Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983) : long-term results of a randomised, controlled, phase 3 trial
University of Paris1, Haukeland University Hospital2, Uppsala University3, University of Liverpool4, Charité5, Goethe University Frankfurt6, Southampton General Hospital7, Princess Alexandra Hospital8, University of Birmingham9, European Organisation for Research and Treatment of Cancer10, Katholieke Universiteit Leuven11
TL;DR: Overall survival data after long-term follow-up found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer, however, the previously observed benefit in PFS means it should remain the reference treatment for this population of patients.
Abstract: Summary Background Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. Methods This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18–80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m 2 , folinic acid 200 mg/m 2 (DL form) or 100 mg/m 2 (L form) on days 1–2 plus bolus, and fluorouracil 400 mg/m 2 (bolus) and 600 mg/m 2 (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. This trial is registered with ClinicalTrials.gov, number NCT00006479. Findings Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6–9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68–1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0–83·4) in the perioperative chemotherapy group and 54·3 months (41·9–79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6–58·3) in the perioperative chemotherapy group versus 47·8% (40·3–55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. Interpretation We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients. Funding Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.
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Katholieke Universiteit Leuven1, University of Valencia2, Radboud University Nijmegen3, Sheba Medical Center4, University of Turin5, Hospital Clínico San Carlos6, Université Paris-Saclay7, University of Pisa8, Mayo Clinic9, University of São Paulo10, The Chinese University of Hong Kong11, University of Oxford12, University of Helsinki13, Helsinki University Central Hospital14, Institute of Cancer Research15, Bank of Cyprus16, University of Ioannina17, Odense University Hospital18, University of Amsterdam19, Otto-von-Guericke University Magdeburg20, Geneva College21, Medical University of Vienna22, Martin Luther University of Halle-Wittenberg23, Hebron University24, Imperial College Healthcare25
TL;DR: These ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.
2,382 citations
Cites background or methods from "Perioperative FOLFOX4 chemotherapy ..."
...The preferred treatment in this setting should be FOLFOX [or alternatively capecitabine with oxaliplatin (CAPOX)] as reported for the EPOC trial [163, 164]....
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...In the case of ‘fit’ patients with initially resectable metastatic disease, the recommendation is (Recommendation 12 this document) that they can either be referred immediately for potentially curative surgery or for perioperative chemotherapy (FOLFOX) [163, 164], dependent on the available prognostic information and surgical considerations....
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...The panel expressed no clear preference for one option over the other, since the 5-year OS rate reported for the EPOC study with perioperative chemotherapy, 51% (95% CI 45–58) in the perioperative chemotherapy group versus 48% (95% CI 40– 55) in the surgery-only group, is not convincing, despite the fact that the DFS in eligible patients was significantly improved [163]....
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Teikyo University1, Hiroshima University2, Niigata University3, University of Tsukuba4, Saitama Medical University5, Tokyo Medical and Dental University6, University of Tokyo7, Japanese Foundation for Cancer Research8, Kyorin University9, Kyoto University10, National Defense Medical College11, Dokkyo Medical University12, Tohoku University13, Tokyo Metropolitan Komagome Hospital14, Osaka Medical College15, Kurume University16, International University of Health and Welfare17, Toho University18
TL;DR: The English version of the JSCCR Guidelines 2016 is presented, which can be used as a tool for treating colorectal cancer in actual clinical practice settings and as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient.
Abstract: Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms in women and the third largest number in men. Many new treatment methods have been developed over the last few decades. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer (JSCCR Guidelines 2010) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2010.
1,709 citations
TL;DR: This work presents the results of a randomised, double-blind, placebo-controlled trial conducted at the University Hospitals Leuven and at the urging of the ESMO Guidelines Working Group to evaluate the safety and effectiveness of chemotherapy for Digestive Oncology patients with Hashimoto's disease.
954 citations
Northwestern University1, University of California, San Francisco2, University of Michigan3, City of Hope National Medical Center4, Vanderbilt University5, Seattle Cancer Care Alliance6, Fox Chase Cancer Center7, University of Wisconsin-Madison8, University of Texas Southwestern Medical Center9, University of Utah10, University of Nebraska Medical Center11, University of Alabama at Birmingham12, University of California, Los Angeles13, University of South Florida14, Mayo Clinic15, Washington University in St. Louis16, Yale Cancer Center17, Stanford University18, Case Western Reserve University19, University of Colorado Boulder20, Brigham and Women's Hospital21, Ohio State University22, Roswell Park Cancer Institute23, University of Texas MD Anderson Cancer Center24, Harvard University25, University of California, San Diego26, Memorial Sloan Kettering Cancer Center27, University of Pennsylvania28, University of Tennessee29, Johns Hopkins University30, Duke University31, National Comprehensive Cancer Network32
TL;DR: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section as discussed by the authors.
Abstract: This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.
589 citations
TL;DR: In patients undergoing parenchyma-sparing liver resection for colorectal metastases, laparoscopic surgery was associated with significantly less postoperative complications compared to open surgery.
Abstract: Objective:To perform the first randomized controlled trial to compare laparoscopic and open liver resection.Summary Background Data:Laparoscopic liver resection is increasingly used for the surgical treatment of liver tumors. However, high-level evidence to conclude that laparoscopic liver resection
469 citations
Additional excerpts
...Complications, z mean (SD), $ (n 1⁄414 LLR/ n1⁄419 OLR) 3,174 (3,345) 6,771 (8,716) 3,597 0....
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...954 Complications, z mean (SD), $ 419 (1,603) 735 (3,491) 316 0....
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...Surgical ward, mean (SD), $ 5,371 (2,855) 3,973 (3,725) -1,398 0....
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References
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TL;DR: In this article, the product-limit (PL) estimator was proposed to estimate the proportion of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t).
Abstract: In lifetesting, medical follow-up, and other fields the observation of the time of occurrence of the event of interest (called a death) may be prevented for some of the items of the sample by the previous occurrence of some other event (called a loss). Losses may be either accidental or controlled, the latter resulting from a decision to terminate certain observations. In either case it is usually assumed in this paper that the lifetime (age at death) is independent of the potential loss time; in practice this assumption deserves careful scrutiny. Despite the resulting incompleteness of the data, it is desired to estimate the proportion P(t) of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t). The observation for each item of a suitable initial event, marking the beginning of its lifetime, is presupposed. For random samples of size N the product-limit (PL) estimate can be defined as follows: L...
52,450 citations
TL;DR: In this paper, a class of tests developed for comparing the cumulative incidence of a particular type of failure among different groups is presented. The tests are based on comparing weighted averages of the hazards of the subdistribution for the failure type of interest.
Abstract: In this paper, for right censored competing risks data, a class of tests developed for comparing the cumulative incidence of a particular type of failure among different groups. The tests are based on comparing weighted averages of the hazards of the subdistribution for the failure type of interest. Asymptotic results are derived by expressing the statistics in terms of counting processes and using martingale central limit theory. It is proposed that weight functions very similar to those for the $G^p$ tests from ordinary survival analysis be used. Simulation results indicate that the asymptotic distributions provide adequate approximations in moderate sized samples.
4,469 citations
TL;DR: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.
Abstract: PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m2/d) followed by a 5FU bolus (400 mg/m2/d) and 22-hour infusion (600 mg/m2/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P = .0003) and better response rate (50.7% v 22.3%; P = .0001) when compared with the control arm. The imp...
3,738 citations
TL;DR: Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III disease.
Abstract: Purpose Three-year disease-free survival (DFS) was significantly improved in patients who had undergone resection with curative intent for stage II or III colon cancer who received bolus plus continuousinfusion fluorouracil plus leucovorin (LV5FU2) with the addition of oxaliplatin (FOLFOX4). Final results of the study, including 6-year overall survival (OS) and 5-year updated DFS, are reported. Patients and Methods A total of 2,246 patients were randomly assigned to receive LV5FU2 or FOLFOX4 for 6 months. The primary end point was DFS. Secondary end points were OS and safety. Results Five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5FU2 groups, respectively (hazard ratio [HR] 0.80; 95% CI, 0.68 to 0.93; P .003). Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 and LV5FU2 groups, respectively (HR 0.84; 95% CI, 0.71 to 1.00; P .046); corresponding 6-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively (HR 0.80; 95% CI, 0.65 to 0.97; P .023). No difference in OS was seen in the stage II population. The incidence of second noncolorectal cancers was 5.5% and 6.1% in the FOLFOX4 and LV5FU2 groups, respectively. Among patients receiving oxaliplatin, the frequency of grade 3 peripheral sensory neuropathy was 1.3% 12 months after treatment and 0.7% at 48 months. Conclusion Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III disease. J Clin Oncol 27:3109-3116. © 2009 by American Society of Clinical Oncology
1,910 citations
Haukeland University Hospital1, Uppsala University2, Karolinska Institutet3, University of Liverpool4, Humboldt University of Berlin5, Goethe University Frankfurt6, Southampton General Hospital7, Princess Alexandra Hospital8, Bristol Royal Infirmary9, University of Birmingham10, European Organisation for Research and Treatment of Cancer11, Katholieke Universiteit Leuven12
TL;DR: In this article, the authors compared the combination of perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer.
1,741 citations