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Abstract

Women with metastatic breast cancer require tailored chemotherapy that improves outcomes without compromising quality of life. Capecitabine, a pro-drug of 5-fluorouracil, is an oral fluoropyrimidine carbamate that is sequentially activated in a three-step process. This results in the preferential production of 5-fluorouracil in tumors rather than in normal surrounding tissue, improving the tolerability and efficacy of 5-fluorouracil. In combination with docetaxel, capecitabine is the first agent that has shown superior activity to single-agent docetaxel, and it is a particularly appropriate option for younger, fitter patients with rapidly progressing disease and/or visceral metastases. However, for older patients and those with comorbidities and/or after progression to taxanes, single-agent capecitabine may be the best option. Its role in earlier disease stages (adjuvant therapy) is being investigated.

Keywords

advanced breast cancer capecitabine oral administration thymidine phosphorylase

Breast cancer is the most common malignancy in women, accounting for nearly 30% of all cancers in British women, with more than 41,700 cases in 2002 [101]. In North America, a total of 215,990 new cases and 40,110 deaths during 2004 have been reported [1]. Approximately 50% of all patients treated with curative intent will develop metastatic disease and the average survival time for these patients is 18–24 months [2]. In addition, approximately 10% of patients present with metastatic disease at first diagnosis.

There is strong evidence to suggest that poly-chemotherapy decreases mortality compared with single-agent treatment in women with metastatic breast cancer (MBC) [102]. Chemotherapy regimens available for advanced or MBC include cyclophosphamide, methotrexate and 5-fluorouracil (5-FU) (CMF), and anthracycline-containing regimens [3]. In the last decade, taxane-containing regimens (paclitaxel and docetaxel) appear to be the most active in the management of MBC [103].

With the increasing use of anthracyclines and taxanes in adjuvant and first-line metastatic settings, there is a need for effective therapeutic agents for patients in whom disease progresses. Capecitabine has been used both as monotherapy and in combination with other chemotherapy and targeted agents, both in first-line regimes and previously treated patients. The results of such studies were excellent in terms of efficacy and tolerability.

Overview of the market

There is an increasing need for new agents that provide an alternative to taxanes and anthracyclines since the trend towards more aggressive treatment of breast cancer in the earlier stages has led to an increase in the number of patients presenting with advanced or metastatic disease that is resistant to, or has failed, taxane and anthracycline therapies. Commonly used agents include capecitabine, vinorelbine and gemcitabine. Unfortunately, there are few randomized trials in the literature comparing the efficacy of these agents with anthracycline and taxane therapies in patients with refractory disease.

Capecitabine (Xeloda®, F Hoffmann-La Roche) shows several advantages over 5-FU in the treatment of MBC. First, its oral administration mimics continuous 5-FU infusion while presenting higher patient acceptance and compliance rates and avoiding intravenous administration-associated complications and financial costs. Second, it provides intratumor selective activation, thus potentially facilitating local management and therefore improved antitumor activity, as well as reduced systemic toxicity. Furthermore, the oral administration of capecitabine is an attractive feature; treatment at home is associated with improved quality of life in patients with advanced cancer [4], and patients are known to prefer oral to intravenous therapy, as demonstrated in several studies [5,6].

Introduction to capecitabine

Capecitabine is the first drug in a new fluoropyrimidine class that offers distinct characteristics. The aim of this paper is to review the pharmacology and clinical effectiveness of capecitabine for locally advanced and MBC.

Chemistry

Capecitabine (5′-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine) is a fluoropyrimidine carbamate with a molecular weight of 359.35. Its chemical structure is depicted in Figure 1. It is a chiral molecule synthesized in a three-step process where three chiral centers come from the starting material and the fourth is created through stereospecific synthesis. The data provided indicate that the stereochemistry is not changed during manufacture or storage of the active substance. It is a white to off-white crystalline powder with an aqueous solubility of 26 mg/ml at 20°C.

Figure 1.

Capecitabine.

Pharmacodynamics

Capecitabine was synthesized in the 1990s by Japanese researchers as an oral formulation designed to circumvent the unacceptable toxicity of 5-FU. The main limitation of 5-FU derives from its gastrointestinal toxicity, attributed to liberation of 5-FU in the small intestine under the action of thymidine phosphorylase (TP), a tumor-associated angiogenesis factor [7,8]. Capecitabine was thus designed as a prodrug of 5-FU that could not be metabolized by TP in the intestine. Furthermore, differences in the activities between healthy and tumor tissue of the enzymes involved in the biotransformation process to the active cytotoxic compound 5-FU have been demonstrated by capecitabine, as opposed to 5-FU, which does not demonstrate any tumor selectivity. The enzyme involved in the final conversion to 5-FU (TP) is found in tumor tissues, but also in normal tissues, albeit usually at lower levels [9]. Recent investigations have shown that, in breast cancer, TP is located not just in the cancer cells, but also in the surrounding inflammatory cells, including the granules of the macrophages and the mitochondria of the neutrophils [10].

The antitumor activity of capecitabine is enhanced by upregulation of TP activity, which increases in tumor cells after exposure to cytotoxics such as taxanes, cyclophosphamide, gemcitabine or vinorelbine, as well as tumor irradiation, resulting in synergistic activity [11 –13].

There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of DNA. The incorporation of 5-FU also leads to inhibition of RNA and protein synthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5-FU may be to create a thymidine deficiency that leads to unbalanced growth and cell death. The effects of DNA and RNA deprivation are more pronounced in those cells that proliferate more rapidly and metabolize 5-FU at a faster rate.

Pharmacokinetics & metabolism

The pharmacokinetic properties of capecitabine are summarized in Box 1. After oral administration, the absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine [14,15]. In tumor tissues capecitabine is subsequently activated by a cascade of three enzymes to 5′-deoxy-5-fluorocytidine (5′-DFCR), then to 5′-deoxy-5-fluorouridine (5′-DFUR), resulting in an intratumoral release of 5-FU [9]. Maximum plasma concentrations of capecitabine and its metabolites are reached approximately 2 h following administration.

A two-way crossover study was conducted in patients with advanced colorectal cancer to investigate the influence of food intake on the pharmacokinetics of capecitabine. The investigators found that the influence of food intake on the pharmacokinetics of capecitabine and its metabolites varied considerably, but the effect on the area under the concentration–time curve of 5′-DFUR and 5-FU was minimal, with no impact on the apparent elimination half-lives of the metabolites [16]. It is recommended that capecitabine is administered within 30 min of food ingestion as this was the procedure used in clinical trials. Similarly antacids, such as aluminium hydroxide and magnesium hydroxide, have not been found to have a major negative impact upon capecitabine absorption [17]. No significant differences in the pharmacokinetics of capecitabine and its metabolites were observed in patients with mild-to-moderate hepatic dysfunction compared with patients with normal liver function [18].

Box 1.

Summary of the main pharmacokinetic characteristics of capecitabine.

Peak plasma concentrations for the drug and its two main metabolites (5′-DFCR and 5′-DFUR) are reached shortly (0.5-1.5 h) after administration. Concentrations then decline exponentially with a half-life of 0.5–1 h.

Following administration of 829 mg/m², the largest AUC is obtained for 5′-DFUR (11.8 μg × ml/h; CV: 44%; n = 15).

At the dose level of 1657 mg/m²/day (MTD for the continuous schedule), the average plasma concentrations of 5-FU (17 ng/ml) are similar to those obtained after protracted continuous infusion of 5-FU (300 mg/m²/day)

Similar PK parameters were obtained on days 1 and 15 ± 1. • The PK of capecitabine and its metabolites are dose proportional up to 1657 mg/m²/day

The PK results demonstrate a good gastrointestinal absorption of capecitabine, followed by an extensive conversion to the main metabolite, 5′-DFUR.

Capecitabine and its metabolites are excreted in the urine at a rate of 95%, mainly as α-fluoro-β-alanine.

5′-DFCR: 5′-deoxy-5-fluorocytidine; 5′-DFUR: 5′-deoxy-5-fluorouridine

5-FU: 5-fluorouracil; AUC: Area under the curve; MTD: Maximum tolerated dose; PK: Pharmacokinetic. From [18].

Although an evaluation of the effect of renal insufficiency on the pharmacokinetics found no impact of renal function upon 5-FU or capecitabine, patients with severe renal dysfunction (creatinine clearance <30 ml/min) had significantly higher incidence of severe toxicity. Therefore, it is recommended that patients with moderate renal dysfunction (creatinine clearance 35–50 ml/min) start therapy with a 25% reduction from the recommended dose and that those with severe impairment not be treated with capecitabine [19].

Clinical efficacy

Capecitabine, both as single agent and in combination, has shown its efficacy in Phase II–III studies including patients with anthracycline- and/or taxane-pretreated MBC.

Overview of Phase I trials

Several Phase I dose-finding and pharmacokinetic studies were conducted to investigate capecitabine as monotherapy (two different schedules) or in combination with leucovorin. The maximum tolerated dose of capecitabine was determined in three open-label, Phase I studies in patients with solid tumors, predominantly breast and colorectal cancer. Capecitabine was administered either continuously or intermittently (2-week treatment followed by a 1-week rest period) and in one study both schedules of capecitabine were administered in combination with leucovorin [20 –22]. After a complete evaluation, the intermittent schedule with capecitabine 1250 mg/m² twice-daily monotherapy was ultimately the schedule investigated in Phase II–III trials owing to its safer profile and higher dose intensity.

Numerous Phase I trials with combinations containing capecitabine and other anticancer agents (taxanes, oxaliplatin, CPT-11, vinorelbine, gemcitabine, R1 15777 [a farnesyl transferase inhibitor], CI-994 [a histone deacetylase inhibitor], or epirubicin combined with docetaxel, cisplatin or cyclophosphamide) or radiotherapy (RT) have been investigated [23]. Special mention should be given to two Phase I trials that have studied intermittent capecitabine in combination with paclitaxel and docetaxel [24,25]. The recommended doses for further Phase II studies for both taxane combinations were:

Intermittent capecitabine 825 mg/m² twice daily, days 1–14 plus paclitaxel 175 mg/m² every 3 weeks.

Intermittent capecitabine 1250 mg/m² twice daily, days 1–14 plus docetaxel 75 mg/m² on day 1 of a 3-week treatment cycle.

Phase II–III trials in metastatic breast cancer

Capecitabine in combination

The demonstration of a statistically significant survival benefit with the addition of capecitabine to docetaxel heralded a major advance in the treatment of MBC [26]. In this Phase III trial, 511 women with MBC who had previously received an anthracycline were stratified according to previous exposure to paclitaxel and randomized to receive 3-weekly cycles of either capecitabine (1250 mg/m² twice daily on days 1–14) plus docetaxel (75 mg/m² on day 1) or monotherapy with docetaxel (100 mg/m² on day 1). The patient cohort represented a poor-prognosis group, with approximately two-thirds of patients having at least three tumor sites; two-thirds had received anthracyclines and 50% had received prior endocrine therapy for metastatic disease. Tumor response rate (RR) was significantly higher in the combination group, as was time to progression (TTP) ( Table 1 ).

Table 1.

Summary of randomized Phase II–III trials of capecitabine in metastatic breast cancer.

Study	Treatment	ORR (%)	TTP (months)	OS (months)	Ref.
O'Shaughnessy et al. (2001)	Capecitabine + docetaxel vs docetaxel	42 vs 30	6.1 vs 4.2	14.5 vs 11.5	[38]
Miller et al. (2005)	Capecitabine + bevacizumab vs capecitabine	19.8 vs 9.1	4.86 vs 4.17*	15.1 vs 14.5	[35]
O'Shaughnessy et al. (2001)	Capecitabine vs CMF	30 vs 16	4.1 vs 3.0	19.6 vs 17.2	[38]
Talbot et al. (2001)	Capecitabine vs paclitaxel	36 vs 26	3.0 vs 3.1	7.6 vs 9.4	[39]

Progression-free survival.

CMF: Cyclophosphamide, methotrexate and 5-fluorouracil; ORR: Objective response rate; OS: Overall survival; TTP: Median time to progression.

Most importantly, capecitabine plus docetaxel conferred a 3-month survival benefit compared with single-agent docetaxel (log-rank, p = 0.0126; hazard ratio: 0.775; median 14.5 vs 11.5 months, respectively). Moreover, the survival benefit was seen early in the course of treatment. Since patients in the combination arm received a lower dose of docetaxel, the survival benefit must be attributable to the addition of capecitabine. It is the only trial that has shown a significant survival benefit with combination chemotherapy compared with single-agent docetaxel.

Combination therapy composed of capecitabine and paclitaxel has also shown good activity in anthracycline-pretreated advanced or MBC patients [27]. The RR was 52% (38/73 patients), with a complete response reported in 8 patients (11%) and disease stabilization in a further 29% of patients (disease control rate of 81%): median TTP was 8.1 months and median overall survival (OS) was 16.5 months. These results confirm that of an earlier multicenter Phase II trial of the same combination as first- or second-line treatment in 48 patients with MBC [28]. Clearly, capecitabine is an effective combination partner for both taxanes.

In patients with MBC, capecitabine has also been studied in combination with other agents such as vinorelbine [29], trastuzumab [30 –34] and bevacizumab [35], showing a consistently high activity with limited added toxicity. Bonnefoi and colleagues evaluated capecitabine administered in combination with fixed doses of epirubicin and cyclophosphamide (100 and 600 mg/m² every 3 weeks) as primary treatment for large operable or locally advanced/inflammatory breast cancer without distant metastasis [36]. The recommended dose was capecitabine 900 mg/m² twice daily in combination with epirubicin 100 mg/m² and cyclophosphamide 600 mg/m². The acceptable toxicity profile and encouraging activity of this regimen warrant further evaluation in the adjuvant setting.

More recently, a randomized Phase III trial compared the time to progression (TTP) of patients with human epidermal growth factor receptor (HER)2-positive breast cancer, resistant to trastuzumab, treated with capecitabine in combination with lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 small molecule inhibitor, versus capecitabine alone [37]. Patients received treatment with standard-dose capecitabine in the intermittent schedule or lapatinib 1250 mg once daily continuously in combination with capecitabine 1000 mg/m² twice daily for 14 days every 21 days. With 321 patients analyzed, the study has shown that the combined treatment group had a statistically significant improvement in TTP from 17.9 to 36.9 weeks (hazard ratio: 0.48; 95% confidence interval [CI]: 0.33–0.7; p = 0.000045). The overall pattern of adverse events was similar, with higher incidence of diarrhea in the combined arm (58 vs 39%).

Capecitabine monotherapy

Capecitabine has also been evaluated as a single agent in MBC, mainly in specific populations, such as older patients or after taxane failure. Clinical trial data show that first-line capecitabine demonstrates consistently high activity and a favorable safety profile plus convenience compared with other intravenous treatments, including paclitaxel and CMF ( Table 1 ) [38,39].

A randomized Phase II trial compared capecitabine with CMF every 3 weeks as initial chemotherapy for women aged over 55 years (median ages of 69 and 70 years, respectively) [38]. Capecitabine compared favorably with CMF in terms of RR, TTP and OS. To further evaluate the clinical utility of capecitabine in elderly patients with MBC, a Phase II study was conducted in 73 older patients (median age 73 years; range 65–89 years) with locally advanced or MBC [40]. The first 30 patients received capecitabine 1250 mg/m² (twice daily, days 1–14 every 21 days) and the dose was reduced to 1000 mg/m² in the next 43 patients following the recommendation of a 25% dose reduction in elderly patients. No significant differences in response between the lower and higher dose groups were observed. In the standard-dose group, the response rate was 36.7% (95% CI: 19.9–56.1%), with an additional seven patients having disease stabilization at 24 weeks or later. In the low-dose group, the response rate was 34.9% (95% CI: 21–50.9%), with an additional 15 patients having prolonged stabilization. The median TTP was 4 months in both groups; the median survival in the higher and lower dose groups was 10 and 16 months, respectively. The authors concluded that capecitabine is safe and effective in elderly breast cancer patients. Based on the overall results, the dose of 1000 mg/m² twice daily merits consideration as standard treatment for older patients who do not have severely impaired renal function.

The use of first-line capecitabine as an alternative to paclitaxel in MBC is also supported by the high activity observed in a randomized Phase II trial in anthracycline-pretreated patients with MBC [39]. Based on the intent-to-treat analysis, an objective RR of 36% (95% CI: 17–59%) was observed in patients receiving intermittent capecitabine, with three patients (14%) showing a complete response. In patients randomized to paclitaxel the response rate was 26% (95% CI: 9–51%), with no complete responses. The median TTP was 3.0 and 3.1 months in the capecitabine and paclitaxel groups, respectively. OS was similar in the two treatment groups, with a median survival of 7.6 months with capecitabine and 9.4 months with paclitaxel.

Furthermore, standard intermittent capecitabine monotherapy has been extensively evaluated in numerous studies including more than 700 patients with taxane-pretreated MBC. Capecitabine produced consistently impressive response rates and OS of approximately 1 year [41 –45].

Therefore, there is a considerable body of evidence to support the use of single-agent capecitabine in the first-line treatment of MBC. Indeed, oral capecitabine is an attractive and more convenient alternative to standard intravenous regimens in the first-line treatment of MBC, with particular benefits in patients with slowly progressing disease, those who prefer oral treatment, are older, or have early recurrence after adjuvant anthracyclines and/or taxanes and in whom single-agent therapy is considered an appropriate treatment.

Safety & tolerability

Orally administered capecitabine is well tolerated, with palmar–plantar erythrodysaesthesia (PPE) and diarrhea the most common toxicities reported ( Table 2 ) [46], similar to those expected from a continuous infusion of 5-FU. Among over 700 taxane-pretreated patients treated in five clinical trials, there were no treatment-related deaths [41 –46]. Myelosuppression was rare and there was minimal alopecia, with none at grade 3.

Table 2.

Main reported adverse events per patient during Phase II–III trials with capecitabine.

Adverse event	Grade 3–4 (%)	Overall (%)
Palmar–plantar erythrodysesthesia	15–20	40–50
Diarrhoea	8–17	50
Nausea and vomiting	4–10	40
Stomatitis	2–11	15–30
Myelosuppression (neutropenia or thrombocytopenia)	<10	−
Fatigue	2–8	25

PPE is a cutaneous side effect that usually presents initially as discomfort in the palms or soles, followed later by erythema and frank pain and blistering and desquamation in the most severe cases [47]. After the cessation of capecitabine, the symptoms abate over a period of days or weeks. The frequency of PPE does not appear to be influenced by the cumulative dose of capecitabine. Grade 2 PPE can be treated effectively with dose interruption and, if necessary, dose modification. The impact of dose reduction was evaluated retrospectively from four Phase II trials (2510 mg/m²/day, intermittent regimen) including 321 patients with advanced or MBC. A total of 131 patients with dose reductions were compared with 190 patients with no dose reductions. There was little differences in duration of response (220 vs 211 days), time to treatment failure (234 vs 218 days), and survival time (350 vs 243 days) [48]. The basic pathogenesis of this syndrome is not known. A recent study conducted with liposomal doxorubicin, which also causes PPE, showed that the drug accumulates in the stratum corneum where it is stored for a long period of time and is converted into free radicals that destroy the tissues. As in the case of other toxicities, it is very important that patients are educated to recognize grade 1–2 PPE, and seek medical advice if it occurs: this can reduce the incidence of grade 3/4 adverse events. The twice-daily dosing schedule for capecitabine allows a responsive, flexible strategy for the management of side effects, offering frequent opportunities for dose modification. No effective treatment exists but topical application of antioxidants could be effective based on the pathogenic information presented above [49].

Gastrointestinal adverse events are the next most common side effects, but the majority of these adverse events are mild to moderate in intensity and can be effectively managed with medical intervention (e.g. loperamide and rehydration for diarrhea, mouthwash and fluconazole for stomatitis). Stomatitis and fatigue are less common toxicities and myelosuppression is uncommon. Notably, capecitabine 1000 mg/m² twice daily was particularly well tolerated in older women with locally advanced or MBC, with lower incidences (2 vs 13%) of grade 3/4 diarrhea and fewer (5 vs 30%) dose reductions compared with capecitabine 1250 mg/m² twice daily [40]. Fatigue was the only grade 3/4 toxicity to occur in more than 10% of the 1000 mg/m² cohort: indeed, it is particularly difficult, especially in an elderly population, to ascertain whether fatigue is treatment-related. Table 3 summarizes the main toxicities reported from capecitabine and other active agents in MBC [39 –45,50 –56].

Table 3.

Tolerability characteristics of main active agents in pretreated.

Adverse event	Capecitabine	Vinorelbine	Gemcitabine	Taxanes
Hand–foot syndrome	+++	−	−	−
Diarrhoea	++	+	++	++
Nausea and vomiting	++	++	++	++
Stomatitis	++	+	++	++
Fatigue	+	++	+	++
Myelosuppression	+	++	++	+++
Neurotoxicity	−	++	++	++
Alopecia	−	++	++	+++
Ref.	[39 –45]	[50,51]	[52 –54]	[39,55,56]

The dose-limiting toxicities found in Phase I trials with combinations containing capecitabine and other chemotherapy agents were mainly PPE and neutropenia with taxanes, and neutropenia, diarrhea and nausea/vomiting with vinorelbine [23]. In combination with trastuzumab, the adverse events were mild and resolved in all patients, PPE being the most common grade 1/2 adverse event [31]. As reported in studies of capecitabine alone, retrospective analyses of the docetaxel plus capecitabine Phase III study showed that when capecitabine and docetaxel were reduced by 25% from the starting dose, the proportion of treatment cycles with grade 3/4 treatment-related adverse events was approximately halved, without evidence that early dose reduction of both agents had a negative impact on efficacy [57].

In the Phase III study where capecitabine with or without bevacizumab were studied, no significant differences were found in the incidence of adverse events between both arms [35].

Owing to its good tolerability, capecitabine is being increasingly utilized in elderly populations with breast and colorectal cancers. One potential problem that is more likely to be a concern in older patients is the concomitant use of warfarin and the interactions between both drugs. Although the mechanism of action for the interaction is not clear, it may be related to downregulation of cytochrome P450 2C9 by capecitabine or its metabolites or a pharmacodynamic interaction with warfarin. This clinical interaction has resulted in the addition of a ‘black box’ warning from the US FDA [58,59]. It has also been noted that patients treated with capecitabine frequently develop macrocytosis that is benign and does not require any additional evaluations. More serious is the recently described syndrome of multifocal leukoencephalopathy in five patients treated with the drug [60,61].

Regulatory affairs

Capecitabine in combination with docetaxel is indicated for the treatment of patients with locally advanced or MBC after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline. Capecitabine is also indicated as monotherapy for the treatment of patients with locally advanced or MBC after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated.

Beyond breast cancer, capecitabine is indicated for the adjuvant treatment of patients following surgery of Stage III (Dukes' stage C) colon cancer and for first-line monotherapy of metastatic colorectal cancer.

Conclusion

A large body of clinical data supports the use of capecitabine in treatment course for women with breast cancer. However, the optimal time and strategy for capecitabine treatment depends on the individual disease and patient characteristics. The favorable safety profile of capecitabine makes it a well-tolerated and effective combination partner: it has shown strong additive efficacy when combined with docetaxel, paclitaxel, vinorelbine and trastuzumab, with limited added toxicity. As shown in the pivotal Phase III trial in combination with docetaxel, capecitabine can form the basis of a standard of care for extending survival in patients with aggressive and rapidly progressing disease, with or without visceral metastases. As a single agent, oral capecitabine is an attractive and more convenient alternative to standard intravenous regimens in patients with more indolent MBC, who are older or who have recurrence after anthracyclines and/or taxanes.

As well as achieving high activity, its safety profile compares favorably with other active agents in MBC, such as vinorelbine, gemcitabine and taxanes, with a low incidence of myelosuppression and no complete hair loss. Importantly, dosing flexibility allows for the management of side effects without compromising efficacy: indeed, its more frequent toxicity, PPE, is easily managed by dose reduction.

After reviewing all available data, it seems clear that capecitabine should be offered to a wide range of MBC patients. The ongoing and planned capecitabine trials will show the contribution of this promising oral agent to the natural history of breast cancer.

Future perspective

The high activity and favorable tolerability of capecitabine in MBC have lent support to investigate a number of novel treatment approaches:

Sequential monotherapy

All-oral regimens

Novel schedules of administration

Adjuvant/neoadjuvant trials

Combination with taxanes and anthracyclines

Replacing anthracyclines in adjuvant treatment

Maintenance chemotherapy post adjuvant treatment

Elderly patients

For some patients, particularly those with compromised performance status, older patients or those with less aggressive disease, sequential therapy may be more appropriate than combination therapy. To define the capecitabine/taxane sequential strategies, a randomized Phase III study has been planned to compare the efficacy of sequential capecitabine followed by a taxane with capecitabine/taxane combination treatment (capecitabine with either docetaxel or paclitaxel) [62]. The results recently presented (with a median follow-up of 15.5 months) show no significant differences in progression-free/overall survival between the study arms: all regimens were well tolerated, with minimal grade 4 adverse events. Since there is no clear superiority of sequential versus combined therapy, patient characteristics are likely to be used to decide which regimen is the most appropriate. Another proposed randomized study will evaluate the sequence of capecitabine and taxanes (3-weekly docetaxel or weekly paclitaxel) in first-line treatment of MBC: the primary end point will be time to second-line treatment failure; in addition, proteomics and circulating tumor cells will be studied.

A Phase II, randomized trial is comparing two different capecitabine schedules with similar dose intensities: standard doses and schedules (1250 mg/m² twice daily, days 1–14, every 3 weeks) versus continuous dosing regimen (800 mg/m² twice daily, days 1–21, every 3 weeks). The study plans to recruit 80 patients with HER2-negative MBC who have received up to two prior lines of chemotherapy. The primary end point will be incidence of PPE; secondary end points include tumor response rate and TTP.

Taking into account the patient's opinions, it is clear that there is a need to explore ‘all-oral’ regimens, such as XIC (capecitabine, idarubicin and cyclophosphamide) proposed by Tong and colleagues [63]. A proposal for a European all-oral capecitabine/vinorelbine adjuvant study is also under consideration, as previously tested in MBC [64,65]. Patients should not need to return repeatedly to out-patient clinics for intravenous administration of therapy but rather should be empowered to help control their own therapy.

Finally, capecitabine is currently being evaluated in a comprehensive, worldwide adjuvant and neoadjuvant trial program (Tables 4 & 5). These studies, which together will include more than 20,000 patients with early breast cancer, are aiming to more fully elucidate the clinical utility of capecitabine-based therapy in the adjuvant setting. Preliminary results, presented as abstracts, are encouraging [66 –70].

Table 4.

Capecitabine in the adjuvant treatment of early breast cancer.

Trial	Test arm	Control arm	Patients (n)
US Oncology	AC→XT	AC→T	2410
UK TACT2	E→X	E→CMF	4400
CALGB	X	CMF or AC	600
GEICAM	ET→X	EC→T	1302
CIBOMA	AC/FEC/AT→X	AC/FEC/AT	3538
GAIN	EC→XP	EPC	3130
FinXX	XT→CEX	T→FEC	1500
ICE	Ibandronate→XT	Ibandronate	1394
MINDACT	XT	Anthracycline	6000

A: Adriamycin; C: Cyclophosphamide; CALGB: Cancer And Leukemia Group B; CIBOMA: Coalición Iberoamericana de Investigación en Oncología Mamaria; E: Epirubicin; F: 5-fluorouracil; FinXX: Finnish Phase III study; GAIN: German Adjuvant Intergroup Node-positive study; GEICAM: Grupo Español de Investigación en Cáncer de Mama

ICE: Ifosfamide, carboplatin and etoposide; M: Methotrexate; MINDACT: Microarray In Node negative Disease may Avoid ChemoTherapy; P: Paclitaxel; T: Docetaxel; TACT2: Trial of Accelerated adjuvant Chemotherapy with capeciTabine in early breast cancer 2; X: Capecitabine.

Table 5.

Capecitabine as primary systemic therapy (neoadjuvant) for breast cancer.

Trial	Test arm	Control arm	Patients (n)
MDACC (Neo/adjuvant)	XT→FEC	P→FEC	930
ECTOII	AP→CMX; AC→XT	AP→CMF	486
French	CEX→T	FEC→T	200
Korean	XT	AC	200
NSABP B40	AC→XT; XT→AC	AC→T; T→AC	1200
GeparQuattro	EC→XT/T→X	EC→T	1600
ABCSG 24	ETX	ET	458

A: Adriamycin; ABCSG: Austrian Breast and Colorectal Cancer Study Group; C: Cyclophosphamide; E: Epirubicin; ECTOII: European Cooperative Trial in Operable Breast Cancer II; M: Methotrexate; MDACC: M.D. Anderson Cancer Center; NSABP: National Surgical Adjuvant Breast and Bowel Project; P: Paclitaxel; T: Docetaxel; X: Capecitabine.

As a highly effective, flexible and well-tolerated orally administered agent, capecitabine has the potential to impact favorably on a wide variety of treatment strategies for both metastatic and advanced disease. It is anticipated that the novel approaches currently under investigation will provide further options for tailoring treatment and improving outcomes in breast cancer.

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The National Comprehensive Cancer Network (NCCN), an alliance of 19 of the world's leading cancer centers, is an authoritative source of information to help patients and healthcare professionals make informed decisions about cancer care. Through the collective expertise of its member institutions, the NCCN develops, updates and disseminates a complete library of clinical practice guidelines.

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(Accessed June 2006)

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(Accessed June 2006)

Executive summary

Mechanism of action

Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) that mimics continuous 5-FU infusion. It is activated after absorption by thymidine phosphorylase (TP).

TP is found in higher levels in neoplastic cells than in normal tissue, so the intratumoral concentration of 5-FU exceeds that seen in normal cells.

The antitumor activity of capecitabine is enhanced by upregulation of TP activity, which increases in tumor cells after exposure to several cytotoxics, resulting in synergistic activity.

Pharmacokinetic properties

After oral administration, capecitabine crosses the gastrointestinal barrier intact and is rapidly and almost completely absorbed, minimizing the direct toxicity of 5-FU in the intestine.

Maximum plasma concentrations of capecitabine and its metabolites are reached approximately 2 h following administration.

The effect of food intake on the area under the concentration-time curve of 5′-deoxy-5-fluorouridine and 5-FU is minimal, with no impact on the apparent elimination half-lives of the metabolites. It is recommended that capecitabine is administered within 30 min of food ingestion.

Although no dose adjustment is recommended, capecitabine should be carefully monitored in patients with mild-to-moderate liver dysfunction, regardless of the presence or absence of liver metastasis.

Renal function and not age determines toxicity: it is recommended that patients with moderate renal dysfunction (creatinine clearance 35–50ml/min) start therapy with a 25% reduction from the recommended dose.

Clinical efficacy

Patients have a clear preference for oral chemotherapy: as an oral agent, capecitabine provides home-based treatment, enabling patients to continue a relatively normal lifestyle.

Capecitabine is a highly effective and well-tolerated combination partner for many different chemotherapies, including taxanes, vinorelbine and biological therapies (trastuzumab and bevacizumab), which allows a patient's treatment to be tailored to their individual needs.

Capecitabine/docetaxel provides a clear and significant survival benefit compared with docetaxel, which has been shown to be the superior taxane.

Single-agent, first-line capecitabine demonstrates consistently high activity and a favorable safety profile plus convenience compared with other intravenous treatments, including paclitaxel and cyclophosphamide, methotrexate and 5-FU.

Single-agent capecitabine has shown to be particularly useful in patients with slowly progressing disease, those who are older, and/or after anthracycline and taxane progression.

Executive summary

Safety & tolerability

Capecitabine is well tolerated, with palmar–plantar erythrodysesthesia and diarrhea the most common toxicities reported: both can be treated effectively with dose interruption and, if necessary, dose modification, without significantly affecting the clinical efficacy.

The frequency of hand-foot syndrome does not appear to be influenced by the cumulative dose of capecitabine.

Myelosuppression is rare and there is minimal alopecia.

The twice-daily dosing schedule of capecitabine allows a responsive, flexible strategy for the management of side effects, offering frequent opportunities for dose modification.

A clinical interaction with warfarin has been described, which has resulted in the addition of a ‘black box’ warning from the US FDA.

Dosage & administration

The recommended dose of capecitabine is 1250 mg/m² administered twice daily for 14 days followed by a 7-day rest period. The capecitabine dose of 1000 mg/m² twice daily merits consideration as ‘standard’ chemotherapy for older patients.

In combination with docetaxel, the recommended dose of capecitabine is 1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m² every 3 weeks.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

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Miles

Vukelja

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29.

First and only trial to show a significant survival benefit with combination chemotherapy (capecitabine–docetaxel) compared with single-agent docetaxel. Pivotal study to get the indication of this combination for the treatment of patients with locally advanced or metastatic breast cancer (MBC) after failure of cytotoxic chemotherapy.

30.

Batista

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Constenla

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Gradishar

Meza

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35.

Chan

Tubiana

Ganju

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37.

Yamamoto

Iwase

Kitamura

Odagiri

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38.

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Holmes

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39.

Bonnefoi

Biganzoli

Mauriac

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40.

Phase I study to determine the recommended dose of an interesting combination being tested as neoadjuvant therapy.

41.

Geyer

Cameron

Lindquist

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42.

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43.

Randomized trial evaluating capecitabine versus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in the first-line treatment of elderly women with MBC. Capecitabine compared favorably with CMF in terms of response rate, time to progression and overall survival.

44.

Talbot

Moiseyenko

Van Belle

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45.

Randomized Phase II trial testing the use of first-line capecitabine as an alternative to paclitaxel in anthracycline-pretreated patients with MBC. Capecitabine demonstrated a comparable activity to paclitaxel, and was associated with significantly less myelosuppression and alopecia than paclitaxel.

46.

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Procopio

Celio

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47.

Confirmatory study of utility and safety of capecitabine in elderly patients with MBC. A reduced dose of capecitabine (1000 mg/m² twice daily) is recommended for older patients as it demonstrates improved tolerance without significantly reduced efficacy.

48.

Blum

Dieras

Lo Russo

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Blum

Jones

Buzdar

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50.

A multicenter Phase II trial evaluating the efficacy of capecitabine in paclitaxel-pretreated patients. As a result of this study, capecitabine has been approved for therapy in patients with MBC that has progressed despite prior anthracycline and taxoid therapy.

51.

Reichardt

Von Minckwitz

Thuss-Patience

: Multicenter Phase II study of oral capecitabine (Xeloda) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann. Oncol. 14, 1227–1233 (2003).

52.

Fumoleau

Largillier

Clippe

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53.

Miles

Vukelja

Moiseyenko

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54.

Retrospective analysis of the pivotal Phase III trial of capecitabine/docetaxel versus docetaxel. The data suggest that the sequential administration of docetaxel followed by capecitabine is associated with prolonged survival in patients who are candidates for sequential single-agent therapy.

55.

Hwuang

Marshall

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56.

Lademann

Martschick

Jacobi

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57.

O'Shaughnessy

Blum

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58.

Impact of dose reduction on the efficacy of capecitabine was evaluated retrospectively from four Phase II trials including 321 patients with advanced or MBC. The results suggest that the dose of capecitabine can be reduced to minimize toxicity without compromising efficacy.

59.

Kara

Sahin

Erkisi

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60.

Fazeny

Zifko

Meryn

Huber

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Dittrich

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Barthier

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62.

Smorenburg

Bontenbal

Seynaeve

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63.

Locker

Wenzel

Schmidinger

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Sauer-Heilborn

Kath

Schneider

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Chan

Friedrichs

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66.

Nabholtz

Senn

Bezwoda

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67.

Shah

Ledbetter

Diasio

Saif

: A retrospective study of coagulation abnormalities in patients receiving concomitant capecitabine and warfarin. Clin. Colorectal Cancer 5(5), 354–258 (2006).

68.

Jannley

Waterbury

: Capecitabine-warfarin interaction. Ann. Pharmacother. 3989, 1546–1551 (2005).

69.

Leonard

Miles

Reichardt

Twelves

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70.

Karvellas

Sawyer

Hamilton

Mackey

: Effect of capecitabine on mean corpuscular volume in patients with metastatic breast cancer. Am. J. Clin. Oncol. 27, 364–368 (2004).

71.

Videnovic

Semenov

Chua-Adajar

: Capecitabine-induced multifocal leukoencephalophathy: a report of five cases. Neurology 65(11), 1792–1794 (2005).

72.

Soto

Torrecillas

Reyes

: Capecitabine (X) and taxanes in patients (pts) with anthracycline-pretreated metastatic breast cancer (MBC): Sequential vs. combined therapy results from a MOSG randomized Phase III trial. J. Clin. Oncol. 24(18S) (2006) (Abstract 570).

73.

Phase III study comparing sequential versus combined capecitabine–taxanes therapy in anthracycline-pretreated MBC. Since there is no clear superiority of sequential versus combined therapy, patient characteristics are likely to be used to decide which regimen is the most appropriate.

74.

Tong

Cheng

Chan

Ching S

Wong

Ngor L

Chow

: Phase II study of an ‘all-oral’ regimen of capecitabine, idarubicin and cyclophosphamide for metastatic breast cancer – safety, efficacy and quality of life. Oncology 68(4–6), 520–525 (2005).

75.

Interesting small Phase II study where an ‘all-oral’ regimen seems to be well tolerated and favored by patients with MBC.

76.

Lorusso

Spada

Giampaglia

: Oral vinorelbine plus capecitabine (oral vincap) combination in patients with advanced breast cancer (ABC). A Phase II study of the GOIM (Gruppo Oncologico dell'Italia Meridionale). Ann. Oncol. 17(Suppl. 7), vii15–vii 17 (2006).

77.

Nolè

Catania

Sanna

: Phase II study with dose finding of oral vinorelbine in combination with capecitabine as first-line chemotherapy of metastatic breast cancer (MBC): preliminary results of the Phase II part of the study. Eur. J. Cancer 4(2 Suppl.), 167 (2006) (Abstract 408).

78.

Gerber

von Minckwitz

Blohmer

: Effectiveness of vinorelbine/capecitabine (NX) versus docetaxel/doxorubicin/cyclophosphamide (TAC) in patients non-responding to two cycles of neoadjuvant TAC chemotherapy: First Results of the Phase III GEPARTRIO-Study by the German Breast Group. Eur. J. Cancer 4(2 Suppl.), 148 (2006) (Abstract 347).

79.

Preliminary abstract that reports the first results of a randomized trial evaluating the role of docetaxel, doxorubici and cyclophosphamide (TAC) or vinorelbine/capecitabine after inadequate response to two previous cycles of TAC, as primary therapy of operable or locally advanced breast cancer. These regimens seem to increase the chance of breast conservation.

80.

Gaui

MDF

Amorim

Arcuri

: Neoadjuvant capecitabine chemoradiation (X-RT) for patients (pts) with locally advanced breast cancer (LABC) failing anthracycline-based neoadjuvant therapy: findings from a prospective Phase II trial. Eur. J. Cancer 4(2 Suppl.), 151 (2006) (Abstract 355).

81.

Bernard-Marty

Demonty

Personeni

: Capecitabine as adjuvant therapy for elderly breast cancer (BC) patients (pts): a pilot study. Eur. J. Cancer 4(2 Suppl.), 154 (2006) (Abstract 364).

82.

Preliminary report shows that adjuvant capecitabine is well tolerated in women aged 70 years or over with breast cancer as has been previously demonstrated in older patients with MBC.

83.

Lybaert

Wildiers

Neven

: Neoadjuvant capecitabine (X), docetaxel (T) ± trastuzumab (H) for patients (pts) with locally advanced breast cancer (LABC): preliminary safety and efficacy data from a multicenter Phase II study. Eur. J. Cancer 4(2 Suppl.), 157 (2006) (Abstract 374).

84.

Ricevuto

Grassadonia

Cianchetti

: Preoperative dose-dense sequential chemotherapy of epirubicin & cyclophosphamide followed by docetaxel & capecitabine in patients with early breast cancer: preliminary results. Eur. J. Cancer 4(2 Suppl.), 158 (2006) (Abstract 376).

85.

Cancer Research UK: About cancer: specific cancers. Breast cancer http://info.cancerresearchuk.org/cancerstats/incidence/females (Accessed June 2006)

86.

Carrick

Parker

Wilcken

Ghersi

Marzo

Simes

: Single agent versus combination chemotherapy for metastatic breast cancer. The Cochrane Database of Systematic Reviews 2005, Issue 2. www.update-software.com/Abstracts/ab003372.htm (Accessed June 2006)

87.

Ghersi

Wilcken

Simes

Donoghue

: Taxane containing regimens for metastatic breast cancer. Cochrane Database Syst. Rev. 2005, Issue 2. www.update-software.com/Abstracts/ab003366.htm (Accessed June 2006)

Capecitabine for the Oral Treatment of Metastatic Breast Cancer

Abstract

Keywords

Overview of the market

Introduction to capecitabine

Chemistry

Pharmacodynamics

Pharmacokinetics & metabolism

Clinical efficacy

Overview of Phase I trials

Phase II–III trials in metastatic breast cancer

Capecitabine in combination

Capecitabine monotherapy

Safety & tolerability

Regulatory affairs

Conclusion

Future perspective

Information resources

References