Free Full Text]
-
Zujewski J, Nelson A, Abrams J. Much ado about not...enough data: high-dose chemotherapy with autologous stem cell rescue for breast cancer. J Natl Cancer Inst 1998;90:200-209.[Abstract/Free Full Text]
-
Brockstein BE, Ross AA, Moss TJ et al. Tumor cell contamination of bone marrow harvest products: clinical consequences in a cohort of advanced-stage breast cancer patients undergoing high-dose chemotherapy. J Hematother 1996;5:617-624.[Medline]
-
Cooper BW, Moss TJ, Ross AA et al. Occult tumor contamination of hematopoietic stem-cell products does not affect clinical outcome of autologous transplantation in patients with metastatic breast cancer. J Clin Oncol 1998,16:3509-3517.[Abstract]
-
Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor and target for therapy. STEM CELLS 1998;16:413-428.[Abstract/Free Full Text]
Received November 1, 2000;
accepted for publication January 11, 2001.
Top
Abstract
Introduction
