Introduction

Advances in understanding breast cancer biology have led to a therapy guided by the biologic features of the tumour. HER-2/neu overexpressing is detected in about 25% to 30% of invasive breast cancers and is associated with an aggressive tumour phenotype and reduced survival rates [2–4]. The development of trastuzumab, a humanized monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER-2) protein, has been a major achievement in the management of breast cancer. Trastuzumab was approved for clinical use by the Food and Drug Administration in 1998 and by the European authorities in 2000. In the pivotal trials of single agent trastuzumab in the metastatic setting, response rates of 30% and 15% have been reported in previously untreated [5] and treated HER2-positive patients [6], respectively. Single agent trastuzumab is generally well tolerated and not associated with the typical side effects seen with chemotherapeutic agents. Most side effects are mild to moderate and infusion-related reactions can usually be managed without withdrawal of trastuzumab [6, 7]. The benefits of trastuzumab in women with HER2-overexpressing breast cancer include response rates of 50% in combination with chemotherapy, improved time to progression and time to treatment failure and a significant 25% increase in survival duration at a 35 months of follow up [8]. The clinical benefits and tolerability of trastuzumab have been shown to maintain quality of life (QoL) of the patients [8, 9].

Preclinical studies indicated synergistic or additive interactions of trastuzumab with different chemotherapy agents [10, 11]. These investigations indicate that combinations of trastuzumab with vinorelbine, docetaxel and docetaxel plus platinum agents may have synergistic activity against breast cancer. These in vitro results have been confirmed by studies using mouse xenograft models [12]. Because of the improvement in survival, trastuzumab-based therapy has become a standard of care for women with HER2-positive advanced breast cancer and since 2 to 3 years in the adjuvant situation, too.

For vinorelbine anti-tumour-activity in metastatic breast cancer has been demonstrated in the first-line treatment setting. It appears to be similar to that reported for taxanes in phase II trials with 30–40% when used as first line therapy [13, 14]. However, taxanes are associated with a significant higher toxicity compared to vinorelbine. We performed a clinical study to determine the efficacy and safety of the combination of vinorelbine and trastuzumab in patients with HER-2/neu positive metastatic breast cancer as first line chemotherapy treatment.

Patients and methods

Patient eligibility

Eligible patients had histological confirmed HER2-overexpressing (ICH 3+ or 2+ and FISH+) metastatic breast cancer with measurable lesions in at least one site that has not been irradiated. Any previous adjuvant or neoadjuvant chemotherapy was permitted except vinorelbine or anti-HER2 therapy. Treatment with anthracyclines should have been finished at least six months ago and the cumulative dose should not have exceeded 360 mg/m2 of doxorubicin or 720 mg/m2 epirubicin. Prior hormone therapy for metastatic breast cancer was permitted. Any radiation therapy had to be completed at least three weeks before enrollment.

Other eligibility requirements included age ≥18 and ≤75 years, Karnofsky Index ≥70%, life expectancy ≥16 weeks, adequate hepatic, renal as well as bone marrow function defined by serum bilirubin ≤1.5× upper limit of normal, ALT and AST ≤2.5× upper limit of normal (unless related to liver metastasis), serum creatinine ≤1.5 upper limit of normal, haemoglobin ≥10 g/dl, neutrophils ≥1.5 × 109/l and platelets ≥100 × 109/l. Patients had to have normal cardiac function, with a LVEF not more than 10% below the normal limit.

Patients with pre-existing neuropathy in excess of WHO grade 2 were ineligible as well as patients with serious illness or a medical or psychiatric condition that might influence their ability to provide informed consent or to receive protocol-based therapy and patients with symptoms susceptible of cerebral or meningeal metastases. All patients had provided written informed consent before entering the study. The protocol was reviewed and approved by the institutional review boards of all participating centers.

Patients were enrolled between February 2002 and February 2003.

Treatment regimen

Treatment was administered in an outpatient setting. The initial trastuzumab infusion was 4 mg/kg intravenously (IV), administered over 60 min. Subsequently, trastuzumab was given weekly at 2 mg/kg i.v., administered over 30 min. Vinorelbine was given weekly on the same days as trastuzumab, after trastuzumab administration. At first application, vinorelbine and trastuzumab had to be given with a time interval of 2 h. The dose of vinorelbine was 25 mg/m2 administered in between 250 ml of saline solution prior and after the infusion. Patients were assessed with weekly complete blood count plus differential, and liver function tests every 4 weeks. The protocol called for the vinorelbine dose to be adjusted every week on the day of therapy, on the basis of haematologic toxicity and hepatotoxicity. Neutrophils less than 1 × 109/l required a delay of vinorelbine administration of 1 week. If vinorelbine could not have been given in 3 subsequent weeks due to toxicity, the treatment with vinorelbine was discontinued. Patients had LVEF measured at baseline and every 8 weeks during the study. Trastuzumab was withheld in patients experiencing absolute declines in LVEF of greater than 10% below the normal limit until a reevaluation 1 month later. In case of LVEF-stabilisation treatment with trastuzumab was continued again if further decrease of left ventricular function was noted, the patient was put off treatment. For patients experiencing a cardiac dysfunction of NYHA grade 3 or 4 trastuzumab was stopped immediately.

Any neurological toxicity greater than WHO grade 2 led to a discontinuation of vinorelbine.

Study analysis

Patients received weekly therapy and were assessed every 8 weeks. Tumour response was defined according to the Response Evaluation Criteria in Solid Tumours (RECIST). Patients with stable disease or with either complete response (CR) or partial response (PR) received ongoing treatment. After 24 weeks of combined treatment patients continued on trastuzumab only. Patients with progressive disease were taken off study. The primary endpoint of this study was best overall response rate on the basis of all eligible patients who received al least 8 weeks of protocol therapy. Secondary endpoints were time to tumour progression, median survival and assessment of tolerability. Calculation of the required patients to be enrolled in this study resulted from the two-stage minimax-design according to Simon [1].

Results

Patient characteristics

A total of 41 patients from six participating centers in Germany suffering from HER-2/neu overexpressing (ICH 3+[95%] or 2+ and FISH+) metastatic breast cancer were included in this evaluation. Patient characteristics are shown in Table 1.

Table 1 Patient demographic characteristics
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Chemotherapy

Protocol therapy called for ongoing weekly trastuzumab treatment without dose modification and administration regardless of vinorelbine dosing. The average treatment duration was 120 days (median 138 days range 1 to 205 days; N = 41) and almost half of the patients received 24 applications of chemotherapy (N = 20). Eighteen patients (44%) completed the protocol. Reasons for going off study before completion of the protocol was progression (26%; N = 11), five patients (12%) withdrew consent for physician or patient preference; another five patients went off study due to serious adverse events, which were as follows: infection, allergic reaction, surgical intervention, pathological fracture and decline in LVEF.

Clinical efficacy

Objective response, either CR or PR, was seen in 18 of 41 patients (43.9%, CI 28–60.3%). Four patients reached CR, 14 PR and an additional five patients had stable disease for 18 weeks or longer, for details see Table 2.

Table 2 Overall response rates (N = 41 pts.), intend to treat analysis
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Response rates were analyzed among clinical subsets of patients, defined by hormone-receptor status, prior adjuvant chemotherapy or hormone therapy treatment and menopausal status. Patients were analysed in different subsets: hormone-receptor-positive tumours versus hormone-receptor-negative tumours, patients who had received adjuvant chemotherapy or hormone therapy and patients who had not, or patients who were postmenopausal compared with patients who were not. These result are shown in Table 3.

Table 3 Response rates—subsets of patients
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Time to progression analysis

Six patients (15%) developed primary progression during the first 6 weeks of treatment, or within less than six applications, at a median time of 23 days after registration. Thirty-five patients (85%) experienced progression of disease after a median time to progression of 235 days. About 30% of patients were without disease progression at 1 year (see Fig. 1).

Fig. 1
figure 1

Time to progression. Proportion of patients without progressive disease

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There was no statistically significant difference in time to progression with regard to different locations of metastases, hormone receptor status, adjuvant chemotherapy, palliative hormone therapy or menopausal status, as shown in Table 4.

Table 4 Time to progression—subsets of patients
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About half of the patients died (21 of 41 patients, 51%) with an average overall survival of 429 days (33–850 days) from registration, with a median of 411 days (Fig. 2).

Fig. 2
figure 2

Overall survival. Proportion of patients surviving after registration

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Tolerability analysis

The incidence and severity of acute toxicity associated with combined trastuzumab–vinorelbine therapy was quite low. All treatment-related toxicities that occurred in more than 10% of patients on study or were in excess of CTC grade 2 are shown in Table 5. We documented 14 serious adverse events (SAEs), nine of them clearly not associated with the study drugs (vinorelbine or trastuzumab).

Table 5 Treatment-related toxicity
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Discussion

For women with Her-2/neu overexpressing metastatic breast cancer, treatment with trastuzumab combined with chemotherapy is the standard of care.

While in vitro studies were able to demonstrate an additive anti-tumour effect of docetaxel plus trastuzumab, other substances (vinorelbine, docetaxel, and cisplatin) showed a synergistic effect. In vivo, it was possible to demonstrate, that vinorelbine plus trastuzumab regimens are not only superior to paclitaxel containing regimens in terms of toxicity [15], but also in terms of response and survival [16, 17]. For example the TRAVIOTA study showed 51% remission rate for vinorelbine plus trastuzumab versus 40% for the taxane-containing regimen and a median time to progression of 8.5 versus 6.0 months for the vinorelbine combination [18].

This is in the line with the current phase II trial of vinorelbine and trastuzumab in patients with HER2-neu positive metastatic breast cancer which demonstrated high response rates of clinical activity achieved with limited acute toxicities.

Almost half of the patients had an objective response with 10% CR and 34% PR. About 30% of patients were without disease progression at 1 year. The clinical outcome was not significantly affected by other factors.

This confirms the results of other recent clinical studies of this combination both in untreated and in heavily pre-treated patients with HER-2/neu positive metastatic breast tumours. Different phase II trials have shown high objective response rates (44–78%) [16, 18, 19–22]. The slightly lower objective response rate may be due to the intent-to-treat-analysis and the high number of not evaluable patients in the current trial (n = 8).

The haematologic and non-haematologic toxicities were well within the range expected from different other trials. Cardiotoxicity, a side effect of particular concern in trastuzumab treatment, was acceptably low; only one patient experienced cardiotoxicity of grade 3 (grade 3 arrhythmia), which is not known as caused by trastuzumab, and another patient developed asymptomatic grade 2 decrease of LVEF (<50%).

The favourable safety profile of the vinorelbine/trastuzumab combination has consistently been shown in other trials and the rates of cardiomyopathy were not higher than those reported with trastuzumab as single agent [6]. In the study by Jahanzeb et al. [20] no grade 3–4 cardiac toxicity was seen and Burstein et al. [16] described only one patient with grade 3 cardiac toxicity.

Compared to combination therapy with taxanes, vinorelbine causes only mild alopecia. Docetaxel induced distracting onycholysis is not observed by the vincaalkaloid. Cumulative neurotoxicity observed using vinorelbine is less marked than with other vincaalkaloids such as vincristine and vindesine and less common than using a taxane-containing regimen. Concerning haematologic toxicities vinorelbine is comparable to a taxane regimen. However docetaxel/trastuzumab offers the advantage of a three weeks schedule over the weekly application of vinorelbine combined with the antibody. As many patients with relapsing breast cancer received taxane containing therapy regimens in the adjuvant setting, vinorelbine is a relevant combination partner for trastuzumab in first line treatment. Capecitabine, a potential alternative, offering similar advantages concerning oral administration and non-causing alopezia as vinorelbine, is right now the only compound tested as a chemotherapy partner for lapatinib in patients with advanced HER-2/neu positive breast cancer in case of disease progression in patients receiving trastuzumab and should therefore not be used as a first line substance. Nowadays the oral application of vinorelbine enables a 3 weeks application schedule of trastuzumab, too, and may be preferable to the i.v. administration: The oral regimen showed comparable results in overall response rates (43–68%) and median time to progression (8.9–9.0 months) to our herein presented study [23, 24].

In conclusion, weekly vinorelbine/trastuzumab may be considered an acceptable option for HER2-overexpressing patients as it represents an effective and well-tolerated therapy. At last, the decision which combination therapy is favoured, should always made together with the patient, taking her individual living conditions into consideration.