Originally published as JCO Early Release 10.1200/JCO.2007.11.9776 on August 6 2007

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Capecitabine and Trastuzumab in Heavily Pretreated Metastatic Breast Cancer

Rupert Bartsch, Catharina Wenzel, Gabriela Altorjai, Ursula Pluschnig, Margaretha Rudas, Robert M. Mader, Michael Gnant, Christoph C. Zielinski, Guenther G. Steger

From the First Department of Medicine and Cancer Centre, Clinical Division of Oncology; Department of Pathology, Department of Surgery, Medical University of Vienna, Vienna, Austria

Address reprint requests to Guenther G. Steger, MD, First Department of Medicine and Cancer Centre, Clinical Division of Oncology, Medical University of Vienna, Waehringer Guer A-1090 Vienna, Austria; e-mail: guenther.steger{at}meduniwien.ac.at

	ABSTRACT

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Purpose In human epidermal growth factor 2 (HER-2)–positive advanced breast cancer, taxanes or vinorelbine plus trastuzumab are among the most widely applied options in the first-line setting. We evaluated the efficacy and tolerability of capecitabine plus trastuzumab after anthracycline and docetaxel or vinorelbine failure and prior trastuzumab exposure.

Patients and Methods Forty consecutive patients were included. Capecitabine was administered at a dose of 1,250 mg/m² bid for 14 consecutive days in 3-week cycles, with dose modifications if necessary. Trastuzumab was administered every 3 weeks. Time to progression (TTP) was defined as primary end point. Response was evaluated every 3 months using International Union Against Cancer criteria.

Results TTP was a median of 8 months, and overall survival was 24 months. No significant difference was found for second-line and beyond second-line treatment. A complete response (CR) was observed in 2.5%, partial response (PR) in 17.5%, stable disease lasting at least 6 months (SD) in 50%, resulting in a clinical benefit rate (CR + PR + SD 6 months) of 70%. Diarrhea (5%) and hand-foot syndrome (15%) were the only treatment-related adverse events that occurred with grade 3 or 4 intensity. Three patients (7.5%) developed brain metastases while receiving therapy.

Conclusion Capecitabine plus trastuzumab appears to be an effective and safe option in a heavily pretreated population. Therefore, a direct comparison of this regimen with capecitabine monotherapy in this setting is warranted.

	INTRODUCTION

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Because of screening and recent advances in treatment, mortality in early breast cancer has declined in the last decade. Still, even in stage I and II disease, approximately one third of patients are expected to develop disease recurrence.¹ Although metastatic breast cancer remains an incurable disease, a wide range of treatment options is available, and many further substances are currently evaluated in the clinical and preclinical setting. The decision to choose a certain therapy is usually based on tumor biology, symptoms, metastatic pattern, time to disease recurrence, and patient desire.²

In human epidermal growth factor 2 (HER-2)–positive advanced breast cancer, which is known to be associated with high recurrence rate and poor outcome,^3-6 the use of trastuzumab is firmly established. Trastuzumab is a monoclonal humanized antibody, targeting the extracellular domain of HER-2. Via different mechanisms, trastuzumab inhibits HER-2 receptor signaling and causes cell degradation. The mechanisms identified comprise inhibition of cleavage of the extracellular domain, internalization and degradation of the HER-2 receptor protein, decrease of cyclin-dependent kinase 2 activity via p27 induction, inhibition of DNA repair, and antibody-dependent cellular cytotoxicity.^7,8

Data recommend early use of the antibody in the metastatic setting (ie, from first line).^9,10 Still, concerning treatment continuation after the failure of one trastuzumab-based therapy line, no definitely reliable evidence exists. Different groups reported potential activity of trastuzumab in combination with chemotherapy beyond progression, with response rates (RRs) ranging from 11.8% to 25.9%.^11-13

Capecitabine (N⁴-pentyloxycarbonyl-5'deoxy-5-fluorocytidine) is an orally administered prodrug of fluorouracil (FU). Activation depends mainly on the expression of thymidine phosphorylase, an enzyme with increased expression in tumor tissue.¹⁴ Since its introduction, it has evolved as valuable treatment option in advanced breast cancer. Its role is especially highlighted by the fact that anthracyclines and taxanes are now commonly used in the adjuvant setting, thereby reducing the number of effective first-line therapy options.

Paclitaxel plus trastuzumab was the first combination regimen established.¹⁰ Whereas in vitro studies were able to demonstrate additive antitumor effects of this combination, combination with docetaxel and other substances (eg, vinorelbine, platinum derivatives) showed a synergistic effect.¹⁵ The same preclinical trial suggested a less than additive effect of trastuzumab and FU; this effect was also postulated for capecitabine. Therefore, this combination was not commonly used in early treatment lines, and clinical data are relatively scarce.

In this prospective analysis, we report our experiences with capecitabine and trastuzumab combination as salvage therapy in heavily pretreated patients with metastatic breast cancer after earlier trastuzumab exposure.

	PATIENTS AND METHODS

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All data were collected at the First Department of Medicine and Cancer Centre, Clinical Division of Oncology, at the Medical University of Vienna, Vienna, Austria. All consecutive patients with metastatic breast cancer were included as eligible for trastuzumab plus capecitabine treatment. Treatment was performed in accordance with the ethical regulations of the Medical University of Vienna.

Patients
Overall, 40 consecutive patients were included from March 2004 to September 2006, and followed prospectively; all are currently assessable for toxicity and response. Data were analyzed as of March 2007. All patients were diagnosed with histologically confirmed advanced breast cancer. Criteria for inclusion were as follows: presence of at least one measurable lesion, Karnofsky performance score of at least 70, life expectancy of more than 3 months, adequate hematologic parameters as defined by WBC count of at least 3,500/µL, platelet count of at least 100,000/µL, hemoglobin levels more than 9 g/dL, and adequate hepatic (serum bilirubin < 2.0 mg/dL) and renal (serum creatinine < 1.5 mg/dL) functions. For staging evaluations, computed tomography (CT) scans of the chest and the abdomen, mammography, echocardiography, and gynecologic examination were mandatory. Patients with controlled metastatic disease to the brain (after whole-brain radiotherapy [WBRT], neurosurgical resection, and/or stereotactic radiosurgery of one to three metastases) were also eligible. In those individuals, a magnetic resonance imaging scan was performed 1 and 3 months after WBRT. If cerebral metastases were stable at the second time point, enrolment onto the trial was possible. Patients were required to have had prior adjuvant or palliative anthracycline and taxane or vinorelbine treatment; further, a minimum of one earlier line of trastuzumab-containing therapy for metastatic disease was obligatory.

HER-2 status was assessed using the HercepTest (Dako A/S, Glostrup, Denmark) or dual-color fluorescent in situ hybridization (FISH; PathVision HER-2 DNA probe kit, Vysis Inc, Downers Grove, IL). Tumors were classed as HER-2 positive if they had a staining intensity of +++ on the HercepTest; if a score of ++ was gained, the tumors were reanalyzed using FISH. Tumors with HER-2 gene amplification again were deemed eligible for trastuzumab. Before initiation of trastuzumab treatment, echocardiography was mandatory, and patients with ejection fraction below 50% were excluded. Measurement of left ventricular ejection fraction was repeated every 6 months, or when symptoms of congestive heart failure occurred.

Treatment Plan and Patient Evaluation
Time to progression (TTP) was defined as primary end point; secondary end points were overall RR (ORR), clinical benefit rate (CBR; complete response [CR] + partial response [PR] + stable disease [SD] 6 months), and overall survival (OS).

All treatment was administered in an outpatient setting. Capecitabine was administered orally at a dose of 2,500 mg/m²/day, days 1 to 14; this schedule was repeated in 3-week cycles. Blood count was performed on days 1 and 10 of the first cycle; this was reduced to a single test on day 1 during consecutive cycles if no grade 3 or 4 hematologic toxicity was observed. If hand-foot syndrome or other toxicities grade 2 or worse were reported, treatment was delayed for 1 week or until toxicity resolved to grade 1. At the second occurrence, a dose reduction to 75% was performed. In case of grade 3 adverse events, treatment was held until symptoms resolved to grade 1, and capecitabine dose was immediately reduced to 75% on consecutive cycles. Trastuzumab was administered at a dose of 8 mg/kg body-weight loading dose on the first day of treatment, followed by 6 mg/kg body-weight every 3 weeks.¹⁶

Re-evaluation of patients' tumor status was performed with CT scans of the chest and the abdomen with additional work-up if indicated every 3 months according to International Union Against Cancer criteria. Re-evaluation was also performed at any time point when clinical symptoms of disease progression occurred. CR was defined as the disappearance of all measurable lesions for a minimum of 8 weeks. PR was defined as 50% or greater reduction in sum of products of the greatest diameters of measurable lesions, no increase of lesion size, and no new lesions. SD was defined as less than 50% decrease and less than 25% increase without the appearance of new lesions. Progressive disease (PD) was defined as greater than 25% increase in tumor size or the appearance of new lesions.

Statistical Analysis
TTP was defined as the interval from the first day of capecitabine plus trastuzumab application until tumor progression, and OS as the interval from the first day of treatment until death of any cause. Data was analyzed as of March 2007. TTP and OS were estimated using the Kaplan-Meier product-limit method. To test the difference between TTP curves in and beyond second-line treatment, the log-rank test was used. P values less than .05 were considered to indicate statistical significance. A Cox regression model was used to evaluate factors potentially influencing TTP (adjuvant trastuzumab, age [ 65 v > 65 years], grading, endocrine receptor status, metastatic sites [nonvisceral only v visceral], prior vinorelbine, prior docetaxel, prior therapy with both antimicrotubule agents, and treatment line [second line v beyond second line]. The same factors were used in a multinomial logistic regression model to evaluate their influence on treatment response (clinical benefit/PD). Toxicity was evaluated according to WHO criteria and was recorded per patient as the worst episode that appeared during a cycle of treatment. All statistics were calculated using SPSS version 12.0 (SPSS Inc, Chicago, IL).

	RESULTS

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Patient Characteristics
Forty consecutive patients (median age, 58.5 years; range, 29 to 73 years) diagnosed with metastatic breast cancer were included. Capecitabine was administered as second-line therapy in 21 patients (52.5%), third line in 11 patients (27.5%), fourth line in four patients (10%), and fifth line in four patients (10%). Table 1 lists the characteristics of the patients included.

Efficacy
Median time of observation was 19 months (range, 3 to 42 months). Median TTP was 8 months (range, 2 to 21 months; 95% CI, 6.07 to 9.93 months; Fig 1). Corresponding TTP numbers for second line are 7 months (range, 2 to 21 months; 95% CI, 2.99 to 11.01 months), and 8 months (range, 2 to 21 months; 95% CI, 5.94 to 10.06 months) for beyond second line. Log-rank test revealed no significant difference. Median OS was 24 months (range, 3 to 42+ months; 95% CI, 20.23 to 27.77 months).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Time to progression (TTP) in months for all patients.

Three patients (7.5%) developed new cerebral metastases as first site of disease progression while receiving capecitabine plus trastuzumab treatment, and six patients (15%) with preexisting cerebral lesions were included. A further five (12.5%) were diagnosed with cerebral metastases during follow-up. Of the six patients with pre-existing cerebral disease, three (50%) gained clinical benefit from therapy.

Toxicity
Overall, capecitabine plus trastuzumab combination was well tolerated, and we observed no treatment-related death. Forty patients received a total of 375 cycles. Average delivered dose-intensity was 81%. Adverse effects are shown in Table 3. Notably, no case of congestive heart failure or asymptomatic drop in left ventricular ejection fraction of 15% or more was observed under trastuzumab treatment. The main toxicities consisted of hand-foot syndrome and diarrhea.

In 22 patients (55%), a delay of cycles was necessary because of adverse effects, mainly hand-foot syndrome or diarrhea. Overall, 34 (9.1%) of 375 cycles had to be delayed for 1 week. In seven patients (17.5%), a dose reduction to 75% of initial dosage was necessary; in two (5%) of those, capecitabine had to be further reduced to 50%.

	DISCUSSION

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Capecitabine plus trastuzumab appears to be an effective treatment option with manageable toxicity profile in a heavily pretreated population.

Although ORR in our study was low compared with trastuzumab-containing first-line regimens^14,17 and similar to capecitabine monotherapy in a third-line setting,¹⁸ we observed a relatively high CBR of 70%. This is higher than what would be expected from capecitabine monotherapy in this setting. An analysis of 197 patients previously treated with an anthracycline, a taxane, and/or vinorelbine¹⁸ reported a clinical benefit rate of 50%. Furthermore, TTP and OS in this study (TTP, 4.8 months; OS, 14.7 months) was shorter compared with our data (TTP, 8 months; OS, 24 months).¹⁸

Our results are well in line with data from other groups reporting results of trastuzumab beyond disease progression.^12,13 Studies evaluating the efficacy of continued antibody therapy reported RRs in the range from 11.8% to 25.9%, and CBR ranging from 21.5% to 68.5%. TTP in those studies ranged from 5.2 to more than 6 months.^11-13 Furthermore, it must be taken into account that all individuals on our trial had earlier exposure to anthracyclines and at least one antimicrotubule agent (ie, a taxane or vinorelbine), and as mentioned, all had at least one earlier line of trastuzumab-based chemotherapy for advanced disease. Also, as expected in HER-2–positive disease, the large majority of women presented with visceral metastatic disease. In the light of these facts, the observed CBR of 70% and a progression-free survival of 8 months render capecitabine plus trastuzumab an apparently effective salvage regimen.

RRs in patients who received the combination as second-line treatment were similar compared with treatment beyond second line. Also, there was no significant difference in regard to TTP between second and beyond second-line therapy. These results again compare well with data from a trial of trastuzumab beyond disease progression, in which RRs and TTP were maintained from first to beyond second-line treatment (RR: first line, 42.6%; second line, 25.9%; beyond second, line 30%; TTP: first line, 6 months; second line, 6 months; beyond second line, 6 months).¹³ In the multivariate analysis, none of the factors included had any significant influence on TTP and CBR.

Until recently, relatively few clinical data were available concerning the combination of trastuzumab with capecitabine. This stems from the fact that in vitro data suggested an antagonistic effect of FU and trastuzumab.¹⁵ This effect was also proposed for the oral prodrug of FU, capecitabine. Therefore, interest concentrated on combinations for which a synergistic effect was described (docetaxel, vinorelbine, and platinum derivatives). However, the proposed antagonistic effect was not seen in both a mouse model^15,19 and a small clinical study, where an RR of 62% was observed.²⁰ An ongoing clinical trial conducted by Xu et al²¹ reported preliminary results that were also encouraging at the 42nd Annual Meeting of the American Society of Clinical Oncology (June 2-6, 2006, Atlanta, GA). This group presented an RR of 63%, whereas data for TTP and OS were not provided. Differing from this trial, though, we did not use the capecitabine trastuzumab combination as first-line treatment, but rather in a heavily pretreated population.

Toxicity rates observed in our trial were well in line with data from different other groups, with diarrhea and hand-foot syndrome being the main reasons for treatment delays and dose reduction.^22,23 One patient had to be hospitalized for grade 3 diarrhea. In general, treatment was relatively well tolerated. None of the patients discontinued therapy because of toxicity or at own wish. This correlates with the fact that oral chemotherapeutic agents, in general, receive greater acceptance.²⁴ As for the cardiac toxicity of trastuzumab, no case of symptomatic congestive heart failure was observed. A drop of left ventricular ejection fraction not necessitating treatment discontinuation was seen in two individuals.

Three patients (7.5%) developed cerebral metastases as first site of progression while receiving therapy, a problem often encountered in HER-2–positive disease.^25-27 This is probably a result of prolonged OS caused by antibody therapy, in connection with the fact that trastuzumab cannot pass the blood-brain barrier. A recently published trial of capecitabine with or without lapatinib, a novel tyrosine kinase inhibitor of both epidermal growth factor receptor and HER-2, showed superior results in terms of RR and TTP for the combination, compared with chemotherapy alone. Also, a reduced incidence of brain metastases was observed in the lapatinib group.²⁸ TTP (which was defined as primary end point) was 8.4 months in the combination-therapy group, and CBR was 27%. Although TTP data are similar to the results from trastuzumab plus capecitabine in our trial, a direct comparison is not possible because the lapatinib study was a 10-fold larger, randomized, multicenter trial.

We conclude that in contrast to in vitro data, the combination of capecitabine and trastuzumab appears to be an effective treatment option in heavily pretreated patients with advanced breast cancer and earlier trastuzumab exposure. Toxicity was in line with that of capecitabine monotherapy. Our data shed further light on the potential efficacy of trastuzumab treatment beyond disease progression. We would therefore strongly encourage a randomized comparison of this combination to capecitabine monotherapy in this setting, and possibly also to a lapatinib-based combination regimen.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Michael Gnant, SanofiAvents, Novartis, AstraZeneca, Roche, Pfizer Research Funding: Michael Gnant, Amgen, AstraZeneca, Novartis Expert Testimony: None Other Remuneration: Michael Gnant, SanofiAventis, Novartis, AstraZeneca, Roche

	AUTHOR CONTRIBUTIONS

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Conception and design: Rupert Bartsch, Guenther G. Steger

Administrative support: Robert M. Mader, Christoph C. Zielinski, Guenther G. Steger

Provision of study materials or patients: Rupert Bartsch, Catharina Wenzel, Gabriela Altorjai, Ursula Pluschnig, Margaretha Rudas, Robert M. Mader, Michael Gnant

Collection and assembly of data: Rupert Bartsch, Catharina Wenzel, Gabriela Altorjai, Ursula Pluschnig, Michael Gnant

Data analysis and interpretation: Rupert Bartsch, Margaretha Rudas, Robert M. Mader

Manuscript writing: Rupert Bartsch, Catharina Wenzel, Robert M. Mader, Christoph C. Zielinski, Guenther G. Steger

Final approval of manuscript: Christoph C. Zielinski, Guenther G. Steger

	NOTES

 
published online ahead of print at www.jco.org on August 6, 2007.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted March 30, 2007; accepted May 25, 2007.

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