© 2007 Foundation for Promotion of Cancer Research
Combination Chemotherapy with Capecitabine (X) and Cisplatin (P) as First Line Treatment in Advanced Gastric Cancer: Experience of 223 Patients with Prognostic Factor Analysis
Division of Oncology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
For reprints and all correspondence: Yoon-Koo Kang, Section of Oncology, Department of Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-dong, Songpa-ku, Seoul, South Korea 138-736. E-mail: ykkang{at}amc.seoul.kr
Received July 6, 2006; accepted September 7, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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BACKGROUND: The efficacy and safety of the combination of capecitabine (X) and cisplatin (P) in the treatment of advanced gastric cancer (AGC) have already been shown in several prospective clinical trials. In this study, we sought to evaluate the efficacy and feasibility of the XP combination for the treatment of AGC in clinical practice and to determine the prognostic factors affecting treatment outcomes.
METHODS: Clinical data from 223 patients with previously untreated metastatic, unresectable, or recurrent gastric carcinoma who were treated with XP between March 2000 and December 2004 at a single center were reviewed. Each 3-week chemotherapy cycle consisted of oral capecitabine (1000–1250 mg/m2 twice a day on days 1–14) and i.v. cisplatin (60–80 mg/m2 on day 1).
RESULTS: Of the 223 patients, 32 had distant metastases but palliative gastrectomy (resected metastatic), 82 had recurrent disease after previous curative gastrectomy (recurrent), and 109 had distant metastases without gastrectomy (initially metastatic). Patients received a median of five cycles of chemotherapy (range, 1–12 cycles). Among the 123 patients with measurable disease, seven achieved complete responses and 49 had partial responses, giving an overall response rate (RR) of 45.5% in the intention-to-treat population (95% CI, 32.9–50.2%). There were no differences in RR among the groups of resected metastatic, recurrent and initially metastatic patients (66.7 versus 36.5 versus 50.8%, P = 0.35). After a median follow-up of 11.9 months (range, 2.1–51.9 months), the median time to progression (TTP) was 6.3 months (95% CI, 5.2–7.4 months) and the median overall survival (OS) was 11.1 months (95% CI, 9.4–12.9 months). In the resected metastatic, recurrent and initially metastatic groups, TTP was 8.7, 6.8 and 5.8 months (P = 0.02) and median OS was 14.7, 12.4 and 9.6 months (P = 0.03), respectively. Multivariate analysis showed that relatively small tumor burden (resected metastatic or recurrent versus initially metastatic groups) (OR = 1.418, 95% CI, 1.021–1.967, P = 0.037) and good performance status (ECOG 0–1 versus 2) (OR = 3.800, 95% CI, 2.417–5.974, P < 0.001) were independent prognostic factors affecting overall survival.
CONCLUSION: The combination of capecitabine and cisplatin was active and well tolerated as a first line treatment of AGC in general clinical practice. Disease status and performance status of the patients were the most important factors in treatment outcomes.
Key Words: capecitabine • cisplatin • chemotherapy • advanced gastric cancer • prognostic factor
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INTRODUCTION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Despite its earlier detection and reduced mortality, gastric cancer remains the most frequently diagnosed cancer in Korea and one of the leading causes of cancer-related deaths. To date, palliative chemotherapy has been the only reasonable therapeutic option for patients with recurrent or unresectable advanced gastric cancer (AGC), with a median survival of 6–9 months (1). Randomized trials have shown that chemotherapy resulted in a significant survival advantage and an improved quality of life when compared with best supportive care (2–4). Among the agents with known antitumor activity, 5-fluorouracil (5-FU) and cisplatin have been extensively used in AGC, but objective responses with each of these as a single agent tend to be< 20%, partial and of short duration. Combinations of these agents have been tried extensively in AGC and suggested to be more effective than single agents or other drug combinations. For example, the combination of 5-FU and cisplatin (FP) was superior to 5-FU, doxorubicin and mitomycin (FAM) or 5-FU alone in terms of response rate (RR) and time to progression (TTP) in a Korean phase III trial (5). This trend of superiority of FP regimen was also suggested by an European phase III trial which compared it with 5-FU, doxorubicin and methotrexate (FAMTX) or etoposide, leucovorin and bolus 5-FU (ELF) (6). A UK group developed a combination of epirubicin–cisplatin–5-FU in continuous infusion (ECF) and demonstrated that ECF was superior to 5-FU-adriamycin-methotrexate (FAMTX) in terms of RR, TTP and overall survival (OS) (7). Based on these results, these two FP-based chemotherapy regimens, FP and ECF, have been used in clinical practice worldwide for the treatment of AGC. However, these two FP-based chemotherapies include continuous IV infusion of 5-FU and require placement of central venous access device or hospital admission of the patient, which is cumbersome and inconvenient.
The oral fluoropyrimidine capecitabine (Xeloda) was designed to generate 5-FU preferentially in tumor tissue and to mimic continuously infused 5-FU. Because many tumors have significantly higher thymidine phosphorylase activity than do healthy tissues, capecitabine has tumor selectivity (8,9). For example, thymidine phosphorylase is highly expressed in gastric cancer, with a range of 43–61% (10,11). When administered twice daily at a dose of 1250 mg/m2 on days 1–14 of every 3-week cycle, capecitabine has been shown to be active (overall response rate 28%; stable disease 36%) and well tolerated in previously untreated patients with AGC (12). Intermittent administration of capecitabine (828 mg/m2 twice daily for 3 weeks followed by 1 week of rest) has also been shown to produce overall response rates of 24–26% in Japanese patients with AGC (13,14).
The safety profile of oral capecitabine differs from that of cisplatin, with little overlap of key toxicities, suggesting that the combination of capecitabine plus cisplatin may be effective and safe in AGC. Our phase II study in 38 patients with metastatic AGC showed that capecitabine plus cisplatin was active (55% RR) and well tolerated as a first-line chemotherapy (15). Another phase II study showed that this combination of capecitabine and cisplatin was active (28% RR) and well tolerated also in patients who had recurrence after prior fluoropyrimidine-based adjuvant chemotherapy (16). These results suggest that capecitabine/cisplatin may be an active and convenient alternative to 5-FU/cisplatin. Based on these promising results using a combination of capecitabine and cisplatin, an ongoing international phase III trial comparing capecitabine plus cisplatin with 5-FU plus cisplatin in AGC was launched in 2003 (17). However, the feasibility and efficacy of this combination regimen in clinical practice settings are unknown.
In AGC, the outcome of chemotherapy and prognosis depends on the characteristics of patients and tumors. Among the independent prognostic factors identified in clinical trials in AGC are performance status (18,19), the presence of liver and peritoneal metastases (18) and the extent of disease (locally advanced versus metastatic) (18,19). To date, however, little is known regarding prognostic factors in patients treated in clinical practice settings, including patients treated with gastrectomy followed by palliative chemotherapy. We therefore sought to determine the efficacy and tolerability of the capecitabine/cisplatin combination in the treatment of AGC in a clinical practice setting and to analyze prognostic factors in these patients.
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SUBJECTS AND METHODS |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patients
Patients were eligible for this study if they had histologically confirmed AGC, but measurable disease was not required. The computerized database of the Asan Medical Center identified 223 AGC patients (pts) who had been treated with capecitabine plus cisplatin as first line chemotherapy between March 2000 and December 2004. Of these, 70 patients had been already reported in previous articles (15, 16), 38 of whom were enrolled into the phase III study of XP versus FP in AGC (17).
These patients could be grouped into three categories according to disease status at the time of chemotherapy initiation: those with initially metastatic disease (i.e. initially presenting with metastatic disease), those with recurrent disease (i.e. tumor recurrence after previous curative gastrectomy), and those with resected metastatic disease (i.e. those with residual disease after gastrectomy and those with distant metastases who had gastrectomies).
Treatment Schedule and Toxicity Assessment
Capecitabine was administered orally at a dose of 1000–1250 mg/m2 twice a day according to the standard intermittent schedule (14 days of treatment followed by a 7-day rest period, every 3 weeks). Cisplatin was administered intravenously on day 1 (before the first dose of capecitabine) at a dose of 60–80 mg/m2 for 1 h with hydration and was repeated every 3 weeks. The hydration procedure consisted of 1 l of normal saline (containing 20 mEq of KCl and 8 mEq of MgSO4) infused intravenously for 2.5 h before and 2.5 h after cisplatin infusion. In addition, intravenous furosemide (20 mg) was given 30 min before infusing cisplatin. Mannitol was not used. A serotonin antagonist and dexamethasone were routinely administered prior to cisplatin to prevent emesis. Treatment was continued until disease progression or unacceptable toxicity, or if the patient chose to discontinue treatment. Toxicity was assessed before each 3-week cycle using the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0.
Pretreatment, Follow-up and Response Evaluation
Physical examination, chest X-rays, complete blood counts and biochemical tests were performed before each chemotherapy cycle. Computed tomography (CT) scans were performed every 2–3 cycles until the tumor progressed. Tumor response was classified according to the response evaluation criteria defined by RECIST guidelines (20). Confirmation of the response was not required for this study, because repeating CT scans 4 weeks afterwards is not practical in clinical practice.
Statistics
All enrolled patients were included in the intention-to-treat (ITT) analysis of efficacy. TTP and OS were estimated using the Kaplan–Meier method. In patients with measurable disease, the duration of response was defined as the interval from the onset of complete response (CR) or partial response (PR) until first evidence of disease progression. If death occurred before progression was documented, the date of death was assumed to be the date of progression. TTP was calculated from the date of entry to the date of progression. Overall survival (OS) was measured from the date of entry to the date of last follow-up or death.
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RESULTS |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patient Characteristics
The characteristics of the patients are summarized in Table 1. About two-thirds were men and their median age was 54 years (range 28–79 years), and most (85.2%) had good performance status (ECOG 0 or 1). About 60% were Borrmann types 1–3, and 16% were Borrmann type 4. Histologically, 89.2% of patients had adenocarcinoma and 8.5% had signet ring cell carcinoma. In all, 88 patients (49.3%) had multiple metastases involving two or more organ systems. The most common metastatic site was the peritoneum (39.5%), and the most common metastatic organ was the liver (33.6%). Among the 223 patients, 32 underwent gastrectomies but had residual diseases or distant metastases (resected metastatic), 82 had recurrent disease after previous curative gastrectomy (recurrent) and 109 with distant metastases had not had gastrectomies (initially metastatic). In the recurrent group, the median time to relapse after curative gastrectomy was 16.2 months (range: 3–86.4 months). In the resected metastatic group, 10 (31.2%) patients were found to have positive resection margins after gastrectomy, 12 (37.5%) were initially thought to be resectable on pre-operative imaging and subsequently found to have peritoneal metastases during surgery, three (9.4%) had gastrectomies with bilateral salphingoophorectomies for Krukenberg tumors, and seven (21.9%) had gastrectomies for other reasons. Therefore, most (81.3%) of the resected metastatic group did not have measurable disease. The median duration of follow-up at the time of this analysis was 11.9 months (range 2.1–51.9 months).
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Tumor Response
Of the 123 patients with measurable disease, 12 were not evaluable because they were lost to follow-up after the first treatment cycle (Table 2). Confirmed and unconfirmed responses were recorded in 30 and 26 patients, respectively (total RR 45.5% by ITT analysis, 95% CI, 32.9–50.2%), with a total of seven patients achieving a CR (5.7%). The median duration of response in these 56 patients was 5.1 months (range, 1.1–34.7 months). There was no difference in response among the resected metastatic, recurrent and initially metastatic groups (66.7 versus 36.5 versus 50.8%, P = 0.35; Table 2).
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Survival
The median TTP was 6.3 months (95% CI, 5.2–7.4 months) and the median OS was 11.1 months (95% CI, 9.4–12.9 months) (Fig. 1). Both TTP and OS differed significantly among the three groups. Median TTP of 8.7, 6.8 and 5.8 months (P = 0.02) (Fig. 2) and median OS of 14.7, 12.4 and 9.6 months (P = 0.03) (Fig. 3) were observed in the resected metastatic, recurrent and initially metastatic groups, respectively.
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Adverse Events
Patients received a median of five cycles (range, 1–12 cycles) of chemotherapy. Eleven patients were lost to follow-up, and 212 were assessable for safety. The frequencies of treatment-related hematological and nonhematological adverse events are shown in Table 3.
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Toxicity evaluation on patients in a practice setting is different from that of patients enrolled in a study. Study-enrolled patients underwent complete blood counts on a weekly basis. The frequencies of hematological adverse events among study-enrolled patients are more common than those in patients from a practice setting. Accordingly, study-enrolled patients were evaluated 3 weeks before their next chemotherapy, as were patients from a practice setting. Since nonhematologic toxicity could not be assessed well in the practice setting without a case report form, toxicity is likely to be underestimated in chart-based toxicity evaluation. The most common treatment-related hematological adverse events were anemia (94.8%) and neutropenia (80.7%), with grades 3 and 4 anemia occurring in 8.0 and 0.9% of patients, respectively and grades 3 and 4 neutropenia occurring in 24.1 and 5.2%, respectively. Hand–foot syndrome was relatively common, but grade 3 occurred only in 3.3% of patients. Diarrhea was experienced in 30% of patients, but severe cases were extremely rare. Doses were reduced during 246 cycles (22.1%) for hematological toxicities (68.9%), nausea/vomiting (5.6%), diarrhea (5.2%) and hand–foot syndrome (14.2%). Treatment was delayed in 109 cycles (10.4%) for hematologic toxicities (87.2%) and hand–foot syndrome (6.4%).
Prognostic Factors
The results of a univariate analysis of various patient and tumor variables are shown in Table 4. Age, gender, location of primary tumor, Borrmann type, histology, number of metastases and metastatic sites were not significant. Performance status and disease status, however, had significant effects on TTP and OS. Both TTP and OS were better for patients with performance status ECOG 0–1 than for those with ECOG 2 (P < 0.001 for both). In the resected metastatic, recurrent and initially metastatic groups, median TTP was 8.7, 6.8 and 5.8 months, respectively (P = 0.02), and median OS was 14.7, 12.4 and 9.6 months, respectively (P = 0.03). In contrast, the presence or absence of peritoneal metastases had no effect on TTP or OS.
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Multivariate analyses showed that patients in the resected metastatic and recurrent groups (OR = 1.501, 95% CI, 1.074–2.100, P = 0.018) and patients with good performance status (OR = 2.693, 95% CI, 1.688–4.298, P< 0.001) had a significantly increased TTP (Table 5). In addition, patients in the resected metastatic and recurrent groups (OR = 1.418, 95% CI, 1.021–1.967, P = 0.037) and those with good performance status (OR = 3.800, 95% CI, 2.417–5.974, P< 0.001) had significantly increased OS.
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DISCUSSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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In this study, we sought to determine whether XP combination therapy was safe and effective in AGC patients seen during routine clinical practice. Patients with advanced or metastatic gastric cancer usually show poor general condition, undernourishment, advanced age and comorbidity. These features can worsen prognosis, lower response rate and survival and increase toxicity, although these factors do not formally contra-indicate chemotherapy.
The combination of capecitabine and cisplatin has been tested in several malignancies, including gastric (12–16), biliary (21), and head and neck cancer (22,23). Using this combination as first line chemotherapy in patients with AGC, we observed a response rate of 45.5% and an OS of 11.1 months, findings within the ranges of results in clinical trials (RR: 28–54.8%, OS: 10.1–11.2 months) (15,16). We found that grade 1/2 hematological adverse events and hand–foot syndrome were relatively common, but severe cases were not common, findings similar to those observed previously in AGC (15). Thus, our findings indicate that the combination of capecitabine and cisplatin is effective and safe in the treatment of AGC, not only in a clinical trial setting but also in routine clinical practice.
We report a retrospective study of capecitabine/cisplatin combination therapy for metastatic gastric cancer. The doses of capecitabine and cisplatin were not constant. Capecitabine was administered orally at a dose of 1000–1250 mg/m2 twice a day according to a standard intermittent schedule (14 days of treatment followed by a 7-day rest period, every 3 weeks). Cisplatin was administered intravenously on day 1 (before the first dose of capecitabine) at a dose of 60–80 mg/m2 and was repeated every 3 weeks. Previously, our team conducted a phase II study of capecitabine plus cisplatin as a first-line chemotherapy for advanced gastric and biliary cancer (15,21). At that time, patients received 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 capecitabine twice daily on days 1–14. However, because of the relative dose intensity of capecitabine (84.1%) and cisplatin (94%), we concluded that 60 mg/m2 cisplatin on day 1 and 1000 mg/m2 oral capecitabine twice daily on days 1–14 was more feasible in clinical practice. The patients who enrolled into the international phase III study comparing XP with FP received 80 mg/m2 cisplatin on day 1 every 3 weeks to balance the dose intensity of cisplatin with that used in Western countries (100 mg/m2 every 4 weeks). Patients not included in the study or treated thereafter were given 60 mg/m2 cisplatin on day 1 and 1000 mg/m2 capecitabine twice daily on days 1–14.
While our results suggest that capecitabine plus cisplatin may replace FP in the treatment of AGC, we await the results of an ongoing phase III trial comparing the efficacy and tolerability of capecitabine/cisplatin with that of FP (17).
We also found that the prognostic factors of increased TTP and OS in patients treated with capecitabine/cisplatin were performance status and disease status. To our knowledge, this report is the first to determine the prognostic factors in the clinical practice of palliative chemotherapy for AGC. Although previous studies have already recognized that disease status was an important prognostic factor in palliative chemotherapy, the categories of disease status in those studies are different from ours. Previous studies found that locally advanced cases had better prognosis than cases with distant metastases. This probably reflects that tumor burden is an important prognostic variable in the outcome of palliative chemotherapy. In this study, we classified the patients into three groups with regard to disease status: resected metastatic, recurrent and initially metastatic groups. The resected metastatic group has not been identified in previous studies because they have only minimal residual disease or metastasis after gastrectomy and therefore no measurable disease, and are usually not eligible for most of the clinical trials. However, these patients also require palliative chemotherapy in clinical practice and were included in this study.
The resected metastatic group included R1, R2 resected locally advanced status, and pre-operative unidentified peritoneal seeding or liver metastasis. We found that 68% of our patients with resected metastatic disease had no signs of metastases during routine pre-operative examinations, but were found to be resection margin positive or have peritoneal seeding during gastrectomy. The majority of the patients in this group did not have measurable disease and so were not eligible for clinical trials of AGC patients. The natural history of this heterogeneous group of patients has not been well defined. These patients may have had gastrectomies because they were in relatively good condition for surgery.
Patients in the recurrent group should have a lower tumor burden compared with the initially metastatic group. Recurrence is usually diagnosed with low tumor burden because patients are followed up regularly with surveillance examination after curative surgery. This potential difference in tumor burden between recurrent and initially metastatic groups has not been recognized in previous studies. In terms of tumor burden, it was expected that the initially metastatic group has the highest, followed by the recurrent group and the resected metastatic group has the lowest tumor burden. This expectation was supported by significant difference in TTP and OS among the three groups.
Presence in the recurrent and resected metastatic groups was an independent prognostic factor for increased TTP and OS. While this finding is in agreement with those of previous reports, our results should be interpreted with caution because we conducted a retrospective analysis. Performance status has been found to be a prognostic factor in patients with AGC. In addition, patients with locally advanced disease, and thus a lesser tumor burden, had a better prognosis than those with metastatic disease (22,23). While several studies reported that peritoneal metastasis was an important prognostic factor, this was not verified in our study. The patients in our study had more peritoneal metastases (39.5%) than did patients in clinical trials (15.8–18.7%).
This study had several limitations inherent to retrospective analyses. First, we observed a response rate of 45.5% according to ITT analysis. Because this study was performed in a clinical practice setting, we did not routinely perform follow-up imaging studies 4 weeks after the first response, as in clinical trials. In addition, 21% of patients, classified as having unconfirmed responses, were included in our calculation of overall response rate. Thus, we may have overestimated the response rate. In addition, while several studies have reported that laboratory variables were prognostic of response, we did not investigate this in our analysis (18,19).
In conclusion, we have shown here that the combination of capecitabine and cisplatin is safe and effective as a first-line treatment for palliative resected metastatic, recurrent and metastatic gastric cancer in a clinical practice setting. The disease status and performance status of the patients were the most important prognostic factors for outcome of XP chemotherapy.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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