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Journal of Clinical Oncology, Vol 26, No 28 (October 1), 2008: pp. 4544-4550 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.1249
Oxaliplatin Plus Irinotecan Compared With Irinotecan Alone as Second-Line Treatment After Single-Agent Fluoropyrimidine Therapy for Metastatic Colorectal Carcinoma
From the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA; Vanderbilt University Medical Center, Nashville, TN; Tom Baker Cancer Centre, Calgary, Alberta, Canada; Wojewódzki Szpital, Krakow, Poland; McGill University-Jewish General Hospital, Montreal, Quebec, Canada; St László Hospital, Budapest, Hungary; Sanofi-aventis, Bridgewater, NJ; and the Instituto Nacional do Câncer, Rio de Janeiro, Brazil Corresponding author: Daniel G. Haller, MD, Abramson Cancer Center at the University of Pennsylvania, 16 Penn Tower, 3400 Spruce St, Philadelphia, PA 19014-4283; e-mail: daniel.haller{at}uphs.upenn.edu
Purpose To determine whether irinotecan plus oxaliplatin (IROX) is superior to irinotecan alone in patients with metastatic colorectal cancer (CRC) previously treated with single-agent fluoropyrimidines. Patients and Methods A phase III, randomized, open-label, multicenter study of patients with metastatic or recurrent CRC that had progressed or recurred during or after adjuvant or first-line fluoropyrimidines (fluorouracil/leucovorin or capecitabine, the latter only for metastatic CRC). Patients received IROX (irinotecan 200 mg/m2 plus oxaliplatin 85 mg/m2) or irinotecan alone (350 mg/m2) every 3 weeks. Results At the data cutoff (when 447 of 628 randomly assigned patients had died), median overall survival was 13.4 months (95% CI, 12.4 to 14.7 months) and 11.1 month (95% CI, 10.0 to 12.7 months) in the IROX and irinotecan groups, respectively (hazard ratio = 0.78; 95% CI, 0.65 to 0.94; P = .0072). Overall response rate (22% v 7%, respectively; P < .0001), median time to progression (5.3 v 2.8 months, respectively; P < .0001), and improvement in tumor-related symptoms (32% v 19%, respectively; P = .0072) were also improved with IROX as compared with irinotecan. With the exception of granulocytopenia (25% v 13%), diarrhea (28% v 23%), and sensory disturbances (5% v 0%), grade 3 to 4 toxicities were comparable between the IROX and irinotecan groups, respectively. Conclusion IROX is an effective treatment for metastatic CRC that has progressed after first-line fluoropyrimidine therapy. IROX improves efficacy compared with irinotecan alone, providing an additional option in the postadjuvant or second-line treatment setting for patients who experience treatment failure with single-agent fluoropyrimidine therapy.
The benefits of chemotherapy as palliative treatment for advanced colorectal cancer (CRC) have been recognized for more than two decades.1 Although fluorouracil (FU) plus leucovorin (LV) remains a key component of most regimens, the availability of oxaliplatin (Eloxatin; Sanofi-aventis, Bridgewater, NJ) and irinotecan (CPT-11; Camptosar; Pfizer Oncology, New York, NY/Campto; Astra Medical, Cambridge, United Kingdom) has increased the number of therapeutic options, transforming the treatment of advanced CRC. Single-agent irinotecan is active as salvage therapy for metastatic CRC after disease progression on first-line fluoropyrimidines.2,3 Irinotecan significantly improved survival compared with either best supportive care2 or a continuous infusion of FU,3 leading to approval in 1996 in the United States as a second-line treatment for metastatic CRC. Single-agent oxaliplatin is only moderately active for advanced CRC.4,5 However, the combination of oxaliplatin plus bolus/infusional FU and LV (FOLFOX) is superior to a regimen consisting of LV and FU (LV5FU2) alone after failure of irinotecan, bolus FU, and LV (IFL).5 In a phase III study of 821 patients with disease progression with IFL, FOLFOX achieved an objective response rate (ORR) of 9.9% compared with 0% for LV5FU2 alone (P < .0001). Time to disease progression and relief of tumor-related symptoms were also improved with FOLFOX.5 On the basis of these results, FOLFOX was approved for use in patients with advanced CRC after treatment failure of IFL. There are strong clinical and preclinical rationales for combining irinotecan with oxaliplatin in metastatic CRC. First, preclinical studies have demonstrated a synergistic interaction between the two drugs.6-9 Second, the dose-limiting toxicities of the two drugs are largely nonoverlapping (diarrhea and myelosuppression for irinotecan and peripheral sensory neuropathy for oxaliplatin). In phase I/II studies of patients with advanced CRC previously treated with fluoropyrimidine-based chemotherapy, the combination of irinotecan and oxaliplatin (IROX) was active, achieving ORRs of 15% to 64% and median overall survival (OS) durations of 10.5 to 17 months.10-16 The present study was undertaken to compare IROX against the standard regimen of irinotecan alone in patients with metastatic CRC that had progressed or recurred during or after adjuvant or first-line fluoropyrimidines.
Study Design and Treatment This was a randomized, open-label, phase III study conducted at 118 centers in seven countries (Brazil, Canada, Czech Republic, Hungary, Poland, United Kingdom, and the United States). Eligible patients were assigned to IROX (oxaliplatin 85 mg/m2 administered as a 120-minute intravenous [IV] infusion followed by irinotecan 200 mg/m2 administered as a 30- or 90-minute IV infusion) every 3 weeks or to irinotecan alone (350 mg/m2 administered as a 90-minute IV infusion) every 3 weeks. In the irinotecan group, patients age  65 years or those who had received prior abdominal/pelvic radiotherapy or had elevated bilirubin levels received a starting dose of 250 mg/m2, with dose escalations to 300 or 350 mg/m2 in the absence of grade 2 toxicities. Patients were randomly assigned centrally via an interactive voice response system and stratified according to baseline Karnofsky performance status (KPS), number of organs with metastases, pretreatment lactate dehydrogenase, and prior treatment with FU or capecitabine. Treatment was administered until progressive disease. Tumors were evaluated according to the Response Evaluation Criteria in Solid Tumors by computed tomography or magnetic resonance imaging.17 Measurements were made at baseline (within 28 days before the first dose of study drug), every 6 weeks during treatment, 30 days after the last dose, and every 8 weeks after the 30-day poststudy visit until documentation of progression or until 13 months after the first dose of study medication (whichever came first). Any response had to be confirmed within 4 to 6 weeks. Best overall response was recorded at the end of the study. Clinical benefit was assessed at baseline (within 7 days before randomization and the first dose of study drug), every 3 weeks (before receiving chemotherapy), and then every 4 weeks for up to 3 months after the last dose of study medication. The assessment included administration of a tumor-related symptom (TRS) questionnaire (to self-assess pain intensity and KPS), evaluation of analgesic use by daily diaries, and investigator assessment of weight and KPS. The KPS value used in the clinical benefit analysis was the lowest of the assessments by the physician and patient. Patients were followed for survival until death. Treatment-related toxicities were assessed throughout treatment until 30 days after the final administration of study medication. Toxicities were graded according to National Cancer Institute Common Toxicity Criteria version 2.0. An oxaliplatin-specific scale was used to grade neurologic toxicity (grade 1, paresthesias/dysesthesias that may have been cold induced and do not interfere with function; grade 2, paresthesias/dysesthesias that may have been cold induced, interfering with function but not with activities of daily living; grade 3, paresthesias/dysesthesias that may have been cold induced, with pain or functional impairment and that also interfere with activities of daily living; grade 4, paresthesias/dysesthesias that are disabling or life-threatening; acute, during or just after the oxaliplatin infusion). The institutional review board or ethics committee at each site approved the protocol, which complied with the Declaration of Helsinki and all applicable amendments. All patients gave written informed consent. An independent Data and Safety Monitoring Board convened approximately every 6 months to review enrollment procedures, safety, and other issues related to the conduct of the trial.
Patients
Statistical Analysis
The primary clinical benefit parameter, time to tumor-related symptomatic worsening (TTSW), was defined as the time from random assignment until the patients worsened with respect to KPS, pain, or analgesic consumption. Worsening was defined as the date of first observation of a change (> 2 cm increase in pain [on the visual analog scale],
Patient and Tumor Characteristics From January 23, 2001, to April 30, 2004, a total of 628 patients were randomly assigned to receive IROX (n = 318) or irinotecan (n = 310). All patients who received study medication (313 in the IROX group and 301 in the irinotecan group) were included in the safety population. Five patients in the IROX arm were randomly assigned and not treated (three patients because of ineligibility, two patients because of refusal). Nine patients in the irinotecan arm were randomly assigned and not treated (two patients withdrew consent, three patients developed disease progression before treatment, two patients were ineligible, and two patients withdrew).
Patient characteristics and stratification factors were similar between the treatment groups (Table 1). After a meeting of the Data and Safety Monitoring Board (August 2001), the primary statistical test was changed from a stratified (for KPS) log-rank test to an unstratified log-rank test as a result of protocol revisions, which required patients to have a KPS
Treatment Administered The median number of cycles administered per patient was six (range, one to 22 cycles) in the IROX group and four (range, one to 28 cycles) in the irinotecan group. More IROX- than irinotecan-treated patients experienced one or more treatment delay (52% v 31%, respectively). Eight patients (3%) in the IROX group and four patients (1%) in the irinotecan group completed dosing (on study for 1 year having received 15 cycles). Among the intent-to-treat patients who discontinued (IROX, n = 317; irinotecan, n = 310), reasons included disease progression (IROX, 54%; irinotecan, 66%), toxicity (IROX, 13%; irinotecan, 13%), investigator or patient refusal (IROX, 16%; irinotecan, 10%), death (IROX, 1%; irinotecan, < 1%), and other (IROX, 13%; irinotecan, 10%). Toxicity was the most common reason for delay (33% v 13% of patients, respectively). Similarly, more patients in the IROX group had one or more cycle of irinotecan administered at a reduced dose (43% v 23%, respectively). Twenty-six percent of IROX-treated patients had one or more cycle of oxaliplatin administered at a reduced dose. The median relative dose-intensity for irinotecan was 92% and 86% in the IROX and irinotecan groups, respectively. In the IROX group, the median relative dose-intensity for oxaliplatin was 94%. Overall, 57% of IROX-treated patients and 64% of irinotecan-treated patients received third-line treatment; 21% and 28%, respectively, received fourth-line therapy. More patients in the irinotecan group than in the IROX group went on to receive oxaliplatin-containing chemotherapy as third-line (91 [46%] of 198 v 12 [7%] of 181 patients, respectively) or fourth-line therapy (35 [41%] of 86 v 17 [25%] of 68 patients, respectively). Overall, single-agent oxaliplatin was administered to 41 (21%) of 198 versus two (1%) of 181 patients, respectively, as third-line therapy and to 11 (13%) of 86 versus three (4%) of 68 patients, respectively, as fourth-line therapy. Most patients who received oxaliplatin combination therapy received fluoropyrimidine-based chemotherapy.
Response to Therapy
The ORR was significantly higher in the IROX group than in the irinotecan group (Table 2). The tumor control rate and time to onset of response also favored IROX (Table 2). Median TTP was significantly longer in the IROX group (5.3 months; 95% CI, 4.7 to 5.7 months) than in the irinotecan group (2.8 months; 95% CI, 2.6 to 3.3 months; hazard ratio = 0.60; 95% CI, 0.51 to 0.70; P < .0001; Fig 2).
Significantly more patients in the IROX group experienced an overall improvement in TRS (composite score) compared with those in the irinotecan group (P = .0072; Table 3). Pain and analgesic use were the most improved parameters. Median TTSW was 7.6 months (95% CI, 6.4 to 11.5 months) in the IROX group and 4.4 months (95% CI, 3.1 to 5.8 months) in the irinotecan group (P = .0073). A positive correlation was observed between objective tumor response and symptom improvement in the subpopulation of 396 symptomatic patients (Spearman rank correlation coefficient 0.29; P < .0001). A similar positive correlation was observed between tumor control and symptom improvement (correlation coefficient 0.37).
Safety and Tolerability Diarrhea and nausea were the most common toxicities in the treatment groups (diarrhea, 85% and 77% of patients in the IROX group; nausea, 78% and 66% of patients in the irinotecan group). Grade 3 to 4 toxicities that were more common in the IROX group than in the irinotecan group included granulocytopenia, diarrhea, and sensory disturbance (Table 4). The nature and incidence of other individual grade 3 to 4 toxicities were comparable between treatment groups. Although the overall incidence of sensory neuropathy was 58% in the IROX group and 9% in the irinotecan group, the incidence of grade 3 neuropathy was 6% and 0.3%, respectively; no grade 4 neuropathy was observed. Grade 3 cumulative neuropathy (paresthesia) occurred in 1% of patients in the IROX group and in no patients in the irinotecan group.
The proportion of patients with any serious toxicity was similar in the two groups (IROX, 32%; irinotecan, 33%). The most common serious toxicities in the IROX group were diarrhea (9%), febrile neutropenia (6%), vomiting (5%), and neutropenic sepsis (5%). In the irinotecan group, the most common serious toxicities were diarrhea (9%), vomiting (7%), febrile neutropenia (7%), nausea (6%), and neutropenic sepsis (3%). Cause of death overall was attributed to adverse events in nine patients (3%) in the IROX group and five patients (2%) in the irinotecan group. In the IROX group, 13 patients (4.2%) died within 30 days of the last dose of study drug; eight patients (2.6%) died from adverse events and five patients (1.6%) died of progressive disease. On irinotecan alone, 17 patients (5.6%) died within 30 days of last dose; five patients (1.7%) died from adverse events, 11 patients (3.7%) died from disease progression, and one patient died of an unknown cause.
In this difficult-to-treat patient population with refractory or resistant metastatic CRC, second-line IROX demonstrated improved efficacy compared with irinotecan monotherapy for all end points (OS, ORR, onset of response, tumor control rate, TTP, TRS, and TTSW). Notably, IROX improved the median OS by 2.3 months compared with irinotecan, generally accepted as a clinically relevant prolongation of survival in this setting. This benefit was achieved despite the fact that a high proportion of patients who experienced disease progression while being treated with irinotecan alone received salvage treatment with oxaliplatin, either as monotherapy or in combination with FU/LV. Toxicities with IROX were predictable and manageable, and oxaliplatin and irinotecan in combination did not seem to adversely affect safety compared with the toxicity profile of either agent alone. The majority of toxicities were gastrointestinal, and the incidence of serious toxicities and withdrawals because of toxicities was comparable between the two groups. Severe granulocytopenia was more common in the IROX group, but this did not translate into an increased incidence of febrile neutropenia, neutropenic sepsis, or toxicity-related deaths. Although the incidence of severe diarrhea, a dose-limiting toxicity of irinotecan, was slightly higher in IROX-treated patients, the increase of less than 5% was not considered to be clinically significant. All patients who experienced diarrhea received intense loperamide therapy. Clinically significant sensory neuropathy was uncommon in the IROX group, likely because of the dosing schedule and the total dose delivered, and only three patients in this group had cumulative grade 3 neuropathy. Assessment of TRS, pain (analgesic consumption and pain intensity), KPS, and weight provides an indication of the clinical benefit associated with treatment.18,19 Patients treated with IROX experienced a greater improvement in TRS, in particular pain intensity and analgesic use, than patients treated with irinotecan alone, suggesting that treatment with IROX may confer a meaningful clinical benefit to such symptomatic patients. Although TTSW was prolonged with IROX, it is difficult to make any definitive inferences from these data because of heavy censoring, which accounted for approximately 65% of observations in each group. Interestingly, a positive correlation was observed between tumor burden and symptomatic improvement, indicating that patients who respond to treatment or achieve stable disease also have an improvement in TRS. The OS of patients treated with single-agent irinotecan in the present study is similar to or slightly better than that reported previously for phase III studies in similar populations.2,3 In these studies, which compared second-line irinotecan with best supportive care2 or continuous-infusion FU,3 the reported median OS durations for irinotecan were 9.2 and 10.8 months, respectively. The efficacy and tolerability of the IROX combination is similar to previous phase I/II results with this regimen,10-16 which demonstrated ORRs of 15% to 64% and median OS durations of 10.5 to 17 months with second-line IROX after treatment failure with FU. The results of the present study are also in line with observations in the first-line setting, which show the OS benefit of patients receiving all three active agents (oxaliplatin, irinotecan, and FU/LV) over the course of their treatment.20,21 It is still uncertain regarding which patients require first-line combination chemotherapy, and in what sequence. Regarding the relevance of these results, many patients—with estimates as high as 20% to 25%—still receive first-line single-agent fluoropyrimidines, and many need tolerable and easily administered second-line regimens, such as IROX, as do patients who experience treatment failure with adjuvant therapy with FU/LV or capecitabine. In practice, the choice of second-line therapy ultimately depends on the previous therapy received by the patient, in addition to the response and toxicity associated with that therapy. Since the present study was initiated, two regimens (FOLFOX and FOLFIRI [irinotecan plus LV5FU2]) have emerged as standard first-line treatments for metastatic CRC. In addition, targeted agents are increasingly being added to combination chemotherapy regimens in an attempt to further improve outcomes in both the first- and second-line treatment settings. For example, preliminary results from the phase III Eastern Cooperative Oncology Group 3200 study show that second-line FOLFOX plus bevacizumab can significantly improve median OS compared with FOLFOX alone (12.5 v 10.7 months, respectively; P = .0024).22 Even with these advances, IROX offers an additional useful and effective treatment option for appropriate patients with previously treated metastatic CRC.
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: Nassir Habboubi, Sanofi-aventis (C); Carlos Garay, Sanofi-aventis (C) Consultant or Advisory Role: Daniel G. Haller, Sanofi-aventis (C), Pfizer (C); Mace L. Rothenberg, Sanofi-aventis (C); Gyorgy Bodoky, Sanofi-aventis (C) Stock Ownership: Carlos Garay, Sanofi-aventis Honoraria: Daniel G. Haller, Sanofi-aventis, Pfizer; Wilson H. Miller Jr, Sanofi-aventis; Gyorgy Bodoky, Sanofi-aventis Research Funding: Mace L. Rothenberg, Sanofi-aventis Expert Testimony: Mace L. Rothenberg, Sanofi-aventis (C) Other Remuneration: None
Conception and design: Daniel G. Haller, Mace L. Rothenberg, Nassir Habboubi, Carlos Garay Provision of study materials or patients: Daniel G. Haller, Mace Rothenberg, Alfred O. Wong, Piotr M. Koralewski, Wilson H. Miller Jr, Gyorgy Bodoky Collection and assembly of data: Nassir Habboubi, Carlos Garay, Luis O. Olivatto Data analysis and interpretation: Daniel G. Haller, Mace L. Rothenberg, Alfred O. Wong, Wilson H. Miller Jr, Carlos Garay Manuscript writing: Daniel Haller, Mace L. Rothenberg, Alfred O. Wong, Carlos Garay Final approval of manuscript: Daniel G. Haller, Mace L. Rothenberg, Alfred O. Wong, Piotr M. Koralewski, Wilson H. Miller Jr, Gyorgy Bodoky, Carlos Garay, Luis O. Olivatto
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Simmonds PC: Palliative chemotherapy for advanced colorectal cancer: Systematic review and meta-analysis—Colorectal Cancer Collaborative Group. BMJ 321:531-535, 2000 2. Cunningham D, Pyrhönen S, James R, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998[CrossRef][Medline] 3. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998[CrossRef][Medline] 4. Machover D, Diaz-Rubio E, de Gramont A, et al: Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 7:95-98, 1996 5. Rothenberg ML, Oza AM, Bigelow RH, et al: Superiority of oxaliplatin and fluorouracil–leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol 21:2059-2069, 2003 6. Bissery MC, Vrignaud P, Lavelle F, et al: In vivo evaluation of the irinotecan-oxaliplatin combination. Eur J Cancer 33:S177, 1997 (suppl 8; abstr A793) 7. Faivre S, Raymond E, Rixe O, et al: In vitro and in vivo rationale for oxaliplatin in combination with other antitumor agents. Ann Oncol 9:145, 1998 (suppl 2; abstr A554) 8. Guichard SM, Arnould S, Hennebelle I, et al: Combination of oxaliplatin and irinotecan in human colon cancer cell lines in vitro and in vivo. Proc Am Ass Cancer Res 41, 2000 (abstr 1692) 9. Zeghari-Squalli N, Raymond E, Cvitkovic E, et al: Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivate oxaliplatin. Clin Cancer Res 5:1189-1196, 1999 10. Bécouarn Y, Gamelin E, Coudert B, et al: Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. J Clin Oncol 19:4195-4201, 2001 11. Bajetta E, Beretta E, Di Bartolomeo M, et al: Efficacy of treatment with irinotecan and oxaliplatin combination in FU-resistant metastatic colorectal cancer patients. Oncology 66:132-137, 2004[CrossRef][Medline] 12. Goldwasser F, Gross-Goupil M, Tigaud J-M, et al: Dose escalation of CPT-11 in combination with oxaliplatin using an every two weeks schedule: A phase I study in advanced gastrointestinal cancer patients. Ann Oncol 11:1463-1470, 2000 13. Kemeny N, Tong W, Gonen M, et al: Phase I study of weekly oxaliplatin plus irinotecan in previously treated patients with metastatic colorectal cancer. Ann Oncol 13:1490-1496, 2002 14. Rougier P, Lepille D, Bennouna J, et al: Antitumour activity of three second-line treatment combinations in patients with metastatic colorectal cancer after optimal 5-FU regimen failure: A randomised, multicentre phase II study. Ann Oncol 13:1558-1567, 2002 15. Scheithauer W, Kornek G, Raderer M, et al: Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer. J Clin Oncol 17:902-906, 1999 16. Timotheadou E, Papakostas P, Tsavdaridis D, et al: Irinotecan and oxaliplatin combination, as second-line treatment, in fluoropyrimidine-pretreated advanced colorectal cancer: A phase II study by the Hellenic Cooperative Oncology Group (HeCOG). Tumori 91:309-313, 2005[Medline] 17. Therasse P, Arbuck S, Eisenhauer E, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000 18. Burris HA III, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403-2413, 1997 19. Storniolo AM, Enas NH, Brown CA, et al: An investigational new drug treatment program for patients with gemcitabine. Cancer 85:1261-1268, 1999[CrossRef][Medline] 20. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004 21. Grothey A, Sargent D, Goldberg RM, et al: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209-1214, 2004 22. Giantonio B, Catalano PJ, Meropol NJ, et al: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol 23:1s, 2005 (suppl; abstr 2)[CrossRef][Medline] Submitted March 18, 2008; accepted April 29, 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
80%, pain score > 2 cm, consumption of 
2 test. Any improvement had to be sustained for 
