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Abstract

The aim of this review is to examine the evidence available supporting the use of the docetaxel plus trastuzumab combination for patients with HER-2-positive metastatic breast cancer. The results of trials involving this combination are summarized, with an emphasis on efficacy and cardiotoxicity data. Finally, this article attempts to identify areas of uncertainty where new trials are warranted to improve our knowledge regarding optimal care for patients with HER-2-positive metastatic breast cancer.

Keywords

c-erbB-2 docetaxel HER-2 metastatic breast cancer trastuzumab

Breast cancer (BC) is the leading cause of cancer death for women in the world, with approximately half a million deaths per year worldwide. Approximately half of diagnosed patients will eventually develop metastatic disease. Treatment for metastatic breast cancer (MBC) is palliative, and median life expectancy after recurrence is between 24 and 30 months or less [101,102].

Evidence exists showing that BC is a heterogeneous disease. This has been known for sometime, since the discovery that some breast tumors expressed estrogen and progesterone receptors and others did not. Later, a new difference was noted: up to 30% of BC tumors overexpress the HER-2 receptor. The HER-2 or c-erbB-2 protooncogene, located in chromosome 17q, encodes a transmembrane tyrosine kinase receptor that belongs to the EGFR family. This family includes four receptors (HER-1, −2, −3 and −4) that are active in a dimeric form, in either homoor heterodimers. The overexpression of this receptor leads to the activation of molecular pathways causing uncontrolled proliferation, which is responsible for the poor prognosis of patients diagnosed with this kind of tumor. This characteristic is related to more aggressive tumor behavior than is the case with non-HER2-overexpressing counterparts [1].

There are several chemotherapeutic agents that can be used for BC treatment, and taxanes are among the most effective drugs against BC. Since the first published reports more than 10 years ago, paclitaxel and docetaxel have been extensively used for MBC treatment, and later were also incorporated in the adjuvant therapy for early BC. While paclitaxel was the first taxane to be used, docetaxel gained its place in the treatment of MBC. Based on noncomparative clinical trial data, there was an assumption of superiority of docetaxel over paclitaxel in the metastatic setting, and finally a Phase III trial performing a direct comparison between both taxanes confirmed this hypothesis. Docetaxel was statistically superior to paclitaxel in both overall survival (OS) and time to progression (TTP), and also provided a higher response rate (RR) [2]. Docetaxel is currently approved by the US FDA as the first-line treatment for metastatic disease in tumors resistant to anthracyclines and also in the adjuvant setting in combination with anthracyclines.

In the last decade there has been intensive research trying to improve the results obtained with classical cytotoxic drugs. As a result, a group of new drugs called targeted agents started to be tested in trials. These drugs target a specific pathway in the growth and development of a tumor. By interfering with these important targets, the drug therapy helps to fight the tumor itself. The targets themselves are typically various molecules (or small particles) that are known or suspected to play a role in cancer development. The goals of these therapies are, by hitting pathways exclusive to cancer cells, to be more effective and more specific, with fewer side effects, than standard chemotherapy. This has yet to be proven, as targeted therapies are associated with specific forms of toxicity, and so far many of these drugs do not show important response rates when they are used as single agents. However, we are obtaining increasing evidence of their synergistic effect when combined with chemotherapy agents.

A recombinant humanized monoclonal antibody directed against the HER-2 receptor, trastuzumab (Herceptin®, Hoffmann–La Roche, Basel, Switzerland) was developed in the early 1990s. The firsts report of its activity on MBC showed RR of 11 and 15% in pretreated patients with HER-2-positive MBC (and 35% in a trial using trastuzumab single agent as first-line therapy [3], and since then this drug has earned an important place in the management of HER-2-positive disease [4,5]. After these results were made public, a number of important Phase II studies and some Phase III trials investigating the efficacy of different chemotherapy agents in combination with trastuzumab for MBC were published.

There is preclinical evidence that trastuzumab has synergistic properties when combined with various cytotoxic drugs [6]. The first report of a randomized trial studying the impact of the addition of trastuzumab to chemotherapy involved doxorubicin or paclitaxel [7]. The results of this pivotal trial provided two very important conclusions:

Combination of trastuzumab plus doxorubicin was not feasible owing to the unacceptable rate of cardiac toxicity;

Addition of trastuzumab to paclitaxel resulted in a statistically significantly larger RR and TTP, without adding significant toxicity to the one already present with paclitaxel alone. Cardiac toxicity in this arm was within acceptable figures. Therefore, this combination was authorized as first-line therapy for patients with HER-2-positive MBC.

Subsequently, trastuzumab was studied in combination with several other chemotherapy drugs, including docetaxel. There are several reports on trastuzumab combination with either taxanes, but this review will focus on the trastuzumab plus docetaxel combination reports.

Trastuzumab is not only approved for use in the metastatic setting. Different large adjuvant trials reported that the addition of trastuzumab single agent after or concurrently with adjuvant chemotherapy resulted in disease-free survival (DFS) and OS benefits for patients in primary treatment for HER-2-positive early BC [8 –11]. This led to the registration of trastuzumab for adjuvant treatment of breast cancer and the change of standard treatment for patients with HER-2-positive early BC.

Definition of HER-2 positive disease

Correct diagnosis of the HER-2 status of a tumor is of paramount importance for defining a correct treatment. Currently, the guidelines agree that a tumor can be considered as HER-2 positive when the cells’ HER-2 receptor overexpression measured with immuno-histochemistry is 3+, meaning that the receptor is highly overexpressed. Those cases where the result is 0 or 1+ (little or no overexpression) are considered as negative, and those with an intermediate result (2+) are considered as undetermined, and in these cases another test, fluorescent in situ hybridization, should be performed to determine the HER-2 status, and this will be reported as either negative or positive based on the amplification of the gene coding for the HER-2 receptor. This testing algorithm is viewed by many as an acceptable, cost-effective approach [12].

Trastuzumab schedule

Almost all published trials of trastuzumab have used a weekly schedule, starting with a loading dose of 4 mg/kg followed by 2 mg/kg. New evidence suggesting that this drug may have a longer half-life than originally supposed [13] led to the question of whether a more convenient 3-weekly schedule was as effective as the weekly one.

The combination of trastuzumab and paclitaxel, with both drugs administered to 32 patients according to a 3-weekly schedule, was published in 2003 [14]. Trastuzumab was administered with a loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg. No unexpected toxicities were noted, there was no worsening of the cardiac toxicity rate, the combination was well tolerated and the RR was 59% with a median TTP of 12 months. A pharmacokinetics sub-study showed that there were no major differences between the data obtained from trials with either weekly or 3-weekly schedules.

Docetaxel plus trastuzumab for the management of advanced disease

A summary of the results from single-arm Phase II trials using the trastuzumab plus docetaxel combination is presented in Table 1 . Docetaxel has been used at different doses, both in a 3-weekly schedule and on a weekly basis. While it has been shown that trastuzumab can be safe and effectively used every 3 weeks [14], all these trials used the usual trastuzumab weekly administration schedule.

Table 1.

Studies evaluating the trastuzumab plus docetaxel combination in metastatic breast cancer.

Study	Docetaxel schedule	Patients (n)	Response rate (%)	Ref.
Kuzur et al. (2000)	75 mg/m² every 3 weeks	16	44	[20]
Meden et al. (2001)	35 mg/m² once a week	12	50	[21]
Raab et al. (2002)	100 mg/m² every 3 weeks or 35 mg/m² once a week	25	63	[22]
Esteva et al. (2002)	35 mg/m² once a week (three every 4 weeks)	30	63	[23]
Bauer-Kosinska et al. (2003)	100 mg/m² every 3 weeks	18	55	[24]
Raff et al. (2004)	33 mg/m² once a week	17	59	[25]
Takao et al. (2004)	40 mg/m² once a week	35	62	[26]
Montemurro et al. (2004)	75 mg/m² every 3 weeks	23	67	[27]
Julka et al. (2004)	100 mg/m² every 3 weeks	16	75	[28]
Tedesco et al. (2004)	35 mg/m² once a week	26	50	[29]
Sato et al. (2006)	70 mg/m² every 3 weeks	40	65	[30]
Wardley et al. (2006)	100 mg/m² every 3 weeks	110	73	[19]
Pienkowski et al. (2006)	100 mg/m² every 3 weeks	131	73	[16]

As it can be seen, some of these trials reported high RR. This is also the case for the results obtained when combining trastuzumab with other chemotherapeutic drugs. The combinations of trastuzumab with taxanes are the most well known, but there is no evidence of which trastuzumab plus chemotherapy combination is the most effective for MBC treatment. In addition, even if docetaxel was shown to be superior to paclitaxel for MBC treatment, it should be remembered that so far a comparison between paclitaxel plus trastuzumab against docetaxel plus trastuzumab has not been performed.

Docetaxel plus trastuzumab in two randomized trials

Docetaxel was tested in a randomized Phase II trial as either a single agent or in combination with trastuzumab as a first-line therapy in 186 patients [15]. The authors decided to perform a formal comparison between arms, and found a statistically significant difference for RR, TTP and OS favoring the combination arm, without a significant worsening of the docetaxel toxicity. This trial gave definitive proof that the docetaxel plus trastuzumab is effective for HER-2-positive MBC, and its toxicity is manageable. The results of this trial are presented in Table 2 .

Table 2.

Efficacy results of the Phase II trials using docetaxel and trastuzumab plus docetaxel for HER-2-positive metastatic breast cancer.

	RR (%)	Time to progression median (months)	Overall survival median (months)
Docetaxel	34	5.7	22.7
Docetaxel + trastuzumab	61	11.7	31.2

RR: Response rate.

Data from [15].

A Breast Cancer International Research Group (BCIRG) Phase III trial compared docetaxel 100 mg/m² plus trastuzumab (weekly during CT, then 3-weekly) with docetaxel 75 mg/m² plus trastuzumab (weekly during chemotherapy, then 3-weekly) plus carboplatin AUC 6. This BCIRG trial did not show any benefit for the addition of carboplatin to the combination docetaxel plus trastuzumab in either RR, TTP or OS. Results are summarized in Table 3 . Regarding safety, both regimens had a reasonable toxicity but with a different profile. While docetaxel plus trastuzumab was associated with more episodes of neuropathy, myalgia, skin and nail changes and neutropenic infections, docetaxel plus carboplatin plustrastuzumab was associated with more episodes of thrombocytopenia, nausea and vomiting [16]. The efficacy results were somehow disappointing, since it was expected that carboplatin could have a synergistic activity on the docetaxel-trastuzumab combination and therefore improve clinical outcome. The lower docetaxel dose used in the carboplatin arm (difference considered as necessary for toxicity concerns) may have had a role in the lack of difference.

Table 3.

Results of a Phase III trial comparing docetaxel plus trastuzumab with docetaxel plus trastuzumab plus carboplatin.

	RR (%)	Duration of response median (months)
Trastuzumab + docetaxel	73	10.7
Trastuzumab + docetaxel + carboplatin	73	9.4

RR: Reponse rate.

Data from [16].

The results of this trial might be of relevance when considering that this triple combination has been used in one of the trastuzumab adjuvant trials. After seeing this result in the metastatic setting, one may raise the question regarding the exact role of carboplatin in this combination. Taking into account the results of the positive trial, which reported a benefit of the addition of carboplatin to a paclitaxel plus trastuzumab combination (with statistically significant improvements in RR and TTP) [17], it is clear that this is an area that warrants future research.

Docetaxel plus trastuzumab toxicity

Regarding the docetaxel plus trastuzumab combination safety information, frequently reported adverse events in these trials include neutropenia and febrile neutropenia and anemia, which are hematological toxicities that are well known for docetaxel, where the addition of trastuzumab can lead to larger occurrence rates, but within manageable limits. Nonhematological toxicities that have been described to occur frequently are diarrhea, fatigue, nausea and vomiting, neuropathy, dyspepsia, pruritus, nail changes, mood alterations, thrombosis and hyperglycemia. In all these reports, toxicity was manageable and stayed within reasonable occurrence rates.

In summary, as a consequence of the docetaxel plus trastuzumab combination trials results (while there has been one trial reporting that the addition of trastuzumab to chemotherapy derived in a benefit of OS, most of the available evidence comes from single-arm Phase II trials), this treatment has been accepted by the European Medicines Agency for the treatment of MBC and the FDA is evaluating to approve it also.

Docetaxel plus trastuzumab cardiotoxicity

The most important adverse effect of trastuzumab is cardiac toxicity, more precisely in the form of a congestive heart failure due to a decrease in the left ventricular ejection fraction (LVEF). The exact mechanism for trastuzumab-related cardiac damage is still not known. The risk of developing cardiac heart failure with the use of trastuzumab rises with an existing large cumulative dose of doxorubicin and advanced age, but it does not seem to be linked with trastuzumab cumulative dose.

Symptomatic cardiac failure developing under trastuzumab usually responds favorably to standard medical treatment. Patients with asymptomatic LVEF drops can recover their cardiac function by simply withdrawing from trastuzumab treatment. Some of the patients may even be able to resume trastuzumab treatment when monitored closely [18].

To perform a joint analysis of the cardiotoxicity of all docetaxel plus trastuzumab trials is complicated by the fact that these trials frequently used different definitions of cardiac end points. The cardiac safety results obtained in the trials evaluating docetaxel plus trastuzumab in at least 100 patients are summarized here: in one of the trials, 17% of the patients receiving this combination had a drop of the LVEF of 15 points or more, and two patients developed symptomatic heart failure. One of these patients died weeks after this diagnosis, and the trastuzumab-related cardiotoxicity could not be ruled out as a possible cause of death [15]. Other trials reported one patient experiencing symptomatic heart failure and 5% of patients had a drop of more than 15 points and below of the lower normal limit for the LVEF [16]. A third trial reported that 13% of patients had a drop of the LVEF of 15 points or more, that 2% of patients got a drop below 40% and that 1% of the patients developed symptomatic heart failure [19].

It is clear that cardiac function needs to be closely monitored in patients under trastuzumab treatment, regardless of whether they are treated with trastuzumab single agent or in combination with CT. Guidelines for the management and follow-up of these patients have been proposed elsewhere [18].

Conclusion

Trastuzumab use is standard treatment for patients with HER-2-positive BC, and it has been authorized both for the metastatic and adjuvant setting. While it is still not known which is the best trastuzumab plus chemotherapy combination, its combination with docetaxel, owing to its response rates and its manageable toxicity, is a reasonable option. However economic considerations have hindered the adoption of trastuzmab plus chemotherapy combinations in several countries due to the higher costs associated with trastuzamab.

Future perspective

There are some unanswered questions regarding the use of trastuzumab in addition to chemotherapy for patients with MBC. Ongoing and future trials should answer at least some of the following questions:

Which is the best trastuzumab plus chemotherapy combination?

Is there enough evidence backing the use of trastuzumab after progression of disease after treatment with a trastuzumab plus chemotherapy combination?

What will be the role of trastuzumab in the metastatic setting in patients treated with adjuvant trastuzumab who develop metastases?

What is the minimal disease-free interval that should be considered?

What would be the optimal drug combinations?

Is there any schedule of administration that is better than the other (weekly vs 3-weekly, question applicable to both docetaxel and trastuzumab)?

How can we identify those patients who are likely to be resistant to a trastuzumab plus chemotherapy combination?

Trastuzumab is a perfect example of drugs that can provide clinical benefit to patients, but at a financial cost that makes it nonavailable in many countries. The issue of cost related to new anticancer therapies needs to be addressed.

Executive summary

Trastuzumab plus chemotherapy is standard treatment for patients diagnosed with a HER-2-positive tumor who develop distant metastases and need chemotherapy.

There is no evidence regarding which chemotherapy plus trastuzumab combination is most effective and safe.

The largest amount of data exists for combinations involving either trastuzumab with either docetaxel or paclitaxel. While docetaxel has proven to be superior to paclitaxel for metastatic breast cancer treatment, a head-to-head comparison of these two combinations is yet to be conducted.

The docetaxel plus trastuzumab combination has been shown to be effective and safe for use in the metastatic setting. The cardiac toxicity encountered with this combination is within acceptable limits.

The exact role of the addition of carboplatin to the docetaxel plus trastuzumab combination remains unclear with the available evidence to date.

Footnotes

The authors have no relevant financial interests including employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties related to this manuscript.

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Docetaxel Plus Trastuzumab as Treatment for Her-2 Positive Metastatic Breast Cancer: Review of the Existing Evidence

Abstract

Keywords

Definition of HER-2 positive disease

Trastuzumab schedule

Docetaxel plus trastuzumab for the management of advanced disease

Docetaxel plus trastuzumab in two randomized trials

Docetaxel plus trastuzumab toxicity

Docetaxel plus trastuzumab cardiotoxicity

Conclusion

Future perspective

Footnotes

References