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  Volume 96
Numero 3
maggio-giugno 2010 		I documenti sono in formato PDF, consultabili utilizzando Acrobat Reader
 
Use of trastuzumab in HER2-positive metastatic breast cancer beyond disease progression: a systematic review of published studies

Alice Mannocci, Emma De Feo, Chiara de Waure, Maria Lucia Specchia, Maria Rosaria Gualano, Carlo Barone, Walter Ricciardi, Giuseppe La Torre
1HTA Public Health Unit, Institute of Hygiene, and 2Clinical Oncology Unit, Institute of Internal Medicine, Catholic University of the Sacred Heart, Rome; 3Clinical Medicine and Public Health Unit, Sapienza University of Rome, Italy

Key words: beyond progression, Herceptin, metastatic breast cancer, trastuzumab.

abstract

Aims and background. Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ErbB, has determined clinical benefit for women affected by metastatic or early stage HER2-positive breast cancer and never previously treated with trastuzumab. Trastuzumab is generally used as first-line treatment of HER2+ metastatic breast cancer and is currently administered beyond progression even without clear evidence supporting such clinical practice. In fact, HER2-positive metastatic breast cancer has a high risk of progressing after first-line therapy, and second-line treatments vary. The aim of the study was to investigate by a systematic review the efficacy of trastuzumab-based treatments beyond progression in HER2-positive metastatic breast cancer.
Materials and methods. We performed a systematic review using Medline, Embase and Cochrane Library data bases and publications in principal meetings or congresses of oncology in Europe and America until September 2008. The main selection criterium was the reporting of time to progression, calculated from the start of each trastuzumab-based therapy to the date of progressive disease or death.
Results. Twelve studies were selected that included a total of 516 patients. The weighted mean time to progression was 23.66 weeks (standard deviation, 4.37) and the median was 26 weeks (range, 13-39). Interestingly, combined trastuzumab plus vinorelbine treatment showed a lower mean and median time to progression (20.59 and 19.57 weeks, respectively), whereas trastuzumab plus capecitabine yielded a mean time to progression of 30.33 weeks.
Conclusions.The added value of the present study has been to provide a quantitative summary measure of time to progression which can be used for comparisons between current and future available regimens. Free full text available at www.tumorionline.it

Introduction
Breast cancer represents a huge public health problem, as it is the first diagnosed cancer in women of all ages in Italy and worldwide1,2. It is also the primary cause of cancer mortality in women worldwide1. The prognosis, as well as treatment success, is influenced by different factors including cancer size and stage, histologic type, age and also genetic and biological markers3,4. Both growth factor receptors ErbB1 and ErbB2 (also known as HER-1 and HER-2/neu) have been shown to be overexpressed in approximately 20-30% of primary breast cancers5-7. In such cases, cancer prognosis is very poor since the ErbB family activates tyrosine kinase-mediated intracellular signals, which promote cell proliferation8. Patients with HER2-positive (HER2+) breast cancer are at high risk of progression and death6,9. HER2+ breast cancers are very difficult to treat and manage because of the high incidence of metastasis to bone, brain and liver10. In fact, they are often diagnosed in stage IV as advanced, not amenable to cure.
The development of new treatment options has expanded the possibility of cure in advanced breast cancer. The National Institute of Clinical Excellence, in 2001, recommended the use of taxanes, docetaxel and paclitaxel to treat patients with advanced breast cancer for whom chemotherapy with anthracyclines was no longer appropriate11, and, in 2002, recommended the use of trastuzumab either in combination or in monotherapy, according to previous treatment options, for women with HER2+ advanced breast cancer9.
Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ErbB2, produces a clear clinical advantage in women affected by metastatic or early stage HER2 over-expressing breast cancers who have never received trastuzumab before12-14. Trastuzumab is approved as first-line treatment of HER2+ metastatic breast cancer (MBC), but currently is also administered beyond progression without clear evidence supporting this clinical practice. In fact, HER2+ MBC has a high risk, about 84%5, of progressing after the first-line therapy, but the outcome of second-line treatments is very different.
In this context, new drugs like lapatinib, an oral, selective, reversible tyrosine kinase inhibitor of both ErbB1 and ErbB2 signaling pathways, is considered a promising alternative to trastuzumab continuation beyond progression. Given the lack of prospective randomized data facing this issue, a systematic review of studies about the use of trastuzumab alone or in combination with other drugs was performed to evaluate the efficacy of trastuzumab-based treatments beyond progression in HER2+ MBC.

Material and methods
Identification of studies
The identification of studies on women affected by HER2+ MBC who continued to receive trastuzumab beyond disease progression was carried out through a search of Medline, Embase and Cochrane Library data bases up to October 2008 using the following terms: trastuzumab or Herceptin and MBC or MBC and beyond progression. Search strategies are reported in Appendices 1 and 2.
Additional studies were identified by the hand searching of references of the original studies and among abstracts or posters presented in the period from January 2007 to October 2008 in the following meetings: American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), European Cancer Organization (ECCO), San Gallen, Sanantonio, National Cancer Institute European Organization for Research (NCI/EORTC), and the Associazione Italiana di Oncologia Medica (AIOM). The search was restricted to papers written in English and French.
Eligible studies were those which fulfilled the following inclusion criteria. 1) Randomized clinical trials (RCT) or observational studies evaluating the efficacy of continuing trastuzumab in women affected by HER2+ MBC, previously treated with trastuzumab-based therapies (trastuzumab either alone or in combination with chemo- and/or hormone therapy) in the presence of clinical evidence of disease progression. 2) Reporting estimates of clinical outcome, in particular of the time to progression (TTP), calculated from the start of each second-line trastuzumab-based therapy to the date of objective evidence of progressive disease or death. Letters and case reports were thus excluded from the systematic review. When more than one article was published by the same author using the same cases series, the largest study was selected.

Data extraction
Two investigators independently extracted data from each article using a structured sheet and entered them into an Excel data base. The following items were considered: year and design of the study, sample size, median TTP in weeks (given that one year is made up of 52 weeks) for each trastuzumab-based regimen where possible, and details on administered drugs.

Statistical analysis
The weighted median, mean, standard deviation (SD) and standard error (SE) of median TTP were computed. In order to evaluate the year of publication as a potential predictive variable of TTP estimate, a bivariate analysis was performed using Spearman’s coefficient (r). Moreover, a multivariate analysis was performed to estimate the relationship between TTP, year of publication and sample size. The goodness of fit was evaluated using the R2 coefficient. In order to carry out a sensitivity analysis, a subgroup analysis was performed according to trastuzumab-based regimens (selecting those with trastuzumab plus vinorelbine or trastuzumab plus capecitabine) and sample size greater than or equal to 25 and 30. The statistical significance level was set at P <0.05. Analyses were carried out using the software SPSS version 12.00 for Windows.

Results
Of the 194 articles retrieved, 44 were eligible after abstract selection (Figure 1)15.






After reading full texts, only 16 studies16-31 were finally considered eligible for our systematic review (Table 1). Among these, only one study, von Minckwitz et al.28, was an RCT, published in April 2009 (previously presented as a poster in 2008 ASCO Annual Meeting)29, so it was not included in the same evaluation performed for observational studies, in order to maintain the homogeneity of study design. Owing to data overlap between the previous studies, 3 of them were excluded from the final analysis30-32 (legend, Table 1).
In the only RCT, median TTP was 8.2 months (34 weeks) in the experimental arm (trastuzumab + capecitabine) compared to 5.6 months (24 weeks) in the control arm (capecitabine alone). Further analysis was not possible due to the lack of other RCT28.
Concerning nonrandomized studies, overall 12 observational studies were considered16-27, comprising a total of 516 patients affected by HER2+ MBC. The weighted mean TTP was 23.66 weeks (SD = 4.37; SE = 1.17) and the median, 26 weeks (range, 13-39) (Table 2).

Table 2 - Descriptive data of the selected studies (16-27). Pooled measures weighted by the number of observations

Authors (year)

Treatment°

No.

% weight

Median TTP

Range (weeks)

95% CI

 

 

 

on total

(weeks)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Min

Max

Low

High

 

 

 

 

 

 

 

 

 

Adamo et al.21 (2007)

H + V/TXN/DOX/G

26

 4.13

39.00

13.00

 99.67

NR

NR

Bartsch et al.20 (2006)

H + V/X/G/D

54

 8.57

26.00

 4.33

104.00

NR

NR

Bartsch et al.22 (2007)

H + X

21

 3.33

30.33

 8.67

 91.00

12.96

47.71

Bartsch et al.24 (2008)

H + G

 9

 1.43

26.00

 4.33

 30.33

21.23

30.77

Cancello et al.25 (2008)

H + A/TXN

55

 8.73

22.75

 5.42

148.20

NR

NR

Fabi et al.26 (2008)

H + V/TXN/X/CTX/G/ CBDCA

37

 5.87

29.03

NR

NR

16.90

40.73

Fountzilas et al.16 (2003)

H + V/G

80

12.70

22.53

 2.17

  7.37

NR

NR

Garcia-Sáenz et al.19 (2005)

H + TXN/V

31

 4.92

13.00

 4.33

 95.33

NR

NR

Gelmon et al.18 (2004)

H + V

33

 5.24

26.00

 3.00

108.00

NR

NR

Gelmon et al.18 (2004)

H + P

20

 3.17

24.00

 3.00

 72.00

NR

NR

Gelmon et al.18 (2004)

H

10

 1.59

30.50

18.00

 68.00

NR

NR

Montemurro et al.23 (2007)*

H + V/TXN/DOX/X

83

13.17

36.40

NR

NR

NR

NR

Suzuki et al.17 (2003)

H + V

24

 3.81

13.14

 5.14

 32.14

NR

NR

Tokajuk et al.27 (2008)*

H

33

 5.24

19.93

 0.00

190.67

NR

NR

Total

516

 

 

 

 

 

 

 

Median TTP (wks)

26

 

 

 

 

 

 

 

Minimum TTP (wks)

13.00

 

 

 

 

 

 

 

Maximum TTP (wks)

39.00

 

 

 

 

 

 

 

Weighted mean (wks)

23.66

 

 

 

 

 

 

 

Weighted SD (wks)

4.37

 

 

 

 

 

 

 

Weighted SE (wks)

1.17

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CBDCA, carboplatin; CI, cisplatin; CT, chemotherapy; CTX, cyclophosphamide; D, docetaxel; DOX, doxorubicin; G, gemcitabine; H, Herceptin, trastuzumab; P, paclitaxel; TXN, taxane; V, vinorelbine; X, capecitabine; NR, not reported.

° / = or, + = and.

*Congress abstract.





Figure 2 shows that there was a positive but not significant correlation between TTP and publication year, with a Spearman’s coefficient of r = 0.246 (P = 0.397). The correlation between TTP and sample size was negative and not significant, r = -0.075 (P = 0.798). Multivariate analysis did not show a significant association between TTP and publication year (β = 1.43; P =0.202) or sample size (β = 0.034; P = 0.712). The goodness of fit for the model was summarized by the coefficient R2 = 0.153 (Table 3).

Table 3 - Multivariate linear regression

Covariates

Coeff.

P

95% CI

 

 

 

 

Publication year

1.434

0.202

-0.892; 3.760

Sample size

0.034

0.712

-0.162; 0.230

 

 

R2 = 0.153

 

Table 4 - Sensitivity analysis according to sample size and treatment combination

 

Pooled

N ≥25

N ≥30

H + V

 

 

 

 

 

Number of studies*

14

9

8

2

Number of patients

516

432

406

57

Median TTP (weeks)

26.00

26.00

24.38

19.57

Minimum TTP

13.00

13.00

13.00

3.00

Maximum TTP

39.00

39.00

36.40

28.00

Weighted mean TTP

23.66

23.69

22.71

20.59

Weighted SD

4.37

7.27

7.44

40.30

Weighted SE

1.17

2.42

2.63

28.49

 

 

 

 

 

*Observations represent the number of selected studies stratified by treatment.

N, sample size; H, Herceptin, trastuzumab; V, vinorelbine.


The subgroup analyses for observational studies are reported in Table 4. There were 9 studies with a sample size ≥25 and 8 with ≥30. The combination trastuzumab + vinorelbine was evaluated in two studies, whereas only Bartsch et al.22 investigated the combination trastu­zumab + capecitabine. After grouping for sample size, it resulted that the mean and the median values of TTP of the group with sample size ≥25 were similar to the pooled ones; in the group with sample size ≥30 a slight decrease in mean and median was observed. However, the trastuzumab + vinorelbine combination on aggregate showed a weighted mean TTP of 20.59 weeks, which was lower than the mean and median TTP reported by Bartsch et al.22, who investigated trastu­zumab + capecitabine combination therapy (mean, 30.33 weeks, Table 2).

Discussion
The current clinical practice of continuing trastuzumab beyond disease progression in women with HER2+ MBC is still debated due to a substantial lack of scientific evidence since randomized studies adequately powered have not been completed. In addition, this therapeutic strategy deviates from a well-established paradigm of stopping and switching drugs or interventions when disease progression becomes clinically evident. The safety and feasibility of continuing trastuzumab beyond progression have been mostly evaluated by retrospectively collecting medical records of patients who stopped or continued trastuzumab 16-28.
The same critical question has been recently addressed by von Minckwitz et al.28,29, who randomly assigned HER2+ MBC patients progressing during previous treatment with trastuzumab to receive either capecitabine alone or with trastuzumab. A significant improvement in overall response and TTP with the capecitabine + trastuzumab regimen was observed, even though a statistically significant impact on survival could not be demonstrated. According to Jahanzeb33, however, the results of that clinical trial should be interpreted with caution, because the trial was prematurely interrupted due to slow accrual when less than 200 patients had been accrued in 45 months, far less than the intended 482, resulting in a very low or valueless statistical power.
Another reason for closing the trial was the availability of lapatinib + capecitabine data indicating that the same authors were not very confident about data until then obtained. In fact, they observed that their results could not be easily compared with those of the lapatinib trial34. A trial in which patients are randomly assigned to capecitabine + trastuzumab or lapatinib + capecitabine would better address the objective of directly comparing these combination regimens. To date, only preliminary results of a randomized study35 of lapatinib alone or in combination versus trastuzumab in HER2+ MBC patients progressing on T-based therapy have been reported. The study showed the superiority of the doublet (progression-free survival, 12 vs 8.1 weeks, P = 0.008), demonstrating for the first time the synergy of lapatinib + trastuzumab in a phase III setting and improved clinical outcome without a substantial change in the side effect profile.
In the present study, a systematic review was carried out in order to answer the critical question about effectiveness of continuing trastuzumab therapy beyond progression. Firstly, we searched for phase III trials aiming to provide summary estimates of clinical outcomes (overall survival, TTP, response rate) by means of meta-analysis. However, we found only the aforementioned study of von Minckwitz et al.28,29, so data pooling was not statistically possible. Therefore, according to the fact that most data come from observational studies, we systematically reviewed 12 available studies, obtaining a weighted mean TTP of 23.66 weeks (SD = 4.37; SE = 1.17). No significant differences resulted in the analysis of subgroups obtained by stratifying the eligible studies according to sample size (≥25 and ≥30 patients) or type of trastuzumab-containing combination therapy (capecitabine or vinorelbine). Interestingly, in the study of Bartsch et al.22 concerning the combination trastu­zumab + capecitabine, median TTP was higher than the weighted pooled estimated mean TTP (30.33 vs 23.66 weeks).
The absolute value of the present review is limited by the characteristics of the study sample, including small and heterogeneous series of mainly observational and retrospective investigations. This introduces a bias in our evaluation derived from the design of studies used in the analysis and decreases the strength of our data. However, we can conclude that trastuzumab-based regimens might have activity in HER2+ MBC beyond progression, but only well-designed phase III studies will possibly identify patients who will progress after trastuzumab by keeping in mind other drugs potentially targeting the same biological pathway. In this context, a multidisciplinary approach aimed at evaluating the different aspects of the treatment choice in HER2+ MBC could be useful to bridge current gaps 36.

Appendix 1
Search Algorithm (RCT OR randomised clinical trial OR randomized clinical trial) AND (herceptin OR trastuzumab OR "her-2 overexpression") AND (advanced breast cancer OR breast cancer OR metastases).

Appendix 2
Search Algorithm (trastuzumab OR Herceptin) AND (disease progression OR beyond progression) AND metastatic breast cancer.

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