A multicenter phase II trial of docetaxel and capecitabine as salvage ...

Cancer Chemother Pharmacol (2012) 70:169–176 DOI 10.1007/s00280-012-1901-3

ORIGINAL ARTICLE

A multicenter phase II trial of docetaxel and capecitabine as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer N. Karachaliou • N. Ziras • K. Syrigos • K. Tryfonidis • E. Papadimitraki • E. Kontopodis • V. Bozionelou • A. Kalykaki V. Georgoulias • D. Mavroudis

•

Received: 29 March 2012 / Accepted: 21 May 2012 / Published online: 6 June 2012 Ó Springer-Verlag 2012

Abstract Objective To evaluate the efficacy and safety of docetaxel plus capecitabine (DC) combination as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC). Patients and treatment Patients with MBC who had disease progression after initial chemotherapy with anthracyclines (n = 29; 100 %) and taxanes (n = 11; 37.9 %) were treated with oral capecitabine 950 mg/m2 twice daily on days 1–14 and docetaxel 75 mg/m2 on day 1 every 3 weeks. Nineteen (65.5 %) patients received this regimen as second line and 10 (34.5 %) as C3rd line of therapy. All patients were evaluable for response and toxicity. Results Complete response occurred in two (6.9 %) patients and partial response in eleven (37.9 %) for an overall response rate of 44.8 % (95 % CI 26.7–62.9 %). Eleven women (37.9 %) had stable disease and five (17.2 %) progressive disease. Of the eleven patients previously treated with anthracyclines and taxanes, five (45.5 %) responded to DC combination. The median duration of response was 5.7 months (range 3.4–64.2), the median time to disease progression 9.3 months (range 1.2–58), and the median overall survival 25.5 months. No toxic death occurred. Neutropenia grade 4 occurred in 58.6 % of patients and three of them (10.3 %) developed

N. Karachaliou N. Ziras K. Syrigos K. Tryfonidis E. Papadimitraki E. Kontopodis V. Bozionelou A. Kalykaki V. Georgoulias D. Mavroudis Hellenic Oncology Research Group (HORG), 55 Lomvardou str, 11470 Athens, Greece D. Mavroudis (&) Department of Medical Oncology, University Hospital of Heraklion, PO BOX 1352, 71110 Heraklion, Crete, Greece e-mail: [email protected]

neutropenic fever. Non-hematological toxicities were manageable with grade 3 hand-foot syndrome occurring in 6.9 % of the patients, fatigue in 3.4 %, and neurotoxicity in 3.4 %. Conclusion The DC combination is a valuable regimen as salvage treatment in anthracycline- or anthracycline and taxane-pretreated patients with MBC. Keywords Docetaxel Capecitabine Salvage chemotherapy Metastatic breast cancer

Introduction Breast cancer is one of the most common malignancies affecting women, with 8–11 % of all women expected to develop breast cancer at some time during their life [1]. Nearly half of these women will develop metastatic disease, and their average survival time from diagnosis of recurrence ranges from 18 to 30 months [1]. The shift in the use of anthracyclines and taxanes earlier in the course of disease in the adjuvant setting has increased the likelihood that patients presenting with metastatic breast cancer (MBC) have already been exposed to these most active agents [2]. The oral fluoropyrimidine capecitabine was rationally designed to generate 5-FU preferentially in tumor tissue and to mimic continuous infusion 5-FU [2]. Clinical studies have shown that single-agent capecitabine is an active and well-tolerated treatment in MBC progressing during or after anthracycline and taxane therapy, and achieves response rates of 20–26 % and a median survival in excess of 1 year [3, 4]. However, for patients in whom only anthracyclines have failed, taxane-based chemotherapy is the current standard of care [2].

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Preclinical synergy between capecitabine and docetaxel was demonstrated in the late 1990s [2]. When used as single agents, capecitabine and docetaxel slowed tumor growth, but when combined, the two agents produced a reduction in tumor burden that was the result of synergistic effect [5]. Capecitabine is activated by a cascade of enzymes culminating in conversion to 5-fluorouracil by thymidine phosphorylase (TP) [1]. While TP is known to be upregulated in cancers, it can also be upregulated by other chemotherapy agents and radiotherapy [1]. In mice bearing the WiDr human colon cancer xenograft, taxanes have been shown to induce the expression of TNF-a, which upregulates TP [5]. Based on these preclinical models, several different studies have been carried out with the aim to exploit the in vivo interactions between these agents observed in preclinical experiments. The pivotal trial leading to US Food and Drug administration approval of capecitabine and docetaxel combination in patients with MBC was a multinational, multicenter, open-label, randomized phase III trial by O’Shaughnessy et al. [2]. This study compared the efficacy and tolerability of capecitabine/docetaxel therapy (1,250 mg/m2 twice a day for 2 weeks of every 3-week cycle plus docetaxel 75 mg/m2 on day 1) with single-agent docetaxel (100 mg/ m2 on day 1) in anthracycline-pretreated patients with MBC[2]. The combined treatment was proven to be superior for the primary efficacy end point of time to progression (6.1 vs. 4.2 months; p = 0.001), as well as for secondary end points including median survival (14.5 vs. 11.5 months) and tumor response rate (42 vs. 30 %) [2]. When the present study was initiated, it was already known from the trial by O’Shaughnessy et al. that the combination of docetaxel with capecitabine was superior to docetaxel alone. However, few data were available for patients whose disease had progressed following anthracycline and taxane therapy. This multicenter phase II study in anthracycline- or anthracycline and taxane-pretreated patients with MBC was initiated to confirm the efficacy and safety of DC combination as salvage treatment in this setting.

Patients and methods Eligibility The study included women aged [19 years with histologically confirmed, measurable MBC who had disease progression during or following anthracycline- or anthracycline/taxane-containing therapy administered in the adjuvant or metastatic disease setting. Patients were also required to meet the following eligibility criteria: HER2 negative disease (score 0–1 by immunohistochemistry or FISH negative), life expectancy [3 months, a World Health

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Cancer Chemother Pharmacol (2012) 70:169–176

Organization (WHO) performance status (PS) of 0–2, absolute neutrophil count (ANC) C1,500 ll, platelet count C100,000 ll, total bilirubin \1.59 the upper normal limit (UNL), aspartate transaminase (AST) and/or alanine transaminase (ALT) B39 UNL, and serum creatinine concentration B1.5 mg/dl. Prior radiation therapy was permitted if less than 25 % of active bone marrow was treated. Patients were ineligible if they had evidence of clinically unstable central nervous system (CNS) metastasis, active infection unless adequately treated, other serious concomitant systematic disorders or secondary primary malignancies (except adequately treated basal cell carcinoma of skin and carcinoma in situ of uterine cervix). Patients with lack of physical integrity of the upper gastrointestinal tract or known malabsorption were excluded. Written informed consent was obtained from all patients prior to study entry. The protocol was approved by the Scientific and Ethics Committees of the participating institutions of the Hellenic Oncology Research Group. Treatment plan Oral capecitabine (Xeloda; Hoffmann-La Roche, Nutley, NJ) 950 mg/m2 was administered twice daily on days 1–14 of each 3-week treatment cycle. Docetaxel (Taxotere; Sanofi Aventis Pharma, Collegeville, USA) was administered at the dose of 75 mg/m2 (in 250 ml 0.9 % normal saline) by intravenous (IV) infusion over 60 min on day 1 every 3 weeks, following premedication with oral dexamethasone (16 mg) 12, 8, and 1 h prior to docetaxel infusion. Dexamethasone 8 mg b.i.d. was continued for two additional days. Hemopoietic growth factors could be used at the discretion of the responsible physician to treat symptomatic neutropenia or anemia. Response evaluation Baseline investigations included medical history, physical examination, complete blood cell count with differential and platelets count, full biochemical profile, and tumor markers (CEA and CA-15.3). An electrocardiogram (ECG) was also carried out along with baseline thoracic and abdominal computed tomography (CT) scans. Patients underwent follow-up CT scans for the assessment of response after every three cycles of therapy. Evaluation of response was classified on the basis of Response Evaluation Criteria in Solid Tumors (RECIST) guidelines [7]. Patients were treated until best response or until there was evidence of disease progression, unacceptable toxicity, or consent withdrawal. Safety was evaluated in all patients receiving at least one dose of study treatment. Adverse events and abnormal laboratory parameters were graded according to the National Cancer Institute Common


Toxicity Criteria [8]. The doses for both capecitabine and docetaxel were reduced by 25 % in case of dose-limiting toxicities (febrile neutropenia, grade 4 neutropenia, grade 3–4 thrombocytopenia, or Cgrade 3 non-hematological toxicity and mainly diarrhea, asthenia or neurotoxicity).

171 Table 1 Patient characteristics N (%) Patients enrolled Median (min–max)

Statistical methods The primary end point of this phase II study was to evaluate the response rate of DC combination as salvage therapy in patients with anthracycline- or anthracycline/taxane-pretreated MBC. Secondary end points were toxicity assessment, duration of response, time to progression, and overall survival. The two-step Simon design of phase II trials was adopted in order to define the required number of patients to enroll [9]. Two levels of response rate as end points were used as follows: p0 the level of response below which pursuit of therapy would be of no interest was set at 20 %, and p1 a level above which there would be clinically relevant response was set at 50 %. The first stage consisted of 10 patients. If C2 responses were observed, the trial continued to a total of 30 patients. The combination would be recommended for further study if C15 responses were observed (p0 = 0.2; p1 = 0.5; a = 0.1; b = 0.1). All clinical data were centrally collected and analyzed (Clinical Trial Office, Department of Medical Oncology, University Hospital of Heraklion, Crete, Greece) using the SPSS version 10.0 statistical software. Analysis was performed on an intent-totreat basis. Survival curves were plotted according to the method of Kaplan–Meier [10] and tested for differences by using the log-rank test. All tests were two-sided and considered significant when the resulting p value was B0.05.

Patients’ characteristics A total of 29 patients with MBC were enrolled. All patients were assessable for toxicity and tumor response. Patients’ characteristics are presented in Table 1. The patients’ median age was 58 years (range 39–73) and the majority of them had a PS of 0–1 (93.1 %). Infiltrating ductal carcinoma was the predominant histological type in 21 (72.4 %) patients and 16 (55 %) had hormone receptor-positive tumors. Nineteen (65.5 %) and 10 (34.5 %) patients received the study treatment as 2nd and C3rd line of chemotherapy, respectively. All patients had previously received anthracycline-based regimens and 11 (37.9 %) both anthracycline- and taxanebased regimens in either the adjuvant or metastatic setting. Ten women (34.4 %) had resistant or refractory disease to anthracyclines and three (10.3 %) to taxanes. Resistance to anthracyclines and taxanes has been defined clinically as

58 (39–73)

Performance status 0

18 (62.1)

1

9 (31.0)

2

2 (6.9)

Menopausal status Premenopausal

5 (17.2)

Postmenopausal

24 (82.8)

Histology Ductal

24 (82,8)

Lobular

2 (6.9)

Other

1 (3.4)

Unknown

2 (6.9)

Stage IIIB

3 (9.4)

IV

26 (89.6)

Line of therapy 2

19 (65.5)

C3

10 (34.5 %)

Interval from previous chemo (median, min–max) Hormone receptor status

5.4 months (0.5–76.8)

Positive (ER?/PR?, ER?/PR-, ER-PR?)

16 (55.7)

Negative (ER-/PR-)

6 (20.7)

Unknown

8 (24.1)

No of organs involved 1

Results

29

Age

12 (41.4)

2

9 (31)

C3

8 (27.6)

Median (min–max)

2 (1–5)

Organs involved Local

7 (24.1)

Lung ? pleura Liver

22 (75.9) 17 (58.6)

Lymph nodes

11 (37.9)

Bones

10 (34.5)

Other breast

1 (3.4)

Other

2 (6.9)

disease recurrence or progression occurring within 6–12 months of completing adjuvant or neoadjuvant treatment using these drugs or disease progression occurring during treatment or within 3–6 months after the treatment with these agents in the metastatic setting, while those whose disease is deemed ‘‘refractory’’ are progressing while receiving the drug [2, 4].

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The median time since last exposure to chemotherapy was 5.4 months (range 0.5–76.8). Seventeen (58.6 %) patients had multiple metastases ([2 or more organs involved), while the liver was involved in 58.6 % of the patients. Treatment administration A total of 183 cycles of DC were administered. The median number of administered cycles was 6 per patient (range 1–12). The median interval between cycles was 21 days (range 21–31). Seventeen (58.6 %) tolerated the full planned doses of the two drugs in all cycles. Dose reductions were required in 30 (16.4 %) of 183 cycles. The reasons for dose reductions were hematological (14 cycles) and non-hematological (13 cycles) toxicity or both (3 cycles). Treatment delay was necessitated in 27 (14.8 %) cycles because of hematological (n = 3 cycles) and nonhematological (n = 1 cycle) toxicity as well as for reasons unrelated to treatment (e.g., late admissions due to patients’ request or pending imaging studies for treatment evaluation; n = 23 cycles). Therapy was discontinued in 12 (41.3 %) patients, primarily because of disease progression (n = 9 patients), consent withdrawn (n = 1 patient), or treatment-related toxicity (n = 2 patients). Delivered dose intensity, defined as administered dose/planned dose, was 82 % for capecitabine and 88 % for docetaxel. Treatment efficacy Overall investigator-assessed response rate in all 29 women was 44.8 % (95 % CI 26.7–62.9 %) consisting of two

(6.9 %) CRs and 11 (37.9 %) PRs. Stable disease was documented in 11 (37.9 %) patients and progressive disease in five (17.2 %). The disease control rate (CR ? PR ? SD) achieved was 82.7 %. Among the 11 patients who had previously received anthracycline- and taxanecontaining regimens, five (45.5 %) responded to DC combination. The median duration of response was 5.7 months (range 1–18). After a median follow-up of 58 months (range 3.4–64.2), a total of 23 deaths had occurred because of disease progression (n = 21 patients) or other reasons (n = 2 patients). The median time to progression was 9.3 months (range 1.2–58), and median overall survival was 25.5 months (range 3.4–64.2). The 1-year survival rate was 78 %. Treatment toxicity All patients were assessed for toxicity. No treatment-related death occurred during the study. Table 2 summarizes the hematological and non-hematological toxicities for all patients. Two patients (6.9 %) discontinued study treatment due to toxicity (febrile neutropenia). The most common grade 4 hematological toxicity was neutropenia occurring in 58.6 % of patients. There was no patient who developed grade 3–4 anemia or thrombocytopenia. Febrile neutropenia was reported in three (10.3 %) patients. The nonhematological adverse events consisted of grade 2–4 handfoot syndrome in four (13.8 %) patients, fatigue in four (13.8 %), and grade 3 neurotoxicity in one (3.4 %). The other adverse events of any grade were mild (grade 1–2) and easily manageable (nausea/vomiting in 48.3 %, diarrhea in 17.2 %, and mucositis in 17.2 % of the patients).

Table 2 Adverse events possibly or probably related to study treatment per patient Grade 1 N Neutropenia

Grade 2

Grade 3

Grade 4

%

N

%

N

%

N

%

–

–

4

13.8

6

20.7

7

24.1

16

55.2

3

10.3

–

–

–

–

Thrombocytopenia

8

27.6

1

3.4

–

–

–

–

Febrile neutropenia

–

–

1

3.4

–

–

2

6.9

Nausea

5

17.2

2

6.9

–

–

–

–

Vomiting

3

10.3

1

3.4

–

–

–

–

Diarrhea Constipation

2 1

6.9 3.4

3 –

10.3 –

– –

– –

– –

– –

Mucositis

3

10.3

2

6.9

–

–

–

–

Neurotoxicity

3

10.3

–

–

1

3.4

–

–

Allergy

1

3.4

–

–

–

–

–

–

Fatigue

9

31.0

3

10.3

1

3.4

–

–

Hand-foot syndrome

2

6.9

2

6.9

2

6.9

–

–

Anemia

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173

Discussion Many challenges exist in the management of MBC. Several international guidelines for adjuvant therapy are widely used, but consensus statements regarding the management in the metastatic setting are lacking [11]. Combination chemotherapy is commonly used in the treatment of MBC with higher response rates and longer duration of response than single-agent therapy; however, survival is not always prolonged and the toxicity of combination therapy is certainly increased compared to monotherapy [6]. The results of this open-label phase II study confirm previous reports that oral capecitabine and docetaxel are an effective combination for the treatment of patients with MBC previously treated with anthracycline- and taxanebased chemotherapy. Indeed, the overall tumor control rate was 82.7 %, comprising two CRs and 11 PRs. Moreover, the median time to progression was 9.3 months and the median overall survival 25.5 months. These results compare favorably with those reported in five other studies assessing the DC combination in this setting [13–17]. Overall response rates of 41.9–51 %, median time to progression of 5.5–8.2 months, and overall survival of 20.5–23 months have been reported (Table 3). Interestingly, subgroup analysis revealed that among the 11 patients who had received at least one taxane-containing regimen before enrollment in this trial, five (45.5 %) responded to DC combination. This level of activity could probably relate to an in vivo synergy of the two drugs. The DC combination was well tolerated in this study, and the safety profile was consistent with that seen in previous studies [12–14, 16]. Discouraging toxicity was only reported in the phase II study of Mackey et al. [16] of weekly docetaxel in combination with capecitabine. In our study, the majority of treatment-related adverse events were mild or moderate in intensity while no treatmentrelated death occurred. However, it should be noted that two patients refused further treatment after an episode of

treatment-related febrile neutropenia, whereas another withdrew her consent. The most common grade 4 hematological toxicity was neutropenia, whereas the most frequent grade 2–4 non-hematological toxicity was hand-foot syndrome. Other adverse events were predictable and manageable with appropriate treatment and temporary chemotherapy interruption or, if necessary, dose adjustment. The interest in using the DC combination is reflected in the large number of phase III clinical trials that compare the docetaxel/capecitabine combination with other ‘‘standard’’ chemotherapeutic regimens [18]. Table 4 provides a summary of published data from randomized clinical trials involving docetaxel with capecitabine. In the first two trials of O’Shaughnessy et al. [2] and Lee et al. [19], significantly superior response rate was achieved with combined docetaxel plus capecitabine compared to docetaxel monotherapy and doxorubicin/cyclophosphamide combination, respectively; this was also translated into superior TTP and survival in the first trial. In the trial by Mavroudis et al. [20], the primary objective of the study was not met since the efficacy of docetaxel/capecitabine and docetaxel/epirubicin regimens was similar in terms of ORR, TTP, and OS. Chan et al. [21] showed no statistically significant differences in ORR and OS between the docetaxel/gemcitabine and docetaxel/capecitabine arms; however, TTP was borderline superior for docetaxel/gemcitabine combination. Questions were raised as to whether the survival benefit of combined therapy would have been the same if capecitabine had been universally available to all patients after progression on docetaxel. In fact, a lack of superiority for the combination as compared to sequential single-agent therapy was subsequently shown in a phase III trial of Soto et al. [22] in which women with anthracycline-pretreated MBC were randomly assigned to sequential capecitabine followed by taxane monotherapy at progression, or combined capecitabine plus either paclitaxel or docetaxel. These results support the notion that for most patients with MBC, sequential monotherapy rather than combination

Table 3 Results of phase II trials with docetaxel/capecitabine combination in MBC Study

Regimen

No. of pts

Anthracycline pretreated

Taxane pretreated

ORR (%)

Median TTP

Duration of response

Median OS

Michalaki et al. [13]

Docetaxel/capecitabine, first-line therapy

45

45 (adjuvant)

NR

42

8 months

NR

23 months

Mrozek et al. [15]

Docetaxel/capecitabine, first-line therapy

39

NR

NR

44

5.5 months

9.1 months

NR

Mackey et al. [16]

Weekly docetaxel and capecitabine, first-line therapy

20

18

NR

NR

26 weeks

9 weeks

82 weeks

Wang Xiao-Xiao et al. [17]

Docetaxel/capecitabine, first- and second-line therapy

31

31

15

41.9

5.7 months

NR

NR

pts Patients, ORR objective response rate, TTP time to progression, OS overall survival, NR not reported

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174


Table 4 Phase III trials comparing docetaxel/capecitabine combination with other regimens Study

Regimen

No. of pts

Line of therapy

Anthracycline pretreated

Taxane pretreated

ORR (%)

Median TTP (months)

Median OS (months)

O’Shaughnessy et al. [2]

Docetaxel

256

1/3:1st; 2/3:2nd or 3rd

256

9

30

4.2

11.5

Capecitabine/docetaxel

255

255

10

Lee et al. [19]

Doxorubicin/ cyclophosphamide

101


103

Neoadjuvant

42

6.1

14.5

p = 0.006

p = 0.001

p = 0.0126

65

NR

NR

84

NR

NR

11.1

32

p = 0.003 Mavroudis et al. [20]

Chan et al. [21]

Soto et al. [22]

Beslija et al. [23]

Epirubicin/docetaxel

112


109

Gemcitabine/docetaxel

153


152

Capecitabine/paclitaxel

95


91

Capecitabine ? taxane

91


50

Capecitabine ? docetaxel

50

1st

65 %: 1st; 35 %: 2nd

2nd

37

11

50

13

153

18

152

15

95

NR

91 91 1st

50 (adj)

NR

50 (adj)

49 49

9.8

35

p = 0.9

p = 0.5

p = 0.9

32

4.24

19.29

32

4.07

21.45

p = 0.933

p0.059

p0.983

65

NR

33.1

74

NR

28.6

46

NR

31.5

68

9.3

22

40 p = 0.004

7.7 p = 0.001

19 p = 0.006

pts Patients, ORR objective response rate, TTP time to progression, OS overall survival, NR not reported

treatment is preferable primarily due to reduced toxicity. However, in a small study by Beslija et al. [23], the DC combination was superior to the sequential monotherapy of the same drugs perhaps due to the in vivo synergy as previously reported. The optimal treatment of patients with MBC has yet to be defined perhaps due to the heterogeneity of disease and the number of available active agents [24]. The subsequent therapy of patients with MBC pretreated with anthracyclines and/or taxanes presents a particular challenge, and new therapeutic strategies are required for this growing patient population. The ideal chemotherapeutic agent or combination in this setting would reduce tumor burden and associated symptoms, improve survival, and maintain quality of life with minimal toxicity. It is common that in patients with prior exposure to anthracyclines and taxanes, capecitabine is used given its efficacy and ease of administration. For patients with previous response to a taxane, rechallenging with a taxane is an option since paclitaxel and docetaxel do not show complete cross-resistance. Except from the DC combination, paclitaxel and gemcitabine regimen have demonstrated improved

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survival compared to single-agent taxane and are approved in the United States, for first-line treatment of MBC after failure of anthracycline-based adjuvant therapy [25]. Combinations of gemcitabine and docetaxel were not found to differ in objective response rate, time to progression, or overall survival when compared to sequential therapy or to capecitabine and docetaxel [26]. However, non-hematological toxicity (diarrhea, mucositis, and hand-foot syndrome) favored gemcitabine and docetaxel [27]. Ixabepilone is approved by the United States Food and Drug Administration (FDA) as monotherapy in patients whose tumors are resistant to anthracyclines, taxanes, and capecitabine, and in combination with capecitabine for the treatment of patients with MBC who are resistant to an anthracycline and a taxane [28, 29]. While ixabepilone has demonstrated significant activity in heavily pretreated patients, toxicity, especially peripheral neuropathy, is a concern. It was refused marketing authorization by the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) in 2008 due to its marginal benefit with significant peripheral neuropathy [30]. Ixabepilone as monotherapy and in combination with


capecitabine may be best reserved for selected patients with aggressive disease and limited treatment options. The cyclophosphamide, methotrexate, and fluorouracil (CMF) regimen remains an option for the treatment of MBC [31, 32]. There are also other combination regimens with gemcitabine, cisplatin, vinorelbine, epirubicin, or etoposide with high response rates often in heavily pretreated patients, but without superior survival when compared to less toxic regimens or even single agents. An exception may be the case of triple-negative breast cancer and breast cancer 1 gene (BRCA1)-associated carcinomas, where platinum agents may have increased activity [33–39]. Recently was found that treatment with eribulin, a non-taxane microtubule dynamics inhibitor with a novel mode of action, improved overall survival in women with MBC whose disease progressed despite multiple rounds of prior chemotherapy, according to the results of a phase III clinical trial called EMBRACE [40]. It was the first study to compare overall survival with this new chemotherapeutic agent to real-life choices in heavily pretreated patients with MBC [40]. In the present study, we reported that capecitabine is an active therapy for patients with heavily pretreated MBC and it has the additional benefits of oral administration and improved convenience for patients. However, attention must be paid to dose reduction and the fact that, perhaps due to relatively poor tolerability at the licensed doses, few clinicians in the UK and Europe use the DC combination. Also, an interaction between capecitabine and coumarin has been observed, and the pharmacokinetics of coumarin are affected by capecitabine. Therefore, careful monitoring of coagulation parameters in patients receiving concomitant coumarin derivatives (e.g., warfarin) is essential. Patients likely to be good candidates for the DC combination might include those with a good performance status who due to the presence of visceral and aggressive disease maximal opportunity for reduction in tumor burden is required. Docetaxel is also active in heavily pretreated MBC, and the DC combination has a significant survival benefit compared with docetaxel alone [2]. There are several disadvantages associated with docetaxel as a palliative treatment in patients who have failed anthracycline therapy. The toxic effects of docetaxel may be severe and potentially life threatening; they include neutropenic fever, asthenia, infection, stomatitis, neurosensory changes, myalgia, and diarrhea [41, 42]. Additional disadvantages are that docetaxel needs to be given as an intravenous infusion with steroid premedication, and close patient monitoring is required to minimize the risks of toxic effects. Whether DC combination can provide superior benefit compared with sequential administration of the same agents in the treatment of MBC is not known and it is a question of significant clinical interest. Capecitabine is an

175

oral prodrug converting to 5-fluorouracil, a pyrimidine analogue that blocks DNA replication at the tumor site. Docetaxel is a microtubule inhibitor with marked antitumor activity as single agent in patients with previously untreated or pretreated MBC [1]. Since the converting enzyme TP mediates the tumor-selective conversion of capecitabine into 5-FU, combination with an agent that may enhance the activity of TP (such as taxanes) may increase the antitumor activity of capecitabine [5]. Rather than simply treating everyone with these agents, we will need to develop genomic and biomarker tools to identify exactly which individual tumors should be treated with precisely what specific agents. Intra-tumoral changes in 5-FU metabolizing enzymes and molecular markers (apoptosis, gene expression profile) of response to chemotherapy should be evaluated in order to find specific subsets of patients who will respond to this treatment. The results of the present clinical trial of DC as salvage treatment in anthracycline- or anthracycline and taxanepretreated patients with MBC support a beneficial antitumor interaction between these agents. The anticipated high efficacy and predictable manageable toxicity make it an attractive salvage regimen for use in the MBC setting. Acknowledgments This work was partially supported by the Cretan Association for Biomedical Research (CABR).

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