Review of capecitabine as oral treatment of gastric, gastroesophageal, and esophageal cancers

Authors

  • Jaffer Ajani MD

    Corresponding author
    1. Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
    • Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Box 426, 1515 Holcombe Boulevard, Houston, TX 77030-4009
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Abstract

Capecitabine is a novel, orally administered fluoropyrimidine carbamate that has been approved for adjuvant treatment in patients with Stage III colon cancer, first-line metastatic colorectal cancer, and metastatic breast cancer, both as a single agent (for patients who are resistant to paclitaxel and anthracyclines) and in combination with docetaxel (after failure on anthracycline-based therapy). Capecitabine is being investigated in Phase I and II trials for the treatment of gastric, gastroesophageal, and esophageal cancers, primarily in the first-line metastatic setting but also in the adjuvant setting. The MEDLINE data base was searched for English-language clinical trials that were published from 1996 through October 2005 along with relevant abstracts that were presented at the American Society of Clinical Oncology and at meetings of the European Cancer Conference and the European Society of Medical Oncology. The most frequently investigated combinations were capecitabine with docetaxel, paclitaxel, cisplatin, or oxaliplatin, and capecitabine also has been combined with irinotecan. These therapies have yielded efficacy data that compare favorably with data from Phase III trials of parenteral 5-fluorouracil (5-FU) in the first-line metastatic setting, and they mostly are well tolerated. Capecitabine, when combined in doses <1250 mg/m2 twice daily, consistently resulted in a lower frequency of Grade 3 or 4 toxic effects. Capecitabine, as a representative of oral fluoropymidine, is a promising agent in gastroesophageal cancers. Although some Phase III trials are completed, additional Phase III trials of capecitabine-based combinations that compare its efficacy and safety with parenteral 5-FU–based combinations, in both first-line metastatic and adjuvant settings, would be important. Cancer 2006. © 2006 American Cancer Society.

Gastric cancer is the fourth most common cancer worldwide, with 934,000 new diagnoses annually, and it is the second most common cause of cancer-related death, with 700,000 deaths annually.1 Parenteral 5-fluorouracil (5-FU) has been used since the early 1980s to treat chemonaive patients with advanced gastroesophageal cancer. In a randomized controlled trial (RCT), Cullinan et al.2 treated 151 patients with continuous intravenous infusion (CIV) 5-FU with doxorubicin and mitomycin-C (FAM), CIV 5-FU with doxorubicin (FA), or CIV 5-FU alone. Patients who received FAM had superior disease-free survival compared with patients who received 5-FU alone (P = .005), but they did not have superior overall survival (P = .17). Since that trial, several RCTs have compared parenteral 5-FU–based regimens for the treatment of gastric cancer in chemonaive patients (Table 1). In an RCT that compared 2 combinations of 5-FU/doxorubicin, with methotrexate (FAMTX) or mitomycin-C (FAM),3 patients who received FAMTX had a significantly longer median survival (P = .004). In a subsequent RCT,4 patients who received epirubicin, cisplatin (CDDP), and CIV 5-FU (ECF) had significantly superior median progression-free survival (P = .0009) and median overall survival (P = .00006) compared with patients who received FAMTX. That trial was plagued with multiple clinical trial methodology problems. Most RCTs have employed poor clinical methodology and monitoring of studies, often lacking stratifications, data monitoring committees, appropriate endpoints, inclusion of esophageal cancer, resection of localized cancer, and mixture of locally advanced versus metastatic patients. Another RCT of patients with gastroesophageal cancer showed no significant difference in response rates (RRs), progression-free survival, or overall survival among patients who received FAMTX, combination CIV 5-FU with CDDP, or combination bolus 5-FU with leucovorin (LV) and etoposide.5 Chemotherapy overall largely has been palliative, with poor response and survival rates, and without a standard regimen,6, 7 although meta-analyses have shown that chemotherapy is superior to best supportive care alone.8, 9 Recently, a combination of parenteral 5-FU, CDDP, and docetaxel was investigated for first-line treatment of metastatic gastric cancer.10, 11 Meta-analyses of adjuvant chemotherapies have yielded conflicting efficacies.12–14

Table 1. Selected Phase II or III Parenteral or Oral 5-Fluorouracil–Based Therapies for the Treatment of Advanced or Metastatic Gastric,Gastroesophageal, or Esophageal Cancer
StudyCancer/Treatment linePhaseRegimenNo.*Activity (%)Median survival, months
  • 5-FU indicates 5-fluorouracil; RCT, randomized controlled trial; Dox, doxorubicin; MTX, methotrexate; CR, complete response rate; RR, (objective) response rate; MMC, mitomycin-C; GE, gastroesophageal; CIV, continuous intravenous infusion; CDDP, cisplatin; LV, leucovorin; UFT, uracil and tegafur; S-1, an oral 5-FU chemotherapeutic agent that contains tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate.

  • *

    The number of patients included in the survival analysis.

  • P < .05.

Parenteral: 5-FU
 Wils et al., 19913Gastric, 1st lineIII (RCT)FAMTX: 5-FU (bolus) + Dox + MTX105CR, 5; RR, 339.7
FAM: 5-FU (bolus) + Dox + MMC103RR, 76.7
 Waters et al., 19994GE, 1st lineIII (RCT)ECF: 5-FU (CIV) + epirubicin + CDDP126CR, 8; RR, 468.7
FAMTX130CR, 2; RR, 216.1
 Vanhoefer et al., 20005Gastric, 1st lineIII (RCT)ELF: 5-FU (bolus)/LV + etoposide129RR, 97.2
FUP: 5-FU (CIV) + CDDP127RR, 207.2
FAMTX122RR, 126.7
Oral: UFT
 Kim et al., 199615Gastric, included previous treatmentIIUFT/LV14CR, 7; RR, 295.8
 Ravaud et al., 200116Gastric, 1st line metastaticIIUFT/LV25CR, 4; RR, 16NA
 Ohtsu et al., 200317Gastric, 1st lineIII (RCT)UFT + MMC70RR, 97.1
(CIV) 5-FU105RR, 347.3
(CIV) 5-FU + CDDP105RR, 116.0
 Oh et al., 200518Gastric, 1st lineIIUFT/LV + CDDP + docetaxel52CR, 8; RR, 5011.1
 Jeen et al., 200119Gastric, 1st lineIIUFT/LV + CDDP + epirubicin59CR, 6; RR, 5815.0
 Woo et al., 200520Gastric, 1st lineIIUFT + CDDP + epirubicin32RR, 418.5
Oral: S-1
 Sakata et al., 199821Gastric, 1st lineIIS-151CR, 2; RR, 498.2
 Koizumi et al., 200022Gastric, 1st lineIIS-150RR, 4416.7
 Chollet et al., 200323Gastric, 1st lineIIS-123CR, 5; RR, 32NA
 Iwase et al., 200524Gastric, 1st lineIIS-1 + CDDP42CR, 5; RR, 5011.3

Oral FU-based therapies are being investigated for advanced or metastatic gastric (and gastroesophageal and/or esophageal) cancer in the first-line setting (Table 1). UFT, an oral fluoropyrimidine that contains tegafur (1-[2-tetrahydrofuryl]-5-FU) and uracil, although it is not available in the United States, has been used in combination with LV,15, 16 mitomycin-C,17 and CDDP regimens combined with docetaxel18 or epirubicin.19, 20 RRs have ranged from 9% to 41%, with the median time to progression (TTP) ranging from 1.9 months to 5.6 months and the median survival ranging from 5.8 months to 15.0 months. However, a Phase III RCT showed no significant survival benefit with UFT and mitomycin-C compared with CIV 5-FU, with or without CDDP.17 Another oral 5-FU chemotherapeutic agent, S-1, which contains tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate, has been used as a single agent21–23 and with CDDP.24

Capecitabine is a novel, orally administered fluoropyrimidine carbamate that is absorbed readily by the gastrointestinal tract and is metabolized by the liver, where it is converted initially to 5′-deoxy-5-fluorocytidine (5′-DFCR) and subsequently, to 5′-deoxy-5-fluorouridine (5′-DFUR).25, 26 Designed to mimic CIV 5-FU, oral capecitabine predominantly concentrates in tumor tissue (Fig. 1).26 Capecitabine currently is approved as a single agent for the adjuvant treatment of Stage III colon cancer, as first-line treatment for metastatic colorectal cancer (when fluoropyrimidine therapy alone is preferred), and for metastatic breast cancer both as a single agent (for patients who have disease that is resistant to paclitaxel and anthracyclines) and in combination with docetaxel (after failure on anthracycline-based therapy).27 This article summarizes the efficacy and safety of oral capecitabine for the treatment of gastric, gastroesophageal, and esophageal cancers.

Figure 1.

Enzymatic activation of capecitabine. Capecitabine is absorbed readily from the gastrointestinal (GI) tract and is activated in a 3-step process. 1) In the liver, a carboxylesterase hydrolyzes much of capecitabine to 5′-deoxy-5-fluorocytidine (5′-DFCR); 2) cytidine deaminase subsequently converts 5′-DRCR to 5′-deoxy-5-fluorouridine (5′-DFUR); and 3) the enzyme thymidine phosphorylase (TP) hydrolyzes 5′-DFUR to the active drug 5-fluorouracil (5-FU) preferentially in tumor tissue.

Methodology

The MEDLINE data base was searched for English-language clinical trials that were published from 1996 through October 2005 and that contained the terms “capecitabine” or “Xeloda” and “gastric,” “stomach,” “esophagus,” “esophageal,” and/or “gastro esophageal” in the title or abstract. Potentially relevant abstracts that were presented at annual meetings or gastrointestinal symposia of the American Society of Clinical Oncology and from meetings of the European Cancer Conference and the European Society of Medical Oncology dating back to the Year 2000 were examined. Only the most recent data from reported trials were included. Missing data were designated as “not available,” unless it was possible to infer or extrapolate results from other data supplied by authors.

Efficacy data extracted from trials included complete response (CR) rates, partial response (PR) rates, RRs (CRs plus PRs), stable disease rate (SD), and median survival. Safety data extracted included all reported Grade 3 and/or Grade 4 adverse events (AEs) and treatment-related mortality. If variance data were not supplied for proportions, then 95% confidence intervals (95% CIs) were calculated using the proportions method. Two-tailed Fisher exact tests with significance set at P < .05 were employed within RCTs if they were not provided by trial investigators.

Metastatic Disease

The preponderance of trials of capecitabine for the treatment of metastatic gastric, esophageal, or gastroesophageal cancers have been in the first-line setting.

Single-Agent Capecitabine

Gastric cancer

Several Phase II trials28–30 have evaluated the efficacy and safety of capecitabine as a single agent for the treatment of gastric cancer (Tables 2 and 3). Hong et al.28 treated patients with oral capecitabine 1250 mg/m2 twice daily for 2 weeks on/1 week off, whereas Sakamoto et al.31 treated patients with a reduced dose of capecitabine 828 mg/m2 twice daily for 3 weeks on/1 week off. CRs were infrequent. Overall activity and median survival were similar in both trials. In a trial by Koizumi et al.,30 survival was similar but low (RR, 6%; clinical benefit rate, 19%), possibly because some patients had received prior chemotherapy. Grade 3 or 4 hematologic AEs were rare. The only Grade 3 AE that was observed in >10% of patients was hand-foot syndrome (HFS), which was observed in only 1 trial.31

Table 2. Activity and Survival in Phase II and III Trials of Capecitabine-Based Therapies for Metastatic Gastric, Gastroesophageal, or Esophageal Cancers
StudyCancer/Treatment linePhaseRegimenNo.*Activity (%)Median survival(95%CI), months
CRRR (95%CI)SD
  • CR indicates complete response rate, RR, (objective) response rate; 95%CI, 95% confidence interval; SD, stable disease; X, capecitabine; label, 1250 mg/m2 twice daily for 2 weeks on/1 week off; BID, twice daily; D, day(s); q, every; CDDP, cisplatin; NYR, not yet reached; 5-DFUR, 5′-deoxy-5-fluorouridine; AUC, area under the concentration-time curve; GE, gastroesophageal; MMC, mitomycin-C; NA, not available; RCT, randomized controlled trial; CIV, continuous intravenous infusion.

  • *

    The number of patients in the survival analysis.

Single agent
 Hong et al., 200428Gastric, 1st lineIIX (label)44032 (19–48)329.5 (6.9–13.2)
 Sakamoto et al., 200631Gastric, 1st lineIIX 828 mg/m2 BID D1-21 q 4 weeks55725 (15–39)2910.0 (6.4–13.6)
 Koizumi et al., 200330Gastric, 1st and 2nd linesIIX 828 mg/m2 BID D1-14 q 3 weeks3106 (1–22)138.1 (6.3–10.3)
Capecitabine and cisplatin (X + CDDP)
 Kang et al., 200532Gastric, 1st lineIIX (label) + CDDP 60 mg/m2 D1 q 3 weeks32328 (16–46)5311.2 (5.5–16.9)
 Jin, 200535Gastric, 1st lineIIX 1000 mgm2 BID + CDDP 20 mg/m2 D1-5 q 3 weeks1411046 (38–54)39NYR
 Viteri et al., 200433Gastric, 1st lineIIX (label) + CDDP 60 mg/m2 D1 q 3 weeks16638 (14–61)19NYR
 Kim et al., 200234Gastric, 1st lineIIX (label) + CDDP 60 mg/m2 D1 q 3 weeks38255 (40–70)1710.1
 Cho et al., 200436Gastric, 1st lineIIX 1000 mg/m2 BID + epirubicin 50 mg/m2 D1 + CDDP 60 mg/m2 D1 q 3 weeks50752 (46–72)NA9.6 (8.7–10.5)
 Koizumi et al., 200437Gastric, 1st lineII5′-DFUR 1200 mg/m2 D4-7,11–14,18–21,25–28 + CDDP 70 mg/m2 D1 + MMC 7 mg/m2 D2 q4 weeks v.32025 (13–42)417.9
5′-DFUR 1200 mg/m2 D4-7,11–14,18–21,25–28 + CDDP 70 mg/m2 D1 q4 weeks29017 (7–35)245.9
 Lee et al., 200539Esophageal, 1st lineIIX (label) + CDDP 60 mg/m2 D1 q3 weeks17047 (23–71)3511.1 (9.3–13.0)
Capecitabine and taxanes
 Kim et al., 200540Gastric, 1st lineIIX 1000 mg/m2 BID D1-14 + docetaxel 75 mg/m2 D1 q3 weeks32344 (26–62)258.4 (6.7–10.1)
 Thuss-Patience et al., 200541Gastric/GE, 1st lineIIX 1000 mg/m2 BID + docetaxel 75 mg/m2 D1 q3 weeks11955 (28–79)45NA
 Catalano et al., 200542Gastric, 1st lineIIX 625 mg/m2 BID D5-18 + docetaxel 36 mg/m2 D1,8,15 q4 weeks21637 (21–59)25NA
 Chun et al., 200543Gastric, 1st lineIIX 1000 mg/m2 BID + docetaxel 36 mg/m2 D1,8 q3 weeks47240 (26–55)3412.0 (7.5–16.6)
 Park et al., 200444Gastric, 1st lineIIX (standard) + docetaxel 75 mg/m2 D1 q3 weeks38560 (45–74)1410.5
 Yeon Hee et al., 200345Gastric, 1st lineIIX (standard) + docetaxel 75 mg/m2 D1 q3 weeks30NA67 (56–72)NA17.2
 Kang et al., 200446Gastric, 1st lineIIX 825 mg/m2 BID + paclitaxel 175 mg/m2 D1 q3 weeks33053 (36–70)2714.6 (8.5–20.7)
 Damstrup et al., 200447Gastric/GE, metastaticIIX 1000 mg/m2 BID + docetaxel 60 mg/m2 + carboplatin AUC = 5, q 4 weeks21062 (38–82)3311.3
 Takeyoshi et al., 200548,85Gastric, previous treatmentII5′-DFUR 533 mg/m2 D1-5/week + paclitaxel 80 mg/m2 D1,8,15 q 4 weeks63232 (22–44)409.9
 Lorenzen et al., 200549Esophageal, 1st and 2nd linesIIX 1000 mg/m2 BID + docetaxel 75 mg/m2 D1 q 3 weeks24446 (28–65)1715.8 (7.8–23.9)
Capecitabine and irinotecan (XELIRI)
 Kattan et al., 200450Gastric, 1st lineIIXELIRI: X 625 mg/m2 BID D1-14 + irinotecan 80 mg/m2 D1,8,15 q4 weeks18NA43 (25–66)14NA
 Jackson et al., 200351Gastric, 1st lineIIXELIRI: X 1000 mg/m2 BID D1-9 + irinotecan 180 mg/m2 D1 q2 weeks31032 (19–50)32NA
 Assersohn et al., 200552GE, ≥2nd lineIICapIri: X 1000 mg BID + irinotecan 250 mg/m2 D1 q3 weeks21014 (3–36)146.3
Capecitabine and oxaliplatin (XELOX)
 Jatoi et al., 200553Gastric, GE, esophageal, 1st lineIIXELOX: X 1000 mg/m2 (↓850 mg/m2) BID + oxaliplatin 130 mg/m2 D1 q3 weeks43035 (23–50)06.4 (4.6–10.0)
 Park et al., 200554Gastric, 1st linePilotXELOX: X 1000 mg/m2 BID + oxaliplatin 130 mg/m2 D1 q3 weeks20565 (43–82)5NYR
 Sumpter et al., 200555Gastric, GE, esophageal, 1st lineIII (RCT)ECF: CIV 5-FU daily + epirubicin 50 mg/m2 + CDDP 60 mg/m2 q3 weeks v.48231 (19–46)36NA
EOF: CIV 5-FU daily + epirubicin 50/m2 mg + oxaliplatin 130 mg/m2 v.54639 (26–53)30NA
ECX: X 500-625 mg/m2 BID + epirubicin 50 mg/m2 + CDDP 60 mg/m2 q3 weeks v.46935 (21–50)30NA
EOX: X 500-625 mg/m2 BID + epirubicin 50 mg/m2 + oxaliplatin 130 mg/m248248 (35–62)31NA
 Petrovic et al., 200356Gastric, ≥2nd lineNAXELOX: X (label) + oxaliplatin 85 mg/m2 D1 q3 weeks17025 (9–48)35NA
Table 3. Summary of Grade 3 and 4 Adverse Events Occurring in ≥10% of Patients in Phase II and III Trials of Capecitabine-Based Therapies for Metastatic Gastric, Gastroesophageal, or Esophageal Cancers
Grade 3 and 4 adverse eventsIncidence in studies (%)*
RangeMedian
  • NA indicates not applicable.

  • *

    When reported. If it was not possible to ascertain or infer Grade 3 or 4 incidence, then the adverse event was considered “not available” and was not included in the range and median values.

  • Superscript numerals refer to the list of references (also see Tables 1 and 2).

Single agent
 Hand-foot syndrome30, 313–138
Capecitabine and cisplatin
 Anemia32, 34, 35, 37, 391–167
 Diarrhea32–35, 37, 390–246
 Hand-foot syndrome32–36, 390–103
 Leukopenia32, 34, 36, 373–2211
 Nausea32–370–258
 Neutropenia32–34, 36, 3913–3831
 Thrombocytopenia32, 34, 35, 371–197
 Emesis32–370–259
Capecitabine and taxane
 Diarrhea40, 41, 43, 44, 48, 49, 850–134
 Hand-foot syndrome40, 41, 43–47, 493–5221
 Leukopenia40, 41, 44, 45, 47, 48, 856–5410
 Neutropenia40, 42, 44, 45, 47, 48, 855–4215
 Stomatitis40–443–265
Capecitabine and irinotecan (XELIRI)
 Asthenia51NA19
 Diarrhea51NA16
 Nausea50, 511010
 Neutropenia52NA32
Capecitabine and oxaliplatin (XELOX)
 Anemia54, 550–178
 Asthenia53, 559–2317
 Diarrhea53–560–329
 Hand-foot syndrome54–560–206
 Leukopenia54NA10
 Nausea53, 552–276
 Neutropenia54–565–4034
 Thrombocytopenia54–560–126
 Emesis53, 545–2113

Gastroesophageal or esophageal cancer

To date, there have been no published trials of single-agent capecitabine therapy for the treatment of esophageal or gastroesophageal cancers.

Capecitabine-CDDP Combinations

Gastric cancer

Several Phase II trials have used the labeled dose of capecitabine (1250 mg/m2 twice daily for 2 weeks on/1 week off) with CDDP 60 mg/m2 on Day 1 in 3-week cycles for untreated patients.32–34 The combination was active, with RRs ranging from 28% to 55%. Jin35 used lower-dose capecitabine (1000 mg/m2 twice daily for 2 weeks on/1 week off) with CDDP 20 mg/m2 on Days 1 through 5 and reported a CR rate of 10%. Dose reductions were required in 35% to 63% of patients in trials that used label-dose capecitabine,32, 34 but no dose reductions were needed when lower-dose capecitabine was used.35 Similarly, Grade 3 or 4 toxicities were less frequent in trials that used lower doses of capecitabine.

Cho et al.36 used a lower dose regimen of 3 weeks of capecitabine 1000 mg/m2 twice daily 2 weeks on/1 week off and CDDP 60 mg/m2 on Day 1 in combination with epirubicin 50 mg/m2 on Day 1. In that trial, there was no increase in activity.

In a Phase II RCT, Koizumi et al.37 treated 61 patients on 4-week cycles of oral 5′-DFUR, an oral intermediate of capecitabine, at a dose of 1000 mg/m2 on Days 41 through 7, Days 111 through 14, Days 181 through 21, and Days 251 through 28 and CDDP 70 mg/m2 on Day 1 with or without mitomycin-C 7 mg/m2 on Day 2. Response rates, clinical benefit rates, and median survival were greater in patients who received mitomycin-C (25% vs. 17%, 66% vs. 41%, and 7.9 months vs. 5.9 months, respectively) but were not significant. Grade 3 or 4 toxicities were similar.

Gastroesophageal cancer

Evans et al.38 reported a Phase I/pharmacokinetic trial of escalating doses of oral capecitabine at doses of 500 mg/m2, 825 mg/m2, 1000 mg/m2, and 1250 mg/m2 twice daily for 14 days with fixed-dose epirubicin (50 mg/m2) and CDDP (60 mg/m2) in 3-week cycles in untreated patients. The recommended dose of capecitabine was 1000 mg/m2 twice daily.

Esophageal cancer

In a Phase II trial, Lee et al.39 reported on 20 patients who received label-dose capecitabine and CDDP. Activity and toxicity were similar to those seen in patients with gastric cancer.32–34

Capecitabine-Taxane Combination Therapies

Gastric and gastroesophageal cancer

Tables 2 and 3 summarize the trials of combination of capecitabine and a taxane.40–46 The labeled dose of capecitabine and docetaxel 75 mg on Day 1 in 3-week cycles44, 45 and a variety of lower doses of capecitabine with various doses and schedules of docetaxel or paclitaxel40–43, 46 have been reported, with RRs rates ranging from 37% to 67%. In those trials, the median TTP and overall survival ranged from 4.5 months to 5.3 months and from 10.5 months to 17.2 months, respectively. Generally, capecitabine-taxane regimens were well tolerated. High incidence rates of Grade 3 HFS (23-52%) were reported in trials that used a capecitabine dose ≥1000 mg/m2 twice daily with docetaxel.41, 44, 45 A high incidence of Grade 3 or 4 neutropenia (41% and 15%, respectively) was observed in 2 trials44, 46 but not in others.

Other agents also have been added to combinations of capecitabine and a taxane. In a Phase II trial, Damstrup et al.47 reported on 36 patients with advanced gastric or gastroesophageal cancer who received capecitabine 1000 mg/m2 twice daily, docetaxel 60 mg/m2, and carboplatin (area under the curve = 5) in 4-week cycles. In that trial, the RR was 62%, and the median survival was 11.3 months. The regimen was well tolerated, and ≤6% of patients had Grade 3 or 4 toxicity.

Second-line therapy

The intermediate catabolite of capecitabine, 5′-DFUR, also has been used in combination with paclitaxel. In a Phase II trial,48 72 patients received 5′-DFUR at a dose of 533 mg/m2 on Days 1 through 5 with paclitaxel 80 mg/m2 on Days 1, 8, and 15 in 4-week cycles. The regimen was well tolerated and had the expected activity in this setting.

Esophageal cancer

Lorenzen et al.49 treated 24 patients (16 chemonaive patients and 8 patients who received prior chemotherapy for metastatic disease) with capecitabine at a dose of 1000 mg/m2 twice daily on Days 1 through 14 and docetaxel 75 mg/m2 on Day 1 of 3-week cycles. The RR was 46%. However, 41% of patients in that study required a dose reduction, and there were 2 treatment-related deaths, a high incidence of Grade 3 or 4 neutropenia (42%), and a high incidence of Grade 3 HFS (29%).

Capecitabine-Irinotecan Combination Therapies

Gastric and gastroesophageal cancer

First-line therapy.

In an ongoing Phase II trial, Kattan et al.50 treated 21 previously untreated patients with capecitabine 625 mg/m2 twice daily on Days 1 through 14 and irinotecan 80 mg/m2 on Days 1, 8, and 15 in 4-week cycles (XELIRI) (Tables 2 and 3). The RR was 43%, and the regimen was well tolerated. Jackson et al.51 treated 32 chemonaive patients with capecitabine 1000 mg/m2 twice daily on Days 1 through 9 and irinotecan 150 mg/m2 on Day 1 of 2-week cycles. That regimen resulted in frequent dose reductions and Grade 3 toxicities.

Second-line therapy.

Assersohn et al.52 treated 25 patients with capecitabine 1000 mg/m2 twice daily on Days 11 through 14 and irinotecan 250 mg/m2 on Day 1 of 3-week cycles. The RR was 14%, and there was a 32% rate of Grade 3 or 4 neutropenia.

Esophageal cancer

To date, there have been no reported clinical trials of XELIRI combination therapies for the treatment of metastatic esophageal cancer.

Capecitabine-Oxaliplatin Combination Therapies

Gastric, gastroesophageal, and esophageal cancer

First-line therapy.

Capecitabine 1000 mg/m2 twice daily on Days 1 through 14 (a dose that subsequently was reduced to 850 mg/m2 twice daily after 4 treatment-related deaths) with oxaliplatin 130 mg/m2 on Day 1 in 3-week cycles (XELOX) has been used to treat patients with metastatic gastric, gastroesophageal, or esophageal cancer (Jatoi et al.53) or exclusively in patients with metastatic gastric cancer (Park et al.54) in the first-line setting. The RR was 65% in the trial by Park et al.54 versus 35% in the trial by Jatoi et al.53 Patients with gastric cancer have a lower tolerance to chemotherapy, which is predictable based on experience with other chemotherapy regimens. In the trial by Park et al.,54 there were 3 treatment-related deaths and Grade 3 or 4 diarrhea (32%), nausea (27%), asthenia (23%), and emesis (21%).

XELOX also has been combined with other chemotherapeutic agents. In an ongoing Phase III RCT, Sumpter et al.55 treated 204 untreated patients with 3-week cycles of epirubicin 50 mg/m2 as an intravenous bolus with 1) CDDP 60 mg/m2 every 3 weeks and CIV 5-FU 200 mg/m2 per day (ECF); 2) oxaliplatin 130 mg/m2 every 3 weeks and 5-FU 200 mg/m2 per day; 3) CDDP 60 mg/m2 every 3 weeks and oral capecitabine (500 mg/m2 escalated to) 625 mg/m2 twice daily continuously; or 4) oxaliplatin 130 mg/m2 every 3 weeks and oral capecitabine (500 mg/m2 escalated to) 625 mg/m2 twice daily continuously. All regimens were active (RR range, 31-48%). The RR was greater in capecitabine-treatment arms than in 5-FU-treatment arms (41% vs. 36%, respectively). These are preliminary results, and no survival data are available to date. All 4 regimens were well tolerated.

Second-line therapy.

Petrovic et al.56 treated 17 patients with label-dose capecitabine and oxaliplatin 85 mg/m2 on Day 1 of 3-week cycles. The RR was 25%, and tolerance to the regimen was fair.

Prognostic Factors

Identifying the patient populations that are most likely to respond to treatment or develop significant toxic effects is essential. Thymidine phosphorylase (TP) and/or dihydropyrimidine (DPD) have been associated with tumor response to capecitabine therapy in other cancers.57–66 The data in gastric cancer patients are limited. Koizumi et al.67 stained primary gastric cancers for anti-TP and anti-DPD antibodies in 24 patients who were participants in a Phase II trial of 4-week cycles of capecitabine 828 mg/m2 twice daily on Days 1 through 21. The RR in that trial was 44% among 18 patients with TP-positive primary tumors, 0% among 6 patients with TP-negative tumors, and 67% (6 of 9 patients) in patients with TP-positive/DPD-negative primary tumors (P = .021), indicating that the TP:DPD ratio may provide useful prognostic information. Nishina et al.68 investigated the use of the TP:DPD ratio for predicting clinical responses in 22 patients who received oral 5′-DFUR. By using the median TP:DPD ratio (1.9) as a cut-off level, patients who had a high TP:DPD ratio had a significantly greater RR than patients who had a low TP:DPD ratio (64% vs. 9.1%, respectively; P = .024) and a greater median survival (9.9 months vs. 6.0 months, respectively; P = .047). However, severe AEs did not correlate with the TP:DPD ratio.

Adjuvant Setting

Because it mimics CIV 5-FU and has radiosensitizing properties, capecitabine has been used in conjunction with radiotherapy in the adjuvant setting. In an ongoing Phase I/II trial, Boot et al.69 treated 26 patients with T2-T4,N0-N3,M0 gastric cancer with 45 grays (Gy) (in 25 fractions of 1.8 Gy) in conjunction with oral capecitabine escalated from 600 mg/m2 to 800 mg/m2 twice daily and observed no Grade 3 or 4 AEs. In another ongoing Phase I/II trial, Jansen et al.70 treated patients with capecitabine 1000 mg/m2 twice daily for 2 weeks, followed by 45 Gy (in 25 fractions) with CDDP escalated from 3 mg/m2 to 6 mg/m2 at 1 hour preradiotherapy and capecitabine escalated from 250 mg/m2 to 800 mg/m2 twice daily on radiotherapy days. Sixteen patients on that trial had completed therapy without treatment-related mortality. In a small Phase II trial, Kwon et al.71 treated 21 patients with Stage IIIA to IV, M0 gastric cancer after curative resection with 4 cycles of CIV 5-FU 1000 mg/m2 on Days 1 through 5, CDDP 60 mg/m2 on Day 1, followed by 45 Gy (1.8 Gy per day) with capecitabine 825 mg/m2 twice daily throughout radiotherapy. The recurrence rate was only 10% after a 14.2-month median follow-up. There were no treatment-related deaths, and the most common Grade 3 or 4 AEs were neutropenia (19%), thrombocytopenia (5%), fatigue (5%), and nausea/emesis (5%). These preliminary results indicate that radiotherapy regimens appear to be well tolerated.

Kwon et al.72 also conducted an RCT comparing chemotherapy with radiotherapy (45 Gy) and CIV 5-FU 1000 mg/m2 on Days 1 through 5 or with oral capecitabine 825 mg/m2 twice daily throughout radiotherapy or chemotherapy alone in 81 patients with postoperative, Stage IIIA or IV-M0 disease. No firm conclusions could be drawn because of the small number of patients in that trial; however, there were no significant differences among treatment groups with regard to 2-year disease-free survival (70% vs. 60%, respectively) or overall survival (85% vs. 79%, respectively). However, significantly more Grade 3 and 4 neutropenia was observed with intravenous chemotherapy (49% vs. 23%, respectively; P = .03).

Doxifluridine also has been evaluated as a single-agent in the adjuvant setting. In a Phase III RCT, Takiguchi et al.73 compared oral 5′-DFUR 460 mg/m2 per day with oral 5-FU 115 mg/m2 per day in 482 patients with postoperative Stage II or III gastric cancer. Although the overall 5-year survival was not significantly greater with 5′-DFUR than with oral 5-FU, patients with Stage IIIB disease who received 5′-DFUR had superior 5-year disease-free survival (56.4% vs. 31.4%; P = .023). Multivariate analysis showed that patients with serosal invasion fared better with 5′-DFUR than with oral 5-FU (risk ratio, 1.65; 95% CI, 1.11-2.44).

Future Directions

Ongoing trials are primarily Phase II investigations of capecitabine combination therapies for treatment in the metastatic setting, largely using capecitabine and taxane74–76 or XELOX77, 78 and also using combination therapies of XELOX with irinotecan,79 capecitabine with CDDP and epirubicin,80 and capecitabine with matuzumab,81, 82 which is a monoclonal antibody specific for the epidermal growth factor receptor (EGFR) (Table 4). All but 1 trial is intended for patients who have not received prior chemotherapy for metastatic disease. Agents that target vascular endothelial growth factor (bevacizumab) or EGFR (e.g., erlotinib), which are in early stages of development for the treatment of gastric cancer,83, 84 may yield dynamic, effective therapies when used in combination with capecitabine.

Table 4. Ongoing Trials of Capecitabine for the Treatment of Gastric, Gastroesophageal, or Esophageal Cancers
Trialidentification no.Sr. investigator(Sponsor)*PhaseExpectedenrollment(No.)Regimen/DesignPatient populationPrimary objective
  • NCCTG indicates North Central Cancer Treatment Group; NCI, National Cancer Institute; XT, capecitabine and taxane; BID, twice daily; D, day(s); q, every; CA, cancer; GE, gastroesophageal; QOL, quality of life; XELOX, capecitabine and oxaliplatin; CEX, carboplatin, epirubicin, and capecitabine; MTD, maximum tolerated dose; AUC, area under the curve; EMD, EMD Pharmaceuticals; CDDP: cisplatin.

  • *

    Superscript numbers indicate the list of references.

NCT00142038Thuss-Patience74 (Charite University, Germany)II44XT: Capecitabine 1000 mg/m2 BID D1-14 + docetaxel 75 mg/m2 D1 q3 weeksAdvanced gastric CA; unresectable or metastatic;1st lineResponse rate
NCCTG-N0242Jatoi75 (NCCTG, NCI)II15–43XT: Capecitabine BID D1-14 + docetaxel D1 q3 weeksGastric, esophageal, or GE CA; metastatic or recurrent; 1st lineObjective tumor response; time toprogression; survival; toxic effects; QOL
04–026Ramanathan76 (University of Pittsburgh; Roche, Aventis)II43XT: Capecitabine 825 mg/m2 BID D1-14 + docetaxel 30 mg/m2 D1,8 q3 weeksGastric or GE CA; unresectable or metastatic; prior chemotherapy permittedMedian survival
NCCTG-N0149NCCTG77 (NCI)II44XELOX: Capecitabine BID D1-14 + oxaliplatin D1 q3 weeksGastric or esophageal CA; advanced, unresectable; 1st lineObjective tumor response; time toprogression; survival; toxic effects; QOL
3G-03-4Iqbal78 (Norris Cancer Center; Roche, Sanofi-Aventis)II53XELOX (regimen not available)Gastric or GE CA; unresectable or metastatic; 1st lineProportion of patients with progressivedisease within 4 months of treatment
NCI-6449Brell79 (Ireland Cancer Center, NCI)II40–80XELOX + irinotecan: Capecitabine BID D1-5,8–12,15–19,22–26 + oxaliplatin + irinotecan D1,8,15, 22 q6 weeksGastric or esophageal CA; inoperable or metastatic; 1st lineResponse rate; duration of response
GI-05-0046Sawyer80 (Alberta Cancer Board, Canada)I/II50CEX: Capecitabine 750, 850, or 1000 mg/m2 BID D1-14 + epirubicin 50 mg/m2 D1 + carboplatin fixed AUC = 5 q3 weeksGastric or esophageal CA; locally advanced/metastatic; 1st linePhase I: MTD and recommended Phase II dose; Phase II: antitumor activity
EMD 72000-032Cunningham81 (UK; Merck, EMD)II70EMD 72000 (matuzumab) + ECX (epirubicin + CDDP + capecitabine)GE CA; metastatic; 1st lineResponse rate
EMD 72000-024EMD82 (UK; Merck, EMD)I26EMD 72000 (matuzumab) + ECX (epirubicin + CDDP + capecitabine)Gastric, GE, or esophageal CA; metastatic or recurrent; 1st lineSafety and tolerability

Oral fluoropyrimidines such as S-1 and capecitabine are being investigated actively for the treatment of gastroesophageal cancer in the first-line metastatic and adjuvant settings. Combination therapies include capecitabine with CDDP, taxanes, irinotecan, and oxaliplatin. Phase II trials of capecitabine in combination with CDDP and with docetaxel have shown favorable efficacy data compared with Phase III trials of parenteral 5-FU combinations in the first-line, metastatic setting. Capecitabine-based regimens mostly are well tolerated. Additional Phase III trials are warranted to demonstrate the comparative efficacy and safety of capecitabine-based combination therapies in the metastatic and adjuvant settings. Oral fluoropyrimidines are emerging chemotherapy agents for patients with gastric, gastroesophageal, and esophageal cancers.

Acknowledgements

The author acknowledges Nelson Erlick, DPM, MS, for his editorial assistance in the preparation of this article.

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