BACKGROUND: Gastric cancer is one of the most common types of cancer
and one of the most frequent causes of cancer-related death. The
majority of gastric cancers show distant metastasis at the time of
diagnosis. At present, there is no general agreement over one standard
chemotherapy regimen for metastatic gastric cancer.  AIMS: We evaluated
the activity and toxicity of the combination of 5-Fluorouracil (5-FU),
epirubicin and cisplatin (FEP) in previously untreated patients with
metastatic gastric cancer.  SETTING AND DESIGN: Medical Oncology
Department of Uludag University Faculty of Medicine, Bursa;
retrospective study.  MATERIAL AND METHODS: Sixty-eight patients
received 5-FU 300 mg/m2 on Days 1-5, epirubicin 50 mg/m2 on Day 1 and
cisplatin 60 mg/m2 on Day 1, every 4 weeks. A median of 3.5 cycles was
administered. The response rate, time to disease progression, survival
and toxic effects were analyzed.  STATISTICAL ANALYSIS USED: Overall
survival and time to progression were estimated using Kaplan-Meier
method.  RESULTS: There were 4 partial responses and 1 complete
response (overall response rate 7.3%); 16 patients had stable disease.
Median progression-free and overall survival rates were 3.1 months (95%
CI 1.9-4) and 6 months (95% CI 4.2-7), respectively. The principal
toxicity was myelosupression. Grade 3-4 neutropenia occurred in 27.9%,
anemia in 17.6%, and thrombocytopenia in 11.7% of patients.
Non-hematological toxicity was mild and manageable.  CONCLUSIONS: We
concluded that FEP combination as used at the doses and schedules in
this study has inferior activity against metastatic gastric cancer

Ozkan Kanat, Turkkan Evrensel, Ender Kurt, Mutlu Demiray, Murat Arslan,
Nalan Babacan, Abd\ufclmecit Yildiz, Osman Manavoglu

Bioline International

Indian Journal of Cancer  |  April - June 2005  |  Volume 42 |  Issue 2 85OriginalArticleIntroductionGastric cancer is the second most common cancer inthe world and one of the most frequent causes ofcancer-related mortality. The incidence of gastric canceris particularly high in Asia, South America, and EasternEurope. In some countries there is a wide variation inthe incidence of this disease. For example, the incidenceof gastric cancer is four times higher in Southern Indiacompared with Northern India. [1]At the time of diagnosis, approximately 50% of patientswith gastric cancer have metastatic disease. A numberof randomized clinical trials have established the role ofchemotherapy in the treatment of these patients. In thefour trials that compared chemotherapy plus bestsupportive care with best supportive care alone, patientswho received chemotherapy had longer survival times.[2-5] However, a standard combination chemotherapyregimen for advanced gastric cancer has not been wellestablished.5-Fluorouracil, Epirubicin and Cisplatin inthe Treatment of Metastatic GastricCarcinoma: A Retrospective Analysis of 68PatientsKanat Ozkan, Evrensel Turkkan, Kurt Ender, Demiray Mutlu, Arslan Murat,Babacan Nalan*, Yildiz Abdülmecit*, Manavoglu OsmanUludag University Faculty of Medicine Department of Medical Oncology and *Internal Medicine Gorukle16059, Bursa, TurkeyCorrespondence to: Ozkan Kanat, E-mail: ozkanat@uludag.edu.trAbstractBACKGROUND: Gastric cancer is one of the most common types of cancer and one of the most frequent causes ofcancer-related death. The majority of gastric cancers show distant metastasis at the time of diagnosis. At present,there is no general agreement over one standard chemotherapy regimen for metastatic gastric cancer. AIMS: Weevaluated the activity and toxicity of the combination of 5-Fluorouracil (5-FU), epirubicin and cisplatin (FEP) inpreviously untreated patients with metastatic gastric cancer. SETTING AND DESIGN: Medical Oncology Departmentof Uludag University Faculty of Medicine, Bursa; retrospective study. MATERIAL AND METHODS: Sixty-eight patientsreceived 5-FU 300 mg/m2 on Days 1-5, epirubicin 50 mg/m2 on Day 1 and cisplatin 60 mg/m2 on Day 1, every 4weeks. A median of 3.5 cycles was administered. The response rate, time to disease progression, survival and toxiceffects were analyzed. STATISTICAL ANALYSIS USED: Overall survival and time to progression were estimatedusing Kaplan-Meier method. RESULTS: There were 4 partial responses and 1 complete response (overall responserate 7.3%); 16 patients had stable disease. Median progression-free and overall survival rates were 3.1 months(95% CI 1.9-4) and 6 months (95% CI 4.2-7), respectively. The principal toxicity was myelosupression. Grade 3-4neutropenia occurred in 27.9%, anemia in 17.6%, and thrombocytopenia in 11.7% of patients. Non-hematologicaltoxicity was mild and manageable. CONCLUSIONS: We concluded that FEP combination as used at the doses andschedules in this study has inferior activity against metastatic gastric cancer.Key Words: Metastatic gastric cancer, 5-Fluorouracil, Epirubicin, CisplatinIndian Journal of Cancer  |  April - June 2005  |  Volume 42 |  Issue 286Combination regimens with 5-FU and cisplatin showedpromising activity in Phase II trials and are frequentlyused throughout Europe. Epirubicin was included inthis combination because of anticipated enhancedcytotoxicity. In a randomized Phase III study a regimenconsisting of epirubicin, cisplatin and infusional 5-FU(ECF) showed superior response rates and significantlyprolonged survival compared with the historic referenceregimen 5-FU, doxorubicin and methotrexate(FAMTX). Therefore, the ECF regimen has representeda step ahead in the treatment of advanced gastriccancer. Despite higher response rates and lower toxicity,a potential drawback of the ECF regimen may be thepoor patient acceptability of the indwelling catheter andpresence of the external infusion pump. As analternative, some European investigators have adoptedthe use of weekly or biweekly 24- to 48-hour infusionsof 5-FU to ease the administration of treatment.To reduce the catheter line-associated morbidity of ECF,we modified this regimen and administered 5-FU as ashort infusion. In this article, we report our experiencein patients with metastatic gastric cancer treated withshort infusion of 5-FU, epirubicin and cisplatin (FEP)regimen.Materials and MethodsPatients with metastatic gastric cancer treated with FEP,as first-line chemotherapy from May 1999 to August2003 at Uludag University Faculty of Medicine,Department of Medical Oncology were analyzedretrospectively. Patients treated with FEP if they fulfilledthe following eligibility criteria: (1) a diagnosis ofhistologically or cytologically proven gastric cancer; (2)bidimensionally measurable disease using computedtomography; (3) no previous chemotherapy orradiotherapy; (4) adequate bone marrow and organfunctions (leukocyte count > 4000/mm3, platelet count> 100000/mm3, serum creatinine level < 1.5 mg/dl,biluribin < 1.5 mg/dl, and transaminase < 2.5 X uppernormal limits [< 5 X upper normal limits if livermetastases were present]); (5) Eastern CooperativeOncology Group performance status < 2; (6) normalcardiac function; (7) no other severe medical condition;(8) a life expectancy of at least 3 months; (9) allpatients were required to provide written informedconsent for treatment. There were no age restrictions.The study was approved by the local ethical committee.Epirubicin (50 mg/m2) and cisplatin (60 mg/m2) wereadministered on Day 1. Epirubicin was given as a 5-min bolus injection. Cisplatin was administered as a 4-hour infusion with standard pre- and post-hydrationprotocols, magnesium and potassium supplementationand intravenous antiemetic therapy (5-HT3 antagonistand dexamethasone). 5-FU (300 mg/m2) wasadministered as a 15-min short infusion on Days 1-5.Treatment was repeated every four weeks. A maximumof six cycles of chemotherapy were planned unlessdisease had progressed or intolerable toxicities hadoccurred before.Toxicity was scored according to standard World HealthOrganization (WHO) criteria.[8]  Prior to each courseof chemotherapy, all patients were required to haveadequate haemopoietic recovery (neutrophil count >2000/mm3, platelet count >100000/mm3). If this wasnot possible, chemotherapy was delayed until recoveryof the neutrophil and platelet counts to the above levels.A second episode of treatment delay due tomyelosuppression or an episode of neutropenic sepsisrequired a 25% dose reduction on subsequenttreatments. A 25% dose reduction of 5-FU was appliedin the case of Grade 3 diarrhea or mucositis and 50%dose reduction in the case of Grade 4. Cisplatin wasdiscontinued when the glomerular filtration rate valuewas less than 40 ml/min.Objective response to chemotherapy was classifiedaccording to WHO criteria. [8] A chest radiography andabdominal computed tomography scan were repeatedafter Cycles 2, 4, and 6 or whenever clinically indicated.Time to progression was measured in all patients fromthe beginning of chemotherapy to the first evidence ofprogression. Overall survival was calculated from thebeginning of chemotherapy until the date of death.Overall survival and time to progression were estimatedusing the Kaplan-Meier method.Table 1: Patient characteristicsCharacteristics NoNo. of patients 68Male/female 48/20Median age (years) 58 (31-78)ECOG performance status0-1 532 15Metastatic sitesLiver 48Peritoneum 28Distant lymph nodes 10Lung 7Ovary 3Kanat et al: Treatment of Metastatic Gastric CarcinomaIndian Journal of Cancer  |  April - June 2005  |  Volume 42 |  Issue 2 87ResultSixty-eight eligible patients (48 males, 20 females)received a total of 243 cycles of FEP, with a median of3.5 cycles per patient (range 1-6 cycles). Patients’characteristics are summarized in Table 1. The medianage was 58 yrs (range 31-78) and the median ECOGperformance status was 1 (range 0-2). Metastatic siteswere liver (n = 48), peritoneum (n= 28), lymph node(n = 10), lung (n = 7), and ovary (n = 3). Patientswith peritoneal metastasis had other measurablemetastatic lesions. Alkaline phosphatase level was > 100U/L in 50 patients (73.5%).Grade 3-4 neutropenia was observed in 19 patients(27.9%), anemia in 12 patients (17.6%), andthrombocytopenia in 8 patients (11.7%) (Table 2).Febrile neutropenia was observed in 2 (2.9%) patients.Grade 3-4 vomiting occurred in 9 patients (13.2%),Grade 3 mucositis in 3 patients (4.4%) and Grade 2diarrhea in 4 patients (5.8%). One episode of Grade 2nephrotoxicity developed in one patient (1.4%) withprerenal azotemia but this was reversed withintravenous hydration within 72 h. Six patients requireddose reductions of at least one drug. No treatment-related toxic deaths occurred.Objective response was seen in 5 patients (7.3%), with1 patient achieving a complete response and 4 showingpartial response. Sixteen patients (23.5%) remainedstable, whereas 47 (69%) progressed. The medianprogression-free and overall survivals were 3.1 months(95% CI, 1.9-4) and 6 months (95% CI, 4.2-7),respectively.DiscussionWe retrospectively analyzed 68 patients with metastaticgastric cancer treated with FEP. In this analysis, theresponse rate (7.3%) and survival rates are relativelylower than those reported in previous studies evaluatingactive regimens such as FAMTX, ECF or EAP(etoposide, doxorubicin, cisplatin). [9-11] Short infusion5-FU may be partially responsible for this low responserate in our study. It was shown that continuousintravenous infusion of 5-FU showed comparable orhigher response rates with fewer adverse effects withbolus intravenous administration.[12] Infusional 5-FU asused in the ECF protocol might improve the treatmentresults. However, this necessitates the use of infusionpumps and the presence of permanent central venousaccess, increasing the cost and complexity of treatmentas well as the risk of line-related complications.Alternative regimens, such as weekly 24-houradministration of 5-FU/folinic acid could be alternativesto protracted venous infusion of 5-FU as used in theECF regimen in order to improve patients’ acceptance.The combination of a weekly high dose of 5-FU/folinicacid plus cisplatin was evaluated in a randomized PhaseII trial (EORTC 40953 trial).[13] In this trial, patientsreceiving biomodulated 5-FU fared significantly betterwith respect to survival and response rate. The additionof cisplatin added comparatively little.The protracted intravenous infusion of 5-FU may bereplaced by oral 5-FU pro-drugs such as UFT orcapecitabine. A Phase II trial of epirubicin, cisplatin,UFT and leucovorin showed a 57.5% response rate and15 months median survival duration. [14] Capecitabineoffers the possibility of continuous tumor exposure to5-FU by preferential activation at the tumor site. In aJapanese trial of 60 patients with previously untreatedadvanced gastric cancer, intermittent capecitabine (828mg/m2 twice daily for 3 weeks followed by 1 week ofrest) led to a response rate of 25.5% and a mediansurvival of 8.8 months.[15] Capecitabine is currentlyunder investigation in a British Phase III trial.[16] Thisfour-arm trial is evaluating capecitabine plus 5-FU andoxaliplatin plus cisplatin in patients with advancedesophago-gastric cancer.Modulation of 5-FU by folinic acid may also improvethe response rates and survival. Cocconi et al [17] haveshown that cisplatin, epirubicin, leucovorin and 5-FU(PELF) was more active than FAMTX in advancedgastric carcinoma. In their study, the overall responserates to PELF and FAMTX were 39% and 22%,respectively. The survival rates after 12 months (30.8%vs. 22.4%) and 24 months (15.7% vs. 9.5%) were alsohigher among patients receiving PELF.Recently, four poor prognostic factors, includingperformance status > 2, alkaline phosphatase levele”100 U/L, liver and peritoneal metastases have beenidentified by Chau et al in patients receiving first-linechemotherapy for locally advanced or metastaticesophago-gastric cancer.[18] In our series, peritonealmetastases were present in 28 patients (41%) and liverTable 2: WHO Grade 3 and 4 Toxicities (n = 68)Toxicity Grade 3 n (%) Grade 4 n (%)Neutropenia 16 (23.5) 3 (4.4)Anemia 10 (14.7) 2 (2.9)Thrombocytopenia 6 (8.8) 2 (2.9)Mucositis 3 (4.4) -Vomiting 5 (7.3) 4 (5.8)WHO: World Health OrganizationKanat et al: Treatment of Metastatic Gastric CarcinomaIndian Journal of Cancer  |  April - June 2005  |  Volume 42 |  Issue 288metastases in 48 patients (70.5%). Alkaline phosphataselevel was > 100 U/L in 50 patients (73.5%). Thesepoor prognostic parameters might also explain thedisappointing treatment results.This study demonstrated that FEP is well-toleratedregimen for patients with metastatic gastric cancer. Weobserved Grade 3 or 4 neutropenia in 27.9% ofpatients. However, febrile neutropenia occurred in onlytwo (3%) patients. Grade 3-4 anemia andthrombocytopenia were observed in 17.6% and 11.7%of patients, respectively. These results are comparable tothose with infusional 5-FU regimens. Non-hematological toxicity was mild and manageable.This study has limitations because it was notrandomized or prospective. However, we think that thenegative results of our study provide additional evidencefor the general opinion that the first generationtreatment regimens in metastatic gastric cancer are ofvery little value. Therefore, new agents that are moreactive and less toxic are required. Phase II studies ofnew drugs including the taxanes, irinotecan, oxaliplatin,and capecitabine have shown encouraging results in thetreatment of patients with advanced gastric cancer.Response rates up to 65% have been demonstrated inPhase II trials evaluating combination regimens of thesenew agents. [19-24]In conclusion, the treatment of gastric cancer remains agreat challenge to an oncologist. FEP combination asused at the doses and schedules in this study hasdemonstrated unsatisfactory activity against metastaticgastric cancer. Administration of new cytotoxic drugs inthe treatment of gastric cancer may improve the poorprognosis of this disease in the future. References1. Pavithran K, Doval DC, Pandey KK. Gastric cancer in India. Gas-tric Cancer 2002;5:240-3.2. Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA,Rausch M. Modified therapy with 5-fluorouracil, doxorubicin, andmethotrexate in advanced gastric cancer. Cancer 1993;72:37-41.3. 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5-Fluorouracil, epirubicin and cisplatin in the treatment of metastatic gastric carcinoma: A retrospective analysis of 68 patients

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