Annals of Oncology Advance Access originally published online on January 29, 2007
Annals of Oncology 2007 18(7):1152-1158; doi:10.1093/annonc/mdl476
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© 2007 European Society for Medical Oncology
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A review of the use of trastuzumab (Herceptin®) plus vinorelbine in metastatic breast cancer
Mount Breast Group, Mount Hospital, Perth, Australia
* Correspondence to: Dr A. Chan, Medical Oncologist, Suite 41, 146 Mounts Bay Road, Mount Hospital, Perth 6000, Australia. Tel: +61-8-9481-4522; Fax: +61-8-9481-4544; E-mail: arlene.chan{at}bigpond.com
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Abstract |
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The combination of trastuzumab (Herceptin®) and vinorelbine (Navelbine®) in the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is valuable for several reasons. There is proven synergism of these agents in preclinical models, both agents are well tolerated and there is minimal overlapping toxicity. This article reviews clinical experience with trastuzumab and vinorelbine from phase II/III trials including >450 assessable patients. Results across the trials show objective response rates for the combination in the range of 44%–86% (51%–86% as first-line treatment) and a median duration of response of 10–17.5 months. Approximately 50% of patients experience grade 3/4 neutropenia, which is of short duration and manageable. Symptomatic cardiac events are infrequent (seven episodes of grade 3 toxicity across all trials). Overall, trastuzumab–vinorelbine combination therapy offers patients with HER2-positive MBC, an effective and well-tolerated treatment that is suitable for prolonged duration of use.
Key words: adverse effects, breast neoplasms, combination drug therapy, trastuzumab, treatment outcome, vinorelbine
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introduction |
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Breast cancer is a heterogeneous disease in which knowledge of the biological features of the tumour is key to guiding treatment of any given individual [1–3]. The presence of oestrogen and/or progesterone receptors indicates a high likelihood of response to tamoxifen, aromatase inhibitor or ovarian ablation. Similarly, trastuzumab (Herceptin®), a humanised monoclonal antibody specifically developed to target human epidermal growth factor receptor 2 (HER2), is regarded as standard treatment in those patients with HER2-positive tumours.
For patients with HER2-positive metastatic breast cancer (MBC), the combination of trastuzumab with chemotherapy will usually be warranted at some stage of the illness [4]. Trastuzumab plus a taxane is an established regimen in this setting, with phase III randomised trials showing clinical improvements compared with a taxane alone on all outcomes, including survival [4–6]. In a recent trial, trastuzumab–docetaxel as first-line treatment of HER2-positive MBC approximately doubled the overall response rate compared with docetaxel alone (61% versus 34%; P = 0.0002). In addition, there was a statistically significant improvement in time to disease progression of 5.6 months (P = 0.0001) and overall survival (OS) of 8.5 months (P = 0.03) [5]. There was minimal additional toxicity with the inclusion of trastuzumab.
There is accumulating evidence that trastuzumab is also clinically beneficial when combined with other chemotherapy agents commonly used in the treatment of MBC, including vinorelbine (Navelbine®), capecitabine, gemcitabine, liposomal doxorubicin and platinum salts [4]. This article reviews the clinical experience with trastuzumab given in combination with vinorelbine, a cytostatic antineoplastic drug of the vinca alkaloid family, in the HER2-positive MBC setting.
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rationale for combining trastuzumab with vinorelbine |
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Vinorelbine has been shown to be active as a single agent in MBC, with response rates in the order of 40%–60% in chemonaive disease and with good tolerability [7]. In particular, vinorelbine rarely induces total alopecia or severe gastrointestinal (GI) events (side-effects associated with taxanes) or symptomatic cardiac events. The most frequent dose-limiting haematological toxicity associated with vinorelbine is neutropenia. Common non-haematological side-effects include grade 1/2 peripheral neuropathy, constipation and phlebitis.
In the preclinical setting, synergism between trastuzumab and vinorelbine has been demonstrated. Notably, in a study of trastuzumab combined with various chemotherapy agents in four HER2-overexpressing breast cancer cell lines, the mean combination index value for trastuzumab and vinorelbine ranged from 0.24 (P < 0.001) to 0.78 (P = 0.034), where a statistically significant value of <1.0 indicated synergy [8].
Vinorelbine and trastuzumab have no overlapping toxic effects, which contrast with the use of trastuzumab in combination with conventional anthracyclines (e.g. doxorubicin). Despite studies demonstrating efficacy of this latter combination, there is an unacceptable increase in risk of cardiac events [6, 9]. Improved cardiac safety has been noted in trials of trastuzumab in combination with newer anthracyclines, including epirubicin and liposomal doxorubicin [4, 10]. As a result of the recognition of cardiac toxicity when using trastuzumab, all recent trials of trastuzumab now include stringent cardiac eligibility criteria and regular cardiac monitoring. This has led to a decline in the rate of symptomatic cardiac events to 
2% in trials of trastuzumab in combination with nonanthracycline chemotherapy [5, 11].
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clinical experience with trastuzumab–vinorelbine combination therapy |
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A search of the online PubMed database (all years) was undertaken to identify prospective clinical trials evaluating trastuzumab plus vinorelbine using the search terms of ‘trastuzumab’ (or ‘Herceptin’) and ‘vinorelbine’ (or ‘Navelbine’) in the title. On the basis of this strategy, six published trials were identified for discussion in this article. Additional trials were identified from abstracts published on major oncology congress websites [including American Society of Clinical Oncology (2000–2006), San Antonio Breast Cancer Symposium (2003–2005), European Cancer Conference (2005) and ESMO (2004)].
A phase I dose-finding study evaluated escalating doses of vinorelbine in 12 patients [12]. Vinorelbine was given at doses of 20, 25 and 30 mg/m2 in successive cohorts, on a day 1 and 8 schedule every 21 days, in combination with trastuzumab [without granulocyte colony-stimulating factor (G-CSF) support]. Toxic effects in the study attributable to treatment were primarily haematological; one case of febrile neutropenia and one episode of acute cholecystitis were noted among six assessable patients receiving vinorelbine 30 mg/m2 and this was therefore determined as the maximum tolerated dose.
At least 12 phase II trials [13–24] and one phase III trial [25] have now reported data for trastuzumab in combination with vinorelbine in the HER2-positive MBC setting. The trials have included >450 assessable patients, the majority (94%) having HER2-positive status, defined as an immunohistochemistry (IHC) score of 3+ or by FISH.
activity of weekly intravenous trastuzumab–vinorelbine
Eleven of the trials (with 429 assessable patients) assessed weekly intravenous (i.v.) dosing with trastuzumab (4 mg/kg loading followed by 2 mg/kg thereafter) given concurrently with vinorelbine (25 or 30 mg/m2) (Table 1). In interpreting the results, it is necessary to note that in some trials, a proportion of patients (6%) were included for trastuzumab and vinorelbine treatment when the tumour was FISH– or IHC 2+ and not further evaluated by FISH. Trastuzumab dose modifications were prohibited in all trials. By contrast, vinorelbine dose was adjusted (reduced or delayed, depending on the toxicity) each week on the basis of haematological and/or non-haematological toxicity.
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Across these trials, the trastuzumab–vinorelbine combination demonstrated high activity, with objective response rates (ORRs) in the range of 44%–86% (Table 1). Complete responses rates ranged from 3% to 15%, with partial response rates of 39%–75%. Considering only patients with IHC 3+ tumours, ORRs of 62%–82% were seen. In two trials that included a substantial proportion of patients with FISH– [18] or IHC 2+ (unconfirmed by FISH) [17] tumours, response rates among these patients were 54% and 60%, respectively; this compared with 83% and 80% for the respective patients with FISH+ or IHC 3+ tumours. In a further trial, one patient included with an IHC 2+/FISH– tumour showed no response to the trastuzumab–vinorelbine combination [19].
ORRs were generally highest in patients receiving the trastuzumab–vinorelbine combination as first-line treatment of MBC (range 51%–86%) (Table 1). Encouraging response rates, however, were also observed following prior chemotherapy for MBC [17, 19]. In a trial of 35 assessable patients previously treated in the metastatic setting, the ORR for the combination was 51% [19]. A similar response rate was observed in those patients who had received prior anthracyclines as adjuvant therapy or for MBC (50%), or both prior anthracyclines and taxanes (48%).
Use of adjuvant chemotherapy, and also the type of adjuvant chemotherapy, did not appear to affect response rates [13, 14, 17]. In two trials evaluating first-line treatment, ORRs were 70% in each when adjuvant chemotherapy had not been given, 62% [13] and 63% [14] following adjuvant anthracyclines and 55% and 56% following both adjuvant anthracyclines and taxanes.
There are currently limited data on whether patients with specific sites of metastases benefit more from trastuzumab–vinorelbine combination therapy. The trials considered in this article included patients with either single or multiple metastases, as well as differing disease sites (e.g. liver, lung, bone and soft tissue). In one trial with data available, patients with visceral (liver/lung) metastases had a response rate to first-line treatment of 64%, which was similar to the 60% response rate seen in patients without visceral involvement [13]. In another trial evaluating first-line treatment, in which 84% of patients had visceral metastases, 90% of responses were in the liver or lung [16].
Three trials with median follow-up >1 year demonstrated median OS times of around 2 years or longer, with one trial not having reached median survival at the time of reporting [13, 19, 22] (Table 2). The trial with the longest reported follow-up to date (36.2 months) was a multinational evaluation of first-line trastuzumab–vinorelbine (with vinorelbine at 30 mg/m2) in patients with IHC 3+ or FISH+ tumours, as determined by centralised testing [13]. In 62 assessable patients, the ORR was 63%, median duration of response was 17.5 months, median progression-free survival time was 9.9 months and median OS time was 23.7 months.
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A single-centre trial conducted by Papaldo et al. [19] treated consecutive women with pretreated MBC with vinorelbine (25 mg/m2) alone or in combination with trastuzumab according to the HER2 status of the tumour. Those with HER2-positive tumours (IHC 3+ or FISH+) were given trastuzumab–vinorelbine (n = 35), while those with HER2-negative tumours received vinorelbine monotherapy (n = 33). All patients were assessable for response. The data showed that women with HER2-positive tumours had a superior ORR (51%) than those with HER2-negative tumours (27%). Among the HER2-positive patients, at a median follow-up of 17 months, trastuzumab–vinorelbine yielded a median duration of response of 10 months, time to progression of 9 months and OS time of 27 months; this compares with 8, 6 and 22 months, respectively, for the HER2-negative patients.
A phase III, multicentre, randomised trial was begun in the United States to compare trastuzumab in combination with either vinorelbine or a taxane (paclitaxel with or without carboplatin; or docetaxel) for HER2-positive MBC (IHC 3+ or FISH+): the TRAstuzumab and VInorelbine Or TAxane (TRAVIOTA) study [25]. This study opened in 2001 and planned to accrue 250 patients but was closed in 2003 due to poor accrual, with 81 patients having received study treatment. The available results indicate at least comparable activity between the treatment arms: ORR was 51% with trastuzumab–vinorelbine and 40% with trastuzumab–taxane and median time to progression was 8.5 and 6.0 months, respectively. It should be noted that the study was underpowered to detect statistically significant treatment differences because of early closure.
activity of alternative trastuzumab–vinorelbine treatment schedules
Two further phase II trials evaluated alternative treatment schedules for trastuzumab–vinorelbine combination therapy: use of a three-weekly trastuzumab schedule [23] and use of oral vinorelbine [24].
The three-weekly trastuzumab schedule was evaluated in a single-centre trial in patients with IHC 3+ or FISH+ MBC pretreated with no more than one prior chemotherapy regimen [23]. Trastuzumab was given at a loading dose of 8 mg/kg followed by 6 mg/kg every 21 days, with i.v. vinorelbine at a dose of 30 mg/m2 on days 1 and 8 every 21 days. Reported data are preliminary (from 18 assessable patients) but the ORR of 56% is within the range observed with weekly trastuzumab dosing. This scheduling allows slightly greater patient convenience by obviating the need to attend the clinic in the third week.
Oral vinorelbine is a new formulation of vinorelbine that also offers the benefit of patient convenience compared with i.v. vinorelbine. In a single-centre trial, 78 patients with MBC received weekly oral vinorelbine at 60 mg/m2 (equivalent to an i.v. dose of 25 mg/m2) with or without weekly i.v. trastuzumab (at 4 mg/kg loading followed by 2 mg/kg thereafter) as first-line therapy or after progressing with earlier line chemotherapies [24]. The design was similar to that employed by Papaldo et al. [19] in which patients with IHC 3+ and/or FISH+ tumours received trastuzumab, while those with HER2-negative tumours did not. Among 17 assessable patients treated with trastuzumab–vinorelbine for HER2-positive disease, the ORR was 53%, which is within the range observed with conventional dosing. This compares with an ORR of 20% with vinorelbine monotherapy among 51 assessable patients with HER2-negative disease.
safety and tolerability
As expected with vinorelbine-based treatment, neutropenia was the most frequent grade 3/4 adverse event associated with the combination therapy. Across the 12 phase II trials, the incidence of grade 3/4 neutropenia was in the range of 23%–84% of patients and 8%–35% of treatment courses (Table 3). Three trials commented on the duration of neutropenia as usually being brief and noncumulative [13, 18, 19], with two trials indicating that myelosuppression was manageable with vinorelbine dose adjustments [18, 19]. Patients rarely developed febrile neutropenia, and only one death was reported as a result of neutropenic sepsis [13]. Use of G-CSF support was variable across the trials. In some trials, G-CSF support was scheduled for cases of treatment delays >2 weeks as a result of neutropenia or febrile neutropenia [14, 19], while G-CSF was administered at the discretion of the investigator in others [18]. Grade 3/4 anaemia and thrombocytopenia were infrequent.
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Consistent with the phase II experience, trastuzumab–vinorelbine in the phase III TRAVIOTA study was associated with greater grade 3/4 haematological toxicity [25]. Grade 3/4 neutropenia occurred in 59% of patients with trastuzumab–vinorelbine compared with 13% of patients with trastuzumab–paclitaxel and 8% with trastuzumab–docetaxel. Patients receiving the trastuzumab–taxane combinations experienced increased alopecia, nail toxicity and fluid retention.
Few non-haematological adverse events of grade 3/4 were reported in any of the trials (Table 4). In particular, symptomatic cardiac events were infrequent. The incidence of symptomatic cardiac events was reported for all trials with only seven cases of grade 3 cardiac dysfunction being observed. At least three of these cases resolved with appropriate medication [13, 14, 19]; no outcome information was reported for four cases [20, 25]. Asymptomatic declines in left ventricular ejection fraction (LVEF) of >20% or to LVEF <50% occurred in 
8% of patients in any one trial (Table 4). No grade 4 cardiac events have been reported.
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In the largest trial with full adverse event data available—an evaluation of the weekly i.v. combination as first-line treatment of MBC in 69 patients assessable for safety [13]—the most frequent non-haematological grade 3 adverse events were asthenia (9%), infection (6%), peripheral neuropathy (3%) and constipation (3%). These findings are consistent with the anticipated adverse events seen in vinorelbine-based treatment.
Considering the alternative schedules (use of three-weekly trastuzumab or oral vinorelbine), tolerability appears to be similar to the standard weekly i.v. trastuzumab–vinorelbine schedule [23, 24, 26]. An exception is that oral vinorelbine may carry a slightly increased risk of severe GI toxicity compared with i.v. vinorelbine, though a lower risk of grade 3/4 neutropenia. In the phase II trial of oral vinorelbine, considering the trastuzumab–vinorelbine and vinorelbine-alone groups together, the incidence of grade 3 nausea/vomiting was 4% of patients and the incidence of grade 3/4 neutropenia was 14% of patients [24].
Trastuzumab–vinorelbine combination therapy was usually administered in the outpatient setting. In four trials where hospitalisation rates were reported [17–19, 24], three patients required hospitalisation (3/136, 2%) in each instance as a result of febrile neutropenia. Patients recovered fully with no further neutropenic sepsis following dose adjustment of vinorelbine. Serious adverse events were reported from one trial [21] and included two infusion-related reactions, two cases of dyspnoea and one LVEF decrease to <50%. In addition to the death from neutropenic sepsis [13], one toxic death following the development of renal failure was reported [23].
Regarding dose delivery of vinorelbine, Burstein et al. [14] demonstrated that full-dose vinorelbine could be given in 75% of all weekly treatments, with the need to reduce the dose from 25 mg/m2 to 15 mg/m2 in 15% of treatments and omission of dose in only 10% of treatments. Concurrent trastuzumab and vinorelbine could be given on >90% of treatment dates. An analysis of the relative dose intensity of vinorelbine, normalised at one for patients receiving 25 mg/m2, showed weekly values were well preserved in the range of 0.8–1.0 through >1 year of treatment (median 0.83). Findings were similarly favourable from other trials with dose information available [13, 16–19].
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discussion |
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The ORR range of 51%–86% observed for the trastuzumab–vinorelbine combination as first-line treatment indicates that this is an active regimen in HER2-positive MBC patients. The durability of response compares favourably with previously studied trastuzumab-based combinations [4–6, 27]. ORRs for first-line treatment were 61% with trastuzumab–docetaxel [5], 49% with trastuzumab–paclitaxel [27] and 60% with trastuzumab–doxorubicin/cyclophosphamide (AC) [27], with median durations of response of 12, 11 and 9 months, respectively.
Use of prior adjuvant chemotherapy does not appear to influence the ORR and clinical efficacy exists even in patients with chemotherapy-pretreated HER2-positive MBC. In clinical practice, an increasing number of patients will receive anthracyclines and/or taxanes as adjuvant treatment and/or first-line chemotherapy with or without trastuzumab for MBC. The observation of responses in patients who had received both taxanes and anthracyclines as prior treatment indicates that trastuzumab–vinorelbine is active even in patients who are heavily pretreated. For patients with HER2-positive MBC, there is accumulating evidence that trastuzumab offers clinical benefits when given beyond disease progression in combination with a different chemotherapy agent [4]; vinorelbine may play an important role in this setting.
Trastuzumab–vinorelbine has yielded comparable progression-free and OS results to other trastuzumab–chemotherapy combinations (Table 2), although direct cross-trial comparisons were not intended. With first-line treatment and a median follow-up time of 36.2 months, trastuzumab–vinorelbine had a median progression-free survival time of 9.9 months and a median OS time of 23.7 months [13]. By comparison, in pivotal randomised trials, first-line trastuzumab–docetaxel, trastuzumab–paclitaxel and trastuzumab–AC produced median times to progression of 12, 7 and 8 months, respectively, and OS times of 31, 25 and 31 months, respectively [5, 27].
With >450 patients evaluated in the trials described, there was no excess of unexpected adverse events or mortality. The concurrent use of trastuzumab did not accentuate the toxicity of vinorelbine. Grade 3/4 neutropenia occurred in 23%–84% of patients with i.v. weekly dosing of the combination but this was reversible and rarely developed into febrile neutropenia. The use of G-CSF is generally not indicated in the metastatic setting and dose reduction of vinorelbine, e.g. from 30 mg/m2 to 25 mg/m2, would generally abrogate myelosuppression without compromising efficacy. The risk of haematological events may also be reduced through the use of oral rather than i.v. vinorelbine, although this benefit may be accompanied by a slightly increased risk of grade 3 GI events. Symptomatic cardiac events occurred in only seven patients across the trials, with at least three cases resolving with appropriate medication. Nevertheless, the known cardiac toxicity of trastuzumab monotherapy mandates baseline assessment of cardiac status with appropriate cardiac monitoring in those patients who continue on treatment. The tolerability of trastuzumab–vinorelbine with prolonged use, while maintaining dose intensity of vinorelbine [13, 14, 17], indicates that this combination is suitable for prolonged administration in responding patients.
Other phase III trials evaluating the efficacy and tolerability of trastuzumab–vinorelbine against trastuzumab–taxane combinations would be of interest, since the latter is the most commonly used regimen in countries where trastuzumab is available. The phase III TRAVIOTA study, while terminated early due to poor accrual, provides encouraging evidence that first-line trastuzumab–vinorelbine is at least as active as first-line trastuzumab–docetaxel [25]. An ongoing trial in Norway—the HERceptin plus NAvelbine or TAxotere (HERNATA) study—is also attempting to address this comparison by randomising women to trastuzumab–vinorelbine or trastuzumab–docetaxel. While preliminary results are not yet available, findings from HERNATA may provide evidence to support the use of trastuzumab in combination with vinorelbine in the first-line metastatic setting.
In order to further improve on clinical activity, trials of triplet combinations with trastuzumab and vinorelbine plus other well-tolerated chemotherapies may also be warranted. In a phase II trial of 35 patients with HER2-positive MBC, the addition of docetaxel to vinorelbine and trastuzumab as first-line therapy resulted in a 75% response rate and a median progression-free survival time of 11.3 months [28]. Importantly, toxicity from this regimen was manageable. Furthermore, preliminary results from a multicentre trial using oral vinorelbine in a triplet combination with capecitabine and trastuzumab as first-line treatment in 24 assessable patients with HER2-positive MBC (IHC 3+/2+, confirmed by FISH+) showed a clinical benefit rate (complete or partial response, or stable disease) of 92%. Stable disease is defined as less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions [26]. This triplet combination might prove especially useful for patients due to its favourable safety profile and the convenience of oral formulations.
Clinical trials are also ongoing to assess the use of trastuzumab/vinorelbine-based regimens in the HER2-positive early breast cancer setting [29, 30]. In the FinHer trial [30], significant improvements in disease-free and OS were seen in a subgroup of 232 patients with HER2-positive disease by the addition of trastuzumab to docetaxel or vinorelbine. The small number of patients in the trastuzumab/chemotherapy arm (n = 115) precludes an assessment of whether one chemotherapeutic agent is superior to the other. Notably, patients receiving trastuzumab–vinorelbine had less severe and fewer adverse events.
In conclusion, evidence from several phase II trials indicates that trastuzumab in combination with vinorelbine is an active regimen, has a favourable safety profile and is suitable for prolonged use as first-line treatment in patients with HER2-positive MBC. The combination also offers an attractive second-line option for patients whose disease becomes refractory to taxane-based trastuzumab therapy.
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The author would like to thank Cath Carsberg for medical writing support during the preparation of this manuscript.
Received for publication August 15, 2006. Revision received November 13, 2006. Accepted for publication November 27, 2006.
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1. Goldhirsch A, Glick JH, Gelber RD, et al. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol (2005) 16:1569–1583.
2. Bilous M, Dowsett M, Hanna W, et al. Current perspectives on HER2 testing: a review of national testing guidelines. Mod Pathol (2003) 16:173–182.[CrossRef][ISI][Medline]
3. Bast RC Jr, Ravdin P, Hayes DF, et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol (2001) 19:1865–1878.
4. Bell R, Verma S, Untch M, et al. Maximizing clinical benefit with trastuzumab. Semin Oncol (2004) 31(Suppl 10):35–44.[ISI][Medline]
5. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol (2005) 23:4265–4274.
6. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med (2001) 344:783–792.
7. Gregory RK, Smith IE. Vinorelbine—a clinical review. Br J Cancer (2000) 82:1907–1913.[CrossRef][ISI][Medline]
8. Pegram MD, Konecny GE, O'Callaghan C, et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst (2004) 96:739–749.
9. Minotti G, Menna P, Salvatorelli E, et al. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev (2004) 56:185–229.
10. Untch M, Eidtmann H, du Bois A, et al. Cardiac safety of trastuzumab in combination with epirubicin and cyclophosphamide in women with metastatic breast cancer: results of a phase I trial. Eur J Cancer (2004) 40:988–997.[CrossRef][ISI][Medline]
11. Perez EA, Rodeheffer R. Clinical cardiac tolerability of trastuzumab. J Clin Oncol (2004) 22:322–329.
12. Kaufman PA, Schwartz G, Dragnev K, et al. Phase I trial of Herceptin and Navelbine for patients with HER-2/neu (+) advanced breast cancer. In: Poster 431 presented at the 25th San Antonio Breast Cancer Symposium (2002) December. San Antonio, TX, USA. 11–14.
13. Chan A, Martin M, Untch M, et al. Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial. Br J Cancer (2006) 95:788–793.[CrossRef][ISI][Medline]
14. Burstein HJ, Harris LN, Marcom PK, et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol (2003) 21:2889–2895.
15. Bayo-Calero JL, Mayordomo-Cámara JI, Sánchez-Rovira P, et al. A multicenter study with trastuzumab and vinorelbine as first and 2nd line treatment in patients (pats) with Her2 positive metastatic breast cancer (MBC). Breast Cancer Res Treat (2004) 82(Suppl 1). (Abstr 5069).
16. Bernardo G, Palumbo R, Bernardo A, et al. Final results of phase II study of weekly trastuzumab and vinorelbine in chemonaive patients with HER2-overexpressing metastatic breast cancer. Proc Am Soc Clin Oncol (2004) 23:59. (Abstr 731).
17. Burstein HJ, Kuter I, Campos SM, et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol (2001) 19:2722–2730.
18. Jahanzeb M, Mortimer JE, Yunus F, et al. Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2+ metastatic breast cancer. Oncologist (2002) 7:410–417.
19. Papaldo P, Fabi A, Ferretti G, et al. A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease. Ann Oncol (2006) 17:630–636.
20. Lal A, Alidina A. Interim analysis of a phase II study of biochemotherapy in metastatic breast cancer (MBC). Eur J Cancer (2005) 3(Suppl):131. (Abstr 470).
21. de Wit M, Becker K, Thomssen C, et al. Vinorelbine and trastuzumab as first line therapy in patients with HER2-positive metastatic breast cancer — interim analysis of a prospective, open-label, multicentre phase II trial. Ann Oncol (2004) 15(Suppl 3):37. (Abstr 138P).
22. Franquesa RM, Centelles M, Villadiego K, et al. A multicenter study of trastuzumab (H) and vinorelbine (N) as first and second line therapy for patients (pts) with HER2-positive metastatic breast cancer (HER2+ MBC). J Clin Oncol (2005) 23:94s. (Abstr 868).
23. De Maio E, Pacilio C, Gravina A, et al. A single-centre phase 2 study of vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer. Ann Oncol (2004) 15(Suppl 3):37. (Abstr 139P).
24. Bartsch R, Wenzel C, Pluschnig U, et al. Oral vinorelbine alone or in combination with trastuzumab in advanced breast cancer: results from a pilot trial. Cancer Chemother Pharmacol (2005) 57:554–558.[CrossRef][ISI][Medline]
25. Burstein HJ, Keshaviah A, Baron A, et al. Trastuzumab and vinorelbine or taxane chemotherapy for HER2+ metastatic breast cancer: the TRAVIOTA study. J Clin Oncol (2006) 24:40s. (Abstr 650).[CrossRef]
26. Chan A, Tubiana N, Ganju V. Optimal tolerance of an all-oral combination chemotherapy (CT) of oral vinorelbine (NVBo), capecitabine (C) with/without trastuzumab (T) in metastatic breast cancer (MBC) patients (pts): safety results of two international multicenter studies. J Clin Oncol (Meeting Abstracts) (2006) 24:576s. (Abstr 10607) http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=40&abstractID=31846.
27. Baselga J. Herceptin® alone or in combination with chemotherapy in the treatment of HER2-positive metastatic breast cancer: pivotal trials. Oncology (2001) 61(Suppl 2):14–21.
28. Yardley DA, Greco FA, Porter LL, et al. First line treatment with weekly docetaxel, vinorelbine, and trastuzumab in HER2 overexpressing metastatic breast cancer (HER2+ MBC): a Minnie Pearl Cancer Research Network phase II trial. Proc Am Soc Clin Oncol (2004) 23:37. (Abstr 643).
29. Jahanzeb M, Brufsky A, Erban J, et al. Dose-dense neoadjuvant treatment of women with breast cancer utilizing docetaxel, vinorelbine and trastuzumab with growth factor support. J Clin Oncol (2005) 23:26s. (Abstr 591).
30. Joensuu H, Kellokumpu-Lehtinen P-L, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med (2006) 354:809–820.
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