Annals of Oncology Advance Access published online on February 14, 2008
Annals of Oncology, doi:10.1093/annonc/mdn024
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
review |
The role of UFT in advanced gastric cancer
1 Department of Medical Oncology, Institute of Oncology, Istanbul University, Capa 34390 Istanbul, Turkey
2 Institute of Oncology, Kaplan Medical Center, Rehovot, Israel
* Correspondence to: Prof. N. F. Aykan, Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey. Tel: +90-533-265-8907; Fax: +90-212-661-9028; E-mail: nfaruk{at}superonline.com
 |
Abstract |
|---|
Top
Abstract
introductionBackground: Advanced gastric cancer has a poor prognosis, with a relative 5-year survival rate of 7%–27%. Chemotherapy, which improves overall survival (OS) and quality of life, is the main treatment option. Although numerous regimens have been investigated, there is no standard treatment. Combination chemotherapy, however, is associated with a significant survival benefit compared with monotherapy and i.v. 5-fluorouracil (5-FU) is one of the most widely used agents. UFT (tegafur–uracil) has similar efficacy to continuous infusion 5-FU with improved tolerability and is more convenient for patients.
Design: The efficacy and safety of UFT in the treatment of advanced gastric cancer have been demonstrated in a number of phase II studies.
Results: UFT with leucovorin (folinic acid) monotherapy shows overall response rates (ORRs) of 16%–29% and median OS of 5.8 months. Combination of UFT with cisplatin, etoposide, or paclitaxel shows ORRs of 35%–51% and median OS of 8.3–10.1 months. UFT-based three-drug combinations show ORRs of 41%–57% and median OS of 8.6–15 months. UFT-based combinations have a good tolerability profile, particularly a low incidence of myelosuppression, mucositis, and hand–foot syndrome.
Conclusion: UFT represents a logical replacement for 5-FU in chemotherapy regimens for the treatment of advanced gastric cancer.
advanced gastric cancer, combination therapy, phase II study, tegafur, UFT, uracil
|
introduction |
|---|
Gastric cancer is the fourth most common cancer worldwide, with an estimated 934 000 new cases/year in 2002 (9% of new cancer cases globally), and is approximately twice as common in men as in women [1]. Despite an overall global decrease in incidence, gastric cancer is the second most common cause of cancer death, accounting for
700 000 deaths/year (10% of worldwide cancer mortality) [1]. The incidence of gastric cancer varies widely between different geographical regions. Regions with a high incidence include east Asia (China and Japan), eastern Europe, and parts of Central and South America. Areas with a low incidence include southern Asia, north and East Africa, and North America [1]. While the overall incidence of gastric cancer (especially distal tumors) has declined over several decades [2], the incidence of proximal tumors has increased since the 1970s, particularly among men in developed countries [3]. Risk factors for gastric cancer include Helicobacter pylori infection, male sex, pernicious anemia, smoking, Menetrier's disease, dietary, and genetic factors [2, 4]. Gastric cancer is usually diagnosed at an advanced stage, with >50% of patients having stage 3 or 4 disease at presentation [5]. Stage 4 gastric cancer has a poor prognosis, with a relative 5-year survival rate of 7% in the United States [5] and 9%–27% in Europe [6]. More than half of the patients presenting with early-stage disease undergo surgery but even after a curative resection, 60% of these patients eventually relapse with local or distant metastases [7]. |
current management |
|---|
The management of gastric cancer is usually a multitreatment approach involving surgery, chemotherapy, and radiotherapy. Surgical resection is the standard treatment for the small proportion of patients that present with early-stage gastric cancer and is the only mode of therapy that is potentially curative. However, even after an apparent complete resection, local and distant recurrences are common and the prognosis for patients with locally advanced gastric cancer is poor. Patients with advanced disease are mainly treated with chemotherapy [5]. In addition to improving overall survival (OS), combination chemotherapy is associated with improvements in quality of life (QoL) compared with best supportive care [8]. Because of the essentially palliative nature of chemotherapy for advanced disease, effective regimens should also be well tolerated. Postoperative adjuvant chemotherapy with i.v. 5-fluorouracil (5-FU)/leucovorin (LV) before, during, and after radiotherapy has a survival advantage of
15% after 4–5 years compared with surgery alone [9]. This approach is considered as a standard therapy in the United States but is less popular in Europe because of concerns about the type of surgery used and the toxic effects associated with chemoradiotherapy [5]. |
the role of chemotherapy in advanced gastric cancer |
|---|
Chemotherapy is the main treatment option for patients with advanced disease. Median OS of 8–12 months has been reported in patients undergoing chemotherapy compared with 3–5 months for those treated with best supportive care [8, 10]. These results have been confirmed by a recent meta-analysis that showed a convincing 6-month survival advantage for chemotherapy compared with best supportive care [11]. In a study by Glimelius et al. [8], QoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30. Chemotherapy improved or prolonged QoL compared with best supportive care. In the overall category, 14 (45%) chemotherapy patients were considered to have a favorable QoL outcome compared with 6 (20%) best supportive care patients (P < 0.05). In the best supportive care group, the favorable QoL outcome was attributed to chemotherapy in one patient, irradiation in one patient, the effects of steroids and other palliative efforts in one patient, and a naturally prolonged asymptomatic period in three patients. In the chemotherapy group, 17 (55%) patients had a prolonged symptom-free period or improved symptomatology without severe toxicity compared with six (20%) patients in the best supportive care group (P < 0.01).
Although a large number of chemotherapy regimens have been investigated in clinical trials, there is no standard treatment for advanced gastric cancer. Several drugs, including i.v. 5-FU, cisplatin, and doxorubicin, have shown good single-agent activity. Intravenous 5-FU remains one of the most widely used chemotherapy agents and has been the cornerstone of combination regimens such as FAM (5-FU, doxorubicin, and mitomycin C), FAMTX (5-FU, doxorubicin, and methotrexate), ELF (etoposide, LV, and 5-FU), DCF (docetaxel, cisplatin, and 5-FU), and ECF (epirubicin, cisplatin, and continuous infusion 5-FU) [12–21]. Combination chemotherapy has been shown to be associated with a statistically significant (P = 0.001) survival benefit compared with monotherapy in a meta-analysis of several clinical trials [11]. This corresponded to a small but clinically relevant 1-month mean average survival benefit [11].
This meta-analysis also showed that three-drug combinations have a significant survival benefit compared with two-drug combinations [11]. The mean average survival difference between three- and two-drug regimens was 1–2 months. Three-drug combination neo-adjuvant treatment has also been shown to improve survival compared with surgery alone [12]. In a randomized trial comparing ECF with surgery alone in patients with operable gastroesophageal cancer, ECF decreased tumor size and stage and significantly improved progression-free survival (PFS) (P < 0.001) and OS (P = 0.009) [12].
The survival benefits associated with combination chemotherapy need to be weighed against the additional toxicity and deterioration in QoL. In the treatment of gastric cancer, the combination of cisplatin, epirubicin, LV, and bolus 5-FU (PELF) has been shown to be associated with more toxicity than the continuous infusion 5-FU regimen ECF and a higher rate of treatment-related deaths, 3.3% versus 0.6% for continuous infusion 5-FU, respectively (P = 0.028) [11, 13–15].
|
oral fluoropyrimidines |
|---|
In order to improve tolerability and patient convenience, as well as improve efficacy, oral alternatives to i.v. 5-FU have been developed. The three oral fluoropyrimidines, which are all 5-FU prodrugs, are UFT (tegafur–uracil), capecitabine, and S-1. UFT is a combination of tegafur, an oral prodrug of 5-FU that is metabolized to 5-FU primarily in the liver, and uracil, a natural substrate for the liver enzyme dihydropyrimidine dehydrogenase (DPD), in a 1 : 4 M ratio. Uracil competes with 5-FU for DPD, inhibiting its degradation and leading to higher intratumoral 5-FU levels [22]. Importantly, phosphorylation of 5-FU is not significantly suppressed by uracil [23]. S-1 is a combination of tegafur, the DPD inhibitor gimeracil, and potassium oxonate, which reduces the gastrointestinal side-effects of 5-FU. S-1 is currently only licensed for use in Japan and is in phase III clinical trials for advanced gastric cancer in other regions. Capecitabine is converted to 5-FU via a three-step enzymic process in the liver and tumor cells.
The efficacy of S-1 in the treatment of advanced gastric cancer has been demonstrated in several phase II trials with overall response rates (ORRs) of 26%–49% [7]. The main grade 3/4 toxic effects were hematologic, including leukopenia, granulocytopenia, and decreased hemoglobin and haematocrit, while the most common non-hematologic toxic effect was diarrhea [7]. The results of two phase III studies have been reported [24, 25]. In one phase III study, S-1 was well tolerated and showed significant noninferiority to 5-FU alone in terms of OS (11.4 versus 10.8 months) [24]. In another phase III study, S-1 plus cisplatin was effective and well tolerated and superior to S-1 alone in terms of OS (13.0 versus 11.0 months) and ORR (54% versus 31%) [25]. In these studies, the main grade 3/4 adverse events associated with S-1 monotherapy were decreased hemoglobin (13%), neutropenia (11%), anorexia (12%), and diarrhea (8%) [24, 25]. S-1 has also been shown to be effective and well tolerated as adjuvant therapy for locally advanced gastric cancer [26]. In a phase III clinical trial, the 3-year OS rate with S-1 was significantly greater than with surgery alone (80% versus 70%, P < 0.002) in east Asian patients [26]. The most common grade 3 adverse events were anorexia (6%), nausea (4%), and diarrhea (3%). Only one patient experienced a grade 4 adverse event of anorexia.
UFT has also been shown to be effective and well tolerated as adjuvant therapy for locally advanced gastric cancer in Japanese patients [27]. In this randomized study, the 5-year OS rate was 86% for UFT and 73% in the control group (P = 0·017). The most common grade 3 adverse events were neutropenia (13%), hyperbilirubinemia (9%), and anorexia (7%). Only one patient experienced a grade 4 adverse event of diarrhea.
Capecitabine has been shown to be effective as monotherapy and in combination for the treatment of advanced gastric cancer in a number of phase II studies with ORRs of 6%–34% and 17%–67%, respectively, and median OS of 8.1–10.0 months and 5.9–17.2 months, respectively [28–31]. Capecitabine monotherapy was generally well tolerated with a low incidence of grade 3/4 adverse events. The most frequent grade 3/4 adverse event was hand–foot syndrome (HFS), which was reported by 7%–13% of patients [29, 31]. Other common grade 3/4 adverse events were granulocytopenia (7%) and anorexia (8%) [29]. In a phase III study comparing capecitabine plus cisplatin with continuous infusion 5-FU plus cisplatin, median OS was 10.7 months and 9.5 months, respectively, showing the capecitabine combination was significantly noninferior (P = 0.0146) [32]. Capecitabine plus cisplatin was significantly superior to 5-FU plus cisplatin in terms of ORR: 41% versus 29% (P = 0.0295). Capecitabine was well tolerated: the most common treatment-related grade 3/4 adverse events were neutropenia (16%), vomiting (7%), and diarrhea (5%) [32]. Twenty-two percent of patients receiving capecitabine experienced HFS. Capecitabine has also been shown to be effective in the treatment of advanced esophagogastric cancer in a phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin (the REAL 2 trial) [33]. Patients were randomly assigned to one of four regimens: ECF, epirubicin plus oxaliplatin and fluorouracil (EOF), epirubicin plus cisplatin and capecitabine (ECX), or epirubicin plus oxaliplatin and capecitabine (EOX). Comparing ECF to EOF, ECX, and EOX, there were no significant differences in ORRs (41%, 42%, 46%, and 48%, respectively) and grade 3/4 non-hematologic toxicity (36%, 42%, 33%, and 45%, respectively).
While similar in many respects, the tolerability profiles of UFT and capecitabine differ in the incidence of HFS. HFS is very rarely (<0.01%) observed in patients treated with UFT [34] but occurs in over half of all patients treated with capecitabine [35].
|
rationale for replacing 5-FU with UFT |
|---|
Bolus i.v. 5-FU can result in significant toxic effects and continuous infusion requires portable infusion devices, which can lead to complications such as thrombosis and infection [36, 37], as well as being inconvenient for patients. The complications resulting from the central venous line, which is mandatory for continuous infusion 5-FU, occurred in 15% of ECF-treated patients in a study by Webb et al., while 16% of patients receiving the ECF regimen in a study by Ross et al. had exit-site infections and a further 7% experienced thrombosis [14, 15].
UFT has been shown to provide comparable pharmacokinetics with continuous infusion 5-FU in phase I and phase II studies [38–40]. Tegafur is well absorbed after oral administration, resulting in higher peak plasma levels of 5-FU and a similar area under the curve to those achieved with continuous infusion 5-FU [38, 39]. The main adverse events observed were diarrhea, nausea, and vomiting. The occurrence of these adverse events was significantly correlated with the plasma levels of 5-FU after oral administration of UFT [38, 39].
Studies have shown that patients prefer oral to i.v. therapy provided that efficacy is not compromised and that side-effects are not more frequent [41]. In three randomized phase II studies, two of which were cross over studies [40, 42], patients expressed a preference for oral treatment with UFT over i.v. 5-FU [40, 42, 43]. The main reasons for preferring UFT in these studies were the convenience of oral therapy and improved tolerability. Clinical studies in metastatic colorectal cancer (mCRC) have shown that UFT with LV has comparable efficacy to 5-FU/LV [44, 45]. Importantly, UFT with LV had a significantly better safety profile than 5-FU: the incidence of hematological malignancies was significantly lower in the UFT group, with fewer episodes of febrile neutropenia and documented infection. Notably, there was no evidence of severe (grade 3/4) HFS with UFT.
UFT has similar efficacy to continuous infusion 5-FU and improved tolerability but does not have the inconvenience and associated side-effects of catheterization and portable infusion devices. UFT therefore represents a logical replacement for 5-FU in chemotherapy regimens for the treatment of advanced gastric cancer. Since three-drug regimens have been shown to be the most effective combination chemotherapy for advanced gastric cancer, in terms of ORR and OS [11], UFT-based three-drug combinations are the main focus of this review.
|
UFT phase II clinical studies in advanced gastric cancer |
|---|
monotherapy
UFT with LV monotherapy is effective and well tolerated in the treatment of advanced gastric cancer with response rates of 16%–29% and OS of 5.8 months reported in two trials [46, 47]. In one study, 16 patients received UFT 480 mg/m2/day in three divided doses and LV 25 mg/m2/day in four divided doses on days 1–21 of a 28-day cycle. Patients received a median of four cycles (range 1–9) [46]. The ORR was 29% [95% confidence interval (CI) 4.9% to 52.3%]: one of 14 assessable patients (7%) achieved a complete response (CR) and three (22%) a partial response (PR). Median OS was 5.8 months. The main grade 3/4 adverse events were diarrhea, nausea/vomiting, and oral mucositis. There were no severe infections or treatment-related deaths. In another study, 38 patients received UFT 300 mg/m2/day plus LV 90 mg/day, both in three divided doses, on days 1–28 of a 35-day cycle [47]. The ORR was 16% in 25 assessable patients, with one CR (4%) and three PRs (12%). The main grade 3/4 adverse events were diarrhea and nausea/vomiting. There were no treatment-related deaths. No HFS was reported in either study.
combination therapy
The main studies investigating the efficacy of UFT with LV plus one or more agents in the treatment of advanced gastric cancer are summarized in Table 1.
|
Two-drug combinations
UFT plus cisplatin
This combination was effective and well tolerated in two Japanese studies [48, 49]. In one study, 28 patients received UFT 400 mg/m2/day in two divided doses for 21 days and i.v. cisplatin 90 mg/m2 by 24-h continuous infusion 5–7 days after the start of UFT therapy in a 28-day cycle [48]. The dose of UFT was reduced to 250 mg/m2 after 8 weeks and the dose of cisplatin was reduced to 80 mg/m2 after the first cycle. Fourteen patients (50%) achieved a PR and median OS was 10.1 months. There were no grade 4 adverse events. Grade 3 leucopenia occurred in three (11%) patients. In a second study, 43 patients received UFT 400 mg/m2/day in two divided doses on days 1–21 of a 28-day cycle and i.v. cisplatin 80 mg/m2 on day 8 [49]. The median number of cycles was 3 (range 1–8). The ORR was 51% (95% CI 35.0% to 67.2%) in 41 assessable patients, with 21 patients achieving a PR. Median OS was 8.3 months. The main grade 3/4 adverse events were neutropenia (22% of patients), anemia (12%), leucopenia (10%), thrombocytopenia (10%), and glutamic-oxaloacetic transaminase/glutamic-pyruvic transaminase increase (10%). No HFS was reported in either study.
UFT plus etoposide
This combination was found to be effective, well tolerated, and easy to administer in one study [50]. Forty-six patients received i.v. etoposide 100 mg/m2 on day 1 and 200 mg/m2 on days 2 and 3, UFT 390 mg/m2/day in two divided doses on days 1–14, and i.v. LV 500 mg/m2 on day 1 followed by oral LV 15 mg/day in two divided doses on days 2–14 of a 28-day cycle [50]. Treatment was repeated every 28 days for a minimum of three cycles. The ORR was 35% (95% CI 22% to 51%): four patients (9%) achieved a CR and 12 (26%) a PR. Median OS was 9 months. The main grade 3/4 adverse events were diarrhea (17% of patients), anemia (13%), and nausea/vomiting (11%). Although grade 1/2 HFS was observed in three patients (7%), no severe (grade 3/4) HFS was reported.
UFT plus paclitaxel
This combination was effective, well tolerated, and convenient in a multicenter trial [51]. Fifty-five patients received paclitaxel 100 mg/m2 on days 1 and 8, and UFT 300 mg/m2/day and LV 90 mg/day were given in three divided doses on days 1–14 of a 21-day cycle. The ORR was 50% (95% CI 35% to 65%) in 48 assessable patients: two patients (4%) achieved a CR and 22 patients (46%) a PR. Median OS was 9.8 months. The main grade 3/4 adverse events were neutropenia (45% of patients), leukopenia (18%), and diarrhea (15%). No HFS was reported.
Three-drug combinations
ECF is one of the most effective three-drug combination regimens and has been considered as standard therapy for advanced gastric cancer [52]. Reported ORRs range from 42% to 46% and median OS from 8.7 to 9.4 months [14, 15, 20]. The efficacy ECF has led to the corresponding UFT-based three-drug combinations being investigated in four studies.
UFT, epirubicin, and cisplatin (PELUF)
The combination of UFT with LV, epirubicin, and cisplatin (PELUF) has been the main focus of recent research and has demonstrated significant activity in patients with advanced gastric cancer, as well as an acceptable safety profile in four studies [53–56]. These studies investigated similar regimens but with different doses of UFT and/or LV. In a study by Kim et al. [53], 37 patients received i.v. epirubicin 50 mg/m2 and i.v. cisplatin 60 mg/m2 on day 1 and UFT 360 mg/m2/day in three divided doses with oral LV 25 mg/m2/day in four divided doses on days 1–21 of a 28-day cycle. All 37 patients were assessable and received a median of four cycles of treatment (range 2–12). The ORR was 54% (95% CI 39% to 70%): two patients (5%) achieved a CR and 18 (49%) a PR. Stable disease (SD) was reported in 12 patients (32%). Median OS was 10 months (range 2–15+). The main grade 3/4 adverse events were leucopenia in 14 (38%), nausea/vomiting in 11 (30%), oral mucositis in five (14%), and diarrhea in four (11%) patients. No HFS was reported. There were no severe infections or treatment-related deaths.
In a study by Jeen et al. [54], 52 patients received a similar regimen with the same doses of epirubicin, cisplatin, and UFT but a higher dose of LV than used in the Kim et al. study: i.v. epirubicin 50 mg/m2 and i.v. cisplatin 60 mg/m2 on day 1 and UFT 360 mg/m2/day with LV 45 mg/day in three divided doses on days 1–21 of a 28-day cycle. Patients received a median of five cycles (range 1–10). In 47 assessable patients, the ORR was 57% (95% CI 71.5% to 43.3%): three patients (6%) achieved a CR and 24 a PR (51%). SD was reported in 11 patients (23%). Median OS was 15 months (range 2–33+). The main grade 3/4 adverse events were neutropenia in 22 patients (42%), nausea in 14 (27%), vomiting in nine (18%), and thrombocytopenia in seven (14%) patients. No HFS was reported. There were no severe infections or treatment-related deaths.
Two more recent studies investigated a lower 300 mg daily dose of UFT [55, 56]. In a study by Saglam [55], 19 chemotherapy-naive patients received i.v. epirubicin 50 mg/m2 and i.v. cisplatin 60 mg/m2 on day 1 and UFT 300 mg/m2/day with LV 90 mg/day on days 1–21 of a 28-day cycle. The median number of cycles was 3 (range 1–6). The ORR was 42%: three patients (16%) achieved a CR and five (26%) a PR. Three patients (16%) had SD. Median OS was 14 months. The main grade 3 adverse events were nausea/vomiting in four (21%) patients, diarrhea in one (5%), and hemoglobin toxicity in one (5%) patient. No grade 4 diarrhea, nausea, or vomiting were observed. No HFS was reported. In a study by Idelevich et al. [56], 39 patients received i.v. epirubicin 50 mg/m2 and i.v. cisplatin 60 mg/m2 on day 1 plus UFT 300 mg/m2/day with oral LV 30 mg/m2/day in two divided doses on days 1–22 of a 28-day cycle. Patients received a median of five cycles of treatment (range 2–8). All patients were assessable for efficacy and safety. The ORR was 38% (95% CI 24% to 52%): two patients (5%) achieved a CR and 13 (33%) a PR. Sixteen patients (41%) had SD. Median OS was 9.5 months (range 8.5–13.5). The main grade 3/4 adverse events were leukopenia in 10 (25%) patients, neutropenia in eight (20%), diarrhea in three (8%), and nausea/vomiting in three (8%) patients. No HFS was reported. There were no treatment-related deaths.
Woo et al. [57] assessed a 21-day regimen of i.v. epirubicin 50 mg/m2 and i.v. cisplatin 60 mg/m2 on day 1 and UFT 300 mg/m2/day in three divided doses without LV or a rest period between cycles. The median number of cycles was 4 (range 2–10). Thirty-five patients were included and 32 were assessable: the ORR was (41%), all 13 patients achieving a PR. Ten patients (31%) had SD. Median OS was 8.6 months. Grade 3/4 leukopenia was reported in eight (25%) patients. Grade 3 adverse events included nausea/vomiting in nine (28%) patients and thrombocytopenia in three (9%). Three patients (9%) experienced grade 1/2 HFS. No grade 3/4 diarrhea was observed. There were no treatment-related deaths.
UFT, docetaxel, and cisplatin
In a study of first-line treatment, 52 patients received i.v. docetaxel 60 mg/m2 for 1 h followed by i.v. cisplatin 75 mg/m2 for 2 h on day 1 and UFT 400–600 mg/m2/day with LV 75 mg/m2/day in three divided doses on days 1–21 of a 28-day cycle [58]. The combination was effective and had an acceptable tolerability profile. The ORR was 50% (95% CI 36.4% to 63.6%): four patients achieved a CR (8%) and 22 a PR (42%). Seventeen patients (33%) had SD. Median OS was 11.2 months (range 4–156+). The main grade 3/4 adverse events were neutropenia in 36 patients (69%), nausea/vomiting in 12 patients (23%), diarrhea in nine patients (17%), mucositis in three patients (6%), and thrombocytopenia in three patients (6%). No HFS was reported. There were no treatment-related deaths.
In contrast, docetaxel in combination with cisplatin and 5-FU (DCF) has been shown to be associated with increased hematologic toxicity compared with cisplatin plus 5-FU (CF) [18]. Treatment-related grade 3/4 adverse events occurred in 69% of patients receiving DCF versus 59% of patients receiving CF. Grade 3/4 neutropenia (82% versus 57%), leukopenia (65% versus 31%), and all-grade complicated neutropenia (febrile neutropenia or neutropenic infection: 29% versus 12%) were significantly more frequent in patients receiving DCF than CF (P < 0.05). In patients aged 65 years or older, grade 3/4 treatment-related infection was more frequent with DCF (20%) than CF (9%).
|
new combinations with targeted therapy |
|---|
The combination of chemotherapy plus a targeted therapeutic agent is a promising new area for the treatment of advanced gastric cancer and several combination regimens are being investigated, such as irinotecan plus cisplatin plus bevacizumab and FOLFIRI plus cetuximab, with encouraging response rates, OS, and acceptable toxicity [59, 60]. In a phase II study, 47 patients with metastatic or unresectable gastric/gastroesophageal junction adenocarcinoma received bevacizumab 15 mg/kg on day 1 and irinotecan 65 mg/m2 and cisplatin 30 mg/m2 on days 1 and 8, every 21 days [59]. Among 34 assessable patients, the ORR was 65% (95% CI 46% to 80%), with 20 patients (59%) achieving a PR and two patients (6%) a CR. Twelve patients had SD. Median OS was 12.3 months. There was no increase in chemotherapy-related toxicity. Possible bevacizumab-related adverse events included grade 3 hypertension in 13 patients (28%), gastric perforation in two patients (4%) and near perforation in one patient (2%), and myocardial infarction in one patient (2%). Grade 3/4 thromboembolic events occurred in 12 patients (25%).
In another phase II study, 38 previously untreated patients with confirmed advanced gastric/gastroesophageal adenocarcinoma received i.v. cetuximab at an initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2, i.v. irinotecan 180 mg/m2 on day 1, i.v. LV 100 mg/m2 followed by i.v. bolus 5-FU 400 mg/m2 and 600 mg/m2 22-h continuous infusion on days 1 and 2 every 2 weeks for a maximum of 24 weeks [60]. Cetuximab alone was then permitted in patients with a CR, PR, or SD. All 38 patients were assessed for safety and survival, and 34 patients were assessed for response. The ORR was 44% (95% CI 27.5% to 60.9%) with a CR in four patients (12%) and a PR in 11 patients (32%). Sixteen patients had SD. Median expected OS was 16 months. Grade 3/4 adverse events included neutropenia in 16 patients (42%), acne-like rash in eight patients (21%), diarrhea in three patients (8%), asthenia in two patients (5%), stomatitis in two patients (5%), and hypertransaminasemia in two patients (5%). No cetuximab-related hypersensitivity reaction was reported. There was one (3%) treatment-related death. The combination of PELUF with cetuximab, which is currently being investigated, may achieve similar efficacy results with improved tolerability.
|
discussion |
|---|
Although recent advances in the development of new chemotherapeutic regimens have improved treatment and patient outcomes, advanced gastric cancer still has a poor prognosis. As well as improving response rates and OS, a chemotherapeutic agent should offer improved tolerability and QoL. UFT oral therapy has been shown to have comparable pharmacokinetics to continuous infusion 5-FU with similar efficacy and improved tolerability in the treatment of mCRC [40, 44, 45]. Oral treatment with UFT has also been shown to be preferred by patients to i.v. 5-FU in the treatment of mCRC and to improve QoL [40, 42, 43]. In addition, oral therapy with UFT is more convenient for patients than i.v. 5-FU. UFT therefore represents a logical replacement for 5-FU in chemotherapy regimens for the treatment of advanced gastric cancer.
In advanced gastric cancer, UFT monotherapy is an effective and well-tolerated treatment option with response rates of 16%–29%, OS of 5.8 months, and a low incidence of grade 3/4 adverse events demonstrated in two phase II trials [46, 47]. UFT monotherapy can be particularly useful in elderly or fragile patients who are unwilling or unable to tolerate combination therapy. UFT-based combinations are effective and generally well tolerated, with response rates of 35%–57% and OS of 8–15 months [46, 49–51, 53–58]. The efficacy of UFT-based combinations is comparable with that for other combinations, such as irinotecan- and capecitabine-based regimens, with reported ORRs of 20%–58% and 35%–59%, respectively, and median OS of 7–12 months and 9.6 months, respectively [61].
Three-drug combination regimens have been shown to achieve better survival results than two-drug combinations [11]. ECF is one of the most effective three-drug combination regimens available, with ORRs of 42%–46% and median OS of 8.7–9.4 months, and has been considered as standard therapy for advanced gastric cancer [14, 15, 20, 52]. The three-drug combination of UFT with LV with epirubicin and cisplatin (PELUF) is an effective alternative to the ECF regimen with comparable efficacy, as shown by ORRs of 38%–57% and OS of 9.5–15 months, and improved tolerability [53–56]. In one ECF study, 15% of patients experienced complications due to the central venous line while another 16% of patients experienced exit-site infections and 7% had thrombosis [14, 15]. Compared with 5-FU-based combination regimens, UFT-based combinations have the additional advantage of a good tolerability profile, in particular, a low incidence of myelosuppression, mucositis, and HFS.
In conclusion, UFT-based combinations offer the patient an effective, well-tolerated, and convenient alternative to i.v. bolus and continuous infusion 5-FU regimens. The evidence from published studies supports the role of UFT as a replacement for i.v. 5-FU in the treatment of advanced gastric cancer.
|
Acknowledgements |
|---|
The authors would like to thank Kevin De-Voy, who provided medical writing support on behalf of Merck KGaA.
Received for publication September 30, 2007. Revision received January 9, 2008. Accepted for publication January 10, 2008.
|
References |
|---|
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin (2005) 55:74–108.
2. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol (2006) 12:354–362.[Web of Science][Medline]
3. Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin N Am (2002) 11:235–256.[Medline]
4. Cunningham D, Jost LM, Purkalne G, Oliveira J. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of gastric cancer. Ann Oncol (2005) 16(Suppl 1):i22–i23.
5. Hundahl SA, Phillips JL, Menck HR. The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy. Fifth Edition American Joint Committee on Cancer staging, proximal disease, and the "different disease" hypothesis. Cancer (2000) 88:921–932.[CrossRef][Web of Science][Medline]
6. Faivre J, Forman D, Esteve J, Gatta G. Survival of patients with oesophageal and gastric cancers in Europe. Eur J Cancer (1998) 34:2167–2175.[CrossRef][Web of Science][Medline]
7. Ajani JA. Evolving chemotherapy for advanced gastric cancer. Oncologist (2005) 10:49–58.
8. Glimelius B, Ekstrom K, Hoffman K, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol (1997) 8:163–168.
9. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med (2001) 345:725–730.
10. Hill ME, Cunningham D. Medical management of advanced gastric cancer. Cancer Treat Rev (1998) 248:113–118.
11. Wagner AD, Grothe W, Haerting J, et al. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol (2006) 24:2903–2909.
12. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med (2006) 355:11–20.
13. Cocconi G, Bella M, Zironi S, et al. Fluorouracil, doxorubicin, and mitomycin combination versus PELF chemotherapy in advanced gastric cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research. J Clin Oncol (1994) 12:2687–2693.
14. Ross P, Nicolson M, Cunningham D, et al. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol (2002) 20:1996–2004.
15. Webb A, Cunningham D, Scarfe JH, et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol (1997) 15:261–267.
16. Cullinan SA, Moertel CG, Fleming TR, et al. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma: fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. J Am Med Assoc (1985) 253:2061–2067.
17. Moehler M, Eimermacher A, Siebler J, et al. Randomized phase II evaluation of irinotecan plus high-dose 5-fluorouracil and leucovorin (ILF) versus 5-fluorouracil, leucovorin, and etoposide (ELF) in untreated metastatic gastric cancer. Br J Cancer (2005) 92:2122–2128.[CrossRef][Web of Science][Medline]
18. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol (2006) 24:4991–4997.
19. Vanhoefer U, Rougier P, Wilke H, et al. Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol (2000) 18:2648–2657.
20. Waters JS, Norman A, Cunningham D, et al. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer (1999) 80:269–272.[CrossRef][Web of Science][Medline]
21. Wils JA, Klein HO, Wagener DJ, et al. Sequential high-dose methotrexate and fluorouracil combined with doxorubicin—a step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. J Clin Oncol (1991) 9:827–831.[Abstract]
22. Unemi N, Takeda S. Studies on combination therapy with 1-(tetrahydro-2-furanyl)-5-fluorouracil plus uracil. Effects of uracil on in vitro metabolism of 1-(tetrahydro-2-furanyl)-5-fluorouracil and 5-fluorouracil. Chemotherapy (1981) 29:176–184.[CrossRef][Web of Science]
23. Ikenaka K, Shirasaka T, Kitano S, Fujii S. Effect of uracil on metabolism of 5-fluorouracil in vitro. Gan To Kagaku Ryoho (1979) 70:353–359.
24. Boku N, Yamamoto S, Shirao K, et al. Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912). J Clin Oncol (2007) 25:18S. (Abstr 4513).
25. Narahara H, Koizumi W, Hara T, et al. Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment for advanced gastric cancer (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment for stomach cancer. J Clin Oncol (2007) 25:18S. (Abstr 4514).
26. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med (2007) 357:1810–1820.
27. Nakajima T, Kinoshita T, Nashimoto A, et al. Randomized controlled trial of adjuvant uracil–tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer. Br J Surg (2007) 94:1468–1476.[CrossRef][Web of Science][Medline]
28. Ajani J. Review of capecitabine as oral treatment of gastric, gastroesophageal, and esophageal cancers. Cancer (2006) 107:221–231.[CrossRef][Web of Science][Medline]
29. Kang Y, Lee J, Min Y, et al. A randomized multi-center phase II trial of capecitabine (X) versus S-1 (S) as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer. J Clin Oncol (2007) 25:18S. (Abstr 4546).
30. Okines A, Chau I, Cunningham D. Capecitabine in advanced gastric cancer. Expert Opin Pharmacother (2007) 8:2851–2861.[CrossRef][Web of Science][Medline]
31. Sakamoto J, Chin K, Kondo K, et al. Phase II study of a 4-week capecitabine regimen in advanced or recurrent gastric cancer. Anticancer Drugs (2006) 17:231–236.[CrossRef][Medline]
32. Kang Y, Kang W, Shin D, et al. Capecitabine/cisplatin vs. continuous infusion of 5FU/cisplatin as first-line therapy in patients (pts) with advanced gastric cancer (AGC): a randomised phase III trial. Eur J Cancer Suppl (2007) 5:259. (Abstr 3501).
33. Cunningham D, Rao S, Starling N, et al. Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: the REAL 2 trial. J Clin Oncol (2006) 24:18S. (Abstr 4017).[CrossRef]
34. UFT Summary of Product Characteristics. http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=4399.
35. Xeloda Summary of Product Characteristics. http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=4619.
36. Puig-la Calle J Jr, Lopez Sanchez S, Piedrafita Serra E, et al. Totally implanted device for long-term intravenous chemotherapy: experience in 123 adult patients with solid neoplasms. J Surg Oncol (1996) 62:273–278.[CrossRef][Web of Science][Medline]
37. Verso M, Agnelli G. Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol (2003) 21:3665–3675.
38. Ho DH, Pazdur R, Covington W, et al. Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluourouracil infusion and oral uracil plus N1-(2'-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res (1998) 4:2085–2088.[Abstract]
39. Ho DH, Covington W, Brown N, et al. Oral uracil and ftorafur plus leucovorin: pharmacokinetics and toxicity in patients with metastatic cancer. Cancer Chemother Pharmacol (2000) 46:351–356.[CrossRef][Web of Science][Medline]
40. Borner M, Schoffski P, de Wit R, et al. Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer (2002) 38:349–358.[CrossRef][Web of Science][Medline]
41. Pfeiffer P, Mortensen JP, Bjerregaard B, et al. Patient preference for oral or intravenous chemotherapy: a randomised cross-over trial comparing capecitabine and Nordic fluorouracil/leucovorin in patients with colorectal cancer. Eur J Cancer (2006) 42:2738–2743.[CrossRef][Web of Science][Medline]
42. Rocha Lima AP, Del Giglio A. Randomized crossover trial of intravenous 5-FU versus oral UFT both modulated by leucovorin: a one-centre experience. Eur J Cancer (2005) 14:151–154.[CrossRef][Web of Science]
43. Sizer B, Makris A, Barone C, et al. Quality of life and resource use analysis of tegafur–uracil with leucovorin (LV) or 5-FU/LV in first-line metastatic colorectal cancer: final results of a multicenter phase II study. J Clin Oncol (2006) 24:18S. (Abstr 3631).[CrossRef]
44. Carmichael J, Popiela T, Radstone D, et al. Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol (2002) 20:3617–3627.
45. Douillard J-Y, Hoff PM, Skillings JR, et al. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol (2002) 20:3605–3616.
46. Kim YH, Cheong SK, Lee JD, et al. Phase II trial of oral UFT and leucovorin in advanced gastric carcinoma. Am J Clin Oncol (1996) 19:212–216.[CrossRef][Web of Science][Medline]
47. Ravaud A, Borner M, Schellens JH, et al. UFT and leucovorin in first-line chemotherapy for patients with metastatic gastric cancer. An Early Clinical Studies Group (ECSG)/European Organization for Research Treatment of Cancer (EORTC) phase II trial. Eur J Cancer (2001) 37:1642–1647.[CrossRef][Web of Science][Medline]
48. Suga S, Iwase H, Shimada M, et al. Neoadjuvant chemotherapy in scirrhous cancer of the stomach using uracil and tegafur and cisplatin. Intern Med (1996) 35:930–936.[CrossRef][Web of Science][Medline]
49. Sato A, Kurihara M, Koizumi W, et al. A phase II study of UFT plus cisplatin (UFTP) therapy in patients with advanced gastric cancer. Proc Am Soc Clin Oncol (2000) 19. (Abstr 1087).
50. Feliu J, Gonzalez-Baron M, Garcia-Giron C, et al. Treatment of patients with advanced gastric carcinoma with the combination of etoposide plus oral tegafur modulated by uracil and leucovorin. A phase II study of the ONCOPAZ Cooperative Group. Cancer (1996) 78:211–216.[CrossRef][Web of Science][Medline]
51. Chao Y, Li CP, Chao TY, et al. An open, multi-centre, phase II clinical trial to evaluate the efficacy and safety of paclitaxel, UFT, and leucovorin in patients with advanced gastric cancer. Br J Cancer (2006) 95:159–163.[CrossRef][Web of Science][Medline]
52. Wöhrer SS, Raderer M, Hejna M. Palliative chemotherapy for advanced gastric cancer. Ann Oncol (2004) 15:1585–1595.
53. Kim YH, Kim BS, Seo JH, et al. Epirubicin, cisplatin, oral UFT, and calcium folinate in advanced gastric carcinoma. Oncology (Huntingt) (1999) 13(Suppl 3):64–68.[Medline]
54. Jeen YT, Yoon SY, Shin SW, et al. Phase II trial of epirubicin, cisplatin, oral uracil and tegafur, and leucovorin in patients with advanced gastric carcinoma. Cancer (2001) 91:2288–2293.[CrossRef][Web of Science][Medline]
55. Saglam S. Epirubicine, cisplatin, UFT (ECU Regimen) in advanced gastric carcinoma. Proc Am Soc Clin Oncol GI Cancers Symposium (2006) (Abstr 86).
56. Idelevich E, Karminsky N, Dinerman M, et al. Phase II study of cisplatin, epirubicin, UFT, and leucovorin (PELUF) as first-line chemotherapy in metastatic gastric cancer. Acta Oncol (2007) 46:324–329.[CrossRef][Web of Science][Medline]
57. Woo IS, Moon DH, Shim BY, et al. A phase II study of epirubicin, cisplatin and uracil-tegafur for advanced gastric carcinoma. Jpn J Clin Oncol (2005) 35:13–17.
58. Oh SC, Park KH, Choi IK, et al. Docetaxel (Taxotere), cisplatin, UFT, and leucovorin combination chemotherapy in advanced gastric cancer. Br J Cancer (2005) 92:827–831.[CrossRef][Web of Science][Medline]
59. Shah MA, Ramanathan RK, Ilson DH, et al. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol (2006) 24:5201–5206.
60. Pinto C, Di Fabio F, Siena S, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol (2007) 18:510–517.
61. Sastre J, Garcia-Saenz JA, Diaz-Rubio E. Chemotherapy for gastric cancer. World J Gastroenterol (2006) 12:204–213.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||