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Phase I/II Trial of Cyclophosphamide, Mitoxantrone, and Escalated Doses of Carboplatin Supported by Peripheral-Blood Stem Cells in Women With Metastatic Breast Cancer

From the Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Canada.

Address reprint requests to Michael Crump, MD, FRCPC, Department of Medical Oncology and Hematology, Princess Margaret Hospital, Room 5-108, Toronto, Canada M5G 2M9; email michael.crump{at}uhn.on.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To intensify a regimen of high-dose cyclophosphamide, mitoxantrone, and carboplatin that had previously produced high complete and overall response rates in metastatic breast cancer (MBC).

PATIENTS AND METHODS: Forty-four patients with a median age of 43 years (range, 25 to 57 years) and previously untreated MBC who were responding to anthracycline-based or single-agent taxane chemotherapy received cyclophosphamide 1.5 g/m²/d and mitoxantrone 16 mg/m²/d combined with escalating doses of carboplatin 200 to 500 mg/m²/d, each given daily from days -6 to -3. Hematopoiesis was supported by mobilized peripheral-blood stem cells infused on day 0 and by use of granulocyte-macrophage colony-stimulating factor 300 µg/d subcutaneously starting on day 1.

RESULTS: A total of six dose levels of carboplatin were examined. Grades 3 and 4 toxicity occurred in 10 patients and one patient, respectively, with grade 3 toxicity occurring in only five of 31 patients treated with 400 mg/m² of carboplatin. Major dose-limiting toxicities were cardiac, pulmonary, and renal. Four patients developed congestive heart failure: two had persistently low ejection fraction 11 and 36 months after peripheral-blood stem-cell transplantation (PBSCT), and two recovered. Hematologic recovery to an absolute neutrophil count of greater than 0.5 x 10⁹/L occurred at a median of 11 days (range, 8 to 25 days) and to a platelet count of greater than 20 x 10⁹/L at a median of 10.5 days (range, 6 to 60 days). There were two toxic deaths from sepsis: one on day 27 (level 5) and one from cardiac arrest on day 42 (level 6).

CONCLUSION: The maximum-tolerated dose of carboplatin was 400 mg/m²/d in combination with mitoxantrone 16 mg/m²/d and cyclophosphamide 1,500 mg/m², all drugs given over 4 days. This regimen is being tested in a phase III trial of high-dose chemotherapy and PBSCT versus standard treatment.

	INTRODUCTION

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BREAST CANCER IS NOW the most common indication for high-dose chemotherapy and autologous hematopoietic stem-cell transplantation reported to the North American Autologous Blood and Marrow Transplant Registry (NAAMBTR).¹ The rationale for the use of high-dose therapy is based on in vitro studies and in vivo clinical data that demonstrate a dose-response relationship for a number of chemotherapy agents in adjuvant and metastatic breast cancer (MBC).² Several high-dose regimens have been reported, which consist chiefly of alkylating agents, such as cyclophosphamide in combination with cisplatin and carmustine, thiotepa, or thiotepa and carboplatin.^3-7 The major nonhematologic toxicities of these regimens are pulmonary toxicity, hepatic veno-occlusive disease, and mucositis.^7,8

In vitro studies have suggested that there is a steep dose-response relationship for mitoxantrone in breast cancer,⁹ and previous studies of mitoxantrone-containing high-dose regimens have yielded a high response rate in doxorubicin-resistant breast cancer.^10,11 We and others have previously reported that high-dose bolus administration of cyclophosphamide, carboplatin, and mitoxantrone is active and well tolerated in MBC in single and tandem autologous bone marrow transplantation (ABMT) studies.^12,13 In these studies, the dose of carboplatin was similar to that used in the regimen of cyclophosphamide, carboplatin, and thiotepa 800 mg/m² over 4 days reported by Antman et al.⁷ A report by Stiff et al¹⁴ suggested that higher doses of carboplatin could be tolerated in combination with cyclophosphamide and mitoxantrone when these three agents were given as a continuous infusion. We sought to intensify our regimen further by escalating the dose of carboplatin in a phase I trial in women with chemosensitive, previously untreated MBC.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Women, aged 18 to 60 years, with previously untreated MBC with measurable or assessable visceral, soft tissue, lymphatic, or bony metastases were eligible for this study. Other criteria included an Eastern Cooperative Oncology Group performance status of 0 or 1 and normal organ function (left ventricular ejection fraction > 45%, serum creatinine level < 160 µmol/L, serum bilirubin level < 50 mmol, and transaminases < three times normal [or < five times normal in the presence of liver metastases]). Patients who progressed on standard adjuvant chemotherapy were eligible provided that they responded to induction therapy. Patients were ineligible if there was a history or evidence of brain or leptomeningeal metastases, prior chemotherapy for MBC, concomitant severe medical or psychiatric illness, a prior history of congestive heart failure or recent myocardial infarction within the past year, and pregnancy or lactation. Informed consent was obtained from all patients.

Documentation of tumor response to induction chemotherapy was obtained before proceeding with high-dose chemotherapy and peripheral-blood stem-cell transplantation (PBSCT). Patients with bone metastases or other nonmeasurable disease were required to have stable disease or improvement on chemotherapy with resolution of disease-related symptoms.

Treatment Regimen
Patients were treated with induction chemotherapy, which included an anthracycline (epirubicin or doxorubicin), usually in combination with fluorouracil and cyclophosphamide, given every 3 weeks. Those patients who had received an anthracycline as part of their adjuvant chemotherapy were treated with either paclitaxel 175 mg/m² intravenously (IV) over 3 hours or docetaxel 100 mg/m² IV over 1 hour every 3 weeks. Response was assessed after four cycles. Those who achieved complete response (CR) or partial response (PR; including those with residual positive bone scans as the only evidence of disease) underwent mobilization and collection of peripheral-blood stem cells followed in most cases by one or two further cycles of induction chemotherapy. After confirmation of response and documentation of normal cardiac ejection fraction after completion of induction chemotherapy, patients were admitted to the hospital for high-dose therapy that consisted of cyclophosphamide 1.5 g/m², mitoxantrone 16 mg/m², and carboplatin in escalating doses starting at 200 mg/m². All drugs were administered consecutively, each for 1 hour on days -6 to -3. Mesna uroprotection was given as a bolus injection of 200 mg/m² 1 hour before and as a continuous IV infusion over 18 hours of 700 mg/m² after the completion of each dose of cyclophosphamide. Peripheral-blood stem cells were infused 72 hours after the completion of chemotherapy (day 0). Granulocyte-macrophage colony-stimulating factor (Schering Canada, Inc, Montreal, Canada) 300 µg/d subcutaneously (SC) was started on day +1 after PBSC infusion and continued until the absolute neutrophil count was greater than 1.5 x 10⁹/L on 2 consecutive days. Involved field radiation (usually 30 Gy in 10 to 15 fractions) was administered to those patients with chest-wall recurrence, isolated supraclavicular node or internal mammary node recurrence, or solitary bone metastasis, usually 6 to 8 weeks after PBSCT. All patients were given tamoxifen 20 mg/d on completion of high-dose therapy if the primary tumor was estrogen receptor– and/or progesterone receptor–positive by ligand binding assay or immunohistochemistry and if they had no history of prior recurrence on tamoxifen.

Carboplatin Dose Escalation
The starting dose of carboplatin was 200 mg/m² over 1 hour daily for 4 days, with planned dose levels of 300, 350, 400, 450, and 500 mg/m². A minimum of three patients were treated at each dose level. Dose escalation was not performed until at least three patients had completed treatment at the prior dose level. If two of three patients experienced dose-limiting toxicity (grade 3 or 4 nonhematologic toxicity according to the National Cancer Institute ABMT criteria¹⁵ ), then three more patients were treated at that dose level. The dose level was escalated if no more than two of six patients experienced dose-limiting toxicity. The maximum-tolerated dose was defined as the dose level below which at least three of six patients experienced dose-limiting nonhematologic toxicity.¹⁵

Peripheral-Blood Stem-Cell Mobilization
Chemotherapy mobilization of stem cells occurred during cycle 5 of induction therapy with the regimen of cyclophosphamide 2 g/m², doxorubicin 50 mg/m², and fluorouracil 500 mg/m²¹³ given on day 1 or with cyclophosphamide 2 g/m² alone after cycle 4 if the patient was receiving taxane induction. Granulocyte colony-stimulating factor (Neupogen, Amgen, Inc, Thousand Oaks, CA) 10 µg/kg/d SC was administered on days 4 to 14 after chemotherapy, and leukapheresis was carried out on days 12 to 15. Granulocyte colony-stimulating factor mobilization of stem cells was performed after recovery from myelosuppression after cycle 4, using a dose of 10 µg/kg/d SC once daily for 7 days, with leukapheresis on days 5 to 7. During each leukapheresis procedure, 10 to 12 L of blood was processed. Minimum numbers of cells collected to ensure engraftment were greater than 15 x 10⁴ colony-forming units–granulocyte macrophage per kilogram and greater than 2.5 x 10⁶ CD 34⁺ cells per kilogram of body weight.

Response Criteria
All patients underwent complete radiologic restaging 3 months after high-dose chemotherapy. For patients with measurable and nonmeasurable (assessable) disease, CR was defined as the disappearance of all known disease, compared with pretransplantation assessment. PR was defined as a 50% or greater decrease in bidimensionally measurable lesions. Patients with positive bone scan were considered to have PR as best response unless repeat scanning was normal. Patients with only bone disease required the absence of new lesions on repeat bone scan or the presence of sclerosis on plain x-ray if new lesions appeared during therapy to distinguish tumor flare from disease progression.¹⁶ Tumor markers were not used to define response. Progressive disease was defined as an increase in size of existing lesions or appearance of new lesions. In addition to restaging, cardiac function was assessed by a resting multigated angiogram at 3 months, unless otherwise indicated by the patient’s symptoms.

	RESULTS

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Patient characteristics are listed in Table 1. The median age was 43 years, with a range of 25 to 57 years. Sixteen patients had received prior adjuvant chemotherapy (anthracycline-based in five cases), seven received adjuvant tamoxifen, and three had not received any adjuvant systemic treatment. Twenty patients presented with MBC at the time of primary diagnosis. Solitary organ involvement was observed in 21 patients, whereas 23 had multiple sites of metastatic disease.

Cardiac Toxicity
The median absolute change in cardiac ejection fraction (post-PBSCT ejection fraction minus pre-PBSCT ejection fraction) was -6% (range, +10% to -32%; 95% confidence interval [CI], -9% to -3%). Four patients developed symptomatic congestive heart failure with absolute fall in cardiac ejection fraction measured by radionucleotide angiogram ranging from 13% to 32% at weeks 1, 2, 3, and 8 after PBSCT. Two of these patients had a persistently low ejection fraction 11 and 36 months after PBSCT, whereas the other two recovered after therapy with angiotensin-converting enzyme inhibitors and diuretics. The patient who developed congestive heart failure 8 weeks after therapy had a right ventricular biopsy that showed mild-to-moderate endocardial fibrosis on light microscopy; electron microscopy was not performed. When re-evaluated 11 months after ABMT, her ejection fraction was normal. One patient at dose level 6 had a cardiac arrest from ventricular fibrillation of uncertain etiology day 38 after PBSCT. A two-dimensional echocardiogram performed on day 16 had demonstrated normal ventricular function. One patient at dose level 4 developed symptomatic pericarditis (grade 2 cardiotoxicity) without echocardiogram features of tamponade day 4 after PBSCT. Pericardiocentesis performed on day 24 was negative for malignant cells, and her symptoms resolved with use of corticosteroids. Her cardiac ejection fraction was normal 3 months after PBSCT, and the pericardial effusion had not recurred at the time of this writing.

Hematologic Recovery
The median number of colony-forming units–granulocyte macrophage infused was 99.3 x 10⁴ cells/kg (range, 1.0 to 606.0), and the median number of CD34⁺ cells was 10.8 x 10⁶ cells/kg (range, 1.2 to 25.9). Median time to neutrophil recovery of greater than 0.5 x 10⁹/L was 11 days (range, 8 to 25 days) and to platelet recovery of greater than 20 x 10⁹/L was 10.5 days (range, 6 to 60 days). Febrile neutropenia occurred in 40 of 44 patients, and one patient died of sepsis on day 27 (dose level 5). The median time to hospital discharge was 15 days (range, 1 to 44 days).

Patient Outcome
Forty-two patients were assessable for response at 3 months. After induction chemotherapy, 16 patients (36%) achieved CR and 28 (64%) achieved PR, of whom 19 were defined as PR because of a persistently positive bone scan. The overall response rate assessed at 3 months after PBSCT was 79.5% (95% CI, 68% to 92%), with 13 (30%) in CR (95% CI, 16% to 44%) and 22 (50%) in PR (14 in PR with persistently positive bone scan).

After a median follow-up of 36 months, 10 patients remained alive and continuously free of MBC from 32 to 66 months after transplantation. Nine women were alive with recurrent disease and 25 died (23 from breast cancer and two from treatment-related causes). The median survival time from date of transplantation for all 44 patients was 30 months.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The goals of the current study were to intensify a regimen of mitoxantrone, cyclophosphamide, and carboplatin to increase response rate, while at the same time determine whether this combination could potentially be compatible with broader use, in particular in the high-risk adjuvant setting. At the maximum-tolerated dose of cyclophosphamide (1,500 mg/m²), mitoxantrone (16 mg/m²), and carboplatin (400 mg/m²), each given as a bolus injection daily for 4 days, no fatal toxicity was observed. The regimen was well tolerated, with manageable gastrointestinal toxicity and acceptable hepatic, pulmonary, and renal toxicity. We did not observe any cases of hepatic veno-occlusive disease. There was a single case of reversible grade 3 renal toxicity that required temporary hemodialysis support for 2 weeks.

The major significant toxicity with this combination may be cardiac, unlike that of our previous experience with the same combination in a phase II trial of double autotransplantation.¹³ Cardiotoxicity was manifested principally by congestive heart failure that occurred between days 0 and 50 after PBSCT. Although the overall decline in cardiac ejection fraction was mild (median absolute decrease, 6%; 95% CI, 3% to 9%) and not likely to be of clinical significance, four patients experienced a fall in cardiac ejection fraction that was associated with symptomatic congestive heart failure. Although all patients recovered symptomatically with treatment, two had persistent reductions in ejection fraction and two returned to baseline. In addition, one patient had a sudden cardiac arrest on day 38 of unknown etiology.

High-dose cyclophosphamide used in conditioning regimens for ABMT is the agent most frequently implicated in causing cardiac toxicity.^18-21 Cardiac manifestations of high-dose cyclophosphamide range from the lowering of the electrocardiographic wave complex voltage on ECG to myocarditis, congestive heart failure, pericardial effusions, and death. The onset of symptoms is usually between 1 and 10 days after high-dose cyclophosphamide administration.¹⁹ The precise incidence of cyclophosphamide cardiotoxicity is difficult to ascertain from the literature, given the variability in patient population, dose, and combination with other potentially cardiotoxic agents. The cardiotoxicity associated with high-dose cyclophosphamide has been shown to correlate better with dose per body-surface area than with dose per body weight, with an increased likelihood at doses greater than 1.55 g/m²/d for 4 days.²¹ In a phase II study reported by Antman et al⁷ that used a continuous infusion of high-dose cyclophosphamide, thiotepa, and carboplatin, six (21%) of 29 patients developed clinical evidence of congestive heart failure that lasted 1 to 6 days, at a median of 10 days after marrow reinfusion. One of six patients (3% of the total) developed cardiomegaly, and all had symptomatic resolution with treatment. In the phase I trial of high-dose mitoxantrone, carboplatin, and cyclophosphamide reported by Stiff et al,¹⁴ in which the three drugs were given as a continuous infusion (in contrast to the bolus administration used in our study), grade 3 congestive heart failure occurred in only one (4%) of 25 patients at 60 days after treatment. This patient had a prior history of doxorubicin exposure (250 mg/m²) and symptoms resolved with therapy.¹⁴

Although mitoxantrone-associated cardiotoxicity is well documented, its occurrence is rare (< 3% incidence) with cumulative doses of less than 100 mg/m².²² Furthermore, mitoxantrone cardiotoxicity is usually delayed, often occurring months after the initiation of treatment. Its incidence is greatest in those patients with prior anthracycline treatment, chest-wall irradiation, or underlying cardiac disease.^22,23 It is possible that mitoxantrone contributed to the cardiac changes observed in our patients, because all had been previously treated with anthracyclines, although all had received a total doxorubicin dose 360 mg/m². Although cardiac toxicity with conventional doses of carboplatin is uncommon, congestive heart failure was the dose-limiting toxicity reported in a study of repetitive doses of high-dose carboplatin administered as a 1-hour infusion in combination with paclitaxel and cyclophosphamide, supported by PBSCs,²⁴ which suggests that carboplatin may also have played a role. The incidences of symptomatic congestive heart failure, pericarditis, and fatal cardiac toxicity in our study were 9%, 2%, and 2%, respectively. This seems similar to other high-dose regimens reported in the literature.^7,14,25

More than 3,300 women with MBC who underwent high-dose therapy with autologous hematopoietic stem-cell support have been reported to the NAAMBTR.¹ The majority of these patients were treated with high-dose cyclophosphamide and thiotepa, with or without carboplatin, but the optimum high-dose regimen has not been identified through direct comparative trials. The rate of conversion of patients from PR after induction therapy to CR after high-dose therapy might be considered an indicator of the effectiveness of a particular high-dose regimen. The rate of conversion from PR to CR in phase II trials in the literature is low and has varied from 13% to 25% in most series.^6,7,25-27 This may reflect the frequency of patients with bone metastases in the particular patient cohort, because patients with residual positive bone scans after ABMT would be considered by most investigators to be partial responders. Of note, in the randomized trial recently reported by Stadtmauer et al,²⁸ the frequency of conversion of PR to CR was only 6% overall and was the same in patients who were randomized to receive the regimen of cyclophosphamide, carboplatin, and thiotepa with PBSC support as in those who received maintenance therapy with cyclophosphamide, methotrexate, and fluorouracil. The outcome for patients with only PR to induction therapy seems to be poor regardless, with only 13% alive and disease-free at 4 years.¹ This suggests that such patients still have a considerable burden of resistant breast cancer and that the conversion from PR to CR of patients with high-dose therapy does not confer lasting benefit. From the data reported to the NAAMBTR, no single intensive therapy regimen seems to be superior with respect to progression-free or overall survival (K. Antman, personal communication, February 1999). However, currently used regimens do seem to have different nonhematologic toxicity, and 100-day mortality in the metastatic setting remains 10%¹ despite the use of this therapy earlier in the course of the disease.

The regimen we have studied was well tolerated, with a low incidence of significant gastrointestinal, pulmonary, and renal toxicity, and compares favorably with other mitoxantrone-containing regimens.^25,29 Only 32% of our patients required parenteral narcotics for mucositis, which was grade 3 in 4%. The response rate of 79.5% at 3 months after high-dose therapy is similar to that of other high-dose regimens for chemotherapy-sensitive MBC. The side-effect profile of our regimen makes it amenable to consideration for outpatient use.

Although a large number of phase II studies have been reported and the use of high-dose therapy in chemotherapy-sensitive MBC has, until recently, been increasing, the magnitude of benefit of such therapy remains to be defined by a randomized trial. Currently available data from comparative trials are contradictory.^28,30 In June 1997, the National Cancer Institute of Canada Clinical Trials Group initiated a randomized phase III trial that compared this high-dose regimen, using carboplatin 1,600 mg/m², with standard therapy in women with MBC.³¹

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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5. Williams SF, Bitran JD, Kaminer L, et al: A phase I-II study of bialkylator chemotherapy, high-dose thiotepa, and cyclophosphamide with autologous bone marrow reinfusion in patients with advanced cancer. J Clin Oncol 5:260-265, 1987[Abstract]

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14. Stiff PJ, McKenzie S, Alberts DS, et al: Phase I clinical and pharmacokinetic study of high-dose mitoxantrone combined with carboplatin, cyclophosphamide, and autologous bone marrow rescue: High response rate for refractory ovarian carcinoma. J Clin Oncol 12:176-183, 1994[Abstract]

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Submitted August 25, 1998; accepted March 1, 2000.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Patnaik, A. Articles by Crump, M. Search for Related Content PubMed PubMed Citation Articles by Patnaik, A. Articles by Crump, M.