Annals of Oncology Advance Access published online on September 9, 2007
Annals of Oncology, doi:10.1093/annonc/mdm372
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© 2007 European Society for Medical Oncology
Optimizing clinical care of patients with metastatic breast cancer: a new oral vinorelbine plus trastuzumab combination
1 Division of Medical Oncology, Unit for Medical Care
2 Division of Cardiology
3 Division of Biostatistics and Epidemiology
4 Department of Medicine, European Institute of Oncology, Milan, Italy
* Correspondence to: Dr C. Catania, Unit for Medical Care, Division of Medical Oncology, European Institute of Oncology, Milan 20141, Italy. Tel: +39-02-57489482; Fax: +39-02-57489581; E-mail: chiara.catania{at}ieo.it
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Abstract |
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Background: Trastuzumab (T) combined with i.v. vinorelbine (i.v.VNR) is an active regimen for patients with advanced breast cancer (ABC). In order to further improve quality of life of patients undergoing treatment for ABC, a new regimen using oral vinorelbine (oVNR) (d1 + d3) plus q3wks T was tested (ToVNR).
Patients and methods: Thirty-nine patients with ABC, human epidermal growth factor receptor 2/neu 3+ or FISH positive received 288 treatment cycles with T 6 mg/kg (loading dose, 8 mg/kg) on d1 and oVNR 55 mg/m2 on d1 + d3, q3wks until disease progression or unacceptable toxicity.
Results: Thirty-seven patients and 286 treatment cycles were evaluated (two patients were lost to follow-up). Treatment was very well tolerated. Two patients had complete response (CR), 14 partial response (PR), 17 stable disease (SD) and four disease progression (PD) (overall response rate: 43%). Clinical benefit rate (CR + PR + SD >24 months) was 73%. Median time to progression was 8.9 months (range 2–27) and median duration of response was 10.9 months (range 2–27).
Conclusions: The ToVNR combination is active and very well tolerated. It favorably compares with the combination of T and weekly i.v. administered VNR, allowing a more convenient once every three weeks hospital admission and leaving patients and care providers free from the unpleasant effect of i.v.VNR.
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introduction |
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The human epidermal growth factor receptor 2 (HER2) is a 185-Kd transmembrane tyrosine kinase and is amplified in approximately 25%–30% of human breast cancer [1, 2]. When amplified, the gene produces high levels of HER2 cell surface receptor expression [3].
HER2 overexpression is an adverse prognostic factor characterized by a shorter disease-free period and decreased overall survival [2–4].
Trastuzumab (T) is a humanized monoclonal antibody, with specificity for HER2 protein, which exhibits antitumor activity in patients with breast cancer.
The results of phase II trials [5, 6] indicate that T is active against HER2-overexpressing breast cancer, both in women undergoing first-line treatment, and in those who have previously been treated with chemotherapy for metastatic disease [7].
The combination of T and chemotherapy was evaluated in preclinical and clinical studies. These studies showed a synergy between a number of anticancer drugs and T when used in combination against cancer cells with HER2 overexpressed [8–12], and that the increased cytotoxic effects of chemotherapeutic drugs follow a logarithmic curve [13].
In clinical setting, the addition of T to chemotherapy, in patients with HER2-overexpressing metastatic breast cancer, significantly increased the treatment activity, provided a survival advantage and improved patients quality of life [14, 15]. Overall, clinical studies showed that T has changed the natural history of HER2-positive breast cancer, either in the metastatic [16–18] or the adjuvant setting [19, 20].
Vinorelbine (VNR) is a semi-synthetic vinca alkaloid that showed activity and efficacy in breast cancer patients. Its mechanism of action is only partially known, but it is thought to be similar to vinblastine and vincristine, an antimicrotubule agent, in that it arrests cell division in mitosis [21].
The combination of VNR and T was tested in preclinical studies and appeared to be synergistic against all four HER2-overexpressing cell lines [14] with a reproducible synergism in many preclinical models [10–12].
In the clinical setting, the combination of T and a weekly administration of VNR appeared to be active and well tolerated [22–25]. Women with HER2-overexpressing metastatic breast cancer, when treated with T and weekly VNR, had a better prognosis than those with HER2-negative disease treated with VNR [23].
All previous studies administered T, in combination with VNR, as a weekly i.v. infusion. Our group designed a modified combination regimen in order to improve the patients' clinical advantages, acceptance and compliance. The weekly administration of VNR, which forced patients to undergo a weekly hospital admission, was substituted with a d1 and d3 VNR oral administration q3wks. This allowed them to submit to only a single hospital access once every 3 weeks.
Trastuzumab was given with a three-weekly schedule as well, according to recent clinical and pharmacokinetic findings indicating that T could be administered less frequently, at higher individual doses, without compromising efficacy or tolerability [26].
This schedule of VNR (d1 and 3) is supported by the observation that the plasma concentrations of the drug decrease in a triexponential manner with a terminal phase half-life of about 40 h. Moreover, this schedule appeared to be active and very well tolerated in many phase II studies that we conducted in breast cancer patients, either in metastatic disease or as primary treatment in operable breast cancer [27–30].
The i.v. administration of VNR, which is burdened by complications such as phlebitis at the site of drug injection or right diaphragmatic supraelevation [31], was substituted by an oral VNR administration route which eliminates the risk of these side-effects and frees up the nursing staff. Moreover, we recently observed patients' preference for oral chemotherapy [32] which provides a prevailing sense of freedom and reduces the unpleasantness of having to wait in the Hospital.
The use of oral VNR is supported by results of many studies which show similar levels of variability in pharmacokinetics between oral and i.v. routes [33] and indicate comparable activity and safety profiles [25]. Moreover, preliminary data support the combination of oral VNR and T, showing it to be feasible and well tolerated [34, 35].
We report the results of a monoinstitutional prospective phase II study testing this new treatment schedule, with oral VNR given on d1 and 3 combined with T, given i.v. on d1, repeated every 3 weeks, in patient with HER2-overexpressed metastatic breast cancer. VNR was given at the dose of 55 mg/m2 on d1 and d3 every 3 weeks, this dosage being the equivalent dose of i.v. vinorelbine (i.v.VNR) 22.5 mg/m2. The dose was recommended for further phase II studies in a previous dose-escalation trial that we carried out with oral VNR in combination with capecitabine for patients with metastatic breast cancer [36].
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patients and methods |
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All data were collected at the Department of Medicine, Medical Care Unit, at the European Institute of Oncology, Milan, Italy.
eligibility
Patients with histologically proven metastatic breast cancer and HER2 overexpression were eligible in the study. Eligible patients had measurable disease by physical examination or roentgen graphic imaging according to the Response Evaluation Criteria in Solid Tumors Group Criteria (RECIST), and no central nervous system involvement. They were required to be 18 years of age or older, performance status (Eastern Cooperative Oncology Group) of two or less and a life expectancy >16 weeks. HER2 overexpression was determined by immunohystochemistry (IHC). Patients with tumors scored as 3+, and positive for HER2 were eligible. Cases in which tumors scored 2+, only women with tumors showing HER2 gene amplification (determined by FISH), were considered eligible. Patients pretreated with systemic chemotherapy (inclusive of taxanes- and anthracycline- containing regimens) as well as patients pretreated with T-containing regimens (both resistant and refractory patients) and pretreated, but not refractory to VNR were considered eligible. Patients were neither pregnant nor nursing. Patients who had received radiation therapy and surgery were also eligible, provided that interventions had been completed 3 and 2 weeks, respectively, before treatment starts. Eligibility criteria were also absolute neutrophil count of >1500/mm3, platelet count >100 000/mm3, bilirubin <2 mg/dl, and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) <2.5 upper normal limit and resting left ventricular ejection fraction (LVEF) >50% as measured by echocardiography. Patients were required to have normal organ function. Patients with preexisting neuropathy in excess of grade 1 were ineligible, as were patients with serious illness or a medical or a psychiatric condition.
No concurrent anticancer treatments were allowed.
All patients provided written informed consent (approved by the institutional review board) before entering into the study.
treatment plan
Treatment was given in outpatient clinics. Trastuzumab was administered every 3 weeks, at 6 mg/kg over the course of 90 min (8 mg/kg as loading dose), and VNR was given orally at the dose of 55 mg/m2 on d1 and d3 every 3 weeks. No dose modification of T was permitted. If patients experienced an infusion syndrome, treatment was stopped, patients were assessed and given supportive measures as needed. Treatment was reinstituted when vital signs were stable. The VNR dose was reduced according to hematological or clinical toxicity (any patient who experienced an episode of neutropenia grade 3 during treatment received 75% doses; patients who developed grade 3 or 4 non-hematological toxicity had treatment withheld until the toxicity resolved to less than grade 2; treatment was then resumed using 75% doses of the offending agents). Trastuzumab and VNR were administered until documented disease progression, unacceptable toxicity or patient refusal. Patients were assessed with complete blood cell count every week and liver and renal function every 3 weeks.
LVEF was evaluated every 3 months during the first 12 months and every 6 months afterwards or whenever required by clinical circumstances. Cardiac toxicity was defined as a decrease of LVEF >20% from baseline or less than the lower normal limit (50%) or symptomatic congestive heart failure (grade 
2 National Cancer Institute—Common Toxicity Criteria (NCI-CTC) Toxicity scale Version 2.0). In case of LVEF reduction of 20% from baseline, occurring during treatment, patients were scheduled for interruption of treatment.
Other grade >2 non-hematological toxicity was managed with VNR delay until resolution to grade 1 or less.
study analysis
The study was designed to explore the activity of the treatment, in terms of response rate [complete response (CR) and partial response (PR)] and time to progression (TtP).
Patients had access to the hospital every 3 weeks and were restaged every three cycles by radiological evaluation and physical examination. All patients who met the inclusion criteria were enrolled into the study and were included in the analysis to determine response rate. Eligible patients removed from treatment because of toxicity, withdrawal of consent or death as a result of any cause were counted in the denominator for computing the proportion of responses.
RECIST criteria [37] were retrospectively applied to measurable lesions in order to assess response. Patients with PR or CR or SD and clinical benefit received the treatment for further three cycles before restaging. Patients with progressive disease were taken off study. Toxicity was determined according to NCI-CTC Toxicity scale Version 2.0 [38].
LVEF values were analyzed using a repeated measures model taking into account the correlation among the time periods with an unstructured covariance matrix. Data are expressed as mean ± standard deviation. A P value <0.05 was considered statistically significant.
The Kaplan–Meier method was used to analyze the median follow-up time and the TtP [39]. For each variable, the median survival was evaluated from treatment start, taking into account the presence of censored times (patients alive at the time of the last visit). The confidence intervals (CIs) for the response rates were calculated by using the methods described by Simons [40].
The primary end point of this study was overall response (CR% plus PR%) and TtP. The TtP was defined as the interval from the beginning of the treatment until tumor progression.
The study was designed as a single-stage phase II to explore the activity of the treatment in terms of response rate (primary end point) and TtP.
The study required a minimum of 36 subjects in order to test a response rate of 
60% (null hypothesis or poor drug response rate) versus the alternative of 80% or more with alpha = 0.05 and a power of 80%.
patients characteristic
From January 2004 to January 2006, a total of 39 patients from the European Institute of Oncology in Milan entered the study. Thirty-seven patients were assessable for response and toxicity (two patients continued treatment in other hospitals and were lost to follow-up).
The characteristics of the patients are shown in Table 1.
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The median age was 51 years (range 28–70) years. The majority of women had visceral disease and 32 patients (86%) had two or more metastatic organ sites of disease.
Thirty-four (92%) patients were eligible by virtue of HER2 status determined by IHC, and three patients (8%) by FISH. Fifty percent of the patients had tumors that were estrogen receptor (ER) positive (and HER2 positive).
Twenty-nine patients received treatment as first-line chemotherapy for metastatic disease (among them, 12 patients were chemo naive), six patients received the treatment as second line, one as fourth line and one as fifth line.
Seventeen patients (46%) had received prior chemotherapy as adjuvant or neo-adjuvant treatment and eight patients (22%) for metastatic disease, while 12 patients (32%) were not pretreated. Fifteen patients (41%) received anthracycline in a neo-adjuvant setting (mean dose 268 ± 71 mg/m2). In the metastatic setting, three patients (8%) were previously treated with T, three (8%) had received a taxane-based regimen, three (8%) had received a VNR-containing treatment and one (3%) had anthracycline.
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dosing and toxicity
Protocol consisted of three-weekly T treatments without dose modification, and administration of oral VNR dosing on day of T (d1) infusion and on d3 at home.
Two hundred and eighty-six treatment cycles were administered to 37 patients (median: 7, range: 1–16).
VNR was given at 100% of full planned dose in 80% of cycles; the causes of VNR dose reduction (by 20%–40%) were grade 4 febrile neutropenia in two patients, grade 4 neutropenia in one patient, grade 2 diarrhea in three patients and AST/ALT elevation in three patients. None of the patients omitted or delayed VNR administration; no T dose adjustments were required.
Adverse events observed in this study are summarized in Table 2.
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Grade 3–4 hematological toxicity consisted of neutropenia in six (16%) patients and anemia in one patient. Febrile neutropenia, not requiring hospitalization, was observed in one patient.
Only grade 3 elevation of AST in one patient was registered. Observed neurotoxicity consisted of G1 reversible peripheral neuropathy.
cardiotoxicity
All patients had a baseline LVEF >50% (62 ± 3%) as assessed by protocol. The mean duration of the observation period from baseline evaluation was 20 ± 6 months. In the overall population, LVEF showed a significant reduction, although the average was not below the predefined threshold required to be considered as cardiac toxicity (Figure 1). Only one patient developed a grade 2 cardiac toxicity (decline in LVEF of >20%), with an absolute LVEF of 50%, detected 18 months after the end of the treatment, and it was not associated with symptoms of heart failure. This patient received a total doxorubicin dose of 480 mg/m2 in the adjuvant setting, while the maximum dose received in the remaining doxorubicin-treated patients was not >300 mg/m2. None of the patient developed congestive heart failure or required treatment discontinuation due to cardiotoxicity.
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antitumor activity
Thirty-seven patients are assessable for response, and results are listed in Table 3.
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Sixteen of 37 patients achieved a CR (2 patients) and PR (14 patients), accounting for an overall response rate of 43% (95% CI: 27% to 61%); 17 patients (46%) had stable disease and four (11%) had disease progression. Clinical benefit rate (CBR: CR plus PR plus SD
24 weeks) was 73% (95% CI: 56% to 86%). The median duration of response was 10.9 (range 2–27+; 95% CI: 7.7 to 14+) months and the median TtP was 8.9 months (range 2–27+; 95% CI: 5.1% to 12.7%). Between the two patients who obtained a complete remission, one maintained the response for 15 months and the other is still without evidence of disease after 2 years of follow-up. Both of them had non-visceral metastasis, ER-positive disease and received T as maintenance monotherapy after the best response obtained with the combination.
The analysis of antitumor activity in the subgroup of the 20 patients with ER and progestrone receptor-positive tumors showed two CRs (10%), six PRs (30%), 11 stable diseases (55%) and one progressive disease (5%). Nine patients had stable disease 24 weeks, translating in a clinical benefit of 85% (95% CI: 62% to 97%). The median duration of response was 7.6 months (range 1–24) and the median TtP was 14.3 months [range 2–27, (95% CI: 7.1% to 21.5%].
One of the two patients previously treated with VNR for metastatic disease had a PR, and the other showed a disease progression.
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discussion |
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This is the first study testing both antitumor activity and toxicity of VNR, given orally on d1 and d3 with T administered every 3 weeks in patients with HER2-overexpressing metastatic breast cancer.
This treatment schedule was designed with the aim of taking advantage of the synergism between the two drugs, allowing patients to have a single hospital admission every 3 weeks while avoiding the toxicity and discomfort related to the i.v. administration of VNR.
This treatment appeared to be highly active, with a confirmed objective response rate of 43% and a CBR of 73%, reaching the predetermined cut-off for claiming the treatment worthy of further investigation (Tables 3–
5).
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The combination of three-weekly T and oral VNR was also very well tolerated, with nearly complete absence of cardiotoxiciy, neurotoxicity, febrile neutropenia and G3–4 NCI-CTC Toxicity scale Version 2.0 non-hematological toxicity.
Trastuzumab combined with chemotherapy represent the standard of care for women with HER2-overexpressing metastatic breast cancer. Although the optimal combination of T with chemotherapy is still not known, the synergism between T and VNR has been proven.
Our data on efficacy resemble those previously reported in the literature for i.v.VNR [22, 23, 25], and for a weekly schedule of oral VNR [34], combined with T for patients with metastatic breast cancer. Burstein et al. [25] reported a 60% and 68% response rate in 21 and 54 patients pretreated with prior chemotherapy and treated as first-line therapy, respectively, with a weekly combination of T and i.v.VNR. Papaldo et al. [23] treated patients with metastatic breast cancer with VNR alone (HER2-negative tumors) or VNR plus T (HER2-positive tumors) in a phase II study, enrolling patients already pretreated with chemotherapy for metastatic disease. The combination treatment was given to 35 patients with an observed response rate of 51%. In both these trials, patients could not have received prior VNR and/or T. Bartsch et al. administered oral VNR with a weekly schedule as monotherapy or combined with T, according to HER2 status, in a single study enrolling 78 patients with metastatic breast cancer. In the subset of 21 patients treated with the combination and in a subsequent study where 30 patients with similar inclusion criteria were treated with the combination, a 53% and 68% response rate was, respectively, reported [34, 35].
Interestingly, among our 20 patients with ER-positive tumors, a 40% response rate was reported (Table 4). The observation is of keen interest, and supports this combination as a good treatment option for this subset of patients; however, further data are necessary to demonstrate whether or not there is a particular biological feature of disease related to a higher responsiveness to this treatment. As a matter of fact, several clinical reports have indicated that response rates to first- or second-line therapy with tamoxifen and other antiestrogens are lower in HER2-positive patients than in those who are HER2-negative, making endocrine treatment in this subset of patients of limited efficacy [41]. Furthermore, recent findings demonstrate that the ER-positive HER2-postive subpopulation is heterogeneous, and that there may be common resistance mechanisms affecting the efficacy of agents targeting both ER and HER2 [42].
The absence of relevant cardiotoxicity is a major issue. With the exception of hypersensitivity, cardiotoxicity is the most important adverse effect of T [20], and considerable concern exists when T is administered in combination with chemotherapy.
In our population, a mild reduction in LVEF was observed during the follow-up. Although this reduction was statistically significant, it did not reach the required threshold limit to be considered cardiac toxicity. As a consequence, none of the patients required therapy withdrawal, and the potential clinical benefit of the treatment was not compromised. Indeed, the only patient with a grade 2 NCI-CTC Version 2.0 cardiac toxicity detected after 18 months from the end of study, had a LVEF value still within the normal range, was completely asymptomatic, and did not require any supportive cardiologic treatment. Notably, this patient had a prior doxorubicin exposure >400 mg/m2. This evidence is consistent with literature data, which report a higher risk of cardiac toxicity in patients exposed to a doxorubicin maximal cumulative dose of >400 mg/m2 [43].
This schedule of T and oral VNR is active and very well tolerated in patients with metastatic breast cancer. Observed cardiotoxicity did not differ appreciably from that which was expected from historical experiences [24, 25], and VNR did not seem to enhance T-induced cardiac toxicity. This treatment favorably compares with the combination of T and weekly administered i.v.VNR, allowing a more convenient once every three weeks hospital admission, and leaving patients and care providers free from the unpleasant effect of i.v.VNR.
Received for publication November 28, 2006. Revision received April 20, 2007. Revision received June 25, 2007. Accepted for publication June 28, 2007.
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