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Visual Abstract. Secondary Analysis of Association of Bevacizumab With Oxaliplatin-Based Chemotherapy With DFS Among Patients with Stage II Colon Cancer
Secondary Analysis of Association of Bevacizumab With Oxaliplatin-Based Chemotherapy With DFS Among Patients with Stage II Colon Cancer
Figure 1.  Flowchart of Participants in Bevacizumab-Avastin Adjuvant (AVANT) and Long-term Survival Bevacizumab-Avastin Adjuvant (S-AVANT) Studies
Flowchart of Participants in Bevacizumab-Avastin Adjuvant (AVANT) and Long-term Survival Bevacizumab-Avastin Adjuvant (S-AVANT) Studies

FOLFOX4 indicates 5-fluorouracil, leucovorin, and oxaliplatin; and XELOX, capecitabine and oxaliplatin.

Figure 2.  Disease-Free Survival and Overall Survival, According to Treatment Group, in 318 Patients With High-Risk Stage II Colon Cancer
Disease-Free Survival and Overall Survival, According to Treatment Group, in 318 Patients With High-Risk Stage II Colon Cancer

FOLFOX4 indicates 5-fluorouracil, leucovorin, and oxaliplatin; XELOX, capecitabine and oxaliplatin.

Figure 3.  Overall Survival According to High-Risk Stage II Criteria and to Favorable, Single Unfavorable, or Multiple Unfavorable Criteria in Patients With High-Risk Stage II Colon Cancer
Overall Survival According to High-Risk Stage II Criteria and to Favorable, Single Unfavorable, or Multiple Unfavorable Criteria in Patients With High-Risk Stage II Colon Cancer

Favorable high-risk factors included being younger than 50 years and/or having vascular or perineural invasion. Single unfavorable high-risk factors were having fewer than 12 examined nodes, having stage T4 disease, or having perforation or obstruction. Multiple high-risk factors included all other high-risk factor combinations.

Table 1.  Clinical Characteristics of Patients With Stage II Colon Cancer
Clinical Characteristics of Patients With Stage II Colon Cancer
Table 2.  Overall Survival and High-Risk Factors for Patients with Stage II Colon Cancer
Overall Survival and High-Risk Factors for Patients with Stage II Colon Cancer
1.
Bray  F, Ferlay  J, Soerjomataram  I, Siegel  RL, Torre  LA, Jemal  A.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.   CA Cancer J Clin. 2018;68(6):394-424. doi:10.3322/caac.21492 PubMedGoogle ScholarCrossref
2.
Chen  VW, Hsieh  M-C, Charlton  ME,  et al.  Analysis of stage and clinical/prognostic factors for colon and rectal cancer from SEER registries: AJCC and collaborative stage data collection system.   Cancer. 2014;120(23)(suppl):3793-3806. doi:10.1002/cncr.29056 PubMedGoogle ScholarCrossref
3.
André  T, Boni  C, Mounedji-Boudiaf  L,  et al; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators.  Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.   N Engl J Med. 2004;350(23):2343-2351. doi:10.1056/NEJMoa032709 PubMedGoogle ScholarCrossref
4.
André  T, de Gramont  A, Vernerey  D,  et al.  Adjuvant fluorouracil, leucovorin, and oxaliplatin in atage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC Study.   J Clin Oncol. 2015;33(35):4176-4187. doi:10.1200/JCO.2015.63.4238 PubMedGoogle ScholarCrossref
5.
Moertel  CG, Fleming  TR, Macdonald  JS,  et al.  Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma.   N Engl J Med. 1990;322(6):352-358. doi:10.1056/NEJM199002083220602 PubMedGoogle ScholarCrossref
6.
 Efficacy of adjuvant fluorouracil and folinic acid in colon cancer: International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators.   Lancet. 1995;345(8955):939-944. doi:10.1016/S0140-6736(95)90696-7 PubMedGoogle ScholarCrossref
7.
Wolmark  N, Rockette  H, Mamounas  E,  et al.  Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes’ B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04.   J Clin Oncol. 1999;17(11):3553-3559. doi:10.1200/JCO.1999.17.11.3553 PubMedGoogle ScholarCrossref
8.
André  T, Colin  P, Louvet  C,  et al.  Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial.   J Clin Oncol. 2003;21(15):2896-2903. doi:10.1200/JCO.2003.10.065 PubMedGoogle ScholarCrossref
9.
Gray  R, Barnwell  J, McConkey  C, Hills  RK, Williams  NS, Kerr  DJ; Quasar Collaborative Group.  Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study.   Lancet. 2007;370(9604):2020-2029. doi:10.1016/S0140-6736(07)61866-2 PubMedGoogle ScholarCrossref
10.
Haller  DG, Tabernero  J, Maroun  J,  et al.  Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer.   J Clin Oncol. 2011;29(11):1465-1471. doi:10.1200/JCO.2010.33.6297 PubMedGoogle ScholarCrossref
11.
Kuebler  JP, Wieand  HS, O’Connell  MJ,  et al.  Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07.   J Clin Oncol. 2007;25(16):2198-2204. doi:10.1200/JCO.2006.08.2974 PubMedGoogle ScholarCrossref
12.
Tournigand  C, André  T, Bonnetain  F,  et al.  Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial.   J Clin Oncol. 2012;30(27):3353-3360. doi:10.1200/JCO.2012.42.5645 PubMedGoogle ScholarCrossref
13.
Ferrara  N, Davis-Smyth  T.  The biology of vascular endothelial growth factor.   Endocr Rev. 1997;18(1):4-25. doi:10.1210/edrv.18.1.0287 PubMedGoogle ScholarCrossref
14.
Hurwitz  H, Fehrenbacher  L, Novotny  W,  et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.   N Engl J Med. 2004;350(23):2335-2342. doi:10.1056/NEJMoa032691 PubMedGoogle ScholarCrossref
15.
de Gramont  A, Van Cutsem  E, Schmoll  H-J,  et al.  Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial.   Lancet Oncol. 2012;13(12):1225-1233. doi:10.1016/S1470-2045(12)70509-0 PubMedGoogle ScholarCrossref
16.
Allegra  CJ, Yothers  G, O’Connell  MJ,  et al.  Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08.   J Clin Oncol. 2011;29(1):11-16. doi:10.1200/JCO.2010.30.0855 PubMedGoogle ScholarCrossref
17.
Kerr  RS, Love  S, Segelov  E,  et al.  Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial.   Lancet Oncol. 2016;17(11):1543-1557. doi:10.1016/S1470-2045(16)30172-3 PubMedGoogle ScholarCrossref
18.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
19.
André  T, Vernerey  D, Im  SA,  et al.  Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group.   Ann Oncol. 2020;31(2):246-256. doi:10.1016/j.annonc.2019.12.006 PubMedGoogle ScholarCrossref
20.
Feinstein  AR, Sosin  DM, Wells  CK.  The Will Rogers phenomenon: stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer.   N Engl J Med. 1985;312(25):1604-1608. doi:10.1056/NEJM198506203122504 PubMedGoogle ScholarCrossref
21.
Shi  Q, Andre  T, Grothey  A,  et al.  Comparison of outcomes after fluorouracil-based adjuvant therapy for stages II and III colon cancer between 1978 to 1995 and 1996 to 2007: evidence of stage migration from the ACCENT database.   J Clin Oncol. 2013;31(29):3656-3663. doi:10.1200/JCO.2013.49.4344 PubMedGoogle ScholarCrossref
22.
Almog  N.  Molecular mechanisms underlying tumor dormancy.   Cancer Lett. 2010;294(2):139-146. doi:10.1016/j.canlet.2010.03.004 PubMedGoogle ScholarCrossref
23.
Naumov  GN, Townson  JL, MacDonald  IC,  et al.  Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases.   Breast Cancer Res Treat. 2003;82(3):199-206. doi:10.1023/B:BREA.0000004377.12288.3c PubMedGoogle ScholarCrossref
24.
Grothey  A, Sobrero  AF, Shields  AF,  et al.  Duration of adjuvant chemotherapy for stage III colon cancer.   N Engl J Med. 2018;378(13):1177-1188. doi:10.1056/NEJMoa1713709PubMedGoogle ScholarCrossref
25.
Gunderson  LL, Jessup  JM, Sargent  DJ, Greene  FL, Stewart  A.  Revised tumor and node categorization for rectal cancer based on surveillance, epidemiology, and end results and rectal pooled analysis outcomes.   J Clin Oncol. 2010;28(2):256-263. doi:10.1200/JCO.2009.23.9194 PubMedGoogle ScholarCrossref
26.
US National Library of Medicine. Use of ctDNA for monitoring of Stage III colorectal cancer. Accessed September 17, 2020. https://clinicaltrials.gov/ct2/show/NCT02842203?term=NCT02842203&draw=2&rank=1
27.
US National Library of Medicine. ctDNA as a prognostic marker for postoperative relapse in early and intermediate stage colorectal cancer. Accessed September 17, 2020. https://clinicaltrials.gov/ct2/show/NCT03312374?term=NCT03312374&draw=2&rank=1
28.
US National Library of Medicine. Circulating Tumor DNA Analysis to Optimize Treatment for Patients With Colorectal Cancer (IMPROVE). Accessed September 17, 2020. https://clinicaltrials.gov/ct2/show/NCT03637686?term=NCT03637686&draw=2&rank=1
29.
Tie  J, Wang  Y, Tomasetti  C,  et al.  Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer.   Sci Transl Med. 2016;8(346):346ra92. doi:10.1126/scitranslmed.aaf6219 PubMedGoogle Scholar
Original Investigation
Oncology
October 19, 2020

Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer: A Secondary Analysis of the AVANT Trial

Author Affiliations
  • 1Department of Medical Oncology, Franco-British Hospital–Fondation Cognacq-Jay, Levallois-Perret, France
  • 2Statistical Unit, Aide et Recherche en Cancérologie Digestive, Foundation, Levallois-Perret, France
  • 3Methodology and Quality of Life Unit in Oncology, University Hospital of Besançon, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1098, Besançon, France
  • 4Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tiqva, Tel Aviv University, Tel Aviv, Israel
  • 5Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
  • 6Department of Medical Oncology, Institut Català d'Oncologia-Bellvitge Institute for Biomedical Research, L’Hospitalet, Barcelona, Spain
  • 7Department of Medical Oncology, General Universitario de Elche Hospital, Elche, Spain
  • 8Department of Medical Oncology, Hospital Clinico Universitario de Valencia, Valencia, Spain
  • 9Department of Medical Oncology, Lakeridge Health R.S. McLaughlin Durham Regional Cancer Centre, Oshawa, Ontario, Canada
  • 10Division of Medical Oncology, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
  • 11Department of Gastroenterology and Hepatology, Institut de Cancérologie de l’Ouest Paul Papin, Angers, France
  • 12Department of Radiotherapy and Oncology Gastrointestinal and Liver, Institut Sainte Catherine, Avignon, France
  • 13Medical Oncology Unit, Arcispedale Santa Maria Nuova-Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy
  • 14Department of Oncology, Weston Park Hospital Cancer Research Centre, Sheffield, United Kingdom
  • 15Medical Oncology Unit, Ramathibodi Hospital, Bangkok, Thailand
  • 16Department of Internal Medicine and Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
  • 17Digestive Tumor Unit, Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
  • 18First Department of Internal Medicine, University Hospital of Mainz, Mainz, Germany
  • 19Department of Medical Oncology, Reina Sofía University Hospital, Córdoba, Spain
  • 20Department of Gastroenterology and Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KULeuven, Leuven, Belgium
  • 21Department of Medical Oncology, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Universitat de Vic–Universitat Central de Catalunya, International Oncology Bureau–Quiron, Barcelona, Spain
  • 22Department of Oncology and Hematology, Martin Luther University, Halle, Germany
  • 23Department of Radiology and Oncology, Instituto de Câncer do Estado de São Paulo, São Paulo, Brazil
  • 24Department of Medical Oncology, Hôpital Saint-Antoine, Assitance Publique des Hôpitaux de Paris, Paris, France
JAMA Netw Open. 2020;3(10):e2020425. doi:10.1001/jamanetworkopen.2020.20425
Key Points

Question  What was the efficacy of adjuvant bevacizumab on disease-free and overall survival among patients with curatively resected high-risk stage II colon cancer?

Findings  In this secondary analysis of 573 patients with high-risk stage II colon cancer enrolled in the AVANT trial, the addition of bevacizumab to oxaliplatin-based chemotherapy did not prolong disease-free survival or overall survival. The 5-year survival rates in patients with high-risk stage II colon cancer in this study were 89.7% in the FOLFOX4 control group and in the FOLFOX4 with bevacizumab group and 93.2% in the XELOX with bevacizumab group.

Meaning  The findings of this study suggest that adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II colon cancer and that the definition of high-risk stage II colon cancer needs to be revisited.

Abstract

Importance  In the pivotal Multicenter Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin–based chemotherapy; the Bevacizumab-Avastin Adjuvant (AVANT) trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial.

Objective  To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC.

Design, Setting, and Participants  This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019.

Intervention  Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab.

Main Outcomes and Measures  The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC.

Results  The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4.

Conclusions and Relevance  In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited.

Trial Registration  ClinicalTrial.gov Identifiers: AVANT (NCT00112918); S-AVANT (NCT02228668)

Introduction

Colorectal cancer (CRC) is the fourth most common cancer in the world and the fifth leading cause of death.1 Nearly 25% of colon cancers (CCs) are diagnosed with stage II disease in western countries.2 In the pivotal Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial, which assessed the addition of oxaliplatin to fluorouracil, patients with high-risk stage II CC had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant folinic acid, fluorouracil, oxaliplatin (FOLFOX) chemotherapy.3,4 However, the use of adjuvant therapy for patients with stage II CC remains controversial.

The survival benefit of 6-month adjuvant therapy with bolus 5-fluorouracil/leucovorin (5-FU/LV) in patients with resected, node-positive CC (stage III) was established in the 1990s.5-7 It was later superseded in trials by infusional 5-FU/LV regimens, which showed an improved safety profile.8 The efficacy of 5-FU/LV in adjuvant therapy for stage II CC was established by the Quick and Simple and Reliable (QUASAR) study.9 In the population with stage II disease, this study showed that adjuvant chemotherapy decreased the relative risk of recurrence by 29% (hazard ratio [HR], 0.71; 95% CI, 0.54-0.92), but there was no difference in OS (HR, 0.83; 95% CI, 0.65-1.07). However, the absolute benefit of adjuvant fluoropyrimidine was only 2.9%, leading to an absence of therapeutic consensus.9 Further changes to adjuvant treatment have since been made by the addition of oxaliplatin to fluoropyrimidines (5-FU/LV or capecitabine), reducing the relative risk of recurrence by 20% to 23% in patients with stage III CC.3,10,11 In the MOSAIC study, oxaliplatin added to 5-FU/LV had some activity in patients with high-risk stage II CC. The 5-year disease-free survival (DFS) rate for these patients was 82.3% (vs 74.6% for those receiving only 5-FU/LV; HR, 0.72; 95% CI, 0.50-1.02). However, OS was not increased.12 Considering these results, adjuvant treatment for stage II CC is discussed according to tumor-related prognostic factors and should be balanced with patient’s comorbidity and life expectancy.

Vascular endothelial growth factor inhibition with bevacizumab, a humanized anti–vascular endothelial growth factor monoclonal antibody, has a direct antivascular effect in human tumors, improving OS when given with chemotherapy in patients with metastatic CRC.13,14 The Bevacizumab-Avastin Adjuvant (AVANT) trial, a 3-group multinational phase 3 study, failed to demonstrate the superiority of bevacizumab with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) or capecitabine and oxaliplatin (XELOX) compared with FOLFOX4 alone in terms of DFS in patients who had undergone surgery with curative intent for stage III CC.15

The National Surgical Adjuvant Breast and Bowel Project C-08 phase 3 trial also investigated the efficacy of bevacizumab plus adjuvant oxaliplatin-based chemotherapy in US patients with stage II or III CC.16 Similarly, adding bevacizumab did not increase DFS. In that study,16 the effect of bevacizumab treatment did not vary by stage. QUASAR2 evaluated adjuvant capecitabine plus bevacizumab vs capecitabine alone in patients with high-risk stage II or stage III CRC. The addition of bevacizumab to capecitabine yielded no DFS benefit (HR, 1.06; 95% CI, 0.89-1.25).17 In the present study, we report the updated results of bevacizumab as adjuvant therapy combined with oxaliplatin-based chemotherapy in the exploratory cohort of patients with high-risk stage II CC, who were included in the AVANT trial.

Methods
Study Design and Treatment

The AVANT trial was a prospective, multicenter, randomized, parallel, 3-group phase 3 trial conducted from December 2004 to June 2007. The primary objective was to evaluate the addition of bevacizumab to a standard oxaliplatin-based chemotherapy regimen in patients with stage III CC. Patients with high-risk stage II CC were also eligible for secondary objectives. A total of 2867 patients with stage III CC and 573 patients with stage II were randomized. Full details of the trial design were published in 2012.15

Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with histologically confirmed stage III or high-risk stage II CC (defined by the American Joint Cancer Committee/Union for International Cancer Control). Patients with stage II CC were considered high-risk if they fulfilled at least 1 of the following criteria: younger than 50 years, stage T4, perforation or obstruction, fewer than 12 lymph nodes examined, or vascular (ie, blood and lymphatic vessels) or perineural invasion. Curative surgery was performed 4 to 8 weeks before randomization.

Key exclusion criteria included remaining tumor, carcinoembryonic antigen level greater than 1.5 times the upper reference limit after surgery, previous antiangiogenic treatment, major surgical procedure, open biopsy, significant traumatic injury fewer than 28 days before study treatment start, and abnormal hematological, liver, or renal function.

The study was done in accordance with the Declaration of Helsinki,18 and the protocol (Supplement 1) was approved by the ethics review committees or boards of the institutions involved in this multinational study. Patients provided written informed consent. This study follows the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Randomization was performed after surgery using a centralized interactive computerized system and stratified according to geographic region (n = 8) and disease stage. The study had an open-label design.

Patients were randomly assigned in a 1:1:1 ratio to 1 of 3 treatment options: FOLFOX4 for 24 weeks followed by observation for 24 weeks; FOLFOX4 with bevacizumab for 24 weeks followed by bevacizumab monotherapy for 24 weeks, or XELOX with bevacizumab for 24 weeks followed by bevacizumab monotherapy for 24 weeks. FOLFOX4 and XELOX were given as described previously.3,10 Bevacizumab was administered as a 30-minute to 90-minute intravenous infusion on day 1 before oxaliplatin (5 mg/kg every 2 weeks for FOLFOX4; 7.5 mg/kg every 3 weeks for XELOX). Bevacizumab monotherapy was given at 7.5 mg/kg every 3 weeks.

Study End Points

The primary end point of the AVANT study was the superiority of bevacizumab with FOLFOX4 or XELOX vs FOLFOX4 alone in terms of DFS in patients with stage III CC only. DFS was defined as the time between randomization and recurrence, new occurrence of CRC, or death from any cause, whichever occurred first. Patients who were event free at the clinical cutoff date were censored at the last date at which they were known to be disease free. Recurrences and new occurrences were based on an investigator tumor assessment, prescheduled every 6 months for 4 years following randomization and scheduled annually thereafter. OS was defined as the time from randomization to death. Patients who were still alive at the clinical cutoff date were censored at the date at which they were last confirmed to be alive. Survival status was assessed every 6 months for the first 4 years after randomization and annually thereafter. AVANT was an event and/or time-driven trial. The study continued until 36 months after the last patient was randomized, and results were mature for analysis in 2010 for the study primary objective.

Adverse events were monitored starting 28 days after the last dose of study treatment and/or the end of the observation phase and were graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0. Safety was previously reported in the pooled population of patients with stage II and stage III CC in the AVANT trial.15

Follow-up and Update

Follow-up was initially done by the sponsor Roche with a data lock on June 30, 2010, and a median (range) follow-up of 48 (0-66) months. At that time, DFS but not OS was mature. Given the negative results, Roche decided to close the trial. Consequently, following the investigators’ wish to obtain mature survival data, the database was transferred to Gercor in 2012. The S-AVANT study was designed to obtain the ultimate DFS and OS results with extended follow-up of patients previously randomized in the AVANT trial and to provide estimates of long-term effects of bevacizumab added to adjuvant chemotherapy in patients with stage II and stage III CC. Further analyses were performed using updated individual patient data and focusing on DFS, OS, comorbidities observed during the follow-up period, and reasons of deaths. Adverse events of special interest to bevacizumab and their related serious adverse events were also collected. Long-term survival results in patients with stage III CC were published previously.19 We report here the survival results of patients with high-risk stage II CC.

Statistical Analysis

All patients with high-risk stage II CC who were randomized in the AVANT study were eligible for exploratory analyses. DFS and OS were the primary end points of this prespecified secondary analysis. Continuous and categorical variables were described using the median value with interquartile range (IQR) and frequency with percentage, respectively. DFS and OS were estimated using the Kaplan-Meier method, and the log-rank test was used to assess for treatment differences overall. Follow-up was calculated using the reverse Kaplan-Meier estimation. Cox proportional hazard models were performed to estimate the association of factors with DFS and OS by means of HRs and 95% CIs. To assess the association between DFS and OS and the baseline parameters, univariate Cox analyses were first carried out. Factors with P < .10 were then added to the final multivariate Cox model, after consideration of collinearity among variables. The proportional hazard assumption was checked using statistical tests and graphical diagnostics based on the scaled Schoenfeld residuals. Treatment group associations (FOLFOX4 with bevacizumab vs FOLFOX4 alone, and XELOX with bevacizumab vs FOLFOX4 alone) with DFS and OS were assessed using subgroup analyses, and results were summarized in forest plots. An interaction term in each subgroup was obtained by considering the subgroup, the treatment group, and their interaction in a Cox model. An exploratory analysis of OS according to the number of stage II high-risk factors was performed. Considering that patients with high-risk stage II CC were recruited for exploratory analyses and that their total number was restricted to approximately 16% of all patients, no formal statistical hypotheses were formulated for this prespecified study analysis. P values are shown for exploratory purposes and were not adjusted for multiple testing. All tests were 2-sided. All analyses were performed using R version 3.6.3 software (R Project for Statistical Computing) from March to September 2019.

Results
Patient Characteristics

The AVANT study included 3451 patients, of whom 573 (16.6%) had stage II CC (192 [33.5%] in FOLFOX4 group; 194 [33.9%] in FOLFOX4 with bevacizumab group; 187 [32.6%] in XELOX with bevacizumab group) (Figure 1). With a median (IQR) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). Patient characteristics and high-risk stage II CC criteria are presented in Table 1 and eFigure 1 in Supplement 2. The most frequent high-risk stage II criterion was fewer than 12 examined lymph nodes (243 patients [42.4%]). Of note, 318 patients (55.5%) had a single high-risk stage II criterion, and 255 patients (44.5%) had more than 1. When data were locked for analysis on February 15, 2019, the median (IQR) follow-up for the whole population of high-risk stage II CC was 6.9 (6.1-11.3) years, with 6.9 (6.1-11.3) years in the FOLFOX4 group, 6.8 (6.2-11.3) years in the FOLFOX4 with bevacizumab group, and 6.9 (6.1-11.5) years in the XELOX with bevacizumab group. Of 511 patients (89.2%) with high-risk stage II CC who were still alive after the AVANT study, 217 (42.5%) had an updated median (IQR) follow-up of 11.6 (10.8-12.6) years.

Survival Results

DFS was observed in 38 patients (19.8%) in the FOLFOX4 group, 36 (18.6%) in the FOLFOX4 with bevacizumab group, and 40 (21.4%) in the XELOX with bevacizumab group. The 3-year DFS rate was 88.2% (95% CI, 83.7%-93.0%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) in the XELOX with bevacizumab group (Figure 2A). The DFS HR was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 alone and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4 alone.

The 5-year OS rate was 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group (Figure 2B). The OS HR was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 alone and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4 alone.

Forest plots for main prognostic factors of DFS and OS for the FOLFOX4 with bevacizumab group and the XELOX with bevacizumab group vs the FOLFOX4 group are presented in eFigure 2 in Supplement 2. There was no benefit of bevacizumab when added to FOLFOX4 in patients with right CC in terms of DFS (HR = 0.50; 95% CI, 0.22-1.18) and OS (HR = 0.37; 95% CI, 0.13-1.02).

High-Risk Stage II Classification

Among the 318 patients (55.5%) classified as having high-risk stage II CC based on a single factor, being younger than 50 years was observed in 62 (10.8%); vascular or perineural invasion, 51 (8.9%); stage T4, 67 (11.7%); perforation or obstruction, 38 (6.6%); and fewer than 12 examined lymph nodes in 100 (17.5%). These patients’ OS curves showed that those who were younger than 50 years or who presented with a vascular or perineural invasion had better survival than those with other high-risk factors (Figure 3A). However, the difference was significant only for having fewer than 12 lymph nodes examined (Table 2). Consequently, we defined age and vascular or perineural invasion as favorable high-risk factors and the other high-risk factors (ie, <12 examined lymph nodes, stage T4, and perforation or bowel obstruction) as unfavorable high-risk factors. Comparison of OS for favorable high-risk factors vs a single unfavorable factor and 2 or more high-risk factors was also significant (Figure 3B and Table 2).

Prognostic Factors

For DFS in univariate analysis, stage T4 vs T3, ECOG performance score 1 vs 0, fewer than 12 vs at least 12 examined nodes, and age 50 years or older vs younger than 50 years were prognostic factors (eTable 1 in Supplement 2). In multivariate analysis, stage T4 vs T3 and fewer than 12 vs at least 12 examined nodes remained prognostic (eTable 2 in Supplement 2).

For OS in univariate analysis, stage T4 vs T3, fewer than 12 vs at least 12 examined nodes, and age 50 years or older vs younger than 50 were prognostic factors (eTable 1 in Supplement 2). In multivariate analysis, stage T4 vs T3, fewer than 12 vs at least 12 examined nodes, and age 50 years or older vs younger than 50 years remained prognostic (eTable 2 in Supplement 2).

Late Toxic Effects and Cause of Death

Early safety data of high-risk stage II and stage III CC were previously reported.15 With a total of 84 deaths, CC-related deaths occurred in 55 patients (65.5%) (18 of 30 [60.0%] in FOLFOX4 group; 19 of 28 [67.9%] in FOLFOX4 with bevacizumab group; 18 of 26 [69.2%] in XELOX with bevacizumab group). Deaths related to cardiomyopathy, congestive heart failure, cardiac ischemia, pulmonary embolism, stroke, intracranial hemorrhage, and sudden deaths were reported in 5 patients (16.7%) in the FOLFOX4 group, 6 patients (21.4%) in the FOLFOX4 with bevacizumab group, and in 1 patient (3.8%) in the XELOX with bevacizumab group. Other noncancer deaths or unknown causes of death occurred in 7 patients (23.3%) in the FOLFOX4 group, 3 patients (10.7%) in the FOLFOX4 with bevacizumab group, and 7 patients (26.9%) in the XELOX with bevacizumab group.

Discussion

In this study, the 3-year DFS rates in patients with high-risk stage II CC were 88.2% in the FOLFOX4 group, 86.6% in the FOLFOX4 with bevacizumab group, and 86.7% in the XELOX with bevacizumab group. A Will Rogers20 stage migration phenomenon is likely, given that these results contrast with the 3-year DFS rates of 81.3% achieved in the fluoropyrimidine-alone group and 86.3% in the same FOLFOX4 regimen observed in patients with high-risk stage II CC in the MOSAIC trial.4 In the complete stage II CC population, including high-risk and low-risk patients, the ACCENT analysis of 21 clinical trials with identical treatment (5-FU/LV–based therapy without oxaliplatin), survival rate was better among patients treated from 1996 to 2007 compared with patients treated from 1978 to 1995 (89.0% vs 82.5%; HR, 0.67; 95% CI, 0.58-0.76). This reflects the stage migration over time, challenging historical data related to the benefit of 5-FU/LV–based adjuvant therapy in such patients.21 The 2.9% absolute improvement in OS demonstrated for stage II patients with adjuvant chemotherapy in the QUASAR study might be substantially smaller if repeated in the current clinical setting.

Our study does not suggest that bevacizumab may prolong DFS or OS of patients with high-risk stage II CC even if the small number of patients and the lack of formal hypothesis in this exploratory study must make us cautious. However, the effect of bevacizumab is not deleterious, as shown in patients with stage III CC in the recent AVANT study update.19 The differential effect of bevacizumab on survival between stage II and III could be partly explained by bevacizumab-induced tumor cell dormancy phenomenon, which makes these cells inaccessible to chemotherapy.22,23 The lower risk of having residual cells after the intervention in stage II CC than in stage III CC reduces the potential of this negative effect of tumor dormancy. Besides, we cannot exclude a bevacizumab differential effect according to primary tumor sidedness with a potential benefit in high-risk stage II right CC. This is in accordance with the different prognosis between right and left CC in all settings, which is driven by tumor biology.

The adverse effects remained moderate. The most serious adverse effects associated with bevacizumab (ie, intestinal perforation and arterial thromboses) were not increased compared with the control group.15 The younger age of the study population as well as their generally good health could explain this observation.

Of note, statistically nonsignificant but numerically higher OS rates were observed in the XELOX with bevacizumab group than in either FOLFOX4 group. A potential superiority of XELOX over FOLFOX has been suggested among patients with low-risk stage III CC from the IDEA meta-analysis.24 However, in the IDEA study, patients were not randomized between XELOX and FOLFOX but between 3-month and 6-month durations of chemotherapy.

Limitations

This study has limitations, particularly the debatable definition of high-risk stage II CC. In this study, the high-risk criteria were being younger than 50 years; having a local, stage T4 tumor; having vascular or perineural invasion; having perforation or bowel obstruction; and having fewer than 12 lymph nodes examined. However, among our patients, being younger than 50 years had a good prognosis, and neither vascular nor perineural tumoral invasion conferred negative outcomes. To be more consistent with recent staging, it would have been also judicious to distinguish between tumors with grade T4a and T4b and to separate obstruction from perforation.25

Furthermore, the very high prognostic value of circulating tumor DNA (ctDNA) for OS and recurrence-free survival shown in small cohorts led to the development of larger studies to confirm this prognostic value in stage II and III CC.26-28 The ultimate goal of these studies is to explore the interest of ctDNA-driven adjuvant treatment.29

Conclusions

In this secondary analysis of data from the AVANT trial, bevacizumab did not improve DFS and OS in the adjuvant setting among patients with high-risk stage II CC, but a potential benefit cannot be excluded in patients with right-sided tumors. A better classification of stage II risk factors, including ctDNA, will be useful for future studies, even if it is worth validating in ongoing studies.

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Article Information

Accepted for Publication: June 1, 2020.

Published: October 19, 2020. doi:10.1001/jamanetworkopen.2020.20425

Correction: This article was corrected on February 9, 2021, to fix errors in the Abstract and Figure 3B.

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Chibaudel B et al. JAMA Network Open.

Corresponding Author: Benoist Chibaudel, MD, Department of Medical Oncology, Franco-British Hospital–Fondation Cognacq-Jay, Levallois-Perret, 4 rue Kléber, Levallois-Perret 9230, France (benoist.chibaudel@ihfb.org).

Author Contributions: Dr de Gramont had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Chibaudel, Tabernero, Schmoll, Hoff, André, de Gramont.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Chibaudel, Henriques, Rakez, Martinez-Villacampa, Gallego-Plazas, Dejthevaporn, Moehler, André, de Gramont.

Critical revision of the manuscript for important intellectual content: Chibaudel, Rakez, Brenner, Kim, Cervantes, Shim, Jonker, Guerin-Meyer, Mineur, Banzi, Dewdney, Bloemendal, Roth, Moehler, Aranda, Van Cutsem, Tabernero, Schmoll, Hoff, André.

Statistical analysis: Chibaudel, Henriques, Rakez, Martinez-Villacampa, Moehler, Tabernero, de Gramont.

Obtained funding: Tabernero.

Administrative, technical, or material support: Gallego-Plazas, Mineur, Roth, Moehler, Van Cutsem, Tabernero, Schmoll, Hoff, André.

Supervision: Kim, Moehler, Tabernero, André, de Gramont.

Conflict of Interest Disclosures: Dr Chibaudel reported receiving grants from Roche during the conduct of the study and personal fees from Roche, Bayer, Eli Lilly and Co, Pfizer, Sanofi, Servier, and Beigine outside the submitted work. Dr Gallego-Plazas reported receiving grants from Roche during the conduct of the study; receiving personal fees from Roche, Amgen, Merck, Servier, Bayer, and Eli Lilly and Co; receiving travel fees from Novartis; and serving on the congress of Ipsen outside the submitted work. Dr Cervantes reported receiving grants from and belonging to the speakers bureau of Roche during the conduct of the study. Dr Mineur reported receiving grants from Roche outside the submitted work. Dr Moehler reported receiving grants from MerckSerono during the conduct of the study and receiving personal fees from MerckSerono and Roche outside the submitted work. Dr Aranda reported receiving personal fees for consulting with Amgen, Bayer, Celgene, Merck, Roche, and Sanofi outside the submitted work. Dr Van Cutsem reported receiving grants from Roche outside the submitted work; participating on advisory boards for Array, AstraZeneca, Bayer, Biocartis, Bristol-Myers Squibb, Celgene, Daiichi, GlaxoSmithKline, Pierre-Fabre, Incyte, Ipsen, Eli Lilly and Co, Merck Sharp and Dohme, Merck, Novartis, Roche, Servier, Sirtex, and Taiho; and having research grants from Bayer, Boehringer Ingelheim, Celgene, Ipsen, Eli Lilly and Co, Roche, Merck Sharp and Dohme, Merck , Novartis, Roche, and Servier paid to his institution. Dr Tabernero reported serving as a scientific consultant for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Eli Lilly and Co, Merck Sharp and Dohme, Menarini, MerckSerono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign, Rafael Pharmaceuticals, F. Hoffmann-La Roche, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS, and Roche Diagnostics outside the submitted work. Dr Hoff reported receiving grants from Roche during the conduct of the study. Dr André reported receiving grants from Gercor during the conduct of the study; receiving personal fees from Roche/Ventana, Bristol Myers Squibb, Amgen, AstraZeneca, Merck Sharp and Dohme Oncology, Halliodx, Servier, Sanofi, Pierre Fabre, and Tesaro/GlaxoSmithKline outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by Roche.

Role of the Funder/Sponsor: Roche had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: Magdalena Benetkiewicz, PhD (Gercor), provided editorial assistance. She was compensated for her time.

References
1.
Bray  F, Ferlay  J, Soerjomataram  I, Siegel  RL, Torre  LA, Jemal  A.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.   CA Cancer J Clin. 2018;68(6):394-424. doi:10.3322/caac.21492 PubMedGoogle ScholarCrossref
2.
Chen  VW, Hsieh  M-C, Charlton  ME,  et al.  Analysis of stage and clinical/prognostic factors for colon and rectal cancer from SEER registries: AJCC and collaborative stage data collection system.   Cancer. 2014;120(23)(suppl):3793-3806. doi:10.1002/cncr.29056 PubMedGoogle ScholarCrossref
3.
André  T, Boni  C, Mounedji-Boudiaf  L,  et al; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators.  Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.   N Engl J Med. 2004;350(23):2343-2351. doi:10.1056/NEJMoa032709 PubMedGoogle ScholarCrossref
4.
André  T, de Gramont  A, Vernerey  D,  et al.  Adjuvant fluorouracil, leucovorin, and oxaliplatin in atage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC Study.   J Clin Oncol. 2015;33(35):4176-4187. doi:10.1200/JCO.2015.63.4238 PubMedGoogle ScholarCrossref
5.
Moertel  CG, Fleming  TR, Macdonald  JS,  et al.  Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma.   N Engl J Med. 1990;322(6):352-358. doi:10.1056/NEJM199002083220602 PubMedGoogle ScholarCrossref
6.
 Efficacy of adjuvant fluorouracil and folinic acid in colon cancer: International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators.   Lancet. 1995;345(8955):939-944. doi:10.1016/S0140-6736(95)90696-7 PubMedGoogle ScholarCrossref
7.
Wolmark  N, Rockette  H, Mamounas  E,  et al.  Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes’ B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04.   J Clin Oncol. 1999;17(11):3553-3559. doi:10.1200/JCO.1999.17.11.3553 PubMedGoogle ScholarCrossref
8.
André  T, Colin  P, Louvet  C,  et al.  Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial.   J Clin Oncol. 2003;21(15):2896-2903. doi:10.1200/JCO.2003.10.065 PubMedGoogle ScholarCrossref
9.
Gray  R, Barnwell  J, McConkey  C, Hills  RK, Williams  NS, Kerr  DJ; Quasar Collaborative Group.  Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study.   Lancet. 2007;370(9604):2020-2029. doi:10.1016/S0140-6736(07)61866-2 PubMedGoogle ScholarCrossref
10.
Haller  DG, Tabernero  J, Maroun  J,  et al.  Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer.   J Clin Oncol. 2011;29(11):1465-1471. doi:10.1200/JCO.2010.33.6297 PubMedGoogle ScholarCrossref
11.
Kuebler  JP, Wieand  HS, O’Connell  MJ,  et al.  Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07.   J Clin Oncol. 2007;25(16):2198-2204. doi:10.1200/JCO.2006.08.2974 PubMedGoogle ScholarCrossref
12.
Tournigand  C, André  T, Bonnetain  F,  et al.  Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial.   J Clin Oncol. 2012;30(27):3353-3360. doi:10.1200/JCO.2012.42.5645 PubMedGoogle ScholarCrossref
13.
Ferrara  N, Davis-Smyth  T.  The biology of vascular endothelial growth factor.   Endocr Rev. 1997;18(1):4-25. doi:10.1210/edrv.18.1.0287 PubMedGoogle ScholarCrossref
14.
Hurwitz  H, Fehrenbacher  L, Novotny  W,  et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.   N Engl J Med. 2004;350(23):2335-2342. doi:10.1056/NEJMoa032691 PubMedGoogle ScholarCrossref
15.
de Gramont  A, Van Cutsem  E, Schmoll  H-J,  et al.  Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial.   Lancet Oncol. 2012;13(12):1225-1233. doi:10.1016/S1470-2045(12)70509-0 PubMedGoogle ScholarCrossref
16.
Allegra  CJ, Yothers  G, O’Connell  MJ,  et al.  Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08.   J Clin Oncol. 2011;29(1):11-16. doi:10.1200/JCO.2010.30.0855 PubMedGoogle ScholarCrossref
17.
Kerr  RS, Love  S, Segelov  E,  et al.  Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial.   Lancet Oncol. 2016;17(11):1543-1557. doi:10.1016/S1470-2045(16)30172-3 PubMedGoogle ScholarCrossref
18.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
19.
André  T, Vernerey  D, Im  SA,  et al.  Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group.   Ann Oncol. 2020;31(2):246-256. doi:10.1016/j.annonc.2019.12.006 PubMedGoogle ScholarCrossref
20.
Feinstein  AR, Sosin  DM, Wells  CK.  The Will Rogers phenomenon: stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer.   N Engl J Med. 1985;312(25):1604-1608. doi:10.1056/NEJM198506203122504 PubMedGoogle ScholarCrossref
21.
Shi  Q, Andre  T, Grothey  A,  et al.  Comparison of outcomes after fluorouracil-based adjuvant therapy for stages II and III colon cancer between 1978 to 1995 and 1996 to 2007: evidence of stage migration from the ACCENT database.   J Clin Oncol. 2013;31(29):3656-3663. doi:10.1200/JCO.2013.49.4344 PubMedGoogle ScholarCrossref
22.
Almog  N.  Molecular mechanisms underlying tumor dormancy.   Cancer Lett. 2010;294(2):139-146. doi:10.1016/j.canlet.2010.03.004 PubMedGoogle ScholarCrossref
23.
Naumov  GN, Townson  JL, MacDonald  IC,  et al.  Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases.   Breast Cancer Res Treat. 2003;82(3):199-206. doi:10.1023/B:BREA.0000004377.12288.3c PubMedGoogle ScholarCrossref
24.
Grothey  A, Sobrero  AF, Shields  AF,  et al.  Duration of adjuvant chemotherapy for stage III colon cancer.   N Engl J Med. 2018;378(13):1177-1188. doi:10.1056/NEJMoa1713709PubMedGoogle ScholarCrossref
25.
Gunderson  LL, Jessup  JM, Sargent  DJ, Greene  FL, Stewart  A.  Revised tumor and node categorization for rectal cancer based on surveillance, epidemiology, and end results and rectal pooled analysis outcomes.   J Clin Oncol. 2010;28(2):256-263. doi:10.1200/JCO.2009.23.9194 PubMedGoogle ScholarCrossref
26.
US National Library of Medicine. Use of ctDNA for monitoring of Stage III colorectal cancer. Accessed September 17, 2020. https://clinicaltrials.gov/ct2/show/NCT02842203?term=NCT02842203&draw=2&rank=1
27.
US National Library of Medicine. ctDNA as a prognostic marker for postoperative relapse in early and intermediate stage colorectal cancer. Accessed September 17, 2020. https://clinicaltrials.gov/ct2/show/NCT03312374?term=NCT03312374&draw=2&rank=1
28.
US National Library of Medicine. Circulating Tumor DNA Analysis to Optimize Treatment for Patients With Colorectal Cancer (IMPROVE). Accessed September 17, 2020. https://clinicaltrials.gov/ct2/show/NCT03637686?term=NCT03637686&draw=2&rank=1
29.
Tie  J, Wang  Y, Tomasetti  C,  et al.  Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer.   Sci Transl Med. 2016;8(346):346ra92. doi:10.1126/scitranslmed.aaf6219 PubMedGoogle Scholar
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