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© 1999 American Society for Clinical Oncology Multicycle High-Dose Chemotherapy and Filgrastim-Mobilized Peripheral-Blood Progenitor Cells in Women With High-Risk Stage II or III Breast Cancer: Five-Year Follow-UpFrom the Centre for Developmental Cancer Therapeutics, Parkville, Victoria Australia (affiliates: Austin Ludwig Oncology Unit, Austin Repatriation Medical Centre; Melbourne Tumor Biology Branch, Ludwig Institute for Cancer Research; Department of Hematology and Medical Oncology, Department of Surgery, Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital; Walter and Eliza Hall Institute for Medical Research); Division of Hematology, Hanson Centre for Cancer Research, IMVS, South Australia; Departments of Medical Oncology and Surgery, Royal Adelaide Hospital, South Australia; Department of Hematology, Royal Brisbane Hospital, Queensland; and Bone Marrow Transplant Unit, Alfred Hospital, Victoria. Address reprint requests to Dr Russell Basser, Director, CDCT, c/o Post Office, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; Email basser{at}licre.ludwig.edu.au
PURPOSE: To determine the safety and efficacy of multiple cycles of dose-intensive, nonablative chemotherapy in women with poor-prognosis breast cancer. PATIENTS AND METHODS: Women with stage II breast cancer and 10 or more involved nodes or four or more involved nodes and estrogen receptor–negative tumors and women with stage III disease received three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2, with progenitor cell and filgrastim support every 28 days (n = 79) or 21 days (n = 20). Patients were reviewed at least twice yearly thereafter. Twenty-six patients had bone marrow and apheresis collections assessed for the presence of micrometastatic tumor cells. RESULTS: Ninety-nine women (median age, 43 years; range, 24 to 60 years) were treated. Ninety-two completed all three cycles of chemotherapy. The major toxicity was severe, reversible myelosuppression that was more prolonged with successive cycles, and this did not differ between patients given treatment every 28 days and those treated every 21 days. Febrile neutropenia occurred in 176 (61%) of 287 cycles. Severe mucositis (grade 3 or 4) occurred in 23% of cycles but tended to be short-lived and was reversible. The cardiac ejection fraction fell by a median of 4% during treatment, and three patients developed evidence of cardiac failure after chemotherapy. Two patients (2%) died of acute toxicity. Three of 26 patients had evidence of circulating micrometastatic tumor cells. The actuarial distant disease-free and overall survival rates at 60-month follow-up were 64% (95% confidence interval [CI], 53% to 75%) and 67% (95% CI, 56% to 78%), respectively. CONCLUSION: Multiple cycles of dose-intensive, nonablative chemotherapy is a feasible and safe approach. Disease control and survival are similar to those in other studies of myeloablative chemotherapy in poor-prognosis breast cancer. The regimen is being evaluated in a randomized trial of the International Breast Cancer Study Group.
WOMEN WITH BREAST CANCER and 10 or more involved axillary nodes have a 5-year relapse rate of 70% to 80% if they do not receive treatment.1 Even in the best published results of standard adjuvant chemotherapy in this group, 50% of patients relapse and 30% die within 5 years of diagnosis,2 and within 10 years, 70% relapse and 60% die.3 A poor prognosis is also associated with large tumors and tumors that are estrogen receptor-negative.4,5 When women receive chemotherapy and surgery and/or radiotherapy, their 5-year survival rate with T3 tumors (> 5 cm in diameter) is approximately 45%.6,7 New approaches to the management of these women are necessary. One method is to administer higher-than-standard doses of chemotherapy. There is persuasive clinical evidence that tumor response in patients with breast cancer is related to the dose-intensity of the chemotherapy delivered.8-13 The use of hematopoietic growth factors and stem cells has allowed safe administration of much larger doses of chemotherapy. A number of different strategies for intensifying dose with stem cell support have been described.12,14-17 In a randomized trial, Bezwoda et al12 gave women with untreated metastatic breast cancer two cycles of dose-intensive, nonablative chemotherapy with peripheral-blood progenitor cell (PBPC) support or conventional-dose chemotherapy. The high-dose regimen was associated with a significantly higher overall and complete response rate, response duration, and survival. We designed a regimen of multiple cycles of dose-intensive epirubicin and cyclophosphamide with PBPC support as first-line therapy for women with poor-prognosis, early-stage breast cancer. A pilot study was commenced to assess the safety of the regimen with the intention of conducting a randomized trial under the auspices of the International Breast Cancer Study Group; the feasibility of this approach has previously been reported.16 We continued to refine this treatment, and now report overall acute and delayed toxicities of the regimen and disease control and survival after 5-year follow-up.
Eligibility and Evaluation Eligible patients were between the ages of 18 and 60 years and had histologically confirmed poor-prognosis breast cancer. Poor-prognosis breast cancer was defined as stage II disease with 10 or more positive axillary nodes, stage II disease with an estrogen receptor–negative tumor with at least four positive axillary nodes, or stage III disease. Staging procedures included complete blood count, liver function tests, chest x-ray, bone scan, liver ultrasound or computed tomography (CT) scan, and bone marrow aspirate and trephine. Patients were required to have a resting left ventricular ejection fraction of 50% or greater as measured by radionuclide scan. Women receiving adjuvant therapy commenced treatment on protocol within 8 weeks of surgery.
Collection of Progenitor Cells Apheresis was performed on the 5th, 6th, and 7th days of filgrastim administration, using a modified mononuclear-cell collection program with the red-cell interface set at 020 units on the Fenwal CS-3,000 cell separator (Baxter, Deerfield, IL), as described elsewhere.20 One patient had an additional leukapheresis on the 8th day because of leakage of apheresis product from a faulty collection bag on the 5th day. The product from each apheresis specimen was concentrated,21 divided into three equal fractions, and then cryopreserved. Back-up bone marrow was collected for each patient and stored for use if hematopoietic recovery failed.
Chemotherapy Three cycles of chemotherapy were delivered initially at planned 28-day intervals (n = 79). After the feasibility of the regimen was established,16 the intensity was increased by administration of chemotherapy at 21-day intervals (n = 20). Alterations in chemotherapy dose were not allowed. The hospitalization policy was flexible. If toxicities permitted, patients were discharged after chemotherapy was delivered, and the progenitor cell infusion and filgrastim were administered in the outpatient clinic. Patients were hospitalized if warranted by toxicity. Chemotherapy could commence only if the ANC was 1.5 x 109/L or higher and the platelet count was 100 x 109/L or higher. Patients could proceed with each cycle of chemotherapy only if more than 20 x 104/kg body weight of granulocyte-macrophage colony-forming cells (GM-CFC) were available for infusion. Seven patients did not complete all chemotherapy for the following reasons: withdrawal of consent after one cycle (n = 1), severe hemorrhagic cystitis (n = 1), angioneurotic edema during administration of mesna (n = 1), anaphylactoid reaction after administration of cyclophosphamide (n = 1) during the second cycle, sufficient GM-CFC for only two cycles (n = 2), and death due to intracranial hemorrhage secondary to thrombocytopenia during the third cycle (n = 1). Radiotherapy after chemotherapy was not mandated by the protocol and was carried out according to institutional policy. After completion of chemotherapy, 50 patients received radiotherapy (25 to the left side) to the chest wall after mastectomy (n = 20), to the residual breast after breast-conserving surgery (n = 18), or when there was no prior surgery (n = 12).
Safety Evaluation and Laboratory Studies Clinical assessment and complete blood counts were performed daily during and after high-dose chemotherapy until patients recovered from hematologic and other toxicity. Serum biochemistry tests (electrolytes, urea and creatinine, liver function tests) were performed at least once per cycle. Cardiac ejection fraction was assessed by radionuclide scan before randomization, before the second and third cycles of chemotherapy, and 3 months after completion of chemotherapy.
Immunohistochemistry for Circulating Tumor Cells
Statistics
Patients One hundred patients were enrolled in the study between July 1992 and November 1995 at six institutions. One patient was excluded from analysis because metastatic disease was detected after registration but before treatment, and she received no protocol therapy. The characteristics of the 99 treated women are listed in Table 1. Disease stage, extent of prior surgery, number of positive axillary nodes, and baseline hematology did not differ substantially across cohorts treated with different cytokines for mobilization of PBPC. Ninety-two patients received all three cycles of chemotherapy. The time from surgery to the first day of chemotherapy was 59 days (range, 33 to 132 days).
Progenitor Cell Collection The WBC count during the 6 days of filgrastim treatment rose from a baseline of 6.7 x 109/L (range, 3.6 to 12.1 x 109/L) to 68.3 x 109/L (range, 30.3 to 138 x 109/L) and consisted predominantly of band forms and mature neutrophils. The number of peripheral blood GM-CFC before administration of filgrastim was 56/mL (range, 3 to 1,242/mL); this number rose to 15,380/mL (range, 990 to 106,293/mL) after 5 days, a median increase over baseline of 329-fold (Fig 1). The three leukaphereses yielded 10.1 x 108 mononuclear cells/kg ideal body weight (range, 3.6 to 59.6 x 108 mononuclear cells/kg ideal body weight) and 237.4 x 104 GM-CFC/kg ideal body weight (range, 22.7 to 915.7 x 104 GM-CFC/kg ideal body weight) (Fig 1). There was a weak correlation between the number of mononuclear cells in the apheresis collections and the number of GM-CFC (r = .35, P = .04). Overall, there was a 100-fold variation between patients in the number of progenitor cells obtained.
Chemotherapy
There was a tendency for severe neutropenia to be more prolonged with successive cycles (Table 2, Fig 2A). The number of days with a neutrophil count less than 0.5 x 109/L for cycles 1, 2, and 3 were 5, 6, and 7 days, respectively, although there was no difference in the time after PBPC infusion to neutrophil recovery of 0.5 x 109/L or greater. Neutrophils usually recovered by day 21 after chemotherapy. Febrile neutropenia occurred in 176 (61%) of 287 cycles, and there was no difference in the incidence between women given intravenous prophylactic antibiotics and women given oral prophylactic antibiotics (Table 3). The number of GM-CFC infused after chemotherapy was not a predictor for time to neutrophil recovery (ANC
Slower platelet recovery occurred with successive cycles of chemotherapy (Table 2, Fig 2B). This was reflected in more prolonged severe thrombocytopenia and greater platelet transfusion requirements after the third cycle compared with the first two cycles. The times to recovery to a platelet count of 20 x 109/L or greater, independent of platelet transfusion, were 9, 10, and 11 days for cycles 1, 2, and 3, respectively (P < .001 for trend over successive cycles). The number of patients in whom platelet levels did not fall below 20 x 109/L was 27, 19, and 7 for cycles 1, 2, and 3, respectively (P = .002). Platelets had recovered to 100 x 109/L or greater by 10, 13, and 15 days (P < .001). The number of days with platelet levels of less than 20 x 109/L and the number of platelet transfusions given also increased with successive cycles (Table 2). Platelet recovery did not correlate with the number of granulocyte-macrophage progenitors infused (r = -.16, P > .5). There was one episode of fatal intracranial hemorrhage related to prolonged severe thrombocytopenia after the third cycle of chemotherapy and one episode of grade 3 bleeding (hemorrhagic cystitis due to high-dose cyclophosphamide). Bruising or bleeding was otherwise restricted to grade 1 or 2, which occurred after 44 (15%) of 287 cycles of chemotherapy. Packed red blood cell transfusions were required in 275 of the 287 cycles of chemotherapy delivered, and the median number of units given to each patient during the study was 10 (range, 2 to 10 units). The number of units transfused did not vary with successive cycles (Table 2). Despite the prolongation of hematologic recovery with successive cycles, the duration of hospital stay did not vary significantly. The first 16 patients received intravenous antibiotics for each cycle from the day after PBPC infusion until hematologic recovery or resolution of infective episodes. The total number of days spent as an inpatient for these patients was 49 (range, 37 to 62 days). Subsequently, patients were given prophylactic antibiotics orally (n = 83) unless they required admission for febrile neutropenia or infection. This reduced the median time spent in hospital to 26 days (range, 11 to 64 days) (P < .001). Nonhematologic toxicity. Severe (World Health Organization grade 3 and 4) nonhematologic toxicities are listed in Table 3. Severe mucositis occurred with increasing frequency with successive cycles and lasted a median period of six days (range, 3 to 10 days). All mucositis resolved rapidly at the time of neutrophil recovery; however, two patients were given parenteral nutrition for poor oral intake during severe mucositis. One woman experienced an unexplained episode of sudden collapse during the first cycle of chemotherapy and made an uneventful recovery. She received the next two cycles without recurrence of this event. Three patients experienced severe reactions within 24 hours of infusion of cyclophosphamide after the second (necessitating cessation of treatment in one patient) and third cycles. Typically, these events were characterized by fever, tachycardia, hypotension, rash, and pulmonary infiltrates on chest x-ray. Each of these patients had experienced minor episodes with similar features in earlier cycles. The cause of these events is unclear. The patients were treated at the same institution, and comparable events were not reported at other sites.
Other nonhematologic events were mild to moderate (grade 1 or 2); the most common events (all Delivery of the second and third cycles of chemotherapy was delayed beyond the planned interval in 46% of cycles for a median period of 6 days (range, 4 to 14 days). In most instances (85%), this was because of administrative reasons unrelated to toxicity, such as lack of an available inpatient bed and public holidays. The most common toxicity to delay treatment was unresolved infection. Delays occurred equally in the groups treated every 3 weeks and every 4 weeks. The planned and actual dose-intensity for the three cycles of chemotherapy are listed in Table 4.
The left ventricular ejection fraction fell from a median of 62% (range, 50% to 76%) at baseline to 58% (range, 39% to 70%) at 3 months after completion of chemotherapy (P < .001). Three patients developed signs of cardiac failure in the follow-up period. All three had a mastectomy, and one patient had received radiotherapy to the left chest wall. The cardiac abnormalities were detected approximately 2 years after the third cycle of chemotherapy in all three patients. Two patients had clinical and radiologic signs of cardiac failure, whereas the other patient was asymptomatic. One woman developed acute myeloid leukemia with 11q23 translocation 2 years after treatment. No other hematologic abnormalities have been observed.
Circulating Tumor Cells Two of the three patients with circulating tumor cells relapsed and died (Table 5). One patient developed local recurrence in the chest wall 11 months after treatment commenced and then bone metastases at 13 months. She died 6 months later. The other patient developed mediastinal nodal recurrence after 12 months and died after 20 months. The remaining patient with circulating cells is alive and has no evidence of disease 64 months after treatment. Seven of the 23 patients with no detectable circulating tumor cells relapsed at a median period of 19 months (range, 4 to 33 months).
Treatment-Related Mortality The second patient developed acute cardiac failure after the third cycle of chemotherapy. She subsequently experienced multiorgan failure and died 23 days after the first clinical evidence of cardiac failure. Postmortem examination showed myocardial necrosis, presumed to be caused by high-dose cyclophosphamide.
Disease Outcome
Of the 13 patients with locally advanced breast cancer, five have relapsed and three have died. One patient is alive with no evidence of disease after local relapse treated with mastectomy, and one patient is alive with systemic disease. The actuarial distant DFS and OS rates at 60 months are 60% (95% CI, 24% to 96%) and 75% (95% CI, 48% to 100%), respectively.
Our main findings were that three cycles of high-dose epirubicin and cyclophosphamide supported by PBPC and filgrastim were associated with short-lived and reversible acute toxicities and few long-term adverse effects. Furthermore, no increase in toxicity was observed when the intensity of the regimen was increased by 33% after the intercycle interval was reduced from 28 days to 21 days. The three cycles of chemotherapy could therefore be safely delivered over a total of 6 weeks. Nearly all patients (92%) completed the chemotherapy, despite the fact that dose reductions were not permitted. Importantly, patients could be cared for in the outpatient setting during one third of the cycles. The total time spent as an inpatient was less than 4 weeks, approximately the same duration as after a single course of myeloablative chemotherapy.14 This is one of the largest reported series of high-dose chemotherapy for poor-prognosis, early-stage breast cancer. Treatment-related morbidity and mortality in our patients compare favorably with many of the other published regimens.15,24-31 Indeed, long-term morbidity in the current study (cardiac failure and leukemia) occurred in only four of the 99 patients. In studies of consolidation with a single myeloablative treatment, late toxicity has sometimes been substantial, depending on the agents used in the high-dose regimen.14 Approaches to the delivery of high-dose chemotherapy for breast cancer include consolidation with myeloablative therapy after standard-dose induction treatment,32 high-dose sequential chemotherapy in which a number of non–cross-resistant drugs are given in sequence, each in very high doses,15 and the approach described in the current study. Even though we did not use myeloablative doses of chemotherapy, the DFS and OS rates were similar to those of other high-dose chemotherapy reports that did (Table 6).
The benefit of aggressive treatment of women with high-risk breast cancer has recently been challenged in a report by Rodenhuis et al31 from the Netherlands Cancer Institute. In their study, 97 women with breast cancer and tumor-positive apical axillary lymph nodes, who have a 5-year DFS rate of 20%,33 were initially treated with three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF). Patients with at least a minimal clinical response subsequently underwent definitive surgery. Eighty-one were then randomized to a further cycle of CEF alone or to a cycle of CEF followed by a single cycle of myeloablative chemotherapy with PBPC support. At a median follow-up of 49 months, there was no difference in DFS or OS between treatment groups. This study was powered to detect a 30% difference in relapse-free survival. The importance of patient selection is clearly demonstrated in the Dutch trial. Both treatment groups had superior OS and DFS rates compared with historic controls, and patients who were not randomized had a worse survival than those who were. In another report, Garcia-Carbonero and colleagues34 analyzed patients with more than 10 nodes who had been treated with standard therapy according to whether or not they would have been eligible for high-dose chemotherapy by their institutional selection criteria. These patients were compared with patients treated with high-dose chemotherapy at their institution. Of the patients treated with conventional therapy, those meeting the criteria for high-dose chemotherapy had more favorable DFS and OS rates than those not eligible, and their DFS and OS rates were similar to those of patients treated with high-dose chemotherapy.34 Crump et al35 found that seven (23%) of 30 women screened for a high-dose chemotherapy trial had metastatic disease on CT scan or bone marrow biopsy that was not detected on routine screening. The selective nature of small studies is further emphasized by reports of long-term survivors in single-institution experience of better-than-published outcome of poor-prognosis, early-stage breast cancer treated with standard multimodality therapy.36 How then should we interpret the results of the current and other phase II trials of adjuvant high-dose chemotherapy for breast cancer? While the reports described above33-36 warn against overinterpretation of small trials, it would be just as erroneous to interpret them as "demonstrating" that high-dose therapy is no better than standard-dose therapy. Data from the Dutch study indicate that the benefit of consolidation with a single cycle of high-dose chemotherapy was not great enough to be detected in such a small group, but they do not refute that a substantial clinical benefit might still be achieved with this approach. In addition, more than 20% of patients enrolled were either not randomized or did not receive the allocated treatment. The other studies34-36 described are reviews of departmental experience, and as such, they are subject to the limitations of a retrospective study. Only a weak correlation was found between the rate of hematopoietic recovery after each cycle of chemotherapy and the number of GM-CFC infused. This is not surprising because most cycles were supported by more GM-CFC than the apparent threshold (> 10 x 104/kg) necessary for rapid recovery, above which no further reduction in the period of neutropenia or thrombocytopenia seems to occur.37 The progressive delay in hematologic recovery across the three cycles of chemotherapy suggests that factors other than infusion of large numbers of progenitor cells and filgrastim administration are responsible for rapid hematopoietic reconstitution. The integrity of the marrow microenvironment,38 endogenous cytokine responses,39 and endogenous hematologic recovery may also play a part in this process. Irrespective of the mechanism(s) of delayed recovery, the consequences were not clinically important in this study. We were concerned that the doses of chemotherapy given in this study would be unsafe if the only method of hematologic support was filgrastim; therefore, we gave PBPC with each cycle. We had previously determined that the maximum tolerated doses of epirubicin and cyclophosphamide when supported with filgrastim alone were 150 mg/m2 and 1,500 mg/m2, respectively (M.D. Green et al, unpublished data). One of the dose-limiting toxicities of the regimen was thrombocytopenia. Because the use of PBPC after myeloablative chemotherapy clearly enhances platelet recovery compared with bone marrow,20 we incorporated infusion of PBPC in the current study in the absence of a viable alternative platelet-protecting strategy. The women in the current study seemed to experience substantially shorter periods of severe neutropenia and thrombocytopenia than patients with breast cancer receiving similar but less intensive chemotherapy supported with filgrastim alone.40 The discovery and clinical development of potent thrombopoietic agents, such as megakaryocyte growth and development factor,41-43 provides the opportunity to explore further dose-intensification with cytokines alone and perhaps to improve the safety of multicycle, dose-intensive chemotherapy supported with PBPC. One patient in the current study developed acute myeloid leukemia (AML) with cytogenetic features characteristic of previous exposure to topoisomerase-II inhibitors. The risk of secondary hematologic abnormalities after cytotoxic chemotherapy is well recognized. Five cases of AML were reported in 2,548 patients with node-positive breast cancer treated in National Surgical Adjuvant Breast and Bowel Project B-25, in which adjuvant dose-intensive cyclophosphamide was given with standard-dose doxorubicin and granulocyte colony-stiumulating factor.44 In another report, four cases of secondary AML occurred in 351 women receiving intensive adjuvant epirubicin and cyclophosphamide without growth factors, whereas no leukemia occurred in 359 patients given cyclophosphamide, methotrexate, and fluorouracil.45 It is unclear whether the high incidence of secondary leukemia in these two studies was related to increased DNA damage incurred by more intensive anthracycline treatment or to the addition of growth factor to support hematopoiesis. However, the overall reported incidence of secondary leukemia in women with breast cancer treated with anthracycline plus cyclophosphamide at standard doses is less than 0.2%.46 Given that significant therapeutic benefit may result from dose-intensive therapy, considerations for limiting evaluation of this strategy because of an increased risk of secondary AML must be carefully contemplated against the possibility of improved overall survival. The risk of AML seems to be small and may be balanced by the extremely poor prognosis of patients, such as in the current study. Circulating tumor cells were detected in three (11.5%) of 26 patients. Cells were detected in bone marrow, peripheral blood, and apheresis samples. There were too few patients and too much variability in the number of cells in each sample to determine the relative load of contamination between different sources. Other investigators have suggested that PBPC collections contain fewer tumor cells than bone marrow.47-50 However, it is difficult to compare the frequency of detection of cancer cells between reports. Different antibodies and staining methods have been used, patients with early or metastatic disease have been studied, and patients may or may not have previously received chemotherapy. The finding of circulating tumor cells seems to reflect the biologic behavior of cancer. Micrometastatic cells have phenotypic characteristics, such as loss of HLA class I antigens and high incidence of erb-b2 oncogene expression, that distinguish them from nonmetastatic cells51,52 and that may be associated with more aggressive behavior. The escape of these cancer cells to the circulation also seems to be indicated by the degree of tumor angiogenesis and vascular invasion in the primary cancer,53 suggesting that these processes might contribute to metastases. The detection of circulating micrometastatic cells has been reported to be predictive of a poor prognosis.54-57 However, incorporation of this marker into clinical decision making is questionable until the assay methodology is standardized and controlled clinical trials are conducted. CD34+ cell selection58 and purging of apheresis samples59 have been used to remove tumor cells before reinfusion into patients on the basis that such cells are frequently found47 and contribute to relapse in other diseases.60 If the low frequency of tumor cell contamination of PBPC in women with early-stage, poor-prognosis breast cancer observed in this study is confirmed, such strategies may not be of benefit. There remains a strong scientific rationale for investigating the ability of different strategies of high-dose chemotherapy to improve the outcome of women with breast cancer, and results of randomized trials are required. The current study demonstrates that delivery of three cycles of high-dose epirubicin and cyclophosphamide with PBPC support given every 21 days is feasible and results in promising disease control in women with poor-prognosis, early-stage breast cancer. This regimen is currently being compared with standard chemotherapy in patients with poor-prognosis breast cancer in International Breast Cancer Study Group Trial 15.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
0.5 x 109/L, ANC on day 21 after chemotherapy), days to platelet recovery (days to 
0.5 x 109/L and of platelets 
, n = 99), cycle 2 (|a9, n = 96) and cycle 3 (|a0, n = 92) of chemotherapy: (A) median ANC; (B) median platelet count.
