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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3523-3529 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.4138 Safety and Efficacy of Oxaliplatin and Fluoropyrimidine Regimens With or Without Bevacizumab As First-Line Treatment of Metastatic Colorectal Cancer: Results of the TREE Study
From the New York University Cancer Institute, New York, NY; Florida Cancer Specialists, Fort Myers, FL; University of Pittsburgh Cancer Institute, Pittsburgh, PA; sanofi-aventis, Bridgewater, NJ; Sarah Cannon Cancer Center, Nashville; West Cancer Clinic, Memphis, TN; Rocky Mountain Cancer Center, Denver, CO; Scott & White Hospital, Center for Cancer Prevention and Care, Temple, TX; Department of Oncology/Hematology, Kaiser Permanente, Vallejo Medical Center, Vallejo, CA; Florida Oncology Association, Jacksonville, FL; Yale University School of Medicine, New Haven, CT; and Genentech BioOncology, South San Francisco, CA Corresponding author: Howard S. Hochster, MD, New York University Cancer Institute, 160 East 34th St, New York, NY 10016; e-mail: Howard.Hochster{at}med.nyu.edu
Purpose To evaluate the safety and efficacy of three oxaliplatin and fluoropyrimidine regimens, with or without bevacizumab, as first-line treatment for metastatic colorectal cancer (CRC). Patients and Methods Patients with histologically documented metastatic or recurrent CRC and no prior treatment for advanced disease were randomly assigned to mFOLFOX6 (bolus and infusion fluorouracil [FU] and leucovorin [LV] with oxaliplatin), bFOL (bolus FU and low-dose LV with oxaliplatin), or CapeOx (capecitabine with oxaliplatin), respectively (Three Regimens of Eloxatin Evaluation [TREE-1]). The study was later modified such that subsequent patients were randomized to the same regimens plus bevacizumab (TREE-2). Results A total of 150 and 223 patients were randomly assigned in the TREE-1 and TREE-2 cohorts, respectively. Incidence of grade 3/4 treatment-related adverse events during the first 12 weeks of treatment were 59%, 36%, and 67% for mFOLFOX6, bFOL, and CapeOx, respectively, (TREE-1) and 59%, 51%, and 56% for the corresponding treatments plus bevacizumab (TREE-2; primary end point). CapeOx toxicity in TREE-1 included grade 3/4 diarrhea (31%) and dehydration (27%); capecitabine dose reduction to 1,700 mg/m2/d in TREE-2 resulted in improved tolerance. Overall response rates were 41%, 20%, and 27% (TREE-1) and 52%, 39%, and 46% (TREE-2); median overall survival (OS) was 19.2, 17.9, and 17.2 months (TREE-1) and 26.1, 20.4, and 24.6 months (TREE-2). For all treated patients, median OS was 18.2 months (95% CI, 14.5 to 21.6; TREE-1) and 23.7 months (95% CI, 21.3 to 26.8; TREE-2). Conclusion The addition of bevacizumab to oxaliplatin and fluoropyrimidine regimens is well tolerated as first-line treatment of mCRC and does not markedly change overall toxicity. CapeOx tolerability and efficacy is improved with reduced-dose capecitabine. First-line oxaliplatin and fluoropyrimidine-based therapy plus bevacizumab resulted in a median OS of approximately 2 years.
Oxaliplatin-based therapy is standard first-line treatment for advanced or metastatic colorectal cancer (mCRC). FOLFOX4, a regimen of oxaliplatin added to LV5FU2—bimonthly leucovorin (LV) plus bolus and infusional fluorouracil (FU)—improves progression-free survival (PFS; 9.0 v 6.2 months; P = .0003) and overall response rate (ORR; 50.7% v 22.3%; P = .0001) compared with LV5FU2.1 FOLFOX also improved response and survival compared with irinotecan plus bolus FU and LV (IFL) in US Intergroup Study N9741.2 The Three Regimens of Eloxatin Evaluation (TREE) study in advanced CRC was initiated to investigate the tolerability of oxaliplatin when combined with three different fluoropyrimidine regimens: modified FOLFOX6 (mFOLFOX6) utilizing infusional administration of FU, bFOL including bolus intravenous (IV) administration of FU plus low-dose LV, and CapeOx including an oral agent, capecitabine. Bevacizumab combined with either first-line FU-based chemotherapy (weekly FU/LV or bolus IFL) or second-line FOLFOX4 improved overall survival (OS), PFS, and response rate in patients with mCRC.3-5 In response to emerging data on the efficacy of bevacizumab in mCRC at the time TREE was completing accrual, the study was amended to subsequently evaluate the safety and efficacy of adding bevacizumab to each of the original oxaliplatin and fluoropyrimidine regimens. The resulting two cohorts of this study are hereafter referred to as TREE-1 and TREE-2.
Study Design and Treatment TREE-1 and TREE-2 were two sequentially conducted, randomized, open-label cohorts in this study. TREE-1 was initiated in November 2002 and TREE-2 in October 2003 after a protocol amendment to add bevacizumab to chemotherapy. A central registry was used to randomly assign patients to treatment (1:1:1). In TREE-1, patients received mFOLFOX6 (oxaliplatin 85 mg/m2 IV with LV 350 mg IV over 2 hours plus FU 400 mg/m2 IV bolus and 2,400 mg/m2 continuous infusion over 46 hours every 2 weeks), bFOL (oxaliplatin 85 mg/m2 IV on days 1 and 15 and LV 20 mg/m2 IV over 10 to 20 minutes followed by FU 500 mg/m2 IV push on days 1, 8, and 15 every 4 weeks), or CapeOx (oxaliplatin 130 mg/m2 IV on day 1 and capecitabine 1,000 mg/m2 orally twice daily on days 1 to 15 every 3 weeks). In TREE-2, patients received one of the same three chemotherapy regimens as in TREE-1 but with the addition of bevacizumab; the capecitabine starting dose was also modified (see below). Bevacizumab was administered before chemotherapy at a dosage of 5 mg/kg IV every 2 weeks (FOLFOX and bFOL regimens) or 7.5 mg/kg IV every 3 weeks (CapeOx regimen). Treatment continued until disease progression, unacceptable toxicity, extended toxicity-related dose delay, or withdrawal of consent. Based on preliminary safety data from TREE-1 and data safety monitoring committee recommendation, the capecitabine dose was reduced to 850 mg/m2 twice per day in TREE-2 (650 mg/m2 twice per day for patients with a creatinine clearance of 30 to 50 mL/min). Toxicities were graded by the National Cancer Institute Common Toxicity Criteria, version 2.0, or as mild, moderate, severe, or life-threatening. Neurosensory toxicities were graded on interference with function and/or activities of daily living. One dose reduction was permitted for oxaliplatin (85 to 65 mg/m2 or 130 to 100 mg/m2), two for FU bolus/infusion (bolus, 400 to 300, then 200 mg/m2 or bolus, 500 to 400, then 300 mg/m2; infusion, 2,400 to 1,900, then 1,500 mg/m2), two for capecitabine (TREE-1: 2,000 to 1,500, then 1,000 mg/m2/d; TREE-2: 1,700 to 1,300, then 850 mg/m2/d), and none for LV. Grade 3 paresthesias and dysesthesias lasting longer than 7 days required a 25% oxaliplatin dose reduction. Oxaliplatin was discontinued for grade 4 paresthesia/dysesthesia, or persistent grade 3 paresthesia/dysesthesia. For grade 3 hemorrhage, thrombosis, or requirement for surgery, bevacizumab was withheld until the toxicity resolved, or for 28 days after surgery. Bevacizumab was discontinued for grade 4 or uncontrolled grade 3 hypertension, bleeding, thrombosis, or proteinuria.
Patients The study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by an institutional review board at each participating center.
Evaluations
Statistics
Accrual of 70 patients per arm was deemed sufficient to detect a 15% increase in the overall incidence of grade 3/4 AEs for the experimental treatments compared with historical controls based on a one-group
Patient Characteristics Between December 2002 and November 2003, 150 patients were enrolled in TREE-1 at 33 United States centers and randomly assigned to treatment with mFOLFOX6 (n = 50), bFOL (n = 50), or CapeOx (n = 50). Between November 2003 and April 2004, 223 patients were enrolled in TREE-2 at 57 centers in the United States and randomly assigned to the corresponding treatment arms plus bevacizumab (n = 75, n = 74, n = 74, respectively). Baseline characteristics were similar across all groups, except for prior adjuvant chemotherapy, male:female ratio, and primary site of diagnosis (Table 1).
Treatment In TREE-1, 147 of 150 patients were treated (one was ineligible for prior chemotherapy and two did not start treatment). Discontinuations from mFOLFOX6, bFOL, and CapeOx were mostly attributable to AEs (29%, 46%, and 52%, respectively) or disease progression (43%, 42%, and 25%, respectively); CapeOx was tolerated least well. Treatment delays were most common with mFOLFOX6 (81% of patients) although the number of cycles administered was highest in this arm (Table 2). Most common causes of delay were neutropenia and thrombocytopenia with mFOLFOX6 and bFOL and diarrhea, nausea, and dehydration with CapeOx. Oxaliplatin dose reductions were most common with mFOLFOX6 (50% of patients), reflecting the longest time on study (Table 2). Median relative dose intensity for oxaliplatin was  82% for all arms.
In TREE-2, 213 of 223 patients were treated (six withdrew consent, three had serious AEs or complications pretreatment, and one deteriorated clinically pretreatment). Discontinuations from treatment with mFOLFOX6, bFOL, and CapeOx were mostly for AEs (45%, 47%, and 51%, respectively) or disease progression (27%, 33%, and 25%, respectively). Treatment delay was most frequent with mFOLFOX6 plus bevacizumab (73%; Table 2). Treatment delays were most often attributable to neutropenia (all arms) or diarrhea (CapeOx plus bevacizumab). The oxaliplatin relative dose intensity was 84% for all arms. In TREE-1, 69% of patients received subsequent anticancer therapy, including 41% who received a biologic agent (bevacizumab, n = 31; cetuximab, n = 28; other biologic agents, n = 3); 36 patients received oxaliplatin. Of those patients for whom data are available in TREE-2, 74% received subsequent anticancer treatment and this included a biologic agent in 38% of patients (bevacizumab, n = 70; cetuximab, n = 50; other biologic agents, n = 2); 62 patients received subsequent oxaliplatin.
Safety and Tolerability
In TREE-2, bevacizumab-related toxicity (treatment arms combined) included bowel perforation (n = 5), sepsis (n = 3), impaired wound healing (n = 3), grade 3/4 hypertension (n = 13), and grade 3/4 proteinurea (n = 2). The overall incidence of bleeding events was highest in the mFOLFOX6 with or without bevacizumab treatment arms: (TREE-1, 22%; TREE-2, 45%). However, there were no grade 3/4 bleeding events in the mFOLFOX6 arm in TREE-1 while two (3%) grade 3 bleeding events occurred in the mFOLFOX6 plus bevacizumab arm (TREE-2). Four patients in TREE-1 and six patients in TREE-2 had AEs leading to death within 30 days of the last treatment. In TREE-1, one patient in the CapeOx arm died due to grade 4 dehydration and diarrhea considered treatment related. In TREE-2, deaths arising from treatment-related AEs occurred in three patients in the bFOL plus bevacizumab arm (grade 4 septic shock, perforated ulcer, peritonitis, and intestinal perforation) and in three patients in the CapeOx plus bevacizumab arm (grade 4 cerebrovascular accident and arrhythmia, and grade 3 small intestinal obstruction). No treatment-related deaths were reported in the FOLFOX with or without bevacizumab arms. Overall 60-day mortality was 3.4% and 1.9% in the TREE-1 and TREE-2 cohorts, respectively.
Efficacy
Median TTP and OS results for the individual treatment regimens in TREE-1 and TREE-2 are summarized in Table 4 and Figures 2A and 2B. Median survival was 18.2 months for all TREE-1 patients (95% CI, 14.5 to 21.6) and 23.7 months for the TREE-2 arms combined (95% CI, 21.3 to 26.8; Fig 2C). At the time of follow-up, 70% of patients in TREE-1% and 61% of patients in TREE-2 had died.
The TREE study evaluated the feasibility of administering oxaliplatin in combination with three different fluoropyrimidine regimens (continuous infusion, bolus, and oral), with or without bevacizumab, as first line-therapy for mCRC. All three oxaliplatin and fluoropyrimidine regimens were well tolerated and the addition of bevacizumab did not significantly alter the toxicity profiles. ORR, TTP, and OS were improved in the TREE-2 cohort compared with TREE-1 suggesting that bevacizumab improved the efficacy of oxaliplatin and fluoropyrimidine therapy. Because the study was not designed to compare the TREE-1 and TREE-2 patient cohorts, such a statistical analysis was not conducted. The addition of bevacizumab to oxaliplatin and fluoropyrimidine regimens had no major impact on toxicity. Importantly, the toxicity profile of bevacizumab in TREE-2 was consistent with other reports.3-5,7,8 The incidence of grade 3/4 hypertension in TREE-2 (7% to 15% grade 3) was similar to that with bevacizumab 5 mg/kg in combination with FU/LV (9%) or IFL (11% grade 3) as first-line therapy for mCRC.3,4 The incidences of grade 3/4 proteinuria (TREE-2, 0% to 1% grade 3; IFL plus bevacizumab, 1% grade 3), grade 3/4 bleeding events (TREE-2, 1% to 3% grade 3; IFL plus bevacizumab, 3%), and any grade gastrointestinal perforation (TREE-2, 3% to 4%; IFL plus bevacizumab, 2%) were also comparable with previous data.3 Our results provide the first evidence that bevacizumab can be added to first-line oxaliplatin-based regimens without altering the toxicity profile of chemotherapy, and with predictable bevacizumab-related toxicity. Although CapeOx had the highest overall incidence of grade 3/4 toxicities and the shortest TTF in TREE-1, reducing the capecitabine dose from 2,000 to 1,700 mg/m2/d in TREE-2 improved the toxicity profile. While median dose intensity for capecitabine was 74% in TREE-1% and 79% in TREE-2, the number of cycles requiring more than 25% dose reduction were 55% in TREE-1 and 25% in TREE-2. Notably, the incidence of grade 3/4 dehydration with CapeOx was reduced from 27% in TREE-1 to 8% in TREE-2; and grade 3/4 diarrhea was reduced from 31% in TREE-1 to 19% in TREE-2. Lowering the capecitabine dose also improved efficacy, as patients stayed on treatment longer. In fact, CapeOx had the worst toxicity profile and the shortest TTF in TREE-1, but was comparable with FOLFOX in TREE-2. In this study, CapeOx with a reduced capecitabine dose of 1,700 mg/m2/d was a much improved regimen. ORRs were higher in each of the treatment arms in TREE-2 than in the corresponding arms in TREE-1 and were highest for mFOLFOX6 with (52%) or without bevacizumab (41%). The effect appeared independent of the fact that almost twice as many patients in TREE-2 received calcium and magnesium salts for neurotoxicity. TTF was similar in the two cohorts, apparently due to cumulative neurotoxicity, which was unchanged with the addition of bevacizumab. TTP was also longer for each regimen in the TREE-2 cohort than for the corresponding regimen in the TREE-1 cohort. Although patients were not considered to have progressed until evidence of disease progression, they were censored at the time of second-line therapy in our analysis, possibly before objective evidence of progression. Chemotherapy was stopped for observation in fewer than 5% of cases; however, only five patients continued on study with fluoropyrimidine and bevacizumab alone after reaching the maximum cumulative doses of oxaliplatin resulting in neurotoxicity. Our analysis of general TTP (time until actual disease progression) or an on-study TTP (censoring patients at the time of discontinuing all study drugs) showed no overall difference in the median values or Kaplan-Meier curves. In this study, median OS (20.4 to 26.1 months) was impressive for the TREE-2 cohort and approached 2 years (23.7 months) when data for all three regimens were combined. This is among the longest median OS reported to date in any prospective randomized clinical trial for mCRC. A similar proportion of patients in TREE-1 (69%) and TREE-2 (74%) received poststudy anticancer treatment; however, more patients in TREE-2 received a subsequent biologic agent combined with additional chemotherapy (14% v 38%). We cannot estimate the effect of this difference on OS. The observation that bevacizumab appears to improve the efficacy of oxaliplatin and fluoropyrimidine therapy is consistent with other studies showing high efficacy for first-line chemotherapy regimens plus bevacizumab for mCRC. In these studies, TTP or PFS ranged from 9 to 11 months, representing an increase in disease-free survival of approximately 4 months with the addition of bevacizumab.3,4,9,10 The TREE-2 results are also consistent with the Eastern Cooperative Oncology Group E3200 study in which the addition of bevacizumab to second-line FOLFOX significantly improved PFS (7.3 v 4.7 months; hazard ratio [HR], 0.61; P < .0001) and median OS (12.9 v 10.8 months; HR, 0.75; P = .0011).5 However, these results were not verified in the randomized NO16966 trial, which compared FOLFOX or CapeOx with or without bevacizumab (n = 1,400).11 In that trial a significant improvement in median PFS was reported with the addition of bevacizumab (9.4 v 8.0 months; HR, 0.83, P = .002)11 but there was no effect on OS (21.3 v 19.9 months; HR, 0.89; P = .077; unpublished data presented at the 43rd annual meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007). In conclusion, oxaliplatin and fluoropyrimidine chemotherapy with or without bevacizumab had a predictable safety profile and acceptable tolerability, regardless of the fluoropyrimidine regimen. In this study, based on sequential historical cohorts, bevacizumab appeared to further improve the efficacy of oxaliplatin and fluoropyrimidine chemotherapy in terms of ORR, TTP, and OS, although a preliminary report of a large randomized phase III trial did not show a similar magnitude of effect for PFS or OS.11 It is likely that these differences are a result of variations in treatment patterns during the period leading up to determination of the treatment failure end point, and in subsequent therapy administered, although this cannot be fully determined until final results are available.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Barrett H. Childs, Sanofi-aventis (C); Eric Hedrick, Genentech BioOncology (C) Consultant or Advisory Role: Howard S. Hochster, Sanofi-aventis (C), Genentech BioOncology (C); Lucas Wong, Genentech (C) Stock Ownership: Barrett H. Childs, Sanofi-aventis; Eric Hedrick, Genentech Honoraria: Howard S. Hochster, Sanofi-aventis, Genentech; Ramesh K. Ramanathan, Sanofi-aventis, Genentech; Allen L. Cohn, Genentech, Bristol-Myers Squibb Co, Amgen; Lucas Wong, Genentech; M. Wasif Saif, Roche, Amgen, Genentech, Bristol-Myers Squibb Co, Sanofi-aventis Research Funding: Howard S. Hochster, Sanofi-aventis, Genentech BioOncology; Lowell L. Hart, Sanofi-aventis; Lucas Wong, Sanofi-aventis, Genentech; Louis Fehrenbacher, Genentech; M. Wasif Saif, Taiho, Samyang, Confirma Biotech Expert Testimony: None Other Remuneration: None
Conception and design: Howard S. Hochster, Barrett H. Childs, Eric Hedrick Administrative support: Barrett H. Childs Provision of study materials or patients: Howard S. Hochster, Lowell L. Hart, Ramesh K. Ramanathan, John D. Hainsworth, Allen L. Cohn, Lucas Wong, Louis Fehrenbacher, Yousif Abubakr, M. Wasif Saif, Lee Schwartzberg Collection and assembly of data: Howard S. Hochster, Barrett H. Childs, Lucas Wong, Louis Fehrenbacher, Yousif Abubakr, M. Wasif Saif Data analysis and interpretation: Howard S. Hochster, Barrett H. Childs Manuscript writing: Howard S. Hochster, Barrett H. Childs Final approval of manuscript: Howard S. Hochster, Lowell L. Hart, Ramesh K. Ramanathan, Barrett H. Childs, John D. Hainsworth, Louis Fehrenbacher, M. Wasif Saif, Lee Schwartzberg, Eric Hedrick
We thank Gilbert Jirau-Lucca (sanofi-aventis) and Beth Berry (Prologue Research International) for their help in conducting this trial.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 2. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 3. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 4. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003 5. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539-1544, 2007 6. Gwyther SG, Therasse P, Arbuck SG, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000 7. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an antivascular endothelial cell growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003 8. Kozloff M, Cohn A, Christiansen N, et al: Safety of bevacizumab (BV) among patients (pts) receiving first line chemotherapy for metastatic colorectal cancer: Updated results from a large observational study in the U.S. (BRITE). Gastrointestinal Cancers Symposium, 2006 (abstr 247) http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=41&abstractID=405 Last accessed 20 February 2008 9. Bendell JC, Fernando N, Morse M, et al: A phase II study of oxaliplatin, capecitabine, and bevacizumab in the treatment of metastatic colorectal cancer. J Clin Oncol 24:156s, 2006 (suppl; abstr 3541) 10. Emmanouilides C, Sfakiotaki G, Androulakis N, et al: Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: A multicenter phase II study. BMC Cancer 30;7:91, 2007[CrossRef][Medline] 11. Saltz L, Clarke S, Diaz-Rubio E, et al: Bevacizumab in combination with XELOX or FOLFOX-4: updated efficacy results from XELOX-1/NO16966, a randomized phase III trial in first-line metastatic colorectal cancer. J Clin Oncol 25, 2007 (suppl; abstr 4028) Submitted December 2, 2007; accepted April 1, 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
2.0x upper limit of normal [ULN], serum transaminases 
2 test with a nominal one-sided .05 significance level and 80% power within the 50% to 70% AE rate of historical controls. 
