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Originally published as JCO Early Release 10.1200/JCO.2008.17.3781 on September 15 2008 © 2008 American Society of Clinical Oncology. Adjuvant Chemotherapy After Potentially Curative Resection of Metastases From Colorectal Cancer: A Pooled Analysis of Two Randomized Trials
From the Hôpital Ambroise Paré, Assistance Publique Hôpitaux de Paris, Boulogne and EA4340, Faculty of Medicine, Paris-Ile de France Ouest, Université Versailles, Saint-Quentin; Centre Hospitalier Universitaire Purpan, Toulouse; Institut Gustave Roussy, Villejuif; Centre Hospitalier Universitaire Robert Debré, Reims; and Centre Hospitalier Universitaire Dijon and Fédération Francophone de Cancérologie Digestive, Dijon, France; University of Toronto, and Princess Margaret Hospital, Toronto; National Cancer Institute of Canada Clinical Trials Group, Queens University, Kingston, Ontario; and Alberta Cancer Board, Edmonton, Alberta, Canada; Institute Jules Bordet, Brussels; Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium; Ospedali Riuniti, Bergamo; University of Padova, Padova; and Ospedale San Carlo Borromeo, Milano, Italy Corresponding author: Emmanuel Mitry, MD, PhD, Hépato-gastroentérologie et oncologie digestive, Hôpital Ambroise Paré, 9 ave Charles de Gaulle, 92100 Boulogne, France; e-mail: emmanuel.mitry{at}apr.aphp.fr
Purpose Adjuvant systemic chemotherapy administered after surgical resection of colorectal cancer metastases may reduce the risk of recurrence and improve survival, but its benefit has never been demonstrated. Two phase III trials (Fédération Francophone de Cancérologie Digestive [FFCD] Trial 9002 and the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Clinical Trials Group/Gruppo Italiano di Valutazione Interventi in Oncologia [ENG] trial) used a similar design and showed a trend favoring adjuvant chemotherapy, but both had to close prematurely because of slow accrual, thus lacking the statistical power to demonstrate the predefined difference in survival. We report here a pooled analysis based on individual data from these two trials. Patients and Methods After complete resection of colorectal liver or lung metastases, patients were randomly assigned to chemotherapy (CT arm; fluorouracil [FU] 400 mg/m2 administered intravenously [IV] once daily plus DL-leucovorin 200 mg/m2 [FFCD] x 5 days or FU 370 mg/m2 plus L-leucovorin 100 mg/m2 IV x 5 days [ENG] for six cycles at 28-day intervals) or to surgery alone (S arm). Results A total of 278 patients (CT, n = 138; S, n = 140) were included in the pooled analysis. Median progression-free survival was 27.9 months in the CT arm as compared with 18.8 months in the S arm (hazard ratio = 1.32; 95% CI, 1.00 to 1.76; P = .058). Median overall survival was 62.2 months in the CT arm compared with 47.3 months in the S arm (hazard ratio = 1.32; 95% CI, 0.95 to 1.82; P = .095). Adjuvant chemotherapy was independently associated with both progression-free survival and overall survival in multivariable analysis. Conclusion This pooled analysis shows a marginal statistical significance in favor of adjuvant chemotherapy with an FU bolus–based regimen after complete resection of colorectal cancer metastases.
No more than 10% to 15% of colorectal cancer (CRC) metastases are considered resectable for cure. When feasible, surgery should be performed, as the 5-year overall survival (OS) rate ranged from 28% to 38% in recent series after complete resection of liver metastases.1-3 Relapse after resection will occur in almost 75% of the patients, with a 5-year relapse-free survival rate ranging from 15% to 35%.1-3 Recurrences will mainly occur within the first 2 years after surgery and be located in the liver in approximately 50% of cases.4 In this setting, adjuvant systemic chemotherapy administered after surgery may reduce the risk of recurrence and improve long-term survival. Given the high proportion of patients with liver-only recurrence, hepatic arterial infusion chemotherapy after surgery has been evaluated. Compared with surgery alone, it was shown to reduce hepatic recurrences and increase survival, but the associated technical difficulties and complications have limited its general use.5-7 Two multicenter randomized phase III trials (Fédération Francophone de Cancérologie Digestive Trial 9002/Association de Chirugie Hépato-Biliare et de Transplantation Hépatique/Association Universitaire de Recherche en Chirugie Vasculaire trial [FFCD trial], European Organisation for Research and Treatment of Cancer [EORTC]Trial 40923/National Cancer Institute of Canada Clinical Trials Group Trial CO.7/Gruppo Italiano di Valutazione Interventi in Oncologia CO.3 trial [ENG trial]) aimed to evaluate the efficacy of adjuvant chemotherapy with bolus fluorouracil (FU) plus leucovorin in patients with CRC who are rendered clinically free of cancer by surgical resection of metastatic disease.8,9 Both trials had a similar design and showed a nonsignificant trend for improvement in disease-free survival (DFS; but a statistically significant positive effect of adjuvant chemotherapy on DFS on the Cox multivariable analysis in the FFCD trial) and OS for patients treated with chemotherapy. However, both trials had to close prematurely because of slow accrual, thus lacking statistical power to demonstrate the predefined difference in survival. We report here a pooled analysis based on individual data from both trials. This combined analysis will improve the statistical power to evaluate the benefit of postoperative chemotherapy with bolus FU plus leucovorin compared with surgery alone after potentially curative resection of metastases from CRC.
Patient Population For the FFCD trial, 173 patients were recruited from 47 centers in France, Belgium, and Switzerland between December 1991 and December 2001. For the ENG trial, 129 patients were recruited from 67 centers in Canada and Europe between February 1994 and January 1998 (EORTC, 20 patients; National Cancer Institute of Canada Clinical Trials Group, 54 patients; Gruppo Italiano di Valutazione Interventi in Oncologia, 55 patients). Patients in both studies were required to have histologically proven CRC. They were required to be free of clinically detectable disease by R0 surgical resection of the primary tumor and to have four or fewer metastases located in a single location (liver [FFCD trial]; liver or lung [ENG trial]). Surgical resection margins were required to be negative by histologic examination. Patients with distant lymph nodes, including metastases to the porta hepatis or mediastinal nodes, and patients with metastases to other organs were not eligible, even if metastases were completely excised. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; be younger than 76 years of age (FFCD trial); have biologic tests compatible with chemotherapy administration and no previous primary cancer of any other site; have no previous chemotherapy except adjuvant treatment of their primary tumor, provided that a minimum of 6 months had elapsed between cessation of chemotherapy and the diagnosis of metastatic disease (ENG trial) or that the adjuvant chemotherapy was finished when the metastatic disease was diagnosed (FFCD trial); and to have no uncontrolled medical condition that would be aggravated by treatment. Patients of childbearing potential were required to use adequate contraception; women could not be pregnant or lactating. Pretreatment evaluation included patient history, physical examination, full blood cell count, biochemistry (total bilirubin, AST, ALT, alkaline phosphatase, and serum creatinine), carcinoembryonic antigen (CEA; FFCD trial only), chest x-ray (with computed tomography of chest as indicated), abdominal imaging (ultrasound, computed tomography scan, or magnetic resonance imaging [ENG trial only]). Ethics committees at the local level approved the trial, and written consent was obtained for all participants according to national and Helsinki international guidelines.
Randomization and Treatment The treatment schedule was similar in both trials: FU 400 mg/m2 administered intravenously once daily for 5 days plus DL-leucovorin 200 mg/m2 administered intravenously for 5 days (FFCD) or FU 370 mg/m2 plus L-leucovorin 100 mg/m2 for 5 days (ENG), both given for six cycles at 28-day intervals. Adjuvant chemotherapy started between 10 and 35 days after surgery in the FFCD trial, whereas randomization had to occur within 49 days from surgery and treatment had to begin within 7 days from randomization in the ENG trial.
Evaluation of Patients Treatment of recurrence was left to physicians’ discretion in the FFCD trial, but chemotherapy with the bolus FU plus leucovorin regimen was advised in the protocol in case of unresectable metastatic disease, whereas chemotherapy with the same regimen used in the adjuvant setting was mandatory for patients in the ENG trial with unresectable metastatic disease.
Statistical Analysis In this pooled analysis, DFS was calculated from the date of metastases resection until the date of proven recurrence or death from any cause. For patients lost to follow-up, data were censored on the date the patient was last seen alive without recurrence. OS was calculated from the date of metastases resection until the date of death from any cause. For patients lost to follow-up, data were censored on the date the patient was last seen alive. Survival estimates were derived by the method of Kaplan and Meier, and the log-rank test was used to assess differences in survival estimates among groups. Outcomes were analyzed with the Cox proportional hazards regression model with stratification by trial. The following variables were considered as potential factors for the Cox model (age, performance status, treatment group, number of metastases, maximum size of metastases, previous chemotherapy, and disease-free interval), but only factors associated with survival with a P value less than .1 in univariate analysis were introduced into the Cox regression model (except for the size of metastases, which was not available for the ENG trial). With a total of 149 deaths and 38 recurrences without death in the pooled database, this pooled analysis should have 80% power at a two-sided .05 level to detect a hazard ratio (HR) of 0.66 in DFS between the two arms (corresponding to a reduction from 40% to 28.6% in 2-year relapse rate with adjuvant chemotherapy) and an HR ratio of 0.63 in OS between the two arms (corresponding to an increase from 30% to 46.8% in 5-year OS with adjuvant chemotherapy). All analyses were performed using STATA version 9 (STATA Corp, College Station, TX) and SAS version 8.0 (SAS Institute, Cary, NC). All P values are two-sided.
Population A total of 302 eligible patients were recruited (FFCD, n =173; ENG, n = 129), of whom 148 patients were randomly assigned to the chemotherapy group (CT group) and 155 patients were randomly assigned to the surgery-alone group (S group). Twenty-four patients were excluded for missing data (ENG, 22 patients were excluded because there were no postbaseline data; FFCD, two patients were excluded because of incomplete data), and therefore, 278 patients were included in the present analysis (CT group, 138 patients; S group, 140 patients). At the time of analysis, 66 patients had died, 22 patients were alive with disease recurrence, and 50 patients were alive and disease-free in the CT group. The corresponding numbers for the S group were 83, 16, and 41 patients, respectively (Fig 1).
Patient and tumor characteristics are listed in Table 1 and were similar between treatment groups. There were 169 men (60.8%) and 109 women (39.2%). The median age was 62.5 years (range, 20 to 82 years), and 57 patients (20.5%) were 70 years or older. Most of the patients (71.9%) had not received previous adjuvant chemotherapy for their disease.
Overall, 261 patients (93.9%) of the pooled analysis had liver metastases and 13 patients (4.7%) had lung metastases. The interval between CRC diagnosis and metastases occurrence was greater than 1 year in 56.8% of patients (Table 1).
Adjuvant Chemotherapy Among 52 patients in the ENG trial who were assigned to receive adjuvant chemotherapy and had at least one postbaseline assessment, 48 patients received treatments. Among 48 patients treated, 21 patients (44%) had at least one dose delay and 20 patients (42%) had dose reduction. Twenty-eight patients completed all six cycles of treatments.
Progression-Free Survival
Four factors were associated with DFS in univariate analysis (with a P value < 0.1): treatment group, number of metastases, previous adjuvant chemotherapy, and maximum size of metastases (only available for FFCD patients; Table 2). The treatment group and the number of metastases were significantly associated with DFS in multivariable analysis. The risk of recurrence was significantly increased among patients in the S group as compared with patients in the CT group (HR = 1.39; P = .026) and for patients with two or more metastases compared with those with a single metastasis (HR = 1.43; P = .022; Table 3).
OS The median OS was 62.2 months (95% CI, 45.2 months to not reached) for the CT group compared with 47.3 months (95% CI, 40.6 to 57.2 months) for the S group. Patients from the S group had a higher risk of death than patients from the CT group (HR = 1.32; 95% CI, 0.95 to 1.82; P = .095; Fig 3). The 3-year survival rates were 69.4% (95% CI, 60.5% to 76.8%) for the CT group and 71.0% (95% CI, 62.2% to 78.1%) for the S group. Corresponding 5-year survival rates were 52.8% (95% CI, 43.7% to 61.3%) and 39.6% (95% CI, 30.7% to 48.3%).
Five factors were associated with OS in univariate analysis (with a P value < .1): treatment group, number of metastases, disease-free interval, maximum size of metastases (only available for FFCD patients), and WHO performance status (only available for ENG patients) (Table 2). The treatment group and the number of metastases were significantly associated with survival in multivariable analysis: the risk of death was significantly increased among patients in the S group as compared with patients in the CT group (HR = 1.39; P = .046) and for patients with two or more metastases as compared with those with a single metastasis (HR = 1.49; P = .023; Table 3).
The results of this pooled analysis of two randomized trials do support the use of systemic adjuvant chemotherapy after potentially curative resection of metastases from CRC. There was a marginal statistical significance in favor of adjuvant chemotherapy in the univariate analysis, which became significant after adjusting other factors in the multivariable analyses.
Final results of the FFCD trial have been recently published.9 In the final report of FFCD, adjuvant chemotherapy was associated with a better progression-free survival in multivariable analysis (HR = 0.66; P = .028) but was not significantly associated with a better OS (HR = 0.73; P = .13).9 The results from the ENG trial have not yet been published but have been reported in abstract form.8 We believed that a combined analysis based on individual data of FFCD and ENG trials was feasible and valid because, despite different primary objectives and statistical considerations, both trials had a similar design. Inclusion criteria and period of inclusion, as well as chemotherapy regimens, were almost identical for both trials. Some biases, however, cannot be excluded because of the differences between the two trials’ designs. The fact that the follow-up schedule varied from four visits during the first 24 months for the ENG study to eight visits for the FFCD trial and was also different after 2 years should be pointed out, because it could have introduced some bias into the estimation of the time to disease progression. Another important prognostic factor to consider is the interval between primary tumor resection and liver metastases progression (metachronous v synchronous metastases). This variable was not available and was therefore not included in the pooled analysis, but, because our multivariable analysis has taken into account disease-free interval (< 12 v The objective of pooling data was to improve the statistical power of the survival analysis and therefore better estimate the potential benefit of postoperative chemotherapy. Indeed, trends in survival observed in the FFCD trial were confirmed by the pooled analysis. The association between adjuvant chemotherapy and improvement in median progression-free survival almost reached statistical significance (P = .059), and adjuvant chemotherapy was significantly associated with a better OS in the multivariable analysis (P = .046), although this was not observed in the FFCD trial alone (P = .13). Therefore, if the present results do not definitely demonstrate the advantage of adjuvant chemotherapy in this setting, they strengthen those from the FFCD trial that "provided a proof of concept of adjuvant chemotherapy"10 after curative resection of liver or lung metastases from CRC. It is quite possible that a greater magnitude of benefit of adjuvant treatment would be achieved with currently available chemotherapy regimens that are more effective in the adjuvant stage II or III setting than bolus FU with leucovorin alone. The Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer trial demonstrated that adding oxaliplatin to a regimen of FU and leucovorin improved the rate of DFS at 3 years.11 However, a definitive demonstration of the benefits of chemotherapy, either systemic or by hepatic artery infusion, over surgery alone for resected metastatic disease remains to be formally demonstrated. A control with surgery alone is needed to demonstrate a benefit of adjuvant chemotherapy, but this may be an obstacle for accrual. Japanese investigators recently faced the same problem of low accrual as in the FFCD and ENG trials in a phase III trial comparing surgery alone with adjuvant chemotherapy with oral leucovorin and tegafur/uracil after potentially curative liver resection.12 With the benefit of adjuvant chemotherapy clearly established in resected stage III colon cancer, some consider that surgery alone is unethical after resection of stage IV disease and that adjuvant chemotherapy should be given, even in the absence of unquestionable proof of its benefit. Final efficacy results of the EORTC 40983 trial were recently reported.13 This phase III trial demonstrated that perioperative chemotherapy with infusional fluorouracil, leucovorin, and oxaliplatin regimen plus surgery improved progression-free survival as compared with surgery alone in patients with resectable liver metastases from CRC. Among eligible patients, the 3-year progression-free survival rate was significantly improved from 28.1% to 36.2% (absolute difference, +8.1%; HR = 0.77; P = .041). The additional benefit of the preoperative chemotherapy over effective postoperative chemotherapy remains less clear and is an important question for future study.
The author(s) indicated no potential conflicts of interest.
Conception and design: Emmanuel Mitry, Anthony L.A. Fields, Roberto Labianca, Dongsheng Tu, Donato Nitti, Valter Torri, Dominique Elias, Bernard Langer, Laurent Bedenne, Philippe Rougier Administrative support: Chris O'Callaghan, Laurent Bedenne Provision of study materials or patients: Anthony L.A. Fields, Harry Bleiberg, Roberto Labianca, Guillaume Portier, Donato Nitti, Valter Torri, Dominique Elias, Bernard Langer, Giancarlo Martignoni, Olivier Bouché, Laurent Bedenne, Malcolm J. Moore Collection and assembly of data: Emmanuel Mitry, Guillaume Portier, Dongsheng Tu, Chris O'Callaghan, Bernard Langer, Olivier Bouché, Franck Lazorthes, Eric Van Cutsem, Laurent Bedenne Data analysis and interpretation: Emmanuel Mitry, Anthony L.A. Fields, Dongsheng Tu, Chris O'Callaghan, Bernard Langer, Eric Van Cutsem Manuscript writing: Emmanuel Mitry, Anthony L.A. Fields, Dongsheng Tu, Chris O'Callaghan, Eric Van Cutsem, Malcolm J. Moore, Philippe Rougier Final approval of manuscript: Emmanuel Mitry, Anthony L.A. Fields, Harry Bleiberg, Roberto Labianca, Guillaume Portier, Dongsheng Tu, Donato Nitti, Valter Torri, Dominique Elias, Chris O'Callaghan, Bernard Langer, Giancarlo Martignoni, Olivier Bouché, Franck Lazorthes, Eric Van Cutsem, Laurent Bedenne, Malcolm J. Moore, Philippe Rougier
published online ahead of print at www.jco.org on September 15, 2008. Supported by Association pour la Recherche en Oncologie Digestive. Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Fong Y, Fortner J, Sun RL, et al: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann Surg 230:309-318, 1999; discussion 318-321[CrossRef][Medline] 2. Nordlinger B, Guiguet M, Vaillant JC, et al: Surgical resection of colorectal carcinoma metastases to the liver: A prognostic scoring system to improve case selection, based on 1568 patients. Cancer 77:1254-1262, 1996[CrossRef][Medline] 3. Scheele J, Altendorf-Hofmann A, Grube T, et al: [Resection of colorectal liver metastases. What prognostic factors determine patient selection?] Chirurg 72:547-560, 2001[CrossRef][Medline] 4. Fong Y, Cohen M, Fortner J, et al: Liver resection for colorectal metastases. J Clin Oncol 15:938-946, 1997 5. Kemeny N, Huang Y, Cohen AM, et al: Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341:2039-2048, 1999 6. Kemeny MM, Adak S, Gray B, et al: Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: Surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy—An intergroup study. J Clin Oncol 20:1499-1505, 2002 7. Kemeny NE, Gonen M: Hepatic arterial infusion after liver resection. N Engl J Med 352:734-735, 2005 8. Langer B, Bleiberg H, Labianca R, et al: Fluorouracil (FU) plus l-leucovorin (l-LV) versus observation after potentially curative resection of liver or lung metastases from colorectal cancer (CRC): Results of the ENG (EORTC/NCIC CTG/GIVIO) randomized trial. Proc Am Soc Clin Oncol 21:149a, 2002 (abstr 592) 9. Portier G, Elias D, Bouche O, et al: Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol 24:4976-4982, 2006 10. Alberts SR: Evolving role of chemotherapy in resected liver metastases. J Clin Oncol 24:4952-4953, 2006 11. André T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004 12. Kokudo N, Hasegawa K, Makuuchi M: Control arm for surgery alone is needed but difficult to obtain in randomized trials for adjuvant chemotherapy after liver resection for colorectal metastases. J Clin Oncol 25:1299-1300, 2007; author reply 1300 13. Nordlinger B, Sorbye H, Glimelius B, et al: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): A randomised controlled trial. Lancet 371:1007-1016, 2008[CrossRef][Medline] Submitted March 27, 2008; accepted June 18, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
two), maximum size of metastases (
5 v > 5 cm), disease-free interval between primary tumor resection and liver progression (
level of 5% and a 90% power by observing 134 events from 214 patients. The ENG trial required randomization of 418 patients over 4 years to have a 90% chance of detecting an increase in 5-year survival from 30% to 45% in the adjuvant chemotherapy arm with a two-sided 
