|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 21 (November 1), 2004: pp. 4319-4328 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.140 Randomized Multicenter Phase II Trial of a Biweekly Regimen of Fluorouracil and Leucovorin (LV5FU2), LV5FU2 Plus Cisplatin, or LV5FU2 Plus Irinotecan in Patients With Previously Untreated Metastatic Gastric Cancer: A Fédération Francophone de Cancérologie Digestive Group Study—FFCD 9803From the Centre Hospitalier Universitaire de Reims, Reims; Centre Eugène Marquis, Rennes; Equipe Mixte Inserm 106; Centre Hospitalier Universitaire de Dijon; and Fédération Francophone de Cancérologie Digestive, Faculté de Médecine, Dijon; Institut Paoli Calmettes; and Hôpital La Timone Assistance Publique Hôpitaux de Marseille, Marseille; Clinique Radiologique Armoricaine, Saint Brieuc; Clinique Saint Jean, Lyon; Centre Hospitalier Universitaire de Caen, Caen; Centre Hospitalier de La Rochelle, La Rochelle; Centre Paul Papin, Angers; Centre Hospitalier Universitaire Ambroise Paré Assistance Publique Hôpitaux de Paris, Boulogne; Centre Hospitalier Universitaire de Nantes, Nantes; and Centre Alexis Vautrin, Nancy, France Address reprint requests to Olivier Bouché, MD, Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire Robert Debré, Avenue du Général Koenig, F-51092 Reims Cedex, France; e-mail: obouche{at}chu-reims.fr
PURPOSE: To determine the efficacy and safety of a biweekly regimen of leucovorin (LV) plus fluorouracil (FU) alone or in combination with cisplatin or irinotecan in patients with previously untreated metastatic gastric adenocarcinoma and to select the best arm for a phase III study. PATIENTS AND METHODS: One hundred thirty-six patients (two were ineligible) were enrolled onto the randomized multicenter phase II trial. Patients received LV 200 mg/m2 (2-hour infusion) followed by FU 400 mg/m2 (bolus) and FU 600 mg/m2 (22-hour continuous infusion) on days 1 and 2 every 14 days (LV5FU2; arm A), LV5FU2 plus cisplatin 50 mg/m2 (1-hour infusion) on day 1 or 2 (arm B), or LV5FU2 plus irinotecan 180 mg/m2 (2-hour infusion) on day 1 (arm C). RESULTS: The overall response rates, which were confirmed by an independent expert panel, were 13% (95% CI, 3.4% to 23.3%), 27% (95% CI, 14.1% to 40.4%), and 40% (95% CI, 25.7% to 54.3%) for arms A, B, and C, respectively. Median progression-free survival and overall survival times were 3.2 months (95% CI, 1.8 to 4.6 months) and 6.8 months (95% CI, 2.6 to 11.1 months) with LV5FU2, respectively; 4.9 months (95% CI, 3.5 to 6.3 months) and 9.5 months (95% CI, 6.9 to 12.2 months) with LV5FU2-cisplatin, respectively; and 6.9 months (95% CI, 5.5 to 8.3 months) and 11.3 months (95% CI, 9.3 to 13.3 months) with LV5FU2-irinotecan, respectively. CONCLUSION: Of the three regimens tested, the combination of LV5FU2-irinotecan is the most promising and will be assessed in a phase III trial.
Although the incidence of gastric cancer has decreased in most western countries, it remains a significant problem in global health terms and is the second most common cause of cancer mortality worldwide.1 Surgery is the only potentially curative treatment for localized gastric cancer, but most cases present at an advanced stage. The prognosis for the disease is extremely poor, with overall 5-year survival rates ranging from 10% to 15% in the United States and most developed countries.2 The efficacy of chemotherapy with palliative intent compared with supportive care alone is now widely accepted.3 Studies showed the benefit of combination regimens, such as fluorouracil (FU), doxorubicin, and methotrexate (FAMTX)4, 5 or etoposide, leucovorin (LV), and FU (ELF),6 over best supportive care.7-9 Other combination regimens investigated include epirubicin, cisplatin, and infusional FU (ECF) and 5-day infusional FU plus cisplatin (FUP).4, 6 The survival advantage is small, however, and no internationally accepted standard regimen has emerged.10 ECF is one standard regimen and is associated with median survival times of around 9 months.11, 12 Infusional FU plus cisplatin is another standard treatment that is active, but it failed to demonstrate its superiority over FU monotherapy or other combination regimens in three randomized studies.6, 13-15 Although the current regimens yield overall response rates (ORR) of up to 51%,15 the median survival time in patients with advanced disease remains consistently below 10 months.6, 11, 12 An important issue in patients with gastric cancer is toxicity. The elderly patient population cannot tolerate aggressive combination chemotherapy. The anthracycline-containing regimens can be particularly toxic.16 FU is one of the most effective and widely used drugs in the treatment of advanced gastric cancer, and it forms part of all the current reference regimens. FU monotherapy, a standard treatment in Japan, is associated with a response rate of approximately 20%, manageable toxicity,17 and overall survival (OS) times of between 5 and approximately 7 months in phase III randomized studies.14, 15, 18 The modulation of FU by LV has generally enhanced antitumor efficacy (ORR, 22% to 48%) and produced some complete responses (5% to 9%).19-22 The biweekly FU and LV regimen (LV5FU2), which is popular in Europe,20, 23 combined with low-dose cisplatin was less toxic than FUP in a retrospective study,24 and therefore, LV5FU2 was chosen as the reference FU regimen in this study. There is a clear need for more convenient and active new agents and regimens. Irinotecan is a new cytotoxic agent with promising activity in combination with FU in gastrointestinal cancers.25-27 Irinotecan monotherapy is active in patients with gastric cancer, with response rates in phase II trials of 14% to 23%.28-31 The drug is also active when administered with FU-LV, a combination that yields response rates of 21% to 29% and OS times of 6.4 to 7.6 months.27, 32, 33 Irinotecan plus cisplatin is another active combination with response rates of 27% to 58% and an OS time of 9.0 months.34-36 Therefore, a multicenter randomized phase II study was conducted to compare LV5FU2 administered alone or in combination with cisplatin or irinotecan in patients with previously untreated metastatic gastric or cardial adenocarcinoma. The aim of the study was to select the best regimen for comparison with a reference treatment in a future phase III trial. The end points were ORR, progression-free survival (PFS), OS, safety, duration of hospital stay, and quality of life (QOL).
Patients The study conformed to the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol was reviewed and approved by the Ethics Review Committee of Champagne Ardennes (Reims, France). All patients provided written informed consent before inclusion in the trial. Eligible patients had histologically proven metastatic gastric or cardial adenocarcinoma without linitis, at least one measurable metastatic lesion located outside a previously irradiated area and measuring more than 15 mm in diameter, no symptomatic brain metastases, an age between 18 and 75 years, and a WHO performance status  2 with a life expectancy of more than 2 months. Adjuvant chemotherapy without cisplatin or irinotecan was allowed if completed at least 6 months before randomization. Prior radiotherapy was allowed if completed more than 4 weeks before randomization. All patients had adequate hematologic (neutrophils  1.5 x 109/L and platelets 100 x 109/L), hepatic (bilirubin 25 µmol/L and AST and ALT 5 x the upper normal limit), renal (creatinine 135 µmol/L and no contraindication to hyperhydration), and cardiac function. The main exclusion criteria were chronic diarrhea, prior enteropathy, or extensive intestinal resection.
Study Design and Randomization
Chemotherapy Administration and Dose Adjustments Treatment was continued for at least four cycles or until disease progression, unacceptable toxicity, patient refusal, or physician decision. In the event of toxicity (WHO), the following dose reductions and treatment delays were planned. In cases of insufficient hematologic function (neutrophil count < 1.5 x 109/L and platelet count < 100 x 109/L) on day 14 of any cycle, treatment was delayed for up to 14 days. If recovery did not occur at this point, the treatment was discontinued. Any FU dose reductions were only applied to the continuous infusion. For grade 3 to 4 gastrointestinal toxicities, thrombocytopenia, and neutropenia, there were 25% FU, cisplatin, and irinotecan dose reductions. For grade 2 or greater cardiotoxicity, FU treatment was discontinued. Cisplatin administration was delayed if creatinine levels were more than 135 µmol/L, and irinotecan administration was delayed if bilirubin levels were more than 25 µmol/L. Patients showing a complete response received treatment for up to 1 year.
Study Evaluations All adverse events were graded using the WHO toxicity criteria.37 Planned tumor evaluations were carried out every four cycles during therapy with the appropriate clinical and radiologic examinations and confirmation of responses by further radiologic examinations within 4 weeks. All objective tumor responses and cases of disease stabilization were reviewed retrospectively by an external expert committee. PFS was calculated from the date of randomization to either the date of first progression, the date of the last assessment in the absence of progression if the patient was alive, the date of death from any cause, or the date of last contact. In patients with subsequent complete surgical resection, PFS was measured from the time of randomization to the date of documentation of progression after surgery. OS was measured from the date of randomization until death from any cause.
QOL
Statistical Analysis The QLQ-C30 scores were described as a mean, standard deviation, median, and range at the start of the study and at each 2-month follow-up visit; the mean of available global health scores was graphically reported at each follow-up. The missing data were described as a percentage of the calculated score among patients with follow-up. Prestudy scores were compared between treatment arms using analysis of variance and a Bonferroni test to adjust for multiple comparisons. During the first three follow-ups, the longitudinal change of QLQ-C30 scores was analyzed using a mixed model analysis of variance for repeated measurements43 to study a global time effect whatever the treatment and to calculate differences in mean QOL scores between treatment arms whatever the follow-up (contrast analysis).
Patient Characteristics One hundred thirty-six patients were enrolled between January 1999 and October 2001 in 41 centers in France. Two patients were considered ineligible; one had a lymphoma and the other had no metastatic disease. No arm was closed after the two interim analyses. Thus, the analyses were carried out on an intent-to-treat (ITT) basis with the remaining 134 enrolled patients. All eligible patients received treatment allocated by randomization. The patient characteristics, which are listed in Table 1, were similar between the three arms except for the number of patients with weight loss more than 10%; this was higher in arm C than in the other two treatment arms (P = .05). The median age of all patients was 65 years (range, 37 to 76 years). The most frequent metastatic site was the liver (79% of all patients), and half of the patients had undergone prior curative or palliative surgery for their primary tumor.
Response Rate All of the 134 eligible patients were assessed for response. The response rate data per independent review on ITT basis are listed in Table 2. Ten patients (7%) were not evaluated for response review by the external expert committee because of the loss of computed tomography images. Three additional patients (2%) received insufficient treatment (fewer than four cycles) because of early toxicity (n = 2) or toxic death (n = 1). Early deaths (6%) related to disease progression occurred in three, two, and three patients in arms A, B, and C, respectively. The expert-assessed per protocol ORRs (eligible patients receiving at least four cycles of chemotherapy) were 14% (95% CI, 3.6% to 24.3%; six of 43 patients), 30% (95% CI, 15.8% to 44.2%; 12 of 40 patients), and 47% (95% CI, 31.5% to 63.2%; 18 of 38 patients) for arms A, B, and C, respectively. The investigator-assessed ITT ORRs were 24% (95% CI, 11.9% to 37.0%), 30% (95% CI, 16.1% to 43.0%), and 40% (95% CI, 25.7% to 54.3%), of which 0%, 2%, and 4% were complete responses, for arms A, B, and C, respectively. The rate of agreement between investigator and expert evaluation was 83%. Three patients in arm C underwent subsequent complementary locoregional treatment (one had a resection of liver metastases, one had a resection of pulmonary metastases, and one had radiofrequency ablation of liver metastases). The primary tumor was also resected in one patient.
Survival The median follow-up time was 26 months (95% CI, 20 to 33 months). One hundred sixteen patients (87%) were dead at the cutoff date of October 1, 2002. The numbers of patients still alive were four, eight, and six for arms A, B, and C, respectively. Table 3 lists the survival data, and Figures 1 and 2 show the OS and PFS of the patients in the study. The median PFS times were 3.2 months (95% CI, 1.8 to 4.6 months), 4.9 months (95% CI, 3.5 to 6.3 months), and 6.9 months (95% CI, 5.5 to 8.3 months) for arms A, B, and C, respectively. The median OS times were 6.8 months (95% CI, 2.6 to 11.1 months), 9.5 months (95% CI, 6.9 to 12.2 months), and 11.3 months (95% CI, 9.3 to 13.3 months) for arms A, B, and C, respectively. Patients receiving LV5FU2-irinotecan seemed to have a longer PFS and OS.
Safety The median number of cycles administered per patient, the number of cycles delayed, and the median relative dose-intensities for the three treatment arms are listed in Table 4. Patients received a median of seven cycles (range, one to 20 cycles), seven cycles (range, one to 18 cycles), and 10 cycles (range, one to 25 cycles) of treatment in arms A, B, and C, respectively. The main reason for stopping treatment in all arms was disease progression (37 patients, 82%; 24 patients, 55%; and 27 patients, 60% in arms A, B, and C, respectively). Treatment was discontinued as a result of toxicity in 4%, 16%, and 11% of patients in arms A, B, and C, respectively (Table 5).
The grade 3 and 4 toxicities experienced during treatment are listed in Table 5. The main toxicity was hematologic (neutropenia, febrile neutropenia, and anemia), which was highest in the arm B and lowest in arm A. Gastrointestinal toxicity was also common, with nausea and vomiting experienced by more patients in arm B and diarrhea experienced by more patients in arm C. Stomatitis was uncommon with any treatment. Two deaths occurred that were considered likely to be related to treatment (one each in arms A and B, neutropenic infections). The overall mean duration of hospitalization for toxicity was 1.2 days (range, 0 to 14 days).
Hospital Stay
QOL
Comparison between arms during the third QOL assessment showed that six functional scores were higher in arm C compared with arm A (mean difference in scores: global, 2.2; physical, 2.4; role, 4.6; emotional, 4.1; cognitive, 8.3; and social, 4.7). In addition, with the exception of a worse financial score (2.1), all the symptom scores were improved (range, –1.1 for pain to –11.9 for constipation). Comparison of arms B and C showed that the irinotecan-based therapy was associated with higher global QOL (mean difference in score, 0.8) and functional scores (mean difference in scores ranging from 2.5 for social to 6.7 for emotional) and lower symptom scores (mean difference in scores ranging from –0.3 for constipation to –8.2 for sleep). The only exception was an improvement in dyspnea in patients receiving cisplatin-based therapy (mean difference in score for arm C v arm B, 5.2).
The externally reviewed ORRs reported here for the various regimens studied fall within the range (6% to 56%)6, 12-14, 44-46 reported in phase II and III studies using FU, FU plus cisplatin, FAMTX, ELF, EAP (epirubicin, doxorubicin, cisplatin), and ECF and more recently in studies using taxane- or oxaliplatin-based regimens. For example, in the recent interim analysis of a randomized phase III trial, a response rate of 39% was reported for a docetaxel, cisplatin, and FU combination.47 The 13% ORR (14% per protocol) obtained with the LV5FU2 regimen is similar to the 6% to 15% ORR found in two phase II studies using another infusional FU regimen.13, 48 The 27% ORR (30% as per protocol) for the LV5FU2-cisplatin regimen is similar to the response rates found in studies with other FU-cisplatin combination regimens (20%,6 23%,47 34%,14 and 37%13). It is possible that the two patients considered inassessable may have achieved partial responses, and if this were the case, the number of responses would have been 14, and the ORR would have been 32%. The externally reviewed ORR of 40% (47% per protocol) for the LV5FU2-irinotecan regimen is similar to the 42% ORR reported in abstract form only for another randomized phase II study.44 In that study, irinotecan 80 mg/m2, LV 500 mg/m2, and FU 2 g/m2 over 22 hours were administered weekly for 6 weeks followed by a 1-week rest.44 In both cases, the ORRs for irinotecan combined with infusional FU-LV were higher than the 22% ORR reported for irinotecan combined with bolus FU-LV.27 The median PFS and OS (6.9 and 11.3 months, respectively) for the LV5FU2-irinotecan combination were promising when compared with the PFS and OS reported in previously published randomized studies, and this suggests that this combination is one of the most active to date. The results are even more noteworthy in view of greater pretreatment weight loss in this group, indicating a potentially worse prognostic group, and the fact that all the patients had metastatic disease, in contrast with other studies that included patients with locally advanced gastric cancer. OS times of 8.7 and 6.1 months have been reported for ECF and FAMTX, respectively,4, 12 and OS times of 6.7, 7.2, and 7.2 months have been reported for FAMTX, ELF, and FUP, respectively.6 The results have recently been published from a phase II study of oxaliplatin 100 mg/m2, LV 400 mg/m2 (2-hour infusion), and FU 400 mg/m2 (bolus) followed by 3 g/m2 (46-hour continuous infusion) every 14 days. Although a higher dose of FU was used, the combination resulted in a median time to progression and OS of only 6.2 months and 8.6 months, respectively.49 Also, the interim analysis of a randomized phase III trial involving docetaxel 75 mg/m2 and cisplatin 75 mg/m2 on day 1, then FU 750 mg/m2/d repeated every 3 weeks showed a time to progression of 5.2 months and OS of 10.2 months.47 The LV5FU2-irinotecan regimen was not only active but also well tolerated. Indeed, treatment compliance for all the regimens studied was very good, with the median relative dose-intensity profile favoring the LV5FU2-irinotecan combination and with no study deaths in this arm. As expected, the LV5FU2 regimen was less toxic when delivered alone than when combined with cisplatin or irinotecan. The LV5FU2-cisplatin regimen was associated with the highest rate of nausea and vomiting and hematologic toxicity. As known from studies in patients with colorectal cancer, the LV5FU2-irinotecan regimen was associated with diarrhea.26 Stomatitis was uncommon with any treatment, and the duration of hospital stay was similar for the three regimens. The irinotecan-containing regimen seemed to be less toxic than the regimens used in other studies involving patients with gastric carcinoma. In particular, severe nausea and vomiting occurred less frequently compared with cisplatin-based regimens. Compared with pretreatment scores, chemotherapy seemed to improve social, emotional, and global QOL in the early first three follow-ups. The global QOL increased after the treatment induction and was maintained for 6 months. This finding is consistent with the QOL benefits reported with the ELF regimen.7 The finding also suggests an advantage of the LV5FU2-irinotecan combination over the ECF regimen, which was associated with a maintained but not improved global QOL.11, 12 The reduction in the availability of QOL data during follow-up, together with the small number of patients, prevented an analysis of QOL after the third follow-up. This lack of data could have biased the longitudinal QOL analyses; patients with a shorter survival time and/or progression had a poor compliance in completing the QLQ-C30 assessment and probably a poor QOL. Therefore, it is likely that there is an overestimation in the mean scores, especially in the later follow-ups. To further increase survival of patients with gastric cancer, future studies should investigate new strategies with novel drugs in different settings, including neoadjuvant, adjuvant, first line, and second line. Recent preliminary data have shown that neoadjuvant ECF significantly increases the curative resection rate from 69% to 79%.50 Our observation that three patients in the LV5FU2-irinotecan arm were able to undergo surgery or radiofrequency ablation after their chemotherapy supports the evaluation of this regimen in the neoadjuvant setting. Although the role of chemotherapy in the adjuvant treatment of gastric cancer remains controversial, recent literature-based meta-analyses have suggested a small but statistically significant benefit.51-55 Postoperative bolus FU-LV chemoradiotherapy is emerging as an internationally accepted standard,56 but it is recognized that there is a need for large well-designed randomized trials in this area. The efficacy and tolerability of the LV5FU2-irinotecan regimen reported here support the evaluation of this combination in the adjuvant setting. On the basis of ORR alone, the LV5FU2-cisplatin regimen might have warranted consideration for the phase III study. However, the decision regarding the phase III trial was based on the benefit to risk ratio and the high activity and better safety profile of the LV5FU2-irinotecan regimen makes it a more attractive treatment option. We are awaiting the results of a randomized phase III trial comparing irinotecan plus infusional FU-LV with FUP. A planned randomized French intergroup phase III study aims to compare first-line simplified LV5FU2 plus irinotecan (FOLFIRI) followed by second-line epirubicin, cisplatin, and capecitabine (ECC)46 with ECC followed by FOLFIRI.
The authors indicated no potential conflicts of interest.
We thank the following physicians for their participation in this study: T. Aparicio (Paris), D. Auby (Libourne), F. Audemar (Strasbourg), R. Barraya (Angers), C. Bories (Beauvais), E. Boucher (Rennes), O. Boulat (Avignon), A.C. Braud (Marseille), P. Burtin (Angers), G. Capodano (Marseille), F.X. Caroli-Bosc (Nice), C. Cazalbou (Valence), J. Charneau (Boulogne sur Mer), M.C. Clavero-Fabri (Briis sous Forges), T. Conroy (Nancy), M.A. Coulon (Le Mans), X.R. David (St Jean de Luz), N. Delva (Angers), E. Echinard (Bayonne), P. Feydy (Saint Quentin), M.P. Filipetto (Briey), P. Lefelliatre, (Cherbourg), E. Fleck (La Rochelle), M.P. Galais (Caen), E. Gamelin (Angers), B. Garcia (Reims), P. Geoffroy (Epernay), J. Haem (Lannion), M. Hebbar (Lille), J.L. Jouve (Dijon), H. Lacroix (Nantes), J.P. Lagasse (Orléans), J.R. Lavignasse (Lannion), C. Le Foll (Briis sous Forges), J.L. Legoux (Bordeaux), F. Locatelli (Strasbourg), M. Mabro (Suresnes), R. Mackiewicz (Valence), P. Maillard (Angers), L. Mignot (Suresnes), M. Pelletier (Bourgoin-Jallieu), D. Pezet (Clermond-Ferrand), J.M. Phélip (Dijon), D. Pillon (Bourg en Bresse), E. Rassiat (Dijon), K. Richard (Marseille), J.F. Roche (Verdun), D. Smith (Bordeaux), N. Stremsdoerfer (Bourgoin-Jallieu), E. Suc (Montauban), H. Tossou (Beauvais), A.M. Touchais (Avignon), F. Varlet (Béthune), D. Vetter (Strasbourg), F. Viret (Marseille), and S. Walter (Metz). We also thank M. Ebmeier-Egg (editorial assistance), P. Arveux (QOL study), F. Guiliani and C. Girault (monitoring), and S. Lecouturier and D. Mery-Mignard (study initiation).
Supported by grants from Aventis, Baxter, and the Association pour la Recherche Contre le Cancer. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Parkin DM, Whelan SL, Ferlay J, et al: Cancer Incidence in Five Continents (volume VIII). Lyon, France, International Agency for Research on Cancer, 2002 2. Karpeh MS, Kelsen DP, Tepper JE: Cancer of the stomach, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice on Oncology (ed 6). Philadelphia, PA, Lippincott, Williams & Wilkins, 2001, pp 1092-1126 3. Kohne CH, Wils JA, Wilke HJ: Developments in the treatment of gastric cancer in Europe. Oncology (Huntingt) 14:22-25, 2000 4. 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 80:269-272, 1999[CrossRef][Medline] 5. 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 9:827-831, 1991[Abstract]
6. 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 18:2648-2657, 2000
7. 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 8:163-168, 1997 8. Pyrhonen S, Kuitunen T, Nyandoto P, et al: Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71:587-591, 1995[Medline] 9. Murad AM, Santiago FF, Petroianu A, et al: Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72:37-41, 1993[CrossRef][Medline]
10. Ajani JA: Standard chemotherapy for gastric carcinoma: Is it a myth? J Clin Oncol 18:4001-4003, 2000
11. 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 20:1996-2004, 2002
12. Webb A, Cunningham D, Scarffe JH, et al: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261-267, 1997 13. Vanhoefer U, Wagner T, Lutz M, et al: Randomized phase II study of weekly 24h infusion of high dose 5-FU±folinic acid (HD-FU±FA) versus HD-FU/FA/biweekly cisplatin in advanced gastric cancer. EORTC trial 40953. Eur J Cancer 37:S27, 2001 (suppl 6, abstr 88)
14. Ohtsu A, Shimada Y, Shirao K, et al: Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 21:54-59, 2003 15. Kim NK, Park YS, Heo DS, et al: A phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer 71:3813-3818, 1993[CrossRef][Medline]
16. Kelsen D, Atiq OT, Saltz L, et al: FAMTX versus etoposide, doxorubicin, and cisplatin: A random assignment trial in gastric cancer. J Clin Oncol 10:541-548, 1992 17. Findlay M, Cunningham D: Chemotherapy of carcinoma of the stomach. Cancer Treat Rev 19:29-44, 1993
18. Coombes RC, Chilvers CE, Amadori D, et al: Randomised trial of epirubicin versus fluorouracil in advanced gastric cancer: An International Collaborative Cancer Group (ICCG) study. Ann Oncol 5:33-36, 1994 19. Johnson PW, Thompson PI, Seymour MT, et al: A less toxic regimen of 5-fluorouracil and high-dose folinic acid for advanced gastrointestinal adenocarcinomas. Br J Cancer 64:603-605, 1991[Medline]
20. Louvet C, de Gramont A, Demuynck B, et al: High-dose folinic acid, 5-fluorouracil bolus and continuous infusion in poor-prognosis patients with advanced measurable gastric cancer. Ann Oncol 2:229-230, 1991 21. Rubin J, Gallagher JG, Schroeder G, et al: Phase II trials of 5-fluorouracil and leucovorin in patients with metastatic gastric or pancreatic carcinoma. Cancer 78:1888-1891, 1996[CrossRef][Medline]
22. Machover D, Goldschmidt E, Chollet P, et al: Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol 4:685-696, 1986
23. de Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815, 1997 24. Lecomte TL, Mitry E, Taïeb J, et al: Combination of 5-FU and cisplatin for metastatic pancreatic (P) and gastric (G) cancers: A nonrandomized comparison of two regimens (LV5FU2-P vs FUP). Gut 49, 2001 (suppl III, abstr 2777)
25. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343:905-914, 2000 26. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:1041-1047, 2000[CrossRef][Medline]
27. Blanke CD, Haller DG, Benson AB, et al: A phase II study of irinotecan with 5-fluorouracil and leucovorin in patients with previously untreated gastric adenocarcinoma. Ann Oncol 12:1575-1580, 2001 28. Kohne CH, Catane R, Klein B, et al: Irinotecan is active in chemonaive patients with metastatic gastric cancer: A phase II multicentric trial. Br J Cancer 89:997-1001, 2003[CrossRef][Medline] 29. Lin-Shin L, Hecht J: A phase II trial of irinotecan in patients with advanced adenocarcinoma of the gastroesophageal (GE) junction. Proc Am Soc Clin Oncol 19:289a, 2000 (abstr 1130) 30. Hecht J, Parson M, Lee R: A phase II trial of irinotecan (CPT-11) in patients with adenocarcinoma of the esophagus and gastric cardia. Proc Am Soc Clin Oncol 18:287a, 1999 (abstr 1100) 31. Futatsuki K, Wakui A, Nakao I, et al: Late phase II study of irinotecan hydrochloride (CPT-11) in advanced gastric cancer: CPT-11 Gastrointestinal Cancer Study Group. Gan To Kagaku Ryoho 21:1033-1038, 1994[Medline]
32. Assersohn L, Brown G, Cunningham D, et al: Phase II study of irinotecan and 5-fluorouracil/leucovorin in patients with primary refractory or relapsed advanced oesophageal and gastric carcinoma. Ann Oncol 15:64-69, 2004 33. Findlay MPN, Ackland S, Gebski V, et al: Phase II study of irinotecan, leucovorin and 5FU (ILF) in advanced gastric cancer. Proc Am Soc Clin Oncol 20:165a, 2001 (abstr 655) 34. Ajani JA, Baker J, Pisters PW, et al: CPT-11 plus cisplatin in patients with advanced, untreated gastric or gastroesophageal junction carcinoma: Results of a phase II study. Cancer 94:641-646, 2002[CrossRef][Medline] 35. Er O, Coskun HS, Solak Y, et al: Irinotecan plus cisplatin combination against metastatic gastric adenocarcinoma: Preliminary results of phase II study. Proc Am Soc Clin Oncol 21:2310, 2002 (abstr 2310) 36. Takiuchi H, Kurihara M, Koizumi W, et al: Phase I/II study of CPT-11 plus CDDP in patients with advanced gastric carcinoma. Proc Am Soc Clin Oncol 19:275a, 2000 (abstr 1074) 37. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline]
38. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993 39. Fayers PM, Aaronson NK, Bjordal K, et al: The EORTC QLC-C30 Scoring Manual (ed 3). Brussels, Belgium, European Organization for Research and Treatment of Cancer, 2001 40. Hjermstad MJ, Fossa SD, Bjordal K, et al: Test/retest study of the European Organization for Research and Treatment of Cancer Core Quality-of-Life Questionnaire. J Clin Oncol 13:1249-1254, 1995[Abstract] 41. Ringdal GI, Ringdal K: Testing the EORTC Quality of Life Questionnaire on cancer patients with heterogeneous diagnoses. Qual Life Res 2:129-140, 1993[CrossRef][Medline] 42. Ensign LG, Gehan EA, Kamen DS, et al: An optimal three-stage design for phase II clinical trials. Stat Med 13:1727-1736, 1994[Medline] 43. Cnaan A, Laird NM, Slasor P: Using the general linear mixed model to analyse unbalanced repeated measures and longitudinal data. Stat Med 16:2349-2380, 1997[CrossRef][Medline] 44. Pozzo C, Bugat R, Peschel C, et al: Irinotecan in combination with CDDP or 5-FU and folinic acid is active in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma: Final results of a randomised phase II study. Proc Am Soc Clin Oncol 20:134a, 2001 (abstr 531) 45. Van Cutsem E, Ajani JA, Tjulandin S, et al: Docetaxel (T) in combination with cisplatinum (C) with or without 5-fluorouracil (F) in patients (pts) with advanced gastric or GE junction adenocarcinoma (AGC): Preliminary results. Ann Oncol 11:2860a, 2000 (suppl 4, abstr 2860) 46. Sumpter KA, Harper-Wynne C, Cunningham D, et al: Randomised, multicenter phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer: Confirmation and dose escalation. Proc Am Soc Clin Oncol 22:257a, 2003 (abstr 1031) 47. Ajani JA, Van Cutsem E, Moiseyenko V, et al: Docetaxel (D), cisplatin, 5-fluorouracil compare to cisplatin (C) and 5-fluorouracil (F) for chemotherapy-naive patients with metastatic or locally recurrent, unresectable gastric carcinoma (MGC): Interim results of a randomized phase III trial (V325). Proc Am Soc Clin Oncol 22:249, 2003 (abstr 999) 48. Berenberg JL, Tangen C, Macdonald JS, et al: Phase II study of 5-fluorouracil and folinic acid in the treatment of patients with advanced gastric cancer: A Southwest Oncology Group study. Cancer 76:715-719, 1995[CrossRef][Medline]
49. Louvet C, Andre T, Tigaud JM, et al: Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol 20:4543-4548, 2002 50. Allum W, Cunningham D, Weeden S, et al: Perioperative chemotherapy in operable gastric and lower oesophageal cancer: A randomised, controlled trial (the MAGIC trial, ISRCTN 93793971). Proc Am Soc Clin Oncol 22:249, 2003 (abstr 998) 51. Hu JK, Chen ZX, Zhou ZG, et al: Intravenous chemotherapy for resected gastric cancer: Meta-analysis of randomized controlled trials. World J Gastroenterol 8:1023-1028, 2002[Medline]
52. Hermans J, Bonenkamp JJ, Boon MC, et al: Adjuvant therapy after curative resection for gastric cancer: Meta-analysis of randomized trials. J Clin Oncol 11:1441-1447, 1993 53. Earle CC, Maroun JA: Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: Revisiting a meta-analysis of randomised trials. Eur J Cancer 35:1059-1064, 1999
54. Mari E, Floriani I, Tinazzi A, et al: Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: A meta-analysis of published randomised trials—A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente). Ann Oncol 11:837-843, 2000 55. Panzini I, Gianni L, Fattori PP, et al: Adjuvant chemotherapy in gastric cancer: A meta-analysis of randomized trials and a comparison with previous meta-analyses. Tumori 88:21-27, 2002[Medline]
56. 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 345:725-730, 2001 Submitted January 22, 2004; accepted August 1, 2004.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
