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Phase II study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer

Phase II study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX... Clinical Studies British Journal of Cancer (2005) 93, 190 – 194 & 2005 Cancer Research UK All rights reserved 0007 – 0920/05 $30.00 www.bjcancer.com Phase II study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer ,1 1 1 2 3 4 5 F Lordick , S Lorenzen , J Stollfuss , U Vehling-Kaiser , F Kullmann , M Hentrich , R Zumschlinge , 6 1 1 7 8 1 1 H Dietzfelbinger , J Thoedtmann , M Hennig , T Seroneit , R Bredenkamp , J Duyster and C Peschel 1 2 Clinic Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany; Oncological Outpatient Clinic, Heilig-Geist-Gasse 3 4 411, 84028 Landshut, Germany; University Clinic of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany; Clinic Harlaching, 5 6 Sanatoriumsplatz 2, 81545 Munich, Germany; Clinic Traunstein, Cuno-Niggl-Str. 3, 83278 Traunstein, Germany; Schindlbeck-Clinic, Seestr. 43, 82211 7 8 Herrsching, Germany; Sanofi-Aventis Group, Potsdamer Str. 8, 10785 Berlin, Germany; Center for Clinical Studies, Ismaninger Str. 22, 81675 Munich, Germany Oxaliplatin plus fluorouracil/folinic acid (5-FU/FA) every 2 weeks has shown promising activity in advanced gastric cancer. This study assessed the efficacy and safety of weekly oxaliplatin plus 5-FU/FA (FUFOX regimen) in the metastatic setting. Patients with 2 2 previously untreated metastatic gastric cancer received oxaliplatin (50 mg m ) plus FA (500 mg m , 2-h infusion) followed by 5-FU (2000 mg m , 24-h infusion) given on days 1, 8, 15 and 22 of a 5-week cycle. The primary end point of this multicentre phase II study was the response rate according to RECIST criteria. A total of 48 patients were enrolled. Median age was 62 years and all patients had metastatic disease, with a median number of three involved organs. The most common treatment-related grade 3/4 adverse events were diarrhoea (17%), deep vein thrombosis (15%), neutropenia (8%), nausea (6%), febrile neutropenia (4%), fatigue (4%), anaemia (4%), tumour bleeding (4%), emesis (2%), cardiac ischaemia (2%) and pneumonia (2%). Grade 1/2 sensory neuropathy occurred in 67% of patients but there were no episodes of grade 3 neuropathy. Intent-to-treat analysis showed a response rate of 54% (95% CI, 39–69%), including two complete responses. At a median follow-up of 18.1 months (range 11.2–26.2 months), median survival is 11.4 months (95% CI, 8.0–14.9 months) and the median time to progression is 6.5 months (95% CI, 3.9–9.2 months). The weekly FUFOX regimen is well tolerated and shows notable activity as first-line treatment in metastatic gastric cancer. British Journal of Cancer (2005) 93, 190–194. doi:10.1038/sj.bjc.6602697 www.bjcancer.com Published online 12 July 2005 & 2005 Cancer Research UK Keywords: oxaliplatin; fluorouracil; metastatic gastric cancer; first-line Systemic chemotherapy has been shown to prolong survival and to care in the first-line treatment of metastatic disease. In advanced relieve symptoms in advanced gastric cancer (Glimelius et al, gastric cancer, biweekly oxaliplatin plus 5-FU/FA has shown 1997). However, the number of patients who benefit from considerable antitumour activity in phase II trials (Louvet et al, treatment is still limited and the optimal chemotherapy regimen 2002a; Al-Batran et al, 2004). Oxaliplatin shows a better toxicity has not yet been defined. Platinum-free regimens exhibited profile than cisplatin. Its main and dose-limiting toxicity is acute, disappointing efficacy in randomised trials. Cisplatin-based regi- cumulative peripheral sensory neurotoxicity, resulting in acral mens, for example the combination of epirubicin, cisplatin, and paresthaesia and dysesthaesia, which are exacerbated by cold. 5-FU (ECF), have demonstrated superior efficacy, albeit with The weekly application of oxaliplatin plus infusional 5-FU/FA significant toxicity and inconvenience from the patients’ perspec- (FUFOX), as proposed by the Arbeitsgemeinschaft Internistische tive (Waters et al, 1999; Vanhoefer et al, 2000). Onkologie (AIO), has proven to be highly effective in first-line Oxaliplatin is a third-generation diaminocyclohexane platinum metastatic colorectal cancer. The AIO FUFOX regimen is also compound proven in numerous clinical trials to be active in associated with an acceptable toxicity profile, with a particularly various tumour types. In advanced colorectal cancer, treatment low rate of sensory neuropathy (Grothey et al, 2002). with oxaliplatin plus 5-fluorouracil/folinic acid (5-FU/FA) led to This phase II trial was designed to assess the efficacy and safety significantly increased overall survival and progression-free of the weekly combination of oxaliplatin plus infusional 5-FU/FA survival compared with former standard regimens (de Gramont (FUFOX) in first-line metastatic gastric cancer. et al, 2000; Giacchetti et al, 2000; Goldberg et al, 2004). Therefore, in many countries this combination forms the new standard of METHODS Patient population *Correspondence: Dr F Lordick; E-mail: f.lordick@lrz.tu-muenchen.de Received 27 April 2005; revised 8 June 2005; accepted 9 June 2005; To be eligible for this study, patients had to have histologically published online 12 July 2005 confirmed metastatic adenocarcinoma of the stomach or FUFOX in metastatic gastric cancer F Lordick et al oesophagogastric junction. At least one measurable lesion Statistical considerations previously untreated with radiotherapy had to be present. No The primary end point of this investigator-initiated, multicentre, prior treatment for advanced disease was allowed. Patients were nonrandomised, open-label, phase II study was to determine the allowed to have received prior adjuvant or neoadjuvant chemo- proportion of patients responding to weekly FUFOX. The required therapy/chemoradiation, providing that treatment had been number of patients for this trial was calculated according to the completed X6 months before inclusion in the study. All patients Simon two-stage design (Machin and Campbell, 1997), assuming a were 418 years of age with an ECOG performance status p2 and a minimal response rate (p ) of 30% and a worthwhile-to-detect- life expectancy of X12 weeks. response-rate (p ) of at least 50%. With a power of 80% and a Patients were required to have adequate bone marrow, renal and significance level of 5% for testing the hypothesis H : prp vs H : 0 0 1 hepatic function, defined as an absolute neutrophil count (ANC) pXp this resulted in a sample size of 15 for the first stage. If more 1, X1500ml, platelets X100 000ml, S-creatinineo1.5 upper limit than five out of 15 were observed, another 31 patients were to be of normal (ULN), total bilirubinp1.5 ULN, SGOT and/or recruited in the second stage. The drug combination was to be SGPTp1.5 ULN (p5.0 ULN in the presence of liver meta- rejected if less than 19 out of 46 patients were observed. stasis). Patients with any central nervous system metastases or All eligible patients were included in the response, safety neuropathy Xgrade 2 were excluded. and survival analyses. Time to progression (TTP: time from Pretreatment evaluation included signed written informed study entry until documented tumour progression) and overall consent, complete history and physical examination, laboratory survival (OS: time from study entry until death) were analysed tests, CT scans of all areas affected by the tumour and an ECG. A according to the Kaplan–Meier method, and were updated to urine or serum pregnancy test was performed in female patients 15 October 2004. Statistical computations were performed using of child-bearing age. All patients gave written informed consent SPSS (version 12.0). before enrolment and the study was approved by the ethics committee for human research at the Technical University of Munich. The study conformed to the principles of the Declaration of Helsinki and its subsequent amendments. RESULTS Patient characteristics Treatment plan A total of 48 patients were enrolled at nine study sites between August 2002 and November 2003. Patient baseline characteristics Oxaliplatin (50 mg m ) was administered simultaneously with FA are listed in Table 1. All patients had metastatic disease, with the (500 mg m ) as a 2-h intravenous infusion, followed immediately liver, lymph nodes, peritoneum and lung being the predominant by 5-FU (2000 mg m ) as a continuous infusion over 24 h. sites of metastases. The median number of involved organs was Treatment was repeated every week. One cycle of treatment was three (range 0–5). In total, 37 (77%) patients had newly diagnosed defined as 4 weeks of treatment followed by 1 week of rest. In order to avoid severe neurotoxicity, administration of oxaliplatin was limited to every other week in patients receiving more than four Table 1 Patient baseline characteristics cycles. Patients were treated until best response or until there was evidence of disease progression. Patients going off study were Characteristics allowed to receive any second-line treatment as determined appropriate by their oncologist. Total number of patients 48 Median age (range) 62 (41 – 75) years Gender Study evaluations Male 39 (81%) Female 9 (19%) A baseline CT was performed within 2 weeks prior to study inclusion. After every second cycle of therapy, patients underwent ECOG performance status follow-up CT scans for assessment of response according to 0 23 (48%) RECIST criteria (Therasse et al, 2000). In cases where treatment 1 24 (50%) was discontinued before tumour progression, CT scans were 2 1 (2%) repeated every 3 months. Responses were to be confirmed within 4 weeks and were reviewed centrally by one independent radiologist Disease status (J Stollfuss). Patients were considered evaluable for response if Newly diagnosed 37 (77%) they had received at least two cycles (10 weeks) of treatment, with Recurrent 11 (23%) Locally advanced 0 (0%) at least one follow-up tumour assessment. Nonevaluable patients Metastatic 48 (100%) were included into the intention-to-treat analyses but reported as being not evaluable. Localisation of the primary tumour Patients were monitored every week for laboratory parameters Stomach 23 (48%) and adverse events. With the exception of peripheral sensory Oesophagogastric junction 23 (48%) neuropathy, all adverse events were graded using the National Gastric stump 2 (4%) Cancer Institute Common Toxicity Criteria (NCI-CTC, version 2.0). Peripheral sensory neuropathy was graded according to a Sites of disease modified oxaliplatin-specific scale (Caussanel et al, 1990): grade 1 Liver 30 (63%) Lymph nodes 29 (60%) – paresthaesias/dysesthaesias of short duration with complete Peritoneum 16 (33%) recovery before the next cycle; grade 2 – paresthaesias/dysesthae- Lung 13 (27%) sias persisting between two cycles without functional impairment; Bone 5 (10%) grade 3 – permanent paresthaesias/dysesthaesias resulting in Others 6 (12%) functional impairment. Patients going off study for reasons other than disease progression were evaluated every 3 months during ECOG¼ Eastern Cooperative Oncology Group. Skin (two patients), scrotum, adrenals, spleen and kidney. follow-up visits. & 2005 Cancer Research UK British Journal of Cancer (2005) 93(2), 190 – 194 Clinical Studies Clinical Studies FUFOX in metastatic gastric cancer F Lordick et al primary metastatic disease. In all of those patients, the primary surgery and one patient was treated with external beam radiation tumour had been left in situ whereas 11 (23%) patients had therapy. recurrent disease after previous surgery intending to cure the Median OS was 11.4 months (95% CI, 8.0–14.9 months, primary. Figure 1). Median TTP was 6.5 months (95% CI, 3.9–9.2 months, Figure 2). Median follow-up is 18.1 months (range 11.2–26.2 months). Feasibility and safety The median number of completed cycles was 4 (range 0–6 cycles). Adherence to the planned doses of both oxaliplatin and 5-FU was 1.0 high. Dose reductions of one or both agents to o80% of initial + Censored doses were required in o10% of patients. The median adminis- tered cumulative dose of oxaliplatin was 800 mg m . All grade 1/2 treatment-related adverse events observed in more than 5% of patients are listed in Table 2. While it affected 67% of 0.8 patients, sensory neuropathy was generally mild. All grade 3/4 treatment-related adverse events are listed in Table 2. The most common grade 3/4 events (affecting 45% of patients) were diarrhoea, deep vein thrombosis, neutropenia and nausea. Of note, 0.6 stomatitis and sensory neuropathy 4grade 2 were not reported in any of the patients. Serious adverse events (SAEs) were reported in 14 patients. Two SAEs, one case of septic diarrhoea with neutropenia and one of stroke were fatal. Both deaths occurred during the first two 0.4 treatment cycles. As there were no other early deaths within the first 2 months after study entry, the 60-day mortality rate was 4.2%. 0.2 Efficacy Tumour response was evaluable according to RECIST criteria in 45 patients. Three (6%) patients who did not undergo the first follow-up tumour assessment due to early death or pre- 0 mature termination of therapy (patient preference) were included 05 10 15 20 25 in the intention-to-treat analyses as nonevaluable subjects. There Time (months) were two (4%) complete responses and 24 (50%) patients achieved Figure 1 Kaplan –Meier curve for overall survival in all patients (n¼ 48). a partial remission, resulting in an overall response rate of 54% (95% CI, 39–69%). Eight (17%) patients had stable disease and 11 (23%) had progressive disease at the first follow-up tumour assessment. A total of 25 (52%) patients received second- and third-line 1.0 chemotherapies: 13 irinotecan-based, seven taxane-based, three + Censored platinum-based, one epirubicin, one etoposide, and four investi- gational drugs. Two patients underwent secondary palliative 0.8 Table 2 Treatment-related adverse events No. of patients (%) 0.6 Event Grade 1/2 Grade 3/4 Anaemia 21 (44%) 2 (4%) Neutropenia 6 (13%) 4 (8%) Febrile neutropenia NA 2 (4%) 0.4 Thrombocytopenia 7 (15%) 1 (2%) Diarrhoea 17 (35%) 8 (17%) Constipation 4 (8%) 0 (0%) Stomatitis 7 (15%) 0 (0%) Nausea 33 (69%) 3 (6%) 0.2 Emesis 13 (27%) 1 (2%) Fatigue 21 (44%) 2 (4%) Deep vein thrombosis NA 7 (15%) Tumour bleeding NA 2 (4%) Cardiac ischaemia NA 1 (2%) Pneumonia NA 1 (2%) 0 25 510 15 20 Fever 4 (8%) 0 (0%) Alopecia 7 (15%) NA Time (months) Sensory neuropathy 32 (67%) 0 (0%) Figure 2 Kaplan –Meier curve for time to progression in all patients NA¼ not applicable. (n¼ 48). British Journal of Cancer (2005) 93(2), 190 – 194 & 2005 Cancer Research UK Probability Probability FUFOX in metastatic gastric cancer F Lordick et al DISCUSSION treatment with the most recently available agents may be effective in a considerable number of patients. Evidence from phase II trials Oxaliplatin combinations have become the mainstay of systemic suggests that irinotecan-containing regimens may be particularly treatment for advanced gastrointestinal tumours. As a result of the active in this setting (Ajani et al, 2002; Assersohn et al, 2004). data from randomised phase III trials showing superiority over Therefore, it is important to acknowledge that the use of second- former standard regimens (de Gramont et al, 2000; Giacchetti et al, line chemotherapies may have positively influenced the survival 2000; Andre et al, 2004a; Goldberg et al, 2004), oxaliplatin plus time in our study population. 5-FU/FA has been approved in many countries for the palliative Treatment compliance for the FUFOX regimen was very good treatment of stage IV colorectal cancer and the adjuvant therapy of with a dose adherence to both oxaliplatin and 5-FU of 490%. As stage III colon cancer. Moreover, there is increasing evidence from already observed by the Taiwan and even more by the Frankfurt phase II studies that oxaliplatin combinations have significant group, avoiding the 5-FU bolus administration has led to a activity in other gastrointestinal tumours such as pancreatic cancer dramatic reduction of haematological toxicity. In the French (Louvet et al, 2002b; Ducreux et al, 2004) and biliary tract adeno- regimen, which included a 5-FU bolus on day 1, the rate of grade 3/ carcinoma (Andre et al, 2004b). In combination with radiation 4 neutropenia was 38%. This was associated with an 11% rate of therapy, oxaliplatin and fluoropyrimidines result in promising febrile neutropenia. Thus, in our study using weekly oxaliplatin/5- tumour remissions in locally advanced oesophageal and rectal FU as well as in the modified version of biweekly FOLFOX as used cancer (Freyer et al, 2001; Khushalani et al, 2002; Ro¨del et al, 2003). by the Frankfurt group, bolus 5-FU was omitted. Consequently, the In advanced gastric cancer, two previously published phase II rate of grade 3/4 neutropenia was below 10% and febrile studies have shown consistent results regarding the activity of neutropenia occurred in less than 5% of the patients in both biweekly oxaliplatin-5–FU/FA combinations. These regimens studies. Compared with the other oxaliplatin/5-FU regimens induced objective tumour responses in 43 and 45% of patients, studied in gastric cancer, the rate of severe diarrhoea was relatively respectively, and were associated with a median survival of 9.6 and high (17%) in our study. However, this is comparable with recently 8.6 months, respectively (Louvet et al, 2002a; Al-Batran et al, reported findings with the FUFOX regimen in metastatic colorectal 2004). A study from Taiwan assessed the activity of oxaliplatin-5- cancer, where grade 3/4 diarrhoea affected 21% of patients FU/FA given on days 1 and 8, repeated every 3 weeks. This regimen (Grothey et al, 2002). It would be worthwhile to investigate induced an objective tumour reponse in 56% of the evaluable whether administering a lower dose of FA, which can itself cause patients. The median TTP and survival were 5.2 and 10.0 months, diarrhoea, would reduce this rate. respectively (Chao et al, 2004). Although data from phase III trials Unfortunately, in our study, one patient died as a result of septic have not yet been presented, in daily practice the combination of diarrhoea and neutropenia. The investigators considered this death oxaliplatin plus 5-FU/FA is increasingly used by many oncologists to be treatment-related. However, the relationship between stroke for the treatment of advanced gastric cancer. and death in another patient was judged to be uncertain by the The objective of this study was to assess the efficacy of weekly investigators. Nevertheless, these events highlight the importance of oxaliplatin plus 5-FU/FA given 4 out of 5 weeks (FUFOX regimen) careful monitoring of these highly vulnerable patients, even when a as first-line treatment for metastatic gastric and oesophagogastric generally well-tolerated chemotherapy regimen is administered. adenocarcinoma. Leading to an objective response rate of 54%, the As expected with oxaliplatin-containing regimens, neurotoxicity activity of FUFOX exceeded the expectations of the trial. This affected the majority of patients. However, in contrast to studies unexpectedly high activity of FUFOX seems to translate into a with the FOLFOX-6 regimen, where 21% of patients reported meaningful clinical benefit, as indicated by the median survival functional impairment caused by sensory neuropathy with a time of 11.4 months. 2 median administered oxaliplatin dose of 900 mg m (Louvet et al, One might assume that these promising efficacy results are 2002a), the intensity of neuropathy observed in our trial, where the attributable to a patient selection bias. To encounter this well- 2 median dose of oxaliplatin was 800 mg m , did not exceed mild to known phenomenon in phase II testing, selected study centres moderate grades. This observation corresponds well with the included two university hospitals, two community hospitals and recently reported low rate of severe neuropathy with the weekly five private practices. This represents the typical treatment facilities FUFOX regimen in stage IV colorectal cancer (Grothey et al, 2002). for cancer patients in Germany. As in three studies on oxaliplatin These observations indicate that weekly application of lower doses plus 5-FU/FA in gastric cancer previously published by the French of oxaliplatin may have advantages compared with biweekly group (Louvet et al, 2002a), the Taiwan group (Chao et al, 2004) oxaliplatin-regimens in terms of neurotoxicity. and the Frankfurt group (Al-Batran et al, 2004), the majority of In conclusion, weekly oxaliplatin plus 5-FU/FA has a favourable patients in our study presented with a good performance status and safety profile compared with previous data from studies of the the median age of 62 years was in the same range as in the three biweekly FUFOX regimen. This weekly FUFOX regimen results in a previous trials. Of note, all patients included in our study presented high tumour response rate in first-line metastatic gastric cancer and with metastatic disease. Consequently, none of them underwent is associated with a promising OS time. Therefore, the weekly FUFOX secondary curative treatment. In contrast, the French group regimen can be recommended for phase III studies as well as a reported on seven of 54 (13%) patients with locally advanced combination partner for new investigational drugs in phase I/II trials. disease and on eight (15%) patients undergoing complementary surgery or chemoradiation with curative intent. The three other mentioned studies do not report on the frequency of second-line chemotherapy in their study populations. ACKNOWLEDGEMENTS In our study, the use of second- and even third-line therapies was relatively frequent (450% of patients). The chosen regimens most This study was supported by a grant from the Sanofi-Synthelabo frequently included irinotecan or taxanes. Although no phase III GmbH, Berlin, Germany. We thank Dr Matthias Suermondt and trial has yet defined the clinical benefit of second-line chemo- Dr Marco Schupp for their support. We also thank our research nurses therapy in gastric cancer, there is no doubt that second-line Mrs Nadine Roethling and Mrs Brigitte Lang for their excellent work. REFERENCES Ajani JA, Baker J, Pisters PW, Ho L, Mansfield PF, Feig BW, Charnsangavej esophageal junction carcinoma. Oncology (Huntington) 16(5 Suppl 5): C (2002) Irinotecan/cisplatin in advanced, treated gastric or gastro- 16–18 & 2005 Cancer Research UK British Journal of Cancer (2005) 93(2), 190 – 194 Clinical Studies Clinical Studies FUFOX in metastatic gastric cancer F Lordick et al Al-Batran SE, Atmaca A, Hegewisch-Becker S, Jaeger D, Hahnfeld S, care with best supportive care in advanced gastric cancer. Ann Oncol 8: Rummel MJ, Seipelt G, Rost A, Orth J, Knuth A, Jaeger E (2004) Phase II 163–168 trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, patients with advanced gastric cancer. J Clin Oncol 22: 658–663 Williamson SK, Findlay BP, Pitot HC, Alberts SR (2004) A randomized Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, controlled trial of fluorouracil plus leucovorin, irinotecan and oxaliplatin Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de combinations in patients with previously untreated metastatic colorectal Gramont A, Multicenter International Study of Oxaliplatin/5-Fluoro- cancer. J Clin Oncol 22: 23–30 uracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Grothey A, Deschler B, Kroening H, Ridwelski K, Reichardt P, Kretzschmar Investigators (2004a) Oxaliplatin, fluorouracil, and leucovorin as A, Clemens M, Hirschmann W, Lorenz M, Asperger W, Buechele T, adjuvant treatment for colon cancer. N Engl J Med 350: 2343– 2351 Schmoll HF (2002) Phase III study of bolus 5-fluorouracil (5-FU)/folinic Andre T, Tournigand C, Rosmorduc O, Provent S, Maindrault-Goebel F, acid (FA) (Mayo) vs weekly high-dose 24 h 5-FU infusion/FA+oxaliplatin Avenin D, Selle F, Paye F, Hannoun L, Houry S, Gayet B, Lotz JP, de (OXA) in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol Gramont A, Louvet C, GERCOR Group (2004b) Gemcitabine combined 21: 129a (abstr 512) with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a Khushalani NI, Leichman CG, Proulx G, Nava H, Bodnar L, Klippenstein D, GERCOR study. Ann Oncol 15: 1339 –1343 Litwin A, Smith J, Nava E, Pendyala L, Smith P, Greco W, Berdzik J, Assersohn L, Brown G, Cunningham D, Ward C, Oates J, Waters JS, Hill Douglass H, Leichman L (2002) Oxaliplatin in combination with ME, Norman AR (2004) Phase II study of irinotecan and 5-fluorouracil/ protracted-infusion fluorouracil and radiation: report of a clinical trial leucovorin in patients with primary refractory or relapsed advanced for patients with esophageal cancer. J Clin Oncol 20: 2844–2850 oesophageal and gastric carcinoma. Ann Oncol 15: 64– 69 Louvet C, Andre T, Lledo G, Hammel P, Bleiberg H, Bouleuc C, Gamelin E, Caussanel JP, Levi F, Brienza S, Misset JL, Itzhaki M, Adam R, Milano G, Flesch M, Cvitkovic E, de Gramont A (2002b) Gemcitabine combined Hecquet B, Mathe G (1990) Phase I trial of 5-day continuous venous with oxaliplatin in advanced pancreatic adenocarcinoma: final results of infusion of oxaliplatin at circadian rhythm modulated rate compared a GERCOR multicenter phase II study. J Clin Oncol 20: 1512–1518 with constant rate. J Natl Cancer Inst 82: 1046–1050 Louvet C, Andre T, Tigaud JM, Gamelin E, Douillard JY, Brunet R, Francois Chao Y, Yeh KH, Chang LT, Chao TY, Wu MF, Chang CS, Chang JY, Chung E, Jacob JH, Levoir D, Taamma A, Rougier P, Cvitkovic E, de Gramont A CY, Kao WY, Hsieh RK, Cheng AL (2004) Phase II study of weekly (2002a) Phase II study of oxaliplatin, fluorouracil, and folinic acid in oxaliplatin and 24-h infusion of high-dose 5-fluorouracil and folinic acid locally advanced or metastatic gastric cancer patients. J Clin Oncol 20: in the treatment of advanced gastric cancer. Br J Cancer 91: 453– 458 4543– 4548 de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni Machin D, Campbell MJ (1997) Statistical Tables for the Design of Clinical C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Trials 2nd edn Oxford: Blackwell Scientific Publications, pp 281–282 Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A (2000) Ro¨del C, Grabenbauer GG, Papadopoulos T, Hohenberger W, Schmoll HJ, Leucovorin and fluorouracil with or without oxaliplatin as first-line Sauer R (2003) Phase I/II trial of capecitabine, oxaliplatin, and radiation treatment in advanced colorectal cancer. J Clin Oncol 18: 2938 –2947 for rectal cancer. J Clin Oncol 21: 3098–3104 Ducreux M, Mitry E, Ould-Kaci M, Boige V, Seitz JF, Bugat R, Breau JL, Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein Bouche O, Etienne PL, Tigaud JM, Morvan F, Cvitkovic E, Rougier P L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther (2004) Randomized phase II study evaluating oxaliplatin alone, SG (2000) New guidelines to evaluate the response to treatment in solid oxaliplatin combined with infusional 5-FU, and infusional 5-FU alone tumors. J Natl Cancer Inst 92: 205–216 in advanced pancreatic carcinoma patients. Ann Oncol 15: 467–473 Vanhoefer U, Rougier P, Wilke H, Ducreux MP, Lacave AJ, Van Cutsem E, Freyer G, Bossard N, Romestaing P, Mornex F, Chapet O, Trillet-Lenoir V, Planker M, Santos JG, Piedbois P, Paillot B, Bodenstein H, Schmoll HJ, Gerard JP (2001) Addition of oxaliplatin to continuous fluorouracil, Bleiberg H, Nordlinger B, Couvreur ML, Baron B, Wils JA (2000) Final l-folinic acid, and concomitant radiotherapy in rectal cancer: The Lyon R results of a randomized phase III trial of sequential high-dose 97-03 phase I trial. J Clin Oncol 19: 2433–2438 methotrexate, fluorouracil, and doxorubucin versus etoposide, leuco- Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet vorin, and fluorouracil versus infusional fluorouracil and cisplatin in P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain- advanced gastric cancer: A trial of the European Organization for Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Levi F (2000) Phase Research and Treatment of Cancer Gastrointestinal Tract Cancer III multicenter randomized trial of oxaliplatin added to chronomodu- Cooperative Group. J Clin Oncol 18: 2648–2657 lated fluorouracil-leucovorin as first-line treatment of metastatic colo- Waters JS, Norman A, Cunningham D, Scarffe JH, Webb A, Harper P, Joffe rectal cancer. J Clin Oncol 18: 136– 147 JK, Mackean M, Mansi J, Leahy M, Hill A, Oates J, Rao S, Nicolson M, Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, Hickish T (1999) Long-term survival after epirubicin, cisplatin and Svensson C, Enander LK, Linne T, Sellstrom H, Heuman R (1997) fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer Randomized comparison between chemotherapy plus best supportive 80: 269–272 British Journal of Cancer (2005) 93(2), 190 – 194 & 2005 Cancer Research UK http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Phase II study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer

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References (47)

Publisher
Springer Journals
Copyright
Copyright © 2005 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
ISSN
0007-0920
eISSN
1532-1827
DOI
10.1038/sj.bjc.6602697
Publisher site
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Clinical Studies British Journal of Cancer (2005) 93, 190 – 194 & 2005 Cancer Research UK All rights reserved 0007 – 0920/05 $30.00 www.bjcancer.com Phase II study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer ,1 1 1 2 3 4 5 F Lordick , S Lorenzen , J Stollfuss , U Vehling-Kaiser , F Kullmann , M Hentrich , R Zumschlinge , 6 1 1 7 8 1 1 H Dietzfelbinger , J Thoedtmann , M Hennig , T Seroneit , R Bredenkamp , J Duyster and C Peschel 1 2 Clinic Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany; Oncological Outpatient Clinic, Heilig-Geist-Gasse 3 4 411, 84028 Landshut, Germany; University Clinic of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany; Clinic Harlaching, 5 6 Sanatoriumsplatz 2, 81545 Munich, Germany; Clinic Traunstein, Cuno-Niggl-Str. 3, 83278 Traunstein, Germany; Schindlbeck-Clinic, Seestr. 43, 82211 7 8 Herrsching, Germany; Sanofi-Aventis Group, Potsdamer Str. 8, 10785 Berlin, Germany; Center for Clinical Studies, Ismaninger Str. 22, 81675 Munich, Germany Oxaliplatin plus fluorouracil/folinic acid (5-FU/FA) every 2 weeks has shown promising activity in advanced gastric cancer. This study assessed the efficacy and safety of weekly oxaliplatin plus 5-FU/FA (FUFOX regimen) in the metastatic setting. Patients with 2 2 previously untreated metastatic gastric cancer received oxaliplatin (50 mg m ) plus FA (500 mg m , 2-h infusion) followed by 5-FU (2000 mg m , 24-h infusion) given on days 1, 8, 15 and 22 of a 5-week cycle. The primary end point of this multicentre phase II study was the response rate according to RECIST criteria. A total of 48 patients were enrolled. Median age was 62 years and all patients had metastatic disease, with a median number of three involved organs. The most common treatment-related grade 3/4 adverse events were diarrhoea (17%), deep vein thrombosis (15%), neutropenia (8%), nausea (6%), febrile neutropenia (4%), fatigue (4%), anaemia (4%), tumour bleeding (4%), emesis (2%), cardiac ischaemia (2%) and pneumonia (2%). Grade 1/2 sensory neuropathy occurred in 67% of patients but there were no episodes of grade 3 neuropathy. Intent-to-treat analysis showed a response rate of 54% (95% CI, 39–69%), including two complete responses. At a median follow-up of 18.1 months (range 11.2–26.2 months), median survival is 11.4 months (95% CI, 8.0–14.9 months) and the median time to progression is 6.5 months (95% CI, 3.9–9.2 months). The weekly FUFOX regimen is well tolerated and shows notable activity as first-line treatment in metastatic gastric cancer. British Journal of Cancer (2005) 93, 190–194. doi:10.1038/sj.bjc.6602697 www.bjcancer.com Published online 12 July 2005 & 2005 Cancer Research UK Keywords: oxaliplatin; fluorouracil; metastatic gastric cancer; first-line Systemic chemotherapy has been shown to prolong survival and to care in the first-line treatment of metastatic disease. In advanced relieve symptoms in advanced gastric cancer (Glimelius et al, gastric cancer, biweekly oxaliplatin plus 5-FU/FA has shown 1997). However, the number of patients who benefit from considerable antitumour activity in phase II trials (Louvet et al, treatment is still limited and the optimal chemotherapy regimen 2002a; Al-Batran et al, 2004). Oxaliplatin shows a better toxicity has not yet been defined. Platinum-free regimens exhibited profile than cisplatin. Its main and dose-limiting toxicity is acute, disappointing efficacy in randomised trials. Cisplatin-based regi- cumulative peripheral sensory neurotoxicity, resulting in acral mens, for example the combination of epirubicin, cisplatin, and paresthaesia and dysesthaesia, which are exacerbated by cold. 5-FU (ECF), have demonstrated superior efficacy, albeit with The weekly application of oxaliplatin plus infusional 5-FU/FA significant toxicity and inconvenience from the patients’ perspec- (FUFOX), as proposed by the Arbeitsgemeinschaft Internistische tive (Waters et al, 1999; Vanhoefer et al, 2000). Onkologie (AIO), has proven to be highly effective in first-line Oxaliplatin is a third-generation diaminocyclohexane platinum metastatic colorectal cancer. The AIO FUFOX regimen is also compound proven in numerous clinical trials to be active in associated with an acceptable toxicity profile, with a particularly various tumour types. In advanced colorectal cancer, treatment low rate of sensory neuropathy (Grothey et al, 2002). with oxaliplatin plus 5-fluorouracil/folinic acid (5-FU/FA) led to This phase II trial was designed to assess the efficacy and safety significantly increased overall survival and progression-free of the weekly combination of oxaliplatin plus infusional 5-FU/FA survival compared with former standard regimens (de Gramont (FUFOX) in first-line metastatic gastric cancer. et al, 2000; Giacchetti et al, 2000; Goldberg et al, 2004). Therefore, in many countries this combination forms the new standard of METHODS Patient population *Correspondence: Dr F Lordick; E-mail: f.lordick@lrz.tu-muenchen.de Received 27 April 2005; revised 8 June 2005; accepted 9 June 2005; To be eligible for this study, patients had to have histologically published online 12 July 2005 confirmed metastatic adenocarcinoma of the stomach or FUFOX in metastatic gastric cancer F Lordick et al oesophagogastric junction. At least one measurable lesion Statistical considerations previously untreated with radiotherapy had to be present. No The primary end point of this investigator-initiated, multicentre, prior treatment for advanced disease was allowed. Patients were nonrandomised, open-label, phase II study was to determine the allowed to have received prior adjuvant or neoadjuvant chemo- proportion of patients responding to weekly FUFOX. The required therapy/chemoradiation, providing that treatment had been number of patients for this trial was calculated according to the completed X6 months before inclusion in the study. All patients Simon two-stage design (Machin and Campbell, 1997), assuming a were 418 years of age with an ECOG performance status p2 and a minimal response rate (p ) of 30% and a worthwhile-to-detect- life expectancy of X12 weeks. response-rate (p ) of at least 50%. With a power of 80% and a Patients were required to have adequate bone marrow, renal and significance level of 5% for testing the hypothesis H : prp vs H : 0 0 1 hepatic function, defined as an absolute neutrophil count (ANC) pXp this resulted in a sample size of 15 for the first stage. If more 1, X1500ml, platelets X100 000ml, S-creatinineo1.5 upper limit than five out of 15 were observed, another 31 patients were to be of normal (ULN), total bilirubinp1.5 ULN, SGOT and/or recruited in the second stage. The drug combination was to be SGPTp1.5 ULN (p5.0 ULN in the presence of liver meta- rejected if less than 19 out of 46 patients were observed. stasis). Patients with any central nervous system metastases or All eligible patients were included in the response, safety neuropathy Xgrade 2 were excluded. and survival analyses. Time to progression (TTP: time from Pretreatment evaluation included signed written informed study entry until documented tumour progression) and overall consent, complete history and physical examination, laboratory survival (OS: time from study entry until death) were analysed tests, CT scans of all areas affected by the tumour and an ECG. A according to the Kaplan–Meier method, and were updated to urine or serum pregnancy test was performed in female patients 15 October 2004. Statistical computations were performed using of child-bearing age. All patients gave written informed consent SPSS (version 12.0). before enrolment and the study was approved by the ethics committee for human research at the Technical University of Munich. The study conformed to the principles of the Declaration of Helsinki and its subsequent amendments. RESULTS Patient characteristics Treatment plan A total of 48 patients were enrolled at nine study sites between August 2002 and November 2003. Patient baseline characteristics Oxaliplatin (50 mg m ) was administered simultaneously with FA are listed in Table 1. All patients had metastatic disease, with the (500 mg m ) as a 2-h intravenous infusion, followed immediately liver, lymph nodes, peritoneum and lung being the predominant by 5-FU (2000 mg m ) as a continuous infusion over 24 h. sites of metastases. The median number of involved organs was Treatment was repeated every week. One cycle of treatment was three (range 0–5). In total, 37 (77%) patients had newly diagnosed defined as 4 weeks of treatment followed by 1 week of rest. In order to avoid severe neurotoxicity, administration of oxaliplatin was limited to every other week in patients receiving more than four Table 1 Patient baseline characteristics cycles. Patients were treated until best response or until there was evidence of disease progression. Patients going off study were Characteristics allowed to receive any second-line treatment as determined appropriate by their oncologist. Total number of patients 48 Median age (range) 62 (41 – 75) years Gender Study evaluations Male 39 (81%) Female 9 (19%) A baseline CT was performed within 2 weeks prior to study inclusion. After every second cycle of therapy, patients underwent ECOG performance status follow-up CT scans for assessment of response according to 0 23 (48%) RECIST criteria (Therasse et al, 2000). In cases where treatment 1 24 (50%) was discontinued before tumour progression, CT scans were 2 1 (2%) repeated every 3 months. Responses were to be confirmed within 4 weeks and were reviewed centrally by one independent radiologist Disease status (J Stollfuss). Patients were considered evaluable for response if Newly diagnosed 37 (77%) they had received at least two cycles (10 weeks) of treatment, with Recurrent 11 (23%) Locally advanced 0 (0%) at least one follow-up tumour assessment. Nonevaluable patients Metastatic 48 (100%) were included into the intention-to-treat analyses but reported as being not evaluable. Localisation of the primary tumour Patients were monitored every week for laboratory parameters Stomach 23 (48%) and adverse events. With the exception of peripheral sensory Oesophagogastric junction 23 (48%) neuropathy, all adverse events were graded using the National Gastric stump 2 (4%) Cancer Institute Common Toxicity Criteria (NCI-CTC, version 2.0). Peripheral sensory neuropathy was graded according to a Sites of disease modified oxaliplatin-specific scale (Caussanel et al, 1990): grade 1 Liver 30 (63%) Lymph nodes 29 (60%) – paresthaesias/dysesthaesias of short duration with complete Peritoneum 16 (33%) recovery before the next cycle; grade 2 – paresthaesias/dysesthae- Lung 13 (27%) sias persisting between two cycles without functional impairment; Bone 5 (10%) grade 3 – permanent paresthaesias/dysesthaesias resulting in Others 6 (12%) functional impairment. Patients going off study for reasons other than disease progression were evaluated every 3 months during ECOG¼ Eastern Cooperative Oncology Group. Skin (two patients), scrotum, adrenals, spleen and kidney. follow-up visits. & 2005 Cancer Research UK British Journal of Cancer (2005) 93(2), 190 – 194 Clinical Studies Clinical Studies FUFOX in metastatic gastric cancer F Lordick et al primary metastatic disease. In all of those patients, the primary surgery and one patient was treated with external beam radiation tumour had been left in situ whereas 11 (23%) patients had therapy. recurrent disease after previous surgery intending to cure the Median OS was 11.4 months (95% CI, 8.0–14.9 months, primary. Figure 1). Median TTP was 6.5 months (95% CI, 3.9–9.2 months, Figure 2). Median follow-up is 18.1 months (range 11.2–26.2 months). Feasibility and safety The median number of completed cycles was 4 (range 0–6 cycles). Adherence to the planned doses of both oxaliplatin and 5-FU was 1.0 high. Dose reductions of one or both agents to o80% of initial + Censored doses were required in o10% of patients. The median adminis- tered cumulative dose of oxaliplatin was 800 mg m . All grade 1/2 treatment-related adverse events observed in more than 5% of patients are listed in Table 2. While it affected 67% of 0.8 patients, sensory neuropathy was generally mild. All grade 3/4 treatment-related adverse events are listed in Table 2. The most common grade 3/4 events (affecting 45% of patients) were diarrhoea, deep vein thrombosis, neutropenia and nausea. Of note, 0.6 stomatitis and sensory neuropathy 4grade 2 were not reported in any of the patients. Serious adverse events (SAEs) were reported in 14 patients. Two SAEs, one case of septic diarrhoea with neutropenia and one of stroke were fatal. Both deaths occurred during the first two 0.4 treatment cycles. As there were no other early deaths within the first 2 months after study entry, the 60-day mortality rate was 4.2%. 0.2 Efficacy Tumour response was evaluable according to RECIST criteria in 45 patients. Three (6%) patients who did not undergo the first follow-up tumour assessment due to early death or pre- 0 mature termination of therapy (patient preference) were included 05 10 15 20 25 in the intention-to-treat analyses as nonevaluable subjects. There Time (months) were two (4%) complete responses and 24 (50%) patients achieved Figure 1 Kaplan –Meier curve for overall survival in all patients (n¼ 48). a partial remission, resulting in an overall response rate of 54% (95% CI, 39–69%). Eight (17%) patients had stable disease and 11 (23%) had progressive disease at the first follow-up tumour assessment. A total of 25 (52%) patients received second- and third-line 1.0 chemotherapies: 13 irinotecan-based, seven taxane-based, three + Censored platinum-based, one epirubicin, one etoposide, and four investi- gational drugs. Two patients underwent secondary palliative 0.8 Table 2 Treatment-related adverse events No. of patients (%) 0.6 Event Grade 1/2 Grade 3/4 Anaemia 21 (44%) 2 (4%) Neutropenia 6 (13%) 4 (8%) Febrile neutropenia NA 2 (4%) 0.4 Thrombocytopenia 7 (15%) 1 (2%) Diarrhoea 17 (35%) 8 (17%) Constipation 4 (8%) 0 (0%) Stomatitis 7 (15%) 0 (0%) Nausea 33 (69%) 3 (6%) 0.2 Emesis 13 (27%) 1 (2%) Fatigue 21 (44%) 2 (4%) Deep vein thrombosis NA 7 (15%) Tumour bleeding NA 2 (4%) Cardiac ischaemia NA 1 (2%) Pneumonia NA 1 (2%) 0 25 510 15 20 Fever 4 (8%) 0 (0%) Alopecia 7 (15%) NA Time (months) Sensory neuropathy 32 (67%) 0 (0%) Figure 2 Kaplan –Meier curve for time to progression in all patients NA¼ not applicable. (n¼ 48). British Journal of Cancer (2005) 93(2), 190 – 194 & 2005 Cancer Research UK Probability Probability FUFOX in metastatic gastric cancer F Lordick et al DISCUSSION treatment with the most recently available agents may be effective in a considerable number of patients. Evidence from phase II trials Oxaliplatin combinations have become the mainstay of systemic suggests that irinotecan-containing regimens may be particularly treatment for advanced gastrointestinal tumours. As a result of the active in this setting (Ajani et al, 2002; Assersohn et al, 2004). data from randomised phase III trials showing superiority over Therefore, it is important to acknowledge that the use of second- former standard regimens (de Gramont et al, 2000; Giacchetti et al, line chemotherapies may have positively influenced the survival 2000; Andre et al, 2004a; Goldberg et al, 2004), oxaliplatin plus time in our study population. 5-FU/FA has been approved in many countries for the palliative Treatment compliance for the FUFOX regimen was very good treatment of stage IV colorectal cancer and the adjuvant therapy of with a dose adherence to both oxaliplatin and 5-FU of 490%. As stage III colon cancer. Moreover, there is increasing evidence from already observed by the Taiwan and even more by the Frankfurt phase II studies that oxaliplatin combinations have significant group, avoiding the 5-FU bolus administration has led to a activity in other gastrointestinal tumours such as pancreatic cancer dramatic reduction of haematological toxicity. In the French (Louvet et al, 2002b; Ducreux et al, 2004) and biliary tract adeno- regimen, which included a 5-FU bolus on day 1, the rate of grade 3/ carcinoma (Andre et al, 2004b). In combination with radiation 4 neutropenia was 38%. This was associated with an 11% rate of therapy, oxaliplatin and fluoropyrimidines result in promising febrile neutropenia. Thus, in our study using weekly oxaliplatin/5- tumour remissions in locally advanced oesophageal and rectal FU as well as in the modified version of biweekly FOLFOX as used cancer (Freyer et al, 2001; Khushalani et al, 2002; Ro¨del et al, 2003). by the Frankfurt group, bolus 5-FU was omitted. Consequently, the In advanced gastric cancer, two previously published phase II rate of grade 3/4 neutropenia was below 10% and febrile studies have shown consistent results regarding the activity of neutropenia occurred in less than 5% of the patients in both biweekly oxaliplatin-5–FU/FA combinations. These regimens studies. Compared with the other oxaliplatin/5-FU regimens induced objective tumour responses in 43 and 45% of patients, studied in gastric cancer, the rate of severe diarrhoea was relatively respectively, and were associated with a median survival of 9.6 and high (17%) in our study. However, this is comparable with recently 8.6 months, respectively (Louvet et al, 2002a; Al-Batran et al, reported findings with the FUFOX regimen in metastatic colorectal 2004). A study from Taiwan assessed the activity of oxaliplatin-5- cancer, where grade 3/4 diarrhoea affected 21% of patients FU/FA given on days 1 and 8, repeated every 3 weeks. This regimen (Grothey et al, 2002). It would be worthwhile to investigate induced an objective tumour reponse in 56% of the evaluable whether administering a lower dose of FA, which can itself cause patients. The median TTP and survival were 5.2 and 10.0 months, diarrhoea, would reduce this rate. respectively (Chao et al, 2004). Although data from phase III trials Unfortunately, in our study, one patient died as a result of septic have not yet been presented, in daily practice the combination of diarrhoea and neutropenia. The investigators considered this death oxaliplatin plus 5-FU/FA is increasingly used by many oncologists to be treatment-related. However, the relationship between stroke for the treatment of advanced gastric cancer. and death in another patient was judged to be uncertain by the The objective of this study was to assess the efficacy of weekly investigators. Nevertheless, these events highlight the importance of oxaliplatin plus 5-FU/FA given 4 out of 5 weeks (FUFOX regimen) careful monitoring of these highly vulnerable patients, even when a as first-line treatment for metastatic gastric and oesophagogastric generally well-tolerated chemotherapy regimen is administered. adenocarcinoma. Leading to an objective response rate of 54%, the As expected with oxaliplatin-containing regimens, neurotoxicity activity of FUFOX exceeded the expectations of the trial. This affected the majority of patients. However, in contrast to studies unexpectedly high activity of FUFOX seems to translate into a with the FOLFOX-6 regimen, where 21% of patients reported meaningful clinical benefit, as indicated by the median survival functional impairment caused by sensory neuropathy with a time of 11.4 months. 2 median administered oxaliplatin dose of 900 mg m (Louvet et al, One might assume that these promising efficacy results are 2002a), the intensity of neuropathy observed in our trial, where the attributable to a patient selection bias. To encounter this well- 2 median dose of oxaliplatin was 800 mg m , did not exceed mild to known phenomenon in phase II testing, selected study centres moderate grades. This observation corresponds well with the included two university hospitals, two community hospitals and recently reported low rate of severe neuropathy with the weekly five private practices. This represents the typical treatment facilities FUFOX regimen in stage IV colorectal cancer (Grothey et al, 2002). for cancer patients in Germany. As in three studies on oxaliplatin These observations indicate that weekly application of lower doses plus 5-FU/FA in gastric cancer previously published by the French of oxaliplatin may have advantages compared with biweekly group (Louvet et al, 2002a), the Taiwan group (Chao et al, 2004) oxaliplatin-regimens in terms of neurotoxicity. and the Frankfurt group (Al-Batran et al, 2004), the majority of In conclusion, weekly oxaliplatin plus 5-FU/FA has a favourable patients in our study presented with a good performance status and safety profile compared with previous data from studies of the the median age of 62 years was in the same range as in the three biweekly FUFOX regimen. This weekly FUFOX regimen results in a previous trials. Of note, all patients included in our study presented high tumour response rate in first-line metastatic gastric cancer and with metastatic disease. Consequently, none of them underwent is associated with a promising OS time. Therefore, the weekly FUFOX secondary curative treatment. In contrast, the French group regimen can be recommended for phase III studies as well as a reported on seven of 54 (13%) patients with locally advanced combination partner for new investigational drugs in phase I/II trials. disease and on eight (15%) patients undergoing complementary surgery or chemoradiation with curative intent. The three other mentioned studies do not report on the frequency of second-line chemotherapy in their study populations. ACKNOWLEDGEMENTS In our study, the use of second- and even third-line therapies was relatively frequent (450% of patients). The chosen regimens most This study was supported by a grant from the Sanofi-Synthelabo frequently included irinotecan or taxanes. Although no phase III GmbH, Berlin, Germany. We thank Dr Matthias Suermondt and trial has yet defined the clinical benefit of second-line chemo- Dr Marco Schupp for their support. We also thank our research nurses therapy in gastric cancer, there is no doubt that second-line Mrs Nadine Roethling and Mrs Brigitte Lang for their excellent work. REFERENCES Ajani JA, Baker J, Pisters PW, Ho L, Mansfield PF, Feig BW, Charnsangavej esophageal junction carcinoma. Oncology (Huntington) 16(5 Suppl 5): C (2002) Irinotecan/cisplatin in advanced, treated gastric or gastro- 16–18 & 2005 Cancer Research UK British Journal of Cancer (2005) 93(2), 190 – 194 Clinical Studies Clinical Studies FUFOX in metastatic gastric cancer F Lordick et al Al-Batran SE, Atmaca A, Hegewisch-Becker S, Jaeger D, Hahnfeld S, care with best supportive care in advanced gastric cancer. Ann Oncol 8: Rummel MJ, Seipelt G, Rost A, Orth J, Knuth A, Jaeger E (2004) Phase II 163–168 trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, patients with advanced gastric cancer. J Clin Oncol 22: 658–663 Williamson SK, Findlay BP, Pitot HC, Alberts SR (2004) A randomized Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, controlled trial of fluorouracil plus leucovorin, irinotecan and oxaliplatin Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de combinations in patients with previously untreated metastatic colorectal Gramont A, Multicenter International Study of Oxaliplatin/5-Fluoro- cancer. J Clin Oncol 22: 23–30 uracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Grothey A, Deschler B, Kroening H, Ridwelski K, Reichardt P, Kretzschmar Investigators (2004a) Oxaliplatin, fluorouracil, and leucovorin as A, Clemens M, Hirschmann W, Lorenz M, Asperger W, Buechele T, adjuvant treatment for colon cancer. N Engl J Med 350: 2343– 2351 Schmoll HF (2002) Phase III study of bolus 5-fluorouracil (5-FU)/folinic Andre T, Tournigand C, Rosmorduc O, Provent S, Maindrault-Goebel F, acid (FA) (Mayo) vs weekly high-dose 24 h 5-FU infusion/FA+oxaliplatin Avenin D, Selle F, Paye F, Hannoun L, Houry S, Gayet B, Lotz JP, de (OXA) in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol Gramont A, Louvet C, GERCOR Group (2004b) Gemcitabine combined 21: 129a (abstr 512) with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a Khushalani NI, Leichman CG, Proulx G, Nava H, Bodnar L, Klippenstein D, GERCOR study. Ann Oncol 15: 1339 –1343 Litwin A, Smith J, Nava E, Pendyala L, Smith P, Greco W, Berdzik J, Assersohn L, Brown G, Cunningham D, Ward C, Oates J, Waters JS, Hill Douglass H, Leichman L (2002) Oxaliplatin in combination with ME, Norman AR (2004) Phase II study of irinotecan and 5-fluorouracil/ protracted-infusion fluorouracil and radiation: report of a clinical trial leucovorin in patients with primary refractory or relapsed advanced for patients with esophageal cancer. J Clin Oncol 20: 2844–2850 oesophageal and gastric carcinoma. Ann Oncol 15: 64– 69 Louvet C, Andre T, Lledo G, Hammel P, Bleiberg H, Bouleuc C, Gamelin E, Caussanel JP, Levi F, Brienza S, Misset JL, Itzhaki M, Adam R, Milano G, Flesch M, Cvitkovic E, de Gramont A (2002b) Gemcitabine combined Hecquet B, Mathe G (1990) Phase I trial of 5-day continuous venous with oxaliplatin in advanced pancreatic adenocarcinoma: final results of infusion of oxaliplatin at circadian rhythm modulated rate compared a GERCOR multicenter phase II study. J Clin Oncol 20: 1512–1518 with constant rate. J Natl Cancer Inst 82: 1046–1050 Louvet C, Andre T, Tigaud JM, Gamelin E, Douillard JY, Brunet R, Francois Chao Y, Yeh KH, Chang LT, Chao TY, Wu MF, Chang CS, Chang JY, Chung E, Jacob JH, Levoir D, Taamma A, Rougier P, Cvitkovic E, de Gramont A CY, Kao WY, Hsieh RK, Cheng AL (2004) Phase II study of weekly (2002a) Phase II study of oxaliplatin, fluorouracil, and folinic acid in oxaliplatin and 24-h infusion of high-dose 5-fluorouracil and folinic acid locally advanced or metastatic gastric cancer patients. J Clin Oncol 20: in the treatment of advanced gastric cancer. Br J Cancer 91: 453– 458 4543– 4548 de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni Machin D, Campbell MJ (1997) Statistical Tables for the Design of Clinical C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Trials 2nd edn Oxford: Blackwell Scientific Publications, pp 281–282 Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A (2000) Ro¨del C, Grabenbauer GG, Papadopoulos T, Hohenberger W, Schmoll HJ, Leucovorin and fluorouracil with or without oxaliplatin as first-line Sauer R (2003) Phase I/II trial of capecitabine, oxaliplatin, and radiation treatment in advanced colorectal cancer. J Clin Oncol 18: 2938 –2947 for rectal cancer. J Clin Oncol 21: 3098–3104 Ducreux M, Mitry E, Ould-Kaci M, Boige V, Seitz JF, Bugat R, Breau JL, Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein Bouche O, Etienne PL, Tigaud JM, Morvan F, Cvitkovic E, Rougier P L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther (2004) Randomized phase II study evaluating oxaliplatin alone, SG (2000) New guidelines to evaluate the response to treatment in solid oxaliplatin combined with infusional 5-FU, and infusional 5-FU alone tumors. J Natl Cancer Inst 92: 205–216 in advanced pancreatic carcinoma patients. Ann Oncol 15: 467–473 Vanhoefer U, Rougier P, Wilke H, Ducreux MP, Lacave AJ, Van Cutsem E, Freyer G, Bossard N, Romestaing P, Mornex F, Chapet O, Trillet-Lenoir V, Planker M, Santos JG, Piedbois P, Paillot B, Bodenstein H, Schmoll HJ, Gerard JP (2001) Addition of oxaliplatin to continuous fluorouracil, Bleiberg H, Nordlinger B, Couvreur ML, Baron B, Wils JA (2000) Final l-folinic acid, and concomitant radiotherapy in rectal cancer: The Lyon R results of a randomized phase III trial of sequential high-dose 97-03 phase I trial. J Clin Oncol 19: 2433–2438 methotrexate, fluorouracil, and doxorubucin versus etoposide, leuco- Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet vorin, and fluorouracil versus infusional fluorouracil and cisplatin in P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain- advanced gastric cancer: A trial of the European Organization for Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Levi F (2000) Phase Research and Treatment of Cancer Gastrointestinal Tract Cancer III multicenter randomized trial of oxaliplatin added to chronomodu- Cooperative Group. J Clin Oncol 18: 2648–2657 lated fluorouracil-leucovorin as first-line treatment of metastatic colo- Waters JS, Norman A, Cunningham D, Scarffe JH, Webb A, Harper P, Joffe rectal cancer. J Clin Oncol 18: 136– 147 JK, Mackean M, Mansi J, Leahy M, Hill A, Oates J, Rao S, Nicolson M, Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, Hickish T (1999) Long-term survival after epirubicin, cisplatin and Svensson C, Enander LK, Linne T, Sellstrom H, Heuman R (1997) fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer Randomized comparison between chemotherapy plus best supportive 80: 269–272 British Journal of Cancer (2005) 93(2), 190 – 194 & 2005 Cancer Research UK

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British Journal of CancerSpringer Journals

Published: Jul 12, 2005

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