capecitabine: fulfilling the promise of oral chemotherapy

Drug Evaluation

2002 © Ashley Publications Ltd ISSN 1465-6566 733

Ashley Publicationswww.ashley-pub.com

1. Introduction

2. Compound

3. Pharmacokinetics

4. Clinical efficacy

5. Safety and tolerability

6. Combination chemotherapy

7. Capecitabine and radiation

8. Conclusion

9. Expert Opinion

Capecitabine: fulfilling the promise of oral chemotherapyJimmy J Hwang† & John L Marshall†Georgetown University Medical Center, Lombardi Cancer Center, Washington DC, USA

Capecitabine is a synthetic oral fluoropyrimidine carbamate that is sequen-tially activated in a three-step process, which results in the preferential pro-duction of 5-fluorouracil in tumours, rather than in the normal surroundingtissue. Capecitabine is proven to be as effective as the combination of 5-fluor-ouracil and leucovorin administered on the Mayo clinic schedule in patientswith metastatic colorectal cancer. It has also been proven to be effective inpatients with metastatic breast cancer that has progressed despite prioranthracyclines and taxoids. More recently, it has also been shown to increasesurvival in combination with docetaxel in patients with metastatic breast can-cer in comparison to docetaxel alone. This article reviews the pharmacologyand clinical activity of capecitabine, as well as combinations of capecitabinewith other chemotherapeutic agents and future directions of investigationwith this convenient and widely active antitumour therapy.

Keywords: breast cancer, capecitabine, colorectal cancer, thymidine phosphorylase

Expert Opin. Pharmacother. (2002) 3(6):733-743

1. Introduction

As we make progress in the understanding and treatment of malignancies, two mainavenues of advancement in the treatment of cancer are available: improving the effi-cacy of treatment and minimising the difficulties of treatment, both regarding theadministration and toxicity of drugs. One method of achieving the latter goal is theemployment of oral chemotherapy. Studies have suggested that patients prefer oralto intravenous chemotherapy if there is no accompanying loss of efficacy [1].

Among the hurdles of devising an active oral chemotherapy regimen is the devel-opment of agents that can be absorbed in a relatively consistent fashion and be deliv-ered to the tumour in adequate and consistent amounts. The pyrimidine analogue 5-fluorouracil (5-FU), for example, is hydrolysed by dihydropyrimidine dehydrogenase(DPD). Since DPD is present in large concentrations in the GI tract, oral 5-FU ismetabolised by DPD, essentially preventing the absorption of the 5-FU. Onemethod of overcoming this problem, which is inhibition of DPD, has been evaluatedbut was found to be less effective than intravenous 5-FU regimens [2]. An alternatemethod of developing oral chemotherapy is to design prodrugs that are activatedafter absorption, for example capecitabine (Xeloda™, Hoffmann-La Roche).

2. Compound

Capecitabine (N4-pentoxylcarbonyl-5´-deoxy-5-fluorocytidine; N-[-(5-deoxy-B-D-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyrimidanyl]-n-pentyl carbamate) is afluoropyrimidine carbamate, rationally designed to be preferentially activated intumours after oral ingestion. This synthetic carbamate is a derivative of 5´deoxy-5-fluorouridine (5´-DFUR). The antitumour activity of capecitabine is minimal.However, after ingestion, capecitabine is absorbed intact in the GI tract and sequen-tially metabolised in three steps in the liver and tumour to 5-FU. After absorption,capecitabine is metabolised in the liver by carboxylesterase to 5´deoxy-5-fluorocyti-dine (5´-DFCR). This metabolite is subsequently converted by cytidine deaminase

Capecitabine: fulfilling the promise of oral chemotherapy

734 Expert Opin. Pharmacother. (2002) 3(6)

in the liver and tumour to 5´-DFUR. The pyrimidine nucleo-side phosphorylase thymidine phosphorylase (TP) is overex-pressed in tumours compared to adjacent normal tissue. Thisenzyme metabolises 5´-DFUR to 5-FU [3]. As tumours havehigher quantities of TP than adjacent non-malignant tissues,the tumours will have higher quantities of 5-FU than normaltissues, thus minimising systemic toxicity and potentiallyincreasing antitumour activity [4]. Moreover, preclinical stud-ies suggest that the other metabolites of capecitabine and 5´-DFCR have neither antitumour activity nor toxicity.

Since capecitabine is converted to 5-FU intratumourally,the primary mode of activity of this agent is as an antimetabo-lite. Interestingly, the data also suggests that TP may have arole as an angiogenic factor, so by targeting this enzyme,capecitabine may have antiangiogenic properties [5].

3. Pharmacokinetics

After ingestion, capecitabine is rapidly absorbed, intact,through the GI tract. The peak plasma concentration (Cmax) isattained in ~ 2 h, with a half-life of ~ 1 h [6-8]. Therefore,capecitabine is administered twice-daily to maintain a consist-ent tissue exposure to 5-FU. No significant accumulation ofcapecitabine or its metabolites occurs with chronic dosing.

The speed of capecitabine absorption increases when it isingested without food and the Cmax and area under the con-centration–time curve (AUC) of both capecitabine and itsmetabolites are not significantly higher than when taken withfood. However, the apparent elimination half-life of eachmetabolite of capecitabine remains unchanged. Takentogether, this data suggests food does not have a major impactupon capecitabine absorption [9]. It is recommended thatcapecitabine be administered within 30 min of food inges-tion, as this was the schedule of administration during theclinical trials. Similarly, antacids such as Maalox have notbeen found to have a major negative impact upon the absorp-tion of capecitabine [10]. Thus the time of food ingestion orother concomitant medications do not require a change in theadministered dose of capecitabine.

Although capecitabine is metabolised by carboxylesterase inthe liver after ingestion, a study in patients with mild-to-mod-erate hepatic dysfunction induced by liver metastases has sug-gested that no significant difference in systemic exposure to5´-DFUR or 5-FU occurs in comparison to patients withoutliver dysfunction. At this time, it is recommended thatpatients with mild-to-moderate hepatic dysfunction fromliver metastases not initially undergo dose reduction, althoughthey will require close monitoring. However, as patients withunderlying liver dysfunction in the absence of metastases,such as cirrhosis, were not evaluated, the safety of capecitabinein such patients is uncertain [11]. Capecitabine and its metabo-lites are excreted in the urine at a rate of 95%, mainly as α-fluoro-β-alanine (FBAL). In one study, no clear impact of dif-ferences in creatinine clearance, age or gender upon the clear-ance or pharmacokinetic profile of capecitabine was noted [8].

A more extensive evaluation of the effect of renal insufficiencyupon the pharmacokinetics of capecitabine found no impactof renal function (as assessed by the Cockcroft-Gault formula)upon 5-FU or capecitabine. However, patients with renalinsufficiency did have increased systemic exposure to 5´-DFUR and FBAL and a significantly higher incidence ofsevere toxicities in those with severe renal dysfunction (creati-nine clearance < 30 ml/min). As a result of these findings, it isrecommended that patients with moderate renal dysfunction(creatinine clearance 35 – 50 ml/min) start therapy with a25% reduction from the recommended dose and that thosewith severe impairment not be treated with capecitabine [12].Indeed, an integrated analysis of the Phase III studies compar-ing capecitabine to the 5-FU–leucovorin combination on theMayo clinic schedule in patients with metastatic colorectalcancer has confirmed that patients with moderate renal dys-function have a greater incidence of severe grade 3 or 4 toxici-ties than those with normal kidney function [13].

4. Clinical efficacy

4.1 Phase I studiesCapecitabine as a single agent has been evaluated as a contin-uous schedule and a daily regimen for 2 weeks, followed by a1-week break. Budman et al. determined that the recom-mended dose for Phase II evaluation of capecitabine takencontinuously is 666 mg/m2 b.i.d. [6]. At higher doses, dose-limiting toxicities of diarrhoea, mucositis and palmar plantarerythrodysaesthesia (PPE), also called hand-foot syndrome,were noted. This toxicity, which has frequently been seen withboth capecitabine and continuous infusion 5-FU, has a rangeof presentations ranging from minimal discomfort in thepalms or soles to frank blistering and desquamation. In a dif-ferent study, allowing a 7-day break after every 14 days ofadministration, the recommended dose of capecitabine wasincreased to 1255 mg/m2 b.i.d. [7]. Again, the toxicities whichprevented further dose escalation were GI-based (diarrhoea,nausea and vomiting), PPE and myelosuppression. Anti-tumour activity was noted, including tumour shrinkage inpatients with breast, colon and oesophageal cancers and pro-longed stable disease in a patient with mesothelioma.

Given the benefit of adding leucovorin to 5-FU, Cassidyet al. performed a dose escalation study of capecitabine withleucovorin. When capecitabine and leucovorin were adminis-tered continuously, dose-limiting toxicities of nausea, vomit-ing and diarrhoea were noted in three of six patients assessed,so the administration of these drugs was changed to an inter-mittent schedule, with capecitabine and leucovorin beingadministered twice-daily for 14 days consecutively, followedby a 7-day respite. On the latter schedule, the twice-dailydose of 825 mg/m2 was recommended for further evaluationin combination with 30 mg b.i.d. of leucovorin on days 1 – 4every 3 weeks. At higher doses, the primary toxicities pre-venting continued escalation were nausea, vomiting, diar-rhoea and PPE [14].

Hwang & Marshall

Expert Opin. Pharmacother. (2002) 3(6) 735

4.2 Colon cancer4.2.1 Phase II studiesIn an attempt to better determine the antitumour activity ofcapecitabine, as well as the optimal schedule for further evalu-ation, Van Cutsem et al. performed a randomised, Phase IIstudy in 109 patients with metastatic colorectal cancer, whohad received no prior chemotherapy for metastatic disease,though 33 patients had received prior adjuvant 5-FU-basedchemotherapy. The three schedules determined in Phase Istudies were evaluated. Patients were treated continuously(666 mg/m2 b.i.d.) or for 14 days consecutively, followed by a7-day break (1250 or 825 mg/m2 b.i.d. in combination withleucovorin 30 mg b.i.d.). The objective response rates weresimilar in all three arms but the median time to progressionwas superior in the patients treated with intermittent capecit-abine monotherapy (Table 1). The toxicity in all three armswas similar, consisting primarily of PPE in 10 – 23% ofpatients and asymptomatic increase in bilirubin in 9 – 21% ofpatients. Severe diarrhoea was reported in 5 – 20% ofpatients; most frequently in the leucovorin-treated patients.Based on the increased time to progression, better safety pro-file and the finding that the intermittent schedule of capecit-abine resulted in the highest treatment delivery and doseintensity, this regimen was selected for further evaluation [15].

Before the development of the new generation of chemo-therapies, including irinotecan, oxaliplatin and capecitabine, acontinuous infusion schedule of 5-FU was frequentlyattempted in patients with metastatic colorectal cancer whodeveloped progression of disease despite initial therapy withbolus 5-FU. This regimen may result in tumour response andbenefit, albeit rarely. A Phase III study in the second-line set-ting demonstrated one confirmed partial response out of129 patients, a median survival of 8.5 months and 1-year sur-vival rate of 32.4%. However, the 1-year progression-free sur-vival rate was only 1.5% [16]. Since capecitabine mimics acontinuous infusion of 5-FU, it has been explored in this set-ting. The initial Phase I studies often included patients with

metastatic colorectal cancer who had received prior bolus 5-FU and confirmed minor and partial responses were reportedin several [7,14]. Hoff et al. evaluated capecitabine 1 g/m2 b.i.d.for 14 days consecutively, followed by a 7-day break.Although no objective responses were noted, six patients didhave prolonged stabilisation of disease, suggesting a possiblebenefit in a minority of patients, a finding similar to the out-come produced by a continuous infusion of 5-FU but withless difficulty of administration [17].

4.2.2 Phase III studiesGiven the logistical benefits of administering oral chemother-apy, as well as promising Phase II data, capecitabine 1250 mg/m2 b.i.d. for 14 days every 3 weeks has been compared to the5-FU–leucovorin combination in two large Phase III studies[18,19]. In both of these trials, 5-FU–leucovorin was adminis-tered on the Mayo clinic schedule (daily for 5 days consecu-tively every 28 days). The results of antitumour efficacy can beseen in Table 2. Both studies demonstrate that capecitabine hasactivity at least equal activity to that of 5-FU and leucovorin,as measured by objective response (18.9 and 24.8% forcapecitabine and 15.5 and 15% for 5-FU), median duration ofresponse (7.2 – 9.1 and 9.4 – 9.5 months, respectively), timeto tumour progression (4.1 – 5.2 and 3.1 – 4.7 months,respectively) and median survival (12.5 – 13.2 and 12.1 – 13.3months, respectively). As expected on the basis of earlier stud-ies, the two treatment regimens were generally well-tolerated.Considering all grades of toxicity, there was less diarrhoea, sto-matitis, nausea and alopecia but more PPE in patients treatedwith capecitabine than in those treated with the Mayo clinicschedule of 5-FU. In terms of severe toxicities, patients treatedwith capecitabine were more likely to have severe PPE (16 ver-sus < 1%) and a marked, generally asymptomatic increase inbilirubin (17 – 24 versus 5 – 7%) and patients treated with theMayo clinic schedule of 5-FU and leucovorin were morelikely to experience severe stomatitis (13 – 16 versus 1 – 3%)and neutropenia (19 – 26 versus 1 – 3%), including neutro-

Table 1. Capecitabine in metastatic colorectal cancer.

Author Daily dose*‡

(mg/m2)Response# (%) Median survival Median time

to progressionComment Ref.

Van Cutsem (2000) 2510 8 of 34 (24)21 SD

NR 230 days(37 weeks)

Randomised Phase II [15]

Van Cutsem (2000) 1657 8 of 35 (23) NR 165 days(23 weeks)

With leucovorin, randomised Phase II

[15]

Van Cutsem (2000) 1331§ 8 of 39 (21) NR 127 days(18 weeks)

Randomised Phase II [15]

Hoff (2001) 2500 75 of 302 (25)146 SD

12.5 months 4.1 months Phase III [18]

Van Cutsem (2001) 2500 57 of 301 (19) 13.2 months 5.2 months Phase III [19]

Hoff (2000) 2000¶ 0 of 19 (0) NR NR Phase II after i.v. 5-FU failure [17]

*All administered daily for 14 days every 21 days, except §, which was administered continuously. ‡ All first-line, except ¶, which is second-line. # Number of patients. 5-FU: 5-fluorouracil; NR: Not reported; SD: Stable disease.



penic fever and sepsis, resulting in more hospitalisations forsevere adverse events for patients treated with 5-FU. On thebasis of these results and the easier method of administration,capecitabine has received FDA and European Agency for theEvaluation of Medicinal Products approval for first-line, sin-gle-agent use in patients with metastatic colorectal cancer inwhom combination therapy is not indicated.

4.3 Breast cancer5-FU has long been known to have antitumour activity inpatients with breast cancer, both as an intravenous bolus andas a continuous infusion [20,21]. Capecitabine has also beenextensively evaluated in this patient population. As initialchemotherapy, capecitabine 1250 mg/m2 b.i.d. for 14 daysfollowed by a 7-day respite was compared to the cyclophos-phamide–methotrexate–5-FU (CMF) intravenous combina-tion administered every 3 weeks. After external review of theresults, objective tumour regression was noted in 20% of the61 capecitabine-treated patients (compared to 9% of CMF-treated patients), including three patients with complete reso-lution of radiologically noted tumour. The median survival ofpatients treated with capecitabine was 19.6 months(17.2 months with CMF) and median time to progression ofdisease was 4.1 months (3 months with CMF). Capecitabinetherapy was generally well-tolerated, with severe PPE develop-ing in 15% of patients but severe neutropenia or diarrhoeaonly developing in 8% of patients [22].

A large, multi-centre, Phase II study evaluated the efficacyof capecitabine in patients with disease that had progressed onat least paclitaxel-based therapy. In addition, 91% of the 163patients had received prior anthracyclines and 82% were pre-viously treated with 5-FU. These patients received capecitab-ine 1250 mg/m2 b.i.d. Objective tumour responses werenoted in 20% of 135 evaluable patients, including three com-plete responses. Prior 5-FU did not impede the efficacy ofcapecitabine, as 17 of 27 patients with response had receivedprior 5-FU. An additional 30% of patients had stable disease.The median survival was 384 days (12.8 months) and themedian time to progressive disease was 93 days (3 months).The principal toxicity noted was moderate-to-severe PPE in32 and 10% of patients, respectively. Severe diarrhoea wasreported by 14% of patients and asymptomatic, transient

hyperbilirubinaemia by 10%. On the basis of this study,capecitabine has been approved for therapy in patients withmetastatic breast cancer that has progressed despite prioranthracycline and taxoid therapy [23].

In addition, Phase II studies have demonstrated thatcapecitabine can cause tumour regression in a variety of treat-ment settings, including most promisingly, patients who havedeveloped progressive or recurrent disease after prior high-dose chemotherapy with stem cell transplantation [25,26]. Oth-ers have confirmed that capecitabine has antitumour activityin patients who have breast cancer that has progressed despiteprior taxoids [27-31] (Table 3).

4.4 Other malignanciesBased on the antitumour activity of 5-FU in many differenttumour types, capecitabine has been evaluated in pancreatic,biliary, oesophagogastric, hepatocellular and renal cell carci-nomas. Other ongoing studies have been designed to deter-mine the utility of capecitabine in combination with otherchemotherapy agents in these and other tumour types, includ-ing non-small cell lung cancer.

4.4.1 Pancreaticobiliary cancerUntil the advent of gemcitabine, 5-FU was the mainstay oftherapy for pancreatic cancer. Cartwright et al. performed aPhase II study of capecitabine in 44 patients with advancedpancreatic cancer who had received prior chemotherapy. Thecapecitabine was administered at 1250 mg/m2 b.i.d. for2 weeks, repeated every 21 days. Although the response ratewas unimpressive (3 of 41 patients, 7.3%), the antitumouractivity was similar to that reported for many other chemo-therapeutic agents, including gemcitabine. The toxicity pro-file reported was similar to that from other studies evaluatingcapecitabine on this schedule, including severe diarrhoea in17% of patients, severe PPE in 17% of patients and severenausea and vomiting in 10% of patients [32].

Capecitabine 1 g/m2 b.i.d. for 14 days repeated every 21days was evaluated in hepatobiliary cancers. Preliminary datademonstrated clear antitumour efficacy, with partial responsesin five of 37 patients (13%) with hepatocellular carcinoma,four (including two complete responses) of eight patients withgall bladder carcinoma and one of 18 patients (5%) with

Table 2. Capecitabine versus 5-fluorouracil and leucovorin in metastatic colorectal cancer.

Study Drug Complete response* (%)

Partial response*

Overall response* (%)

Duration of response (months)§

Time to progression (months)§

Survival (months)§

Ref.

Hoff (2001) CAP 3 of 302 (1) 72 of 302 75 of 302 (24.8) 9.1 4.3 12.5 [18]

Hoff (2001) 5-FU 3 of 303 (1) 44 of 303 47 of 303 (15.5) 9.5 4.7 13.3 [18]

Van Cutsem (2001)

CAP 1 of 301 (0.3) 56 of 301 57 of 301 (18.9) 7.2 5.2 13.2 [19]

Van Cutsem (2001)

5-FU 2 of 301 (0.7) 43 of 301 45 of 301 (15) 9.4 4.7 2.1 [19]

*Number of patients. §Median values. CAP: Capecitabine; 5-FU: 5-Fluorouracil.

Hwang & Marshall


cholangiocarcinoma. The 1-year survival rate of patients witheach tumour type was 67, 100 and 60%, respectively. Thetoxicities observed were similar to other studies, includingPPE (of any severity) in 37% of patients. The only other sig-nificant toxicity reported was grade 3 thrombocytopenia in8% of patients with hepatocellular carcinoma [33].

4.4.2 Gastric cancerJapanese investigators performed a Phase II study of capecit-abine administered at a total daily dose of 1657 mg/m2

(divided and administered twice-daily) for 21 days andrepeated every 28 days in patients with advanced gastric can-cer. Responses were reported in 19.4% of 31 patients. Themedian survival time was 248 days, with a median time toprogression of 85 days. Capecitabine was well-tolerated, withsevere toxicity occurring in few patients, most notably asasymptomatic hyperbilirubinaemia in 6.3% of patients [34].

4.4.3 Renal cell carcinomaRenal cell carcinomas are another area in which 5-FU mayplay a therapeutic role. Wenzel et al. treated 26 patients withimmunotherapy-refractory renal cell carcinoma with capecit-abine 1250 mg/m2 b.i.d. for 14 days consecutively, followedby a 7-day break. Partial responses to therapy were noted intwo of these patients (8.7%) and stable disease was seen in 19patients. Severe PPE was noted in two patients and severeanaemia in one. A group of investigators from Germany sub-sequently combined capecitabine with immunotherapy (IL-2, IFN-α and 13-cis-retinoic acid) in patients with chemo-therapy naive metastatic renal cell carcinoma. This combina-tion produced tumour shrinkage in a third of 30 patients,including two complete remissions. The toxicity was rela-tively mild, with severe nausea, vomiting and stomatitis inone patient each and PPE in two patients [35,36]. A Phase IIIevaluation is ongoing.

5. Safety and tolerability

The primary toxicities of capecitabine are similar to thosedefined in the Phase I studies and are, in general, similar tothose expected from a continuous infusion of 5-FU. The mostprominent of these is PPE, which usually presents initially asdiscomfort in the palms or soles, followed later by erythemaand frank pain and blistering and desquamation in the mostsevere cases. After the cessation of capecitabine, the symptomsabate over a period of days or weeks. In Phase II and III stud-ies evaluating a total daily dose of capecitabine of 2000 –2510 mg/m2 for 14 days every 21 days consistently reportedsevere PPE in ~ 15 – 20% of patients, with milder PPE in25 – 30% of patients [15,18,19,22,23,32]. The frequency of PPEdoes not appear to be influenced by the cumulative dose ofcapecitabine and a retrospective evaluation of patients treatedwith capecitabine for breast cancer demonstrated that 92.8%of patients who developed PPE had done so by the secondcycle of therapy and that almost 67.8% of patients experi-enced the most severe PPE by the second cycle of therapy.PPE responded to withholding of subsequent doses ofcapecitabine, followed by a reduction of the dose of capecitab-ine [37]. The use of emollients are advisable but cannot replacethe interruption of therapy, with subsequent dose reduction.It is currently recommended that patients with significantPPE have capecitabine withheld until resolution of the symp-toms, and therapy resumed at a 25% dose reduction, withcontinued close follow-up.

Pyridoxine (vitamin B6) has been considered as a potentialtherapy for PPE. A retrospective evaluation has suggested that2 g/day may result in a greater symptomatic benefit and allowprolonged therapy for patients taking capecitabine [38]. Thispossibility is being prospectively studied.

Besides PPE, GI toxicities dominate the toxicity profile ofcapecitabine. Diarrhoea was classified as severe in 8 – 17% of

Table 3. Capecitabine in metastatic breast cancer.

Study* Patient response rate (%)

Median time to progression

Comment Ref.

O’Shaughnesssy (2001) 9 of 44 (20) 4.1 months Randomised Phase II. Median survival 19.6 months [22]

Blum (1999) 27 of 135 (20) 93 days (13 weeks) Salvage therapy. Median survival 384 days (55 weeks) [23]

Blum (2001) 19 of 75 (26) 3.2 months Salvage therapy after taxanes. Median survival 12.2 months

[24]

Wong (2000) 6 of 22 (27) NR Third-line therapy [27]

Cervantes (2000) 13 of 32 (41) NR Third-line therapy after taxanes [28]

Sundaram (2000) 5 of 7 (71) NR After prior stem cell transplant [25]

Jakob (2001) 7 of 13 (54) 128 days (18 weeks) Median survival 390 days (57 weeks) after prior stem-cell transplant

[26]

Kusama (2001) 13 of 46 (28) 155 days (22 weeks) [29]

Watanabe (2001) 11 of 55 (20) 84 days (12 weeks) Salvage therapy after docetaxel [30]

Thuss-Patience (2001) 18 of 100 (18) NR Salvage therapy after taxanes [31]

*All reports are Phase II studies and are of salvage therapy, except [22]. Standard dosing is capecitabine 1250 mg/m2 b.i.d. over 14 days every 21 days, except [29,30] which are capecitabine 825 mg/m2 b.i.d. over 21 days every 28 days. NR: Not reported.



patients in various studies, occurring in some form in up tohalf of patients overall. Nausea and vomiting is reported in~ 40% of patients and is classed as severe in 4 – 10% of cases.Stomatitis is a less common toxicity, occurring in 15 – 30% ofpatients and is severe in 2 – 11% of patients [14,18,19,22,24,32].

The other common group of toxicities in patients treatedwith capecitabine showed up as laboratory-detected abnormal-ities. Hyperbilirubinaemia was generally transient and asymp-tomatic but was reported as grade 3 or 4 in 5 – 30% ofpatients. Myelosuppression was uncommon, with < 10% ofpatients experiencing severe neutropenia or thrombocytopeniaand infection. An additional toxicity that must be monitored isa potential interaction of capecitabine with warfarin, resultingin an unanticipated increase in the prothrombin time. Thus,patients taking both capecitabine and warfarin should havetheir international normalised ratio checked more frequentlyto avoid complications.

Fatigue is another adverse reaction that has been reportedin patients treated with capecitabine. Although it is difficultto quantify and assess, approximately a quarter of patientsexperience fatigue and it is severe in 2 – 8% of patients.

Because significant toxicity has been observed, patient edu-cation and follow-up remains important, despite the out-patient nature of the therapy. When severe toxicity, such asPPE, diarrhoea, nausea, vomiting or stomatitis, occurs, it isrecommended that the dose of capecitabine be reduced by25%. When these recommendations are followed, tolerabilityusually improves. O’Shaugnessy et al. retrospectively evalu-ated the efficacy of capecitabine in patients whose toxicitieswere treated with dose interruption and reduction andreported that therapy was better tolerated and also as effectiveas in patients who were treated with the usual dose [39]. Therecommendation of a 25% reduction in the starting dose forpatients with moderate renal impairment and those who aremore frail or elderly will avoid toxicity due to higher systemicexposure to active metabolites.

6. Combination chemotherapy

Due to the broad spectrum of activity of capecitabine, its lowtoxicity and ease of administration, it has been combined witha number of different agents in Phase I, II and III trials. Rec-ognising that TP is the key enzyme in the activation ofcapecitabine, the identification of agents that increase the lev-els of TP may enhance the antitumour activity of capecitabineby increasing the intratumoural generation of 5-FU. An addi-tional rationale for combining capecitabine with other chem-otherapeutic agents is the fact that 5-FU has been successfullycombined with a number of drugs, including irinotecan, gem-citabine and the platinum-based drugs, thereby enhancing theantitumour activity of the combination.

6.1 Paclitaxel and docetaxelPreclinical studies have demonstrated that the taxanes (paclit-axel and docetaxel) result in an upregulation of TP, with the

potential for synergistic activity with capecitabine [40]. As aresult, studies evaluating the combination of these therapieshave been launched. Only Phase I results have been fully pub-lished to date. Villalona-Calero et al. evaluated a continuousschedule of capecitabine with paclitaxel administered intrave-nously over 3 h on the first day of every 21-day cycle. Thedoses recommended for further evaluation were capecitabine666 mg/m2 b.i.d. and 175 mg/m2 of paclitaxel, with dose-lim-iting toxicities of neutropenia and neutropenic fever. Theother toxicities noted were diarrhoea, hyperbilirubinaemiaand myalgia/arthralgia. No interactions of the two drugs werenoted, regardless of the sequence of administration of thedrugs [41]. The same combination was evaluated with capecit-abine administered intermittently during the first 14 days ofevery 21 day schedule has also been evaluated. The doses rec-ommended for further evaluation were capecitabine 825 mg/m2 b.i.d. with paclitaxel 175 mg/m2 i.v. every 3 weeks. Thedose-limiting toxicities were PPE and neutropenia. Hyperbi-lirubinaemia and diarrhoea were also noted. No pharmacoki-netic interaction was found in this small group of patients.The activity was intriguing, with objective responses docu-mented in nine of 16 patients, including two completeresponses and responses in patients who had undergone priorhigh-dose chemotherapy [42]. A Phase I study combiningintermittent capecitabine with weekly paclitaxel is ongoing[43]. None of these studies have reported the interaction of thedrugs on the molecular level or with TP.

The intermittent schedule of capecitabine (825 mg/m2

b.i.d. for 14 days every 21 days), with paclitaxel 175 mg/m2

i.v. every 21 days was evaluated in a Phase II study of patientswith breast cancer. The preliminary report noted responses in49% of 37 patients, including 6 of 11 patients previouslytreated with chemotherapy. Overall, toxicities were mild, withsevere neutropenia in 14%, severe PPE in 11% and severefatigue in 11% of patients [44].

Docetaxel, which is a more potent microtubule inhibitorthan paclitaxel in vitro, has also been studied in combinationwith capecitabine. Phase I studies of docetaxel combined withcapecitabine have been performed and Pronk et al. recom-mended capecitabine 1250 mg/m2 b.i.d. for 14 days anddocetaxel 75 mg/m2 i.v. every 21 days for further evaluation,essentially the usual systemic dose of capecitabine and a 25%lower dose of docetaxel than is used individually. The dose-limiting toxicities were aesthenia and fatigue but other impor-tant toxicities included stomatitis, diarrhoea, nausea, vomit-ing and neutropenia. No pharmacokinetic interactions werenoted between capecitabine and docetaxel, although at thehighest doses of capecitabine and docetaxel evaluated, the sys-temic levels of 5-FU were somewhat diminished [45].

Capecitabine–docetaxel combination has undergone PhaseIII evaluation in comparison to docetaxel alone in a study of501 metastatic breast cancer patients after anthracycline fail-ure. The preliminary results of this study show that the combi-nation is superior to docetaxel alone, increasing the mediantime to progression (6.1 versus 4.2 months), median survival

Hwang & Marshall


(14.5 versus 11.5 months) and response rate (42 versus 30%).However, the combination also resulted in greater toxicity,especially severe PPE, stomatitis and diarrhoea. However, agreater incidence of fever, myalgia and neutropenic fever werenoted in the docetaxel monotherapy arm [46]. Based on theseresults, the FDA has approved this combination for use as ini-tial chemotherapy for patients with metastatic breast cancer.

6.2 GemcitabineBecause of complimentary mechanisms of action, a gemcitab-ine–5-FU combination has been evaluated in patients with anumber of malignancies, especially pancreatic and renal cellcancers. A Phase I study combining gemcitabine with capecit-abine has been performed which recommended a dose ofgemcitabine 1 g/m2 i.v. weekly for 3 weeks and capecitabine1660 mg/m2/day (divided twice-daily) for 21 days, repeatedevery 28 days. The only dose-limiting toxicity encounteredwas diarrhoea. Other adverse events were primarily neutrope-nia, which was rarely complicated. Interestingly, objectiveresponses were noted in two of 21 patients who had progres-sive disease despite prior 5-FU therapy, suggesting a possiblesynergy between the two compounds [47].

6.3 IrinotecanThe current reference standard first-line regimen for meta-static colorectal cancer in the US is the irinotecan–5-FU–leu-covorin combination. This has been shown to be superior to5-FU–leucovorin or single-agent irinotecan in terms of sur-vival and tumour response [48]. In an attempt to improveupon this treatment regimen, studies evaluating a irinotecan–capecitabine combination are underway. An Italian studyempirically combined these drugs using capecitabine1250 mg/m2 b.i.d. for 14 days starting on day 2 with irinote-can on two different schedules (arm A 300 mg/m2 on day 1;arm B 150 mg/m2 on days 1 and 8). Both schedules demon-strated antitumour activity but because of toxicity, primarilyPPE, diarrhoea, nausea and myelosuppression, the authorshave elected to study this combination of drugs using differ-ent doses [49]. Other trials evaluating weekly schedules of iri-notecan in combination with capecitabine are ongoing [50].Although this combination appears promising, definitivePhase III trials will be delayed until the optimal combinationof these drugs has been determined.

6.4 OxaliplatinGiven the synergy between oxaliplatin and 5-FU, studies eval-uating oxaliplatin–capecitabine combinations are being per-formed. Diaz-Rubio et al. have recommended a combinationof 130 mg/m2 of oxaliplatin with 2 g/m2 of capecitabine dailyfor 14 days, repeated every 21 days for further evaluation. Inthis study, the primary dose-limiting toxicity was diarrhoea[51]. DeSantis et al. had similar results, recommending a doseof 120 mg/m2 of oxaliplatin and 2500 mg/m2/day of capecit-abine, reporting dose-limiting diarrhoea and stomatitis, aswell as severe vomiting [52]. However, Thomas et al. were

unable to deliver the similar doses of capecitabine(3600 mg/day total, fixed dose) in women because of dose-limiting PPE or diarrhoea. After changing the schedule todays 1 – 5 and 8 – 12 dosing, therapy was more tolerable [53].

Preliminary results suggest that this combination has prom-ising activity. With this combination, Borner et al. reportedobjective responses in 44% of 34 patients in the first-line set-ting, and in 22% of 23 patients as salvage therapy. The toxici-ties were felt to be tolerable and were most notably severediarrhoea in a third and a half of patients, respectively. Severenausea, vomiting and neurosensory toxicity was noted in< 15% of patients [54]. An additional study as first-line ther-apy for metastatic disease using oxaliplatin 130 mg/m2 every3 weeks in combination with capecitabine 1 g/m2 b.i.d. for14 days repeated every 3 weeks has been reported. The pre-liminary results have demonstrated an objective response in55% of the 96 patients treated and a median time to progres-sion of 7.1 months. This combination was well-tolerated,with the main severe toxicities being GI-based (nausea, vomit-ing, diarrhoea) and neuropathy [55].

6.5 Cisplatin and carboplatinA combination of platinum and 5-FU has long been consid-ered to be a standard therapy for patients with metastatic orrecurrent head and neck cancer and an important therapeuticoption for patients with oesophageal and gastric cancer. As aresult of the easier administration of oral capecitabine, thisdrug is also being studied in combination with the platinums.In a preliminary report in patients with metastatic non-smallcell lung cancer, Akhtar et al. have evaluated the combinationof carboplatin (AUC 5) and capecitabine 2 g b.i.d. for 14 daysrepeated every 28 days. With a limited number of patientsenrolled, antitumour activity somewhat greater than expectedwith single-agent carboplatin has been noted. Of the11 patients enrolled, three had to discontinue therapy becauseof diarrhoea (two patients) and vomiting (one patient). Theseearly data suggest that this combination may have at leastadditive but perhaps synergistic toxicity and activity [56].

Kim et al. combined standard dose capecitabine (2500 mg/m2/day for 14 days repeated every 21 days) and cisplatin60 mg/m2 i.v. on day 1 in patients with advanced gastric can-cer without prior chemotherapy. Promising antitumour activ-ity has been reported (partial responses in 11 of 16 patients),with moderate or acceptable toxicity, primarily myelosuppre-sion, including severe neutropenia (36% of patients) andmoderate or severe PPE in 20% of patients. Severe stomatitisand diarrhoea occurred in < 5% of patients [57].

6.6 VinorelbineLike the taxanes, vinorelbine is a chemotherapeutic agentactive against breast cancer, whose primary mode of action isthrough its impact on microtubules. Preclinical data has alsodemonstrated synergistic cytotoxicity with the combination ofcapecitabine and vinorelbine. A Phase I study performed inGermany demonstrated that capecitabine 1 g/m2 b.i.d. for



2 weeks (days 1 – 14 and 22 – 35), with vinorelbine 30 mg/m2 on days 1, 8, 22 and 29 was well-tolerated, with dose-lim-iting toxicities of nausea, vomiting and diarrhoea. In thisgroup of patients who had received prior chemotherapy, clearantitumour efficacy was noted [58].

6.7 New agentsFurther exploration of the interaction of capecitabine withcytotoxic chemotherapy continues and the next phase ofdevelopment of anticancer therapy, the non-cytotoxic and tar-geted therapies, are also being investigated. Preliminary stud-ies are ongoing, including studies on agents such as thehistone deacetylator CI-994, the farnesyl transferase inhibitorR115777 and monoclonal antibody against vascular endothe-lial growth factor.

Investigators at the University of Chicago studied the com-bination of CI994 with capecitabine, with both administeredorally for 14 days every 21 days. The dose recommended forfurther evaluation was 8 mg/m2 of the former and 1650 mg/m2 of the latter daily, the dose-limiting toxicity being PPE.Limited pharmacokinetic data suggests no interactionbetween these drugs [59].

Holden et al. combined capecitabine with R115777 anddetermined the maximally tolerated dose to be 2250 mg/m2/day of the former and 300 mg b.i.d. for 14 days of the latter,every 21 days. The dose-limiting toxicities were diarrhoea andPPE. The doses were essentially those found for each of theagents individually and the lack of significant interaction wasconfirmed by preliminary pharmacokinetic analysis [60].Given the different modes of action and non-overlapping tox-icity of the new targeted and non-cytotoxic therapies withcapecitabine, it is possible that for most of these combinationsthe systemic doses of both drugs will be useable, optimisingthe activity of both agents. This remains to be determined butgenerates much enthusiasm for the future, both for theseagents and for similar therapeutics.

7. Capecitabine and radiation

5-FU is often used to enhance the activity of radiation inpatients with GI malignancies [61]. Moreover, recent evidencehas suggested that a continuous infusion of 5-FU may be supe-rior to bolus 5-FU when combined with radiation in patientswith rectal cancer [62]. Therefore, since capecitabine generates5-FU specifically in the tumour, rather than in adjacent nor-mal tissue, and acts in a similar way to a continuous infusion,capecitabine may improve the therapeutic index chemoradia-tion combinations. In addition, preclinical data suggests thatradiation may upregulate TP, potentially further enhancing theactivity of capecitabine in patients also receiving radiation, inaddition to the radiosensitising activity of 5-FU [63]. Indeed,initial studies are currently ongoing in rectal cancer, due to theimportance of the radiation–5-FU combination in GI malig-nancies. Durst et al. have combined capecitabine with stand-ard once-daily radiation in patients with rectal cancer in a

Phase I study and have recommended capecitabine 825 mg/m2

b.i.d. in this setting. No life-threatening toxicities occurredand the adverse events that defined the recommended dosewere moderate PPE and abdominal pain [64]. Further studiesare being planned in upper GI malignancies.

8. Conclusion

Capecitabine is a fluoropyrimidine carbamate designed tobypass the difficulties of oral chemotherapy by absorption ofthe prodrug, followed by preferential intratumoural metabo-lism and activation of the drug into the active moiety, 5-FU.This results in specific delivery of 5-FU to the tumour. Stud-ies have demonstrated clear antitumour activity in patientswith colorectal and breast cancer, resulting its approval bothas a single agent and in combination with docetaxel.

Capecitabine has clearly demonstrated an important role inthe therapy of patients with metastatic cancer. This drug isadministered orally and results in the generation of 5-FUpreferentially in the tumour, mimicking a continuous sys-temic infusion. In metastatic colorectal cancer, continuousinfusions of 5-FU have been demonstrated to have a greaterlikelihood of inducing tumour shrinkage and superior survivalto bolus 5-FU. Taken together, the data suggests that capecit-abine is a reasonable alternative to 5-FU and indeed, may bebetter than 5-FU. However, the task of replacing 5-FU withcapecitabine in combination regimens will require specificevaluation of such combinations.

Trials incorporating capecitabine into combination regi-mens are ongoing with particular emphasis on the upregula-tion of TP by agents including the taxoids, vinorelbine andradiation are ongoing as well.

Although patients have noted a preference for orallyadministered chemotherapy compared to infused chemother-apy, capecitabine at the recommended dose of 2500 mg/m2

(divided and administered twice-daily) for 14 days every 21days, is not without toxicity. The most common toxicities arePPE, diarrhoea, nausea, vomiting and stomatitis. With closemonitoring and appropriate dose reduction of therapy whentoxicity develops, capecitabine is well-tolerated.

9. Expert Opinion

Although capecitabine has demonstrated an acceptable toxic-ity profile overall, some patients have experienced difficultymaintaining the recommended doses of capecitabine fromPhase II and III studies, which is 1250 mg/m2 b.i.d. At thistime, most chemotherapy is dosed based on body surface area(BSA), in the belief that BSA reflects renal clearance of drugs.However, limited studies in capecitabine [8] and other chemo-therapeutic agents, such as irinotecan, suggest that this maynot be correct [65,66] and that a simpler, fixed dosing regimenmay be worthy of further investigation.

The retrospective study by O’Shaughnessy showed no cleardifference in antitumour activity between patients who were

Hwang & Marshall


treated with capecitabine at reduced doses after experiencingtoxicity and those who were treated at the intended doses.This is quite intriguing [39]. The integrated evaluation of thePhase III studies comparing capecitabine to 5-FU–leucovorinon the Mayo schedule also suggested a similar antitumoureffect of capecitabine in patients who required a dose reduc-tion for toxicity compared to those who received the full dosewithout modification. O’Shaughnessy’s retrospective data andthe integrated Phase III data require confirmation but thesefindings suggest an important shortcoming of the potentiallyoutdated method of drug development in oncology, thenotion of maximum tolerated dose and the evaluation of ther-apy based upon those doses. Further evaluation of chemother-apy, such as capecitabine and other targeted therapies, at doseslower than the maximum tolerated dose in hopes of furtherimproving the tolerability of therapy and the assessment ofactivity at such levels may be an important direction as wecontinue to attempt to optimise cancer therapy and perhapsnot as unethical as once thought.

Owing to its promise as an anticancer agent with an excel-lent toxicity profile, capecitabine continues to undergo exten-sive evaluation in settings where 5-FU was or continues to bean important element of therapy. In particular, the ease ofadministration and benefits of continuous exposure to 5-FUhas resulted in the initiation of studies to assess the properdosage for capecitabine in combination with radiation in vari-

ous GI malignancies. Moreover, extending upon the results ofO’Shaughnessy’s report of superior survival in patients withmetastatic breast cancer treated with docetaxel and capecitab-ine, in comparison to docetaxel alone, studies evaluating thiscombination as an adjuvant therapy in patients with earlybreast cancer are ongoing. Similarly, the potential role of sin-gle-agent capecitabine in early breast cancer are planned.

As we enter an age where therapies targeting specificmechanisms of tumour development, growth and spread, arebecoming a reality, capecitabine has proven to be among thefirst of these rationally designed agents, along with trastuzu-mab and aromatase inhibitors to demonstrate anticancer effi-cacy. Orally-administered capecitabine has beendemonstrated to be at least equivalent to the active com-pound, 5-FU administered as a bolus on the Mayo clinicschedule in patients with metastatic colorectal cancer and hasactivity in other GI malignancies. Moreover, in the treatmentof patients with breast cancer, capecitabine is the only agentapproved for use in patients with progressive disease afteranthracycline and taxoid therapy, as well as in combinationwith docetaxel. In addition to its notable antitumour activity,capecitabine provides an added advantage in the quest forimproving cancer therapy, ease of administration. Patients donot need to return repetitively to out-patient clinics for intra-venous administration of therapy but rather are empoweredto help control their own therapy.

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AffiliationJimmy J Hwang MD† & John L Marshall MD†Author for correspondenceGeorgetown University Medical Center, 3800 Reservoir Road, NW, Lombardi Cancer Center, P-426, Washington DC 20007, USAE-mail: [email protected]

capecitabine: fulfilling the promise of oral chemotherapy

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