Capecitabine in the Treatment of Advanced Gastric Cancer

Jae-Lyun Lee; Yoon-Koo Kang

Disclosures

Future Oncol. 2008;4(2):179-198. 

In This Article

Clinical Efficacy

Phase I Studies

Phase I studies of capecitabine in various dose and administration regimens were used to test its safety, tolerability and pharmacokinetics.[33,44,45] In one, capecitabine was administered twice-daily to outpatients at dose levels of 502-3514 mg/m2/day for 2 weeks followed by 1 week of rest.[33] At daily doses of 3000 mg/m2 capecitabine was not tolerable, with dose-limiting toxicities (DLT) of diarrhea, abdominal pain, hypotension and leucopenia; however, hand-foot syndrome (HFS) was not a DLT in this study. The recommended Phase II dose of capecitabine was set at 2510 mg/m2/day. Other Phase I trials used continuous daily dosing or a 3-weekly intermittent regimen with leucovorin.[44,45] Although randomized studies of three dosing regimens of capecitabine were not performed in patients with AGC, a randomized Phase II study (SO14797) was performed in patients with metastatic colorectal cancer, and capecitabine 2510 mg/m2/day intermittent regimen without leucovorin was selected for further study based on the favorable response rate and TTP.[46]

Noncomparative Clinical Efficacy Study of Capecitabine in AGC

Phase II Study of Single-agent Capecitabine. The efficacy and safety of 3-week intermittent capecitabine monotherapy was tested in a Korean study that included 44 chemonaive patients.[40] The ORR was 34%, with a median TTP of 3.2 months. While this 3-week inter-mittent schedule has been adopted as the global standard, a 4-week on-and-off schedule has been evaluated in Japan.[47,48] In these studies, the ORRs were 19.4-26%, the median OS was 8.2-10.0 months and the toxicity profiles were highly favorable. A randomized Phase II study of the 3-week capecitabine regimen was also evaluated in elderly patients; the ORR was 27% with a median TTP of 4.7 months, and the toxicity profile was favorable.[49]

Trials of Capecitabine-based Two-drug Combinations. Platinum (cisplatin and oxaliplatin), taxanes (paclitaxel and docetaxel) and irinotecan are active agents used to treat gastric cancer. Based on the efficacy and tolerability of capecitabine monotherapy in AGC and its synergism with other cytotoxic agents, Phase I/II trials of these combinations have been performed. The results are described below in detail and summarized in Table 2 .

Cisplatin Plus Capecitabine. Cisplatin was the first chemotherapeutic agent to be combined with capecitabine in the treatment of AGC. In a Phase II study, 42 chemotherapy-naive AGC patients were treated with capecitabine 1250 mg/m2 twice-daily on days 1-14 and cisplatin 60 mg/m2 on day 1 (XP), resulting in an ORR of 54.8% and a median TTP of 6.3 months.[22] The principal adverse events were neutropenia and HFS; however, none of these patients developed febrile neutropenia and there were no treatment-related deaths. The reductions in capecitabine dose intensity over the cycles indicated that 1000 mg/m2 twice-daily would be the optimal capecitabine dose when combined with cisplatin. This combination was also found to be effective as first-line therapy in patients with recurrent gastric cancer after fluoropyrimidine-based adjuvant chemotherapy, with an ORR of 28%, a median TTP of 5.8 months and a median OS of 11.2 months.[39] The efficacy and safety of this combination has been confirmed in a routine clinical-practice setting involving a total of 223 patients.[50]

Oxaliplatin Plus Capecitabine. Oxaliplatin was initially developed to treat colorectal cancer,[51,52,53] but it may also have a role in gastric cancer. In preclinical studies, oxaliplatin had a higher anticancer activity than cisplatin against some gastric cancer cell lines.[54,55] In addition, oxaliplatin had a more favorable toxicity profile, since it is not commonly associated with severe nausea/vomiting, ototoxicity or nephrotoxicity, and its main side effect is a cumulative, peripheral sensory neuropathy that is mostly reversible. Following a dose-finding study[56] the feasibility and activity of oxaliplatin plus capecitabine regimens were demonstrated in Phase II trials ( Table 2 ). In a pilot Phase II study, first-line treatment with capecitabine plus oxaliplatin in AGC patients resulted in an ORR of 65%, with two patients having a complete response (CR).[57] A subsequent multicenter Phase II trial also showed promising results; the ORR was 63%, the median PFS was 5.8 months and the median OS was 11.9 months.[58] The safety profile of the capecitabine plus oxaliplatin combination was encouraging, with grade 3 or higher hematologic and non-hematologic toxicities observed in fewer than 10% of patients, although there was one treatment-related death due to neutropenic sepsis.

Taxanes Plus Capecitabine. Based on their distinctive mechanisms of action, in vitro synergism, and non-overlapping toxicity profiles, several Phase II studies have investigated the combination of capecitabine with docetaxel or paclitaxel in AGC patients ( Table 2 ).[58,59,60,61,62,63] While combinations of capecitabine (2000-2500 mg/m2/day) with docetaxel (75 mg/m2 on day 1 every 3 weeks) were active and easy to administer, they resulted in higher frequencies of severe HFS, febrile neutropenia and stomatitis than observed with either agent alone. Among the 3-week-cycle combination regimens tested, 60 mg/m2 of docetaxel plus 2000 mg/m2/day of capecitabine seemed optimal. To reduce docetaxel-induced myelotoxicity, the combination of weekly docetaxel (36 mg/m2 intravenously on days 1 and 8 every 3 weeks) plus capecitabine (2000 mg/m2 daily for 2 weeks followed by 1-week rest) was tested.[64] Although this regimen resulted in lower rates of neutropenia than administration of docetaxel every 3 weeks, the incidence of febrile neutropenia was not significantly reduced by this schedule and dose.

When the combination of capecitabine (825 mg/m2) twice-daily on days 1-14 of every 3-week cycle plus paclitaxel (175 mg/m2 on day 1) was evaluated in patients with AGC, the ORR was 48.9% (22 out of 43) with a median TTP of 5.6 months and a median OS of 13.8 months.[65] Compared with combination regimens of capecitabine plus docetaxel, this regimen had more favorable toxicity profiles in that no patient developed febrile neutropenia or severe thrombocytopenia, and the incidence of grade 3 or higher HFS was approximately 10%. These improved toxicities may be due, at least in part, to the lower dose intensity of capecitabine utilized in this trial.

Irinotecan Plus Capecitabine. Based on preclinical synergism and clinical activity and safety results of a Phase III trial,[66] the combination of weekly or 3-weekly irinotecan plus capecitabine was evaluated in Phase II trials ( Table 2 ).[67,68] A randomized Phase II trial of 3-weekly capecitabine (1000 mg/m2 twice-daily on days 1-14) plus cisplatin (80 mg/m2 on day 1) versus capecitabine plus irinotecan (250 mg/m2 on day 1) found that the two regimens had comparable efficacy and safety, indicating that irinotecan had no significant advantages over platinum when combined with capecitabine in AGC patients.[68]

Trials of Capecitabine-based Triplets. Based on the hypothesis that the addition of epirubicin would augment the activity of capecitabine and cisplatin, trials of epirubicin, cisplatin and capecitabine (ECX) were conducted.[38,69] In a Phase I study, epirubicin and cisplatin doses were fixed at 50 and 60 mg/m2 every 3 weeks, respectively, and 32 patients were recruited into one of four escalating capecitabine-dose cohorts (1000, 1650, 2000 and 2500 mg/m2/day for 2 weeks out of every 3-week cycle).[38] At the highest dose, two out of five patients experienced DLTs, one with grade 2 stomatitis and the other with grade 3 diarrhea and febrile neutropenia, thus setting the recommended dose for a subsequent Phase II study at 1000 mg/m2 twice-daily.[38] In the subsequent Phase II trial in 50 evaluable patients, the ORR was 64% (32 out of 50), with a median TTP of 6.0 months.[69] However, the encouraging ORR was not translated into survival prolongation, in that the median OS was 9.6 months. In addition, hematologic toxicities were significant; 19% of patients developed febrile neutropenia, including one who died from neutropenic sepsis. Other non-hematologic toxicities were comparable with those seen with capecitabine plus cisplatin. Based on the preclinical synergism and clinical benefits of docetaxel when added to FU and cisplatin,[21] a Phase I-II study of docetaxel, capecitabine and cisplatin (DXP) was conducted in AGC patients.[70] The final recommended Phase II dose was cisplatin and docetaxel 60 mg/m2 on day 1 plus capecitabine 1875 mg/m2 divided into two daily doses on days 1-14 of every 3-week cycle. Out of 40 evaluable patients, four achieved CR and 23 had partial responses, with an ORR of 67.5%. Ten of the patients that responded clinically underwent surgical resection of their primary gastric tumor after 4-9 cycles of chemotherapy, with four of these patients achieving pathologic CR. The median TTP was 7.7 months, and the median OS was 16.9 months.[71] With the exception of febrile neutropenia and asthenia, which occurred in 10 and 37.5% of patients, respectively, the safety profile of this regimen was comparable with those of docetaxel and capecitabine combinations and far less severe than DCF used in the V325 trial.[21] The DXP regimen, in which the dose intensity of docetaxel and cisplatin was reduced and 5-FU was replaced by capecitabine, resulted in significantly reduced severe hematologic toxicities while preserving or even augmenting the efficacy. Of further clinical importance, DXP downstaged patients with AGC, in that ten out of 40 treated patients underwent surgical resection, indicating that the DXP regimen may change an incurable disease into a curable one in selected patients. When DXP was used as neoadjuvant chemotherapy in 49 patients with AGC, deemed unresectable due to local invasion or intra-abdominal metastasis, 31 patients (63%) could later undergo histologically complete resection.[72] In this trial, the DXP regimen had a favorable toxicity profile, with only 4% of patients experiencing febrile neutropenia.[72] These results warrant further investigation.

Phase III Trials of Capecitabine-based Chemotherapy in Advanced Gastric Cancer

Two Phase III trials, designed to reveal the noninferiority of capecitabine compared with infusional 5-FU, have assessed the role of capecitabine in AGC ( Table 3 ).[73,74] In a pivotal Phase III trial comparing capecitabine and cisplatin with FP (ML17032) in patients with AGC,[74] the former regimen did not have a significantly inferior PFS in that the upper limit of the 95% CI for the hazard ratio (HR) (0.81; 95% CI: 0.63-1.04; per-protocol analysis) was below the predefined noninferiority of 1.25 (p = 0.0008). Secondary end points also showed that the capecitabine and cisplatin regimen was at least as effective as the FP regimen. The median OS in the two groups was 10.5 and 9.3 months, respectively (per-protocol analysis), with an HR of 0.85 (95% CI: 0.64-1.13; p = 0.0076 for noninferiority test). Moreover, the ORR was significantly superior in the capecitabine plus cisplatin arm compared with the FP arm (41 vs 29%; p = 0.03). The safety profile of capecitabine plus cisplatin was encouraging, with minimal myelosuppression and fewer than 20% of treated patients experiencing grade 3 or higher neutropenia. The two regimens had comparable frequencies of non-hematologic toxicities with the exception of HFS, which was more frequent in patients treated with capecitabine plus cisplatin. However, in the latter, HFS was manageable with treatment interruption or dose reduction and was never life threatening, and only 5% of patients experienced grade 3 HFS.

Another pivotal Phase III trial in the UK assessed capecitabine in the backbone of the ECF regimen in patients with advanced esophagogastric cancer (REAL-2).[73] In combination with epirubicin (50 mg/m2 intravenously, on day 1), oral capecitabine (625 mg/m2 twice-daily continuously) was compared with 5-FU (200 mg/m2 daily as continuous intravenous infusion) and oxaliplatin (130 mg/m2 intravenously, on day 1) was compared with cisplatin (60 mg/m2 intravenously, on day 1) in a two-by-two factorial design. Patients were randomly assigned to one of the four regimens: ECF, epirubicin, oxaliplatin and fluorouracil (EOF), ECX and epirubicin, oxaliplatin and capecitabine (EOX). The results available in 2006 showed response rates of 40.7, 42.4, 46.4 and 47.9%, respectively, for these regimens. After a median follow-up of 17.1 months, the OS in these four arms was 9.9, 9.3, 9.9 and 11.2 months, respectively, with a significant difference between improved EOX and ECF (HR: 0.8; 95% CI: 0.66-0.97; p = 0.02). The pooled capecitabine-based (ECX and EOX) regimens were noninferior to the pooled FU-based (ECF and EOF) regimens in OS (10.9 vs 9.6 months; HR: 0.86; 95% CI: 0.8-0.99), which met the predefined noninferiority criteria based on the per-protocol population. The HR for patients receiving oxaliplatin versus cisplatin was 0.92 (95% CI: 0.8-1.1). This study clearly showed that capecitabine could replace 5-FU continuous intravenous infusion. In addition, oxaliplatin could replace cisplatin, if patients and physicians accept the trade-off between increased neurotoxicity and diarrhea and decreased nephrotoxicity, alopecia and neutropenia.

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