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European Journal of Cancer (2013) xxx, xxx– xxx Available at www.sciencedirect.com journal homepage: www.ejcancer.info A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study Claus-Henning Köhne a,⇑, Laurent Bedenne b, Alfredo Carrato c, Olivier Bouché d, Ivan Popov e, Losa Gaspà f, Manuel Valladares g, Phillipe Rougier h, Christiane Gog i, Peter Reichardt j, Jacques Wils k, Francesco Pignatti l, Frank Biertz m a Department of Oncology and Hematology, Klinikum Oldenburg, European Medical School Oldenburg/Groningen, Carl von Ossietzky University, Oldenburg, Germany b CHU de Dijon – Complexe du Bocage, Faculté de Medecine, 1, Bd Jeanne d’Arc, F-21079 Dijon Cedex, France c Hospital General Universitario de Elche, Servicio Oncologia Médica, Huertos y molinos s/n, 3203 Elche (Alicante), Spain d University Hospital of Reims, Hôpital Robert Debré, Rue du Général Koënig, 51092 Reims Cedex, France e Institute for Oncology and Radiology, Department for Medical Oncology, Pasterova 14, Belgrade, Serbia f Consorci Creu Roja a Catalunya, Servicio de Oncologı́a Médica, Barcelona, Spain g Complejo Hospitalario Juan Canalejo Marı́timo de Oza, Department of Medical Oncology, Paseo de las Jubias de Arriba, 84, 15006 La Coruña, Spain h Hopital Ambroise Paré, Serv. De Hepato-Gastroent. Concologie digestive, 9, Avenue Charles de Gaulle, 92104 Boulogne Cedex, France i Klinikum der J.W. Goethe Universität, Klinik für Allgemein- und Gefäßchirurgie, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany j Helios-Klinikum Bad Saarow, Pieskower Str. 33, 15526 Bad Saarow, Germany k Laurentius Hospital, Mgr. Driessenstraat 6; 6043 CV Roermond, The Netherlands l The European Medicines Agency (EMA) 7 Westferry Circus, Canary Wharf, London E14 4HB, United Kingdom m Medical School of Hannover, Department of Biomedical Statistics, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany KEYWORDS Colon cancer Adjuvant treatment 5-Flurouracil Abstract Purpose: To investigate whether infusional high-dose 5-flurouracil (HD-FU) provides a significant improvement in recurrence-free survival (RFS) and overall survival (OS) compared with a standard bolus 5-FU regimen (Mayo Clinic) in patients with curatively resectable stage III colon cancer. ⇑ Corresponding author: Address: European Medical School Oldenburg/Groningen, Carl von Ossietzky University of Oldenburg, Klinikum Oldenburg gGmbH, Department of Oncology and Hematology, Rahel-Straus-Str. 10, 26133 Oldenburg, Germany. Tel.: +49 441 403 2611; fax: +49 441 403 2654. E-mail address: [email protected] (C.-H. Köhne). 0959-8049/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2013.01.030 Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http:// dx.doi.org/10.1016/j.ejca.2013.01.030 2 C.-H. Köhne et al. / European Journal of Cancer xxx (2013) xxx–xxx Bolus Infusional High-dose Methods: Patients (n = 1601) were randomised to receive either the Mayo Clinic regimen or one of the three HD-FU regimens; LV5FU2, the Arbeitsgemeinschaft Internistische Onkologie (AIO) or the Grupo Espaňol para el Tratamiento Digestivos (TTD), the data from which were combined to provide the HD-FU arm for final analysis. Results: Patients were evenly balanced for age, TMN, tumor grade and vascular and lymphatic invasion. Median follow-up was approximately 42 months, RFS (hazard ratio [HR] = 0.997) and OS (HR = 0.96) (primary end-point) were not statistically different between the two treatment arms. Infusional HD-FU was generally better tolerated than bolus 5-FU regimen. Conclusions: Infusional HD-FU does not improve RFS and OS in curatively resected stage III colon cancer patients compared to the Mayo Clinic regimen, but is less toxic. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Colorectal cancer (CRC) is the third most frequent cancer in women and the fourth in men and accounted for 500,000 deaths worldwide in 2002.1 Approximately 50% of patients with stage III colon cancer experience a tumor recurrence following curative surgery, with 5year survival rates of 59.5% having been reported.2 A study in the late 1980s reported a reduction in the mortality rate of 33% following the administration of an intravenous (i.v.) bolus of 5-fluorouracil (5-FU) and levamisole in the adjuvant treatment of stage III colon cancer.3 Subsequent investigations confirmed bolus 5-FU plus either high-dose folinic acid (FA) (weekly Roswell Park schedule) or low-dose FA (Mayo-Clinic regimen) administered for 6 months to be the accepted standard treatment for adjuvant colon cancer.4–8 5-FU is active against cells in S-phase, inhibiting thymidylate synthase a key enzyme involved in DNA synthesis.9 The plasma half-life of the drug is relatively short (approximately 11-min) thus with bolus injections only a small proportion of tumor cells can be assumed to be susceptible.10 This has provided a rationale for the use of continuous infusion (CI) of 5-FU (usually delivered over 24 h or 48 h periods) instead of bolus injections in the treatment of colon cancer. In the adjuvant setting studies investigating CI 5-FU have reported similar efficacy but reduced toxicity when compared with standard bolus 5-FU.11,12 An added advantage of using infusional 5-FU-based therapy over 5-FU delivered as a bolus is that a higher-dose intensity of the drug can be achieved. It has been suggested that 4–5 times more 5-FU can be administered and that infusional high-dose 5-flurouracil (HD-FU) and bolus 5-FU behave as different drugs with different mechanisms of cytotoxicity in colon cancer.13 Randomised studies have reported higher response rates in metastatic CRC (mCRC) patients receiving HD-FU modulated by FA, compared to patients receiving standard dose bolus 5FU/FA therapy.14–17 The administration of a HD-FUbased regimen (LV5FU2) in comparison with 5-FU (15 min infusion) and FA was reported to show no difference in efficacy, but confirmed the value of LV5FU2 as a control arm in multicentre international studies investigating the efficacy of oxaliplatin and irinotecan in combination with 5-FU/FA in the adjuvant treatment of colon cancer.18–20 Indeed the LV5FU2 regimen is the recommended choice for combination with oxaliplatin (FOLFOX) for the adjuvant treatment of colon cancer following data from the MOSAIC trial in which a significant increase in 3-year disease-free survival (DFS) rate (78.2% versus 72.9%) was first demonstrated with this combination in patients compared to those receiving LV5FU2 alone.20 The 5-year DFS rate was maintained and a significant improvement in overall survival (OS) reported in patients with a median follow up of 6 years in an update of this study.21 We describe a large randomised intergroup trial that compares the efficacy and the toxicity of HD-FU regimens with the standard Mayo bolus 5-FU regimen (Mayo-Clinic), in the adjuvant treatment of patients with stage III adenocarcinoma of the colon following complete resection of their disease. Patients were recruited and randomised from centres within participating European co-operative groups namely the Arbeitsgemeinschaft Internistische Onkologie (AIO), the Foundation Francßaise de Cancérologie Digestive (FFCD), the Grupo Espaňol para el Tratamiento Digestivos (TTD) and the European Organization for Research and Treatment of Cancer (EORTC). The whole study was coordinated within the framework of the Pan-European Trials in Adjuvant Colon Cancer (PETACC-2). 2. Patients and methods 2.1. Patient eligibility Patients eligible for study inclusion were those with UICC (International Union Against Cancer) stage III, histologically confirmed adenocarcinoma or mucinous adenocarcinoma of the colon who had undergone curative radical resection (R0) within the 8 weeks prior to randomisation. Patients were required to be P18 years, with a World Health Organization (WHO) performance status (PS) of 1 or less, with adequate bone marrow Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http:// dx.doi.org/10.1016/j.ejca.2013.01.030 C.-H. Köhne et al. / European Journal of Cancer xxx (2013) xxx–xxx (leukocytes P3.5 109/l, platelets P100 109/l, Hb > 10 g/l), liver and renal function (total bilirubin 62 mg % = 34 lmol/1; serum creatinine 61.5 mg % = 150 lmol/l). Patients with a history of familial adenomatous polyposis or other hereditary syndromes (Gardner’s, Turcot’s Hereditary Non-Polyposis Coli), Crohn’s disease or ulcerative colitis were excluded. Patients were also excluded if they had any prior history of malignant disease (excluding adequately treated basal cell carcinoma of the skin and cervical cancer) within the previous 10-years, prior chemotherapy or radiotherapy for colon cancer, or any other severe concomitant disease (e.g. coronary heart disease, uncontrolled infection), as were those with known allergy to FA. Pregnant or lactating patients and fertile patients who could not ensure adequate contraception up to 6 months following completion were also excluded from the study. The study was conducted in compliance with the ethical principles of the Declaration of Helsinki (1964) as amended in South Africa (1996). Written informed consent was obtained prior to the initiation of protocol procedures from participating institutions, which granted ethical approval according to their national legislation. 2.2. Study design This was a randomised, intergroup phase III trial to investigate whether infusional HD-FU regimens were superior to bolus 5-FU and FA in patients with resectable stage III colon cancer. The main study endpoints were recurrence-free survival (RFS) and OS and the secondary end-point was to assess safety. Eligible patients were randomised at the National Data Centers (NDC) of the participating co-operative groups namely AIO, FFCD, TTD and EORTC. Patients were randomised to receive either the Mayo-Clinic regimen; days 1–5 of a 4-week cycle, DL-FA, 20 mg/m2, 5-FU, 370–425 mg/m2 i.v. bolus for 6-cycles or one of three HD-FU regimens specific to the geographical region of the NDC. All patients within a participating institution that were randomised to the HD-FU arm received the same HD-FU regimen. HD-FU regimens included, HD-FU alone (the Spanish TTD regimen); day 1, 5-FU, 3500 mg/m2 continuous infusion for 48 h, given weekly during an 8week cycle for 3-cycles or HD-FU plus FA (the German AIO regimen); day 1, FA, 500 mg/m2 i.v. 2-h infusion, followed by 5-FU, 2600 mg/m2 i.v. 24-h infusion, given weekly during a 6-week cycle for 3-cycles or the LV5FU2 schedule (the French de Gramont regimen); day 1–2 of a 2-week cycle, DL-FA, 200 mg/m2 2-h infusion, followed by 5-FU, 400 mg/m2 i.v., bolus, followed by 5-FU, 600 mg/m2 22-h i.v., for 12-cycles. Patients randomised through the EORTC received one of the three HD-FU regimens as predefined by 3 centres. Treatment was administered within 8 days of randomisation for the number of cycles scheduled for each regimen and stopped early in cases of unacceptable toxicity, disease recurrence, withdrawal of consent or the loss of subjects to follow-up. A single independent data monitoring committee (IDMC) annually examined data from interim analyses and safety evaluations from the study and advised the PETACC-2 coordinating unit of any necessary actions. 2.3. Baseline and response evaluation Prior (within 2-weeks) to randomisation a complete patient medical history and blood count were undertaken and an ECG, chest X-ray, abdominal scan and colonoscopy performed. During treatment, prior to each cycle, a physical examination, blood count and blood biochemistry were undertaken and an evaluation of toxicity performed. Patients were evaluated for tumor recurrence during follow-up, at least every 6 months until final analysis (3 years after randomisation of the last patient) and yearly thereafter until death. Tumor recurrence was assessed primarily on radiological evidence (X-ray, ultrasound). Toxicity in the form of adverse events (AE) was evaluated according to the National Cancer Institute of Canada Common Toxicity Criteria (NCIC-CTC). 2.4. Statistical analysis Patients were assigned to treatment arms using the minimisation technique22 and stratified by institution and regional lymph nodal status N1 (1–3 pericolic lymph nodes) versus N2 (>3 pericolic lymph nodes). Patient sample sizes were calculated assuming 5-year survival in the control arm (5-FU/FA) to be 67%, it was estimated that an approximate total of 424 events were required to detect an absolute difference of 7%, which is equivalent to a 5-year survival of 74% for the HD-FU arm, with a power of 90% allowing for onesided type I error of 5%. Assuming 3 years of recruitment and 3 years of follow-up (median follow-up of 4.5 years) it was estimated that approximately 1600 patients were required for randomisation between the treatment arms. The analysis of efficacy (RFS and OS) was conducted in the intent-to-treat population (all randomised) patients. Safety data were presented for all patients treated according to the actual treatment received. Time to event data (RFS and OS) were measured from the date of randomisation; patients not experiencing an event were censored at the most recent date of analysis. RFS was defined as date from randomisation to recurrence or death, which ever occurred first and survival time was defined as date from randomisation to death. In the main statistical analysis, survival curves were estimated using the Kaplan–Meier Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http:// dx.doi.org/10.1016/j.ejca.2013.01.030 4 C.-H. Köhne et al. / European Journal of Cancer xxx (2013) xxx–xxx technique and differences in duration of survival compared using the one-sided log-rank test and the 0.05 level of significance. For both RFS and survival on treatment comparison was made between bolus 5-FU/FA versus all combined HD-FU arms. In exploratory statistical analysis, the main analysis was performed on eligible patients only, retrospective stratification and Cox proportional hazard model were used to adjust for confounding variables in all randomised patients and eligible patients only. Safety data on the different infusional schedules were evaluated and compared using the Kruskal–Wallis test. 3. Results 3.1. Patient characteristics A total of 1601 patients were recruited from 169 European centres between March 1999 and March 2004 and randomised to receive bolus 5-FU/FA (n = 804) or a HD-FU regimen (n = 797). Details of patient disposition are shown in Fig. 1. Five patients recruited to receive HD-FU receive bolus 5-FU and four patients recruited to receive bolus 5-FU/FA received HD-FU. AIO recruited 669 patients, EORTC 188, FFCD 417 and TTD 327. Patient and disease characteristics at baseline are summarised in Table 1. Greater than 50% of patients were male in both treatment arms and both groups were well balanced with respect to patient age, tumor stage and tumor grading (Table 1). Removal and analysis of lymph nodes were balanced between both arms with greater than 50% of patients having between 10 and 19 nodes removed and examined. No difference in lymph node involvement was detected between the treatment arms with greater than 90% of patients in both arms demonstrating less than 10 invaded nodes. Vascular and lymphatic vessel invasion were also balanced between the treatment groups (Table 1). No differences were observed in these characteristics when patients were stratified by co-operative group (data not shown). 3.2. Recurrence-free survival and overall survival The efficacy data for patients receiving bolus 5-FU/ FA or HD-FU regimens are summarised in Table 2. The median follow-up was similar for both treatment arms, 41.6 months for patients receiving bolus 5-FU/ FA and 41.8 months for those receiving a HD-FU regimen. Median RFS and OS times were not achieved for either arm at the time of analysis. No differences were observed in RFS between the two treatment arms (HR = 0.997, p = 0.98) (Fig. 2), 3-year and 5-year RFS rates were also similar (Table 2). No differences in OS were observed between the two treatment arms (HR = 0.96, p = 0.74) (Fig. 3), with 5-year survival rates of 78.9% observed in both arms (Table 2). 3.3. Treatment toxicity Grade 3/4 AEs are summarised in Table 4. Grade 3/4 leucopenia was significantly more common in patients receiving bolus 5-FU than in patients receiving HDFU regimens (6.9% versus 2.1%) as was stomatitis (9.7% versus 3.1%). In contrast grade 3/4 hand–foot syndrome was significantly more common in patients receiving a HD-FU regimen than in those patients receiving bolus 5-FU/FA (4.2% versus 0.4%). The total serious adverse events were similar between the two treatment arms (data not shown), 14.5% in patients receiving bolus 5-FU/FA in which nine patients died Total number of recruited patients (intend to treat population) (N=1601) Treated patients Bolus 5-FU/FA N=804 64 patients did not receive any treatment Randomised by participating cooperative group AIO n=669 FFCD n=417 TTD n=327 EORTC n=188 Treated patients HD FU N=797 AIO regimen n= 341 FFCD regimen n=262 TTD regimen n=182 Unknown n=12 64 patients did not receive any treatment Fig. 1. Disposition of patients. Patient numbers according to randomisation and treatment received are shown. Abbreviations: AIO, Arbeitsgemeinschaft Internistische Onkologie; EORTC, European Organization for Research and Treatment of Cancer; FFCD, Fédération Francophone de Cancérologie Digestive; TTD, The Grupo Espaňol para el Tratamiento de Tumores Digestivos. Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http:// dx.doi.org/10.1016/j.ejca.2013.01.030 C.-H. Köhne et al. / European Journal of Cancer xxx (2013) xxx–xxx Table 1 Characteristics of randomised patients. 5 Table 2 Efficacy data. Bolus 5-FU/FA N = 804 High-dose 5-FU N = 797 Co-operative group, n AIO EORTC FFCD TTD 338 96 206 164 331 92 211 163 Age (years) Median Range 64 22–90 64 24–83 Gender, n (%) Male Female 429 (53.4) 375 (46.6) 434 (54.7) 363 (45.5) WHO performance statusa 0 307 (65.9) 1 159 (34.1) 312 (67.0) 154 (33.0) Grading G1 G2 G3 G4 Low (G1–G2) High (G3–G4) Unknown 161 (20.0) 496 (61.7) 125 (15.5) 9 (1.1) 5 (0.6) 0 (0) 8 (1.0) 153 (19.2) 471 (59.1) 147 (18.4) 8 (1.0) 3 (0.4) 2 (0.3) 13 (1.6) pTMN T1 T2 T3 T4 Tis/Tx 17 (2.1) 65 (8.1) 583 (72.5) 138 (17.2) 1 (0.1) 10 (1.3) 63 (7.9) 594 (74.5) 129 (16.2) 1 90.1) Bolus 5-FU/FA HD-FU RFSa 3-year RFS, % 5-year RFS, % Hazard ratio [95% CI] Log-rank p-value N = 804 63.0 67.1 N = 797 67.0 62.7 OSa 3-year OS, % 5-year OS, % Hazard ratio [95% CI] Log-rank p-value N = 804 84.5 78.9 0.997 [0.84–1.18] 0.98 N = 797 85.0 78.9 0.96 [0.78–1.20] 0.74 Abbreviations: RFS, recurrence-free survival, OS, overall survival; FU, 5-fluorouracil; FA, folinic acid. a Median values not reached. Recurrencefree survival (recurrence of death) 1,00 therapy arm infusional bolus 0,75 0,50 HR 0.997 [0.84 - 1.18] Lymph nodes removed <10 >10 155 (19.3) 647 (80.7) 160 (20.1) 635 (79.9) Lymph nodes invaded <10 >10 753 (93.7) 51 (6.3) 745 (93.6) 51 (6.4) 0,00 Lymphatic vessels invaded No 341 (47.4) Yes 223 (31.0) Unknown 156 (21.7) 322 (44.8) 256 (35.6) 141 (19.6) Vascular invasion No Yes Unknown 444 (55.7) 145 (18.2) 208 (26.1) 446 (55.5) 136 (16.9) 222 (27.6) 0,25 Abbreviations: AIO, Arbeitsgemeinschaft Internistische Onkologie, EORTC, European Organization for Research and Treatment of Cancer, FFCD, Fédération Francophone de Cancérologie Digestive, TTD, The Grupo Espaňol para el Tratamiento de Tumores Digestivos; FU, 5fluorouracil, FA, folinic acid; WHO, World Health Organization. a Available for EORTC, FFCD and TTD recruited patients only. (1.1%) and 15.8% in patients receiving a HD-FU regimen in which 11 patients died (1.4%). 3.4. Sub group analysis An exploratory subgroup analysis was performed of RFS and OS in patients receiving different HD-FU regimens in comparison to bolus 5-FU/FA (Table 3). No 0 2 4 6 8 10 years Fig. 2. Kaplan–Meier plots for recurrence-free survival in patients treated with standard bolus 5-FU/FA and high-dose Infusional 5-FUbased regimen. Abbreviations: FU, fluorouracil; FA, folinic acid. differences in RFS or OS were observed between patients recruited in Germany receiving AIO (RFS HR = 0.84, OS HR = 0.85) or LV5FU2 regimen in patients recruited from France (RFS HR = 0.88, OS HR = 0.99) compared with the bolus 5-FU/FA arms in the corresponding geographical regions. However RFS and OS for patients receiving high-dose 5-FU alone (TTD) recruited in Spain was shorter (RFS HR = 1.38, OS HR = 1.59) than observed in patients receiving bolus 5-FU in that region, although the difference was not statistically significant (Table 3). A subgroup analysis was also performed for toxicity in patients stratified by the treatment regimen they received compared to bolus 5-FU. Similar patterns of Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http:// dx.doi.org/10.1016/j.ejca.2013.01.030 6 C.-H. Köhne et al. / European Journal of Cancer xxx (2013) xxx–xxx recruited in Germany receiving the AIO regimen and Spain receiving the TTD regimen experienced higher grade 3/4 diarrhoea (20.1% and 23.3%) than patients recruited in France who received the LV5FU2 regimen (3.5%). Overall Survival 1,00 therapy arm infusional bolus 0,75 4. Discussion 0,50 HR 0.96 [0.78 - 1.2] 0,25 0,00 0 2 4 6 8 10 Years Fig. 3. Kaplan–Meier plots for recurrence-free survival in patients treated with standard bolus 5-FU/FA and high-dose Infusional 5-FUbased regimen. Abbreviations: FU, fluorouracil; FA, folinic acid. grade 3/4 AE were observed when comparing specific HD-FU regimens with bolus regimen to those observed in the main analysis (Table 4). In comparing treatment regimens between different geographical regions of recruitment and randomisation, grade 3/4 leucopenia was more frequent in patients receiving bolus 5-FU/ FA, treated in Spain (TTD, 13.7%) than in patients treated in Germany (AIO, 3.8%) or France (FFCD, 4.9%). Stomatitis was found to be higher in patients receiving bolus 5-FU/FA treated in Germany and diarrhoea was more frequent in Spanish patients receiving the same treatment. In patients receiving HD-FU regimens those In PETACC-2 we found no statistical difference in RFS and OS in patients with stage III colon cancer following complete resection, treated with adjuvant standard bolus 5-FU or one of the three infusional HD-FU regimens. However significant differences were demonstrated in toxicity profiles, with CI HD-FU exhibiting significantly less haematological toxicity than bolus treatment but significantly more hand–foot syndrome. Our findings confirm previous randomised studies which also demonstrated no statistical difference in DFS and OS but more favourable toxicity with CI 5-FU compared with a standard bolus 5-FU regimen.11,12,19,23 Furthermore our data substantiate the findings from investigations that promote LV5FU2 as the regimen of choice for the control arm in randomised studies to assess the efficacy of combinations of irinotecan and oxaliplatin in adjuvant colon cancer.11,20 We had the opportunity to compare the efficacy and the safety of three different HD-FU regimens to bolus 5-FU therapy in a subgroup analysis of patients stratified by randomising institution. The HD-FU regimens included the weekly 24-h infusion German AIO regimen that has demonstrated improvement efficacy over bolus 5-FU in mCRC patients16 and has been used in adjuvant colon cancer although not in direct comparison with bolus 5-FU.18 The semi-monthly French LV5FU2 regimen and the Spanish high-dose 5-FU were administered as a 48-h weekly infusion alone, both of which had been shown to demonstrate efficacy and to be tolerable in the adjuvant setting.15,23 This analysis should be regarded as Table 3 Efficacy data in patients stratified by treatment-regimen. Treatment RFS OS Patient number HR [95%CI] p-Value Patient number HR [95% CI] p-Value AIOa Bolus FU/FA HD-FU/FA 338 331 0.84 [0.64–1.11] 0.41 338 331 0.85 [0.59–1.2] 0.36 FFCD Bolus FU/FAb LV5FU2a 206 211 0.88 [0.65–1.19] 0.22 206 211 0.9 [0.63–1.30] 0.55 TTDa Bolus FU/FA HD-FU 164 163 1.38 [0.94–2.02] 0.09 164 163 1.59 [0.93–2.7] 0.085 Abbreviations: AIO, Arbeitsgemeinschaft Internistische Onkologie; FFCD, Fédération Francophone de Cancérologie Digestive; TTD, The Grupo Espaňol para el Tratamiento de Tumores Digestivos; FU, 5-fluorouracil; FA, folinic acid; HR, hazard ratio; CI, confidence interval. a Median values not reached. b Median recurrence-free survival = 5.16 months. Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http:// dx.doi.org/10.1016/j.ejca.2013.01.030 C.-H. Köhne et al. / European Journal of Cancer xxx (2013) xxx–xxx Table 4 Grade 3/4 adverse events in treated patients. Bolus 5-FU/FA N = 740 High-dose-FU N = 733 8 (1.1%) 51 (6.9%) 6 (0.8%) 119 (16.1%) 72 (9.7%) 3 (0.4%) 5 (0.7%) 15 (2.1%) 4 (0.6%) 106 (14.5%) 23 (3.1%) 31 (4.2%) Randomising Centre n (%) AIO, n (%) Anaemia Leucopenia* Thrombocytopenia Diarrhoea Stomatitis* Hand–foot syndrome* N = 292 (39.5%) 1 (0.3%) 11 (3.8%) 3 (1.0%) 50 (17.1%) 41 (14.0%) 1 (0.3%) N = 289 (39.4%) 2 (0.7%) 4 (1.4%) 1 (0.3%) 58 (20.1%) 9 (3.1%) 16 (5.5%) EORTC, n (%) Anaemia Leucopenia* Thrombocytopenia Diarrhoea Stomatitis Hand–foot syndrome N = 84 (11.4%) 1 (1.2%) 8 (9.5%) 0 (0.0%) 6 (7.1%) 5 (6.0%) 0 (0.0%) N = 84 (11.5%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 4 (4.8%) 1 (1.2%) 2 (2.4%) FFCD, n (%) Anaemia Leucopenia* Thrombocytopenia Diarrhoea* Stomatitis* Hand–foot syndrome* N = 203 (27.4%) 1 (0.5%) 10 (4.9%) 1 (0.5%) 22 (10.8%) 18 (8.9%) 2 (1.0%) N = 201 (27.4%) 3 (1.5%) 4 (2.0%) 1 (0.5%) 7 (3.5%) 1 (0.5%) 3 (1.5%) TTD, n (%) Anaemia* Leucopenia* Thrombocytopenia Diarrhoea Stomatitis Hand–foot syndrome* N = 161 (21.8%) 5 (3.1%) 22 (13.7%) 2 (1.2%) 41 (25.5%) 8 (5.0%) 0 (0.0%) N = 159 (21.7%) 0 (0.0%) 7 (4.4%) 2 (1.3%) 37 (23.3%) 12 (7.5%) 10 (6.3%) Anaemia Leucopenia* Thrombocytopenia Diarrhoea Stomatitis* Hand–foot-syndrome* Abbreviations: HD-FU, high-dose 5-FU regimen; AIO, Arbeitsgemeinschaft Internistische Onkologie; EORTC, European Organization for Research and Treatment of Cancer; FFCD, Fédération Francophone de Cancérologie Digestive; TTD, the Grupo Espaňol para el Tratamiento de Tumores Digestivos. * p < 0.05. exploratory as the patients were not randomised to receive different HD-FU regimens within the same institutions. No significant differences were found for DFS and OS when comparing each HD-FU regimen to bolus 5-FU/FA, however, although not statistically significant the TTD regimen compared less favourably for RFS (HR = 1.38) and OS (1.59) to bolus 5-FU/FA. The patterns of toxicity of each individual HD-FU regimen compared to standard bolus 5-FU were similar to those found in the main analysis, and support the general view that in addition to LV5FU that AIO and TTD are more tolerable than standard bolus 5-FU. However some different patterns of toxicity between the three HD-FU regimens were observed with grade 3/4 diarrhoea being 7 more common in the Spanish and the German regimens than the French treatment which was generally more tolerable. Thus our exploratory findings support those of the previous studies suggesting the LV5FU regimen may be the most suitable HD-FU backbone of choice for combination with other cytotoxic agents.11,12,19,23 Within the subgroup analysis marked differences in the toxicity of standard bolus 5-FU/FA were noted in the different treatment regions. Thus grade 3/4 leucopenia was more frequent in patients receiving bolus 5FU/FA, treated in Spain than in patients treated in Germany or France. Stomatitis was found to be higher in patients receiving bolus 5-FU/FA treated in Germany whilst diarrhoea was more frequent in Spanish patients receiving the same treatment. Regional differences were also observed for the oral fluoropyrimidine capecitabine.24 This may reflect differences in the delivery of 5-FU/FA between institutions in different countries and/or may reflect the pharmocogenetics of 5-FU activation and metabolism in different populations.25 In summary the large pan European PETACC-2 study has demonstrated that infusional HD-FU regimens were more tolerable than traditional bolus (Mayo Clinic) regimen but did not provide a statistically significant improvement in RFS or OS in the adjuvant treatment of patients with curatively resected stage III colon cancer. These findings are in accordance with previous randomised studies and confirm that infusional HDFU (particularly LVFU2 regimen) remains a treatment option. Conflict of interest statement All authors have no proprietary, financial, professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in the manuscript entitled ‘A randomized phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the PETACC-2 study’. Acknowledgements We would like to thank the patients who took part in this study and all investigators who are not co-authors from the collaborating centres who contributed patients to this study. The manuscript has been drafted by a medical writer (Cancer Communications and Consultancy Ltd.). References 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55(2):74–108. 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Please cite this article in press as: Köhne C.-H. et al., A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: The Pan-European Trial in Adjuvant Colon Cancer 2 study, Eur J Cancer (2013), http:// dx.doi.org/10.1016/j.ejca.2013.01.030