First-line chemotherapy for mCRC-a review and evidence-based algorithm

Nature Reviews Clinical Oncology

Volumn 12, Issue 10, 2015, Pages 607-619

  Cremolini, Chiara ^a   Schirripa, Marta ^a   Antoniotti, Carlotta ^a   Moretto, Roberto ^a   Salvatore, Lisa ^a   Masi, Gianluca ^a   Falcone, Alfredo ^a   Loupakis, Fotios ^a  

^a UNIVERSITY HOSPITAL OF PISA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; B RAF KINASE; BEVACIZUMAB; CETUXIMAB; FLUOROPYRIMIDINE; FLUOROURACIL; FOLINIC ACID; IRINOTECAN; K RAS PROTEIN; OXALIPLATIN; PANITUMUMAB; RAS PROTEIN;

CANCER CHEMOTHERAPY; CANCER COMBINATION CHEMOTHERAPY; CANCER SURVIVAL; CLINICAL TRIAL (TOPIC); GENE MUTATION; HUMAN; METASTATIC COLORECTAL CANCER; MONOTHERAPY; NONHUMAN; ONCOGENE RAS; OVERALL SURVIVAL; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIDE EFFECT; SURVIVAL TIME; TREATMENT OUTCOME; TREATMENT PLANNING; WILD TYPE; ALGORITHM; COLORECTAL NEOPLASMS; DECISION MAKING; MORTALITY; SURVIVAL ANALYSIS;

ALGORITHMS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; COLORECTAL NEOPLASMS; DECISION MAKING; HUMANS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; SURVIVAL ANALYSIS;

EID: 84942295564     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2015.129     Document Type: Review

References (92)

1. Siegel, R., Desantis, C., Jemal, A. Colorectal cancer statistics, 2014. CA Cancer J. Clin. 64, 104-117 (2014).
2. Ferlay, J. et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur. J. Cancer 49, 1374-1403 (2013).
3. Hoff, P. M. et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J. Clin. Oncol. 19, 2282-2292 (2001).
4. Venook, A. et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC) [abstract]. J. Clin. Oncol. 32 (5s Suppl.), LBA3 (2014).
5. Loupakis, F. et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N. Engl. J. Med. 371, 1609-1618 (2014).
6. de Gramont, A. et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J. Clin. Oncol. 18, 2938-2947 (2000).
7. Douillard, J. Y. et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355, 1041-1047 (2000).
8. Falcone, A. et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J. Clin. Oncol. 25, 1670-1676 (2007).
9. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335-2342 (2004).
10. Van Cutsem, E. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408-1417 (2009).
11. Douillard, J. Y. et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J. Clin. Oncol. 28, 4697-4705 (2010).
12. De Roock, W. et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 11, 753-762 (2010).
13. Van Cutsem, E. et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 25 (Suppl. 3), iii1-iii9 (2014).
14. Cunningham, D. et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 14, 1077-1085 (2013).
15. Colucci, G. et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J. Clin. Oncol. 23, 4866-4875 (2005).
16. Tournigand, C. 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).
17. Saltz, L. B. et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J. Clin. Oncol. 26, 2013-2019 (2008).
18. Bokemeyer, C. et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 27, 663-671 (2009).
19. Loupakis, F. et al. Clinical impact of anti-epidermal growth factor receptor monoclonal antibodies in first-line treatment of metastatic colorectal cancer: meta-analytical estimation and implications for therapeutic strategies. Cancer 118, 1523-1532 (2012).
20. Douillard, J. Y. et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N. Engl. J. Med. 369, 1023-1034 (2013).
21. Van Cutsem, E. et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J. Clin. Oncol. 33, 692-700 (2015).
22. Kozloff, M. et al. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist 14, 862-870 (2009).
23. Van Cutsem, E. et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann. Oncol. 20, 1842-1847 (2009).
24. Bendell, J. C. et al. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist 17, 1486-1495 (2012).
25. Loupakis, F. et al. FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur. J. Cancer 50, 57-63 (2014).
26. Chibaudel, B. et al. Platinum-sensitivity in metastatic colorectal cancer: towards a definition. Eur. J. Cancer 49, 3813-3820 (2013).
27. Kidwell, K. M. et al. Long-term neurotoxicity effects of oxaliplatin added to fluorouracil and leucovorin as adjuvant therapy for colon cancer: results from National Surgical Adjuvant Breast and Bowel Project trials C-07 and LTS-01. Cancer 118, 5614-5622 (2012).
28. Innocenti, F. et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J. Clin. Oncol. 22, 1382-1388 (2004).
29. Heinemann, V. et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 15, 1065-1075 (2014).
30. Stintzing, S. et al. Independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306) in the final RAS evaluable population [abstract LBA11]. Ann. Oncol. 25 (Suppl. 4), v1-v41 (2014).
31. Schwartzberg, L. S. et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J. Clin. Oncol. 32, 2240-2247 (2014).
32. Rivera, F. et al. First-line treatment with modified FOLFOX6 (mFOLFOX6) + panitumumab (pmab) or bevacizumab (bev) in wild-type (WT) RAS metastatic colorectal carcinoma (mCRC): tumor response outcomes beyond RECIST [abstract]. J. Clin. Oncol. 33 (Suppl. 3), a660 (2015).
33. Lenz, H. et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5FU/leucovorin (FOLFIRI) or oxaliplatin/5FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with expanded RAS analyses untreated metastatic adenocarcinoma of the colon or rectum (mCRC) [abstract]. Ann. Oncol. 25 (5s Suppl.), LBA3 (2014).
34. Karapetis, C. S. et al. PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer-results from NCIC CTG/AGITG CO.17. Clin. Cancer Res. 20, 744-753 (2014).
35. Peeters, M. et al. Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin. Cancer Res. 19, 1902-1912 (2013).
36. Seymour, M. T. et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 14, 749-759 (2013).
37. Pietrantonio, F. et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur. J. Cancer 51, 587-594 (2015).
38. Ince, W. L. et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J. Natl Cancer Inst. 97, 981-989 (2005).
39. Stintzing, S. et al. Mutations within the EGFR signaling pathway: influence on efficacy in FIRE-3-a randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients [abstract]. J. Clin. Oncol. 32 (Suppl. 3), a445 (2014).
40. de Gramont, A. et al. Reintroduction of oxaliplatin is associated with improved survival in advanced colorectal cancer. J. Clin. Oncol. 25, 3224-3229 (2007).
41. Chibaudel, B. et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancerThe GERCOR OPTIMOX2 Study. J. Clin. Oncol. 27, 5727-5733 (2009).
42. Adams, R. A. et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 12, 642-653 (2011).
43. Labianca, R. et al. Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised 'GISCAD' trial. Ann. Oncol. 22, 1236-1242 (2011).
44. Wasan, H. et al. Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial. Lancet Oncol. 15, 631-639 (2014).
45. Garcia Alfonso, P. et al. Phase II study of first-line mFOLFOX plus cetuximab (C) for 8 cycles followed by mFOLFOX plus C or single agent (s/a) C as maintenance therapy in patients (p) with metastatic colorectal cancer (mCRC): the MACRO-2 trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]) [abstract 499O]. Ann. Oncol. 25 (Suppl. 4), iv167-iv209 (2014).
46. Koeberle, D. et al. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann. Oncol. 26, 709-714 (2015).
47. Simkens, L. H. et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 385, 1843-1852 (2015).
48. Arnold, D. et al. Maintenance strategy with fluoropyrimidines (FP) plus bevacizumab (Bev), Bev alone, or no treatment, following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC): a phase III non-inferiority trial (AIO KRK 0207) [abstract]. J. Clin. Oncol. 32 (5s Suppl.), a3503 (2014).
49. Grothey, A., Sargent, D., Goldberg, R. M., Schmoll, H. J. 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).
50. Mans, D. R., Grivicich, I., Peters, G. J., Schwartsmann, G. Sequence-dependent growth inhibition and DNA damage formation by the irinotecan-5-fluorouracil combination in human colon carcinoma cell lines. Eur. J. Cancer 35, 1851-1861 (1999).
51. Raymond, E. et al. Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers. Anticancer Drugs 8, 876-885 (1997).
52. Falcone, A. et al. Biweekly chemotherapy with oxaliplatin, irinotecan, infusional fluorouracil, and leucovorin: a pilot study in patients with metastatic colorectal cancer. J. Clin. Oncol. 20, 4006-4014 (2002).
53. Souglakos, J. et al. Triplet combination with irinotecan plus oxaliplatin plus continuous-infusion fluorouracil and leucovorin as first-line treatment in metastatic colorectal cancer: a multicenter phase II trial. J. Clin. Oncol. 20, 2651-2657 (2002).
54. Souglakos, J. et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br. J. Cancer 94, 798-805 (2006).
55. Golfinopoulos, V., Salanti, G., Pavlidis, N., Ioannidis, J. P. Survival and disease-progression benefits with treatment regimens for advanced colorectal cancer: a meta-analysis. Lancet Oncol. 8, 898-911 (2007).
56. Masi, G. et al. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol. 11, 845-852 (2010).
57. Cremolini, C. et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (mCRC): updated survival results of the phase III TRIBE trial by the GONO group [abstract]. J. Clin. Oncol. 33 (Suppl. 3), a657 (2015).
58. Cremolini, C. et al. Subgroup analyses in RAS mutant, BRAF mutant and "all-wt" metastatic colorectal cancer patients treated with FOLFOXIRI plus bevacizumab (bev) or FOLFIRI plus bev in the TRIBE study [abstract O-0007]. Ann. Oncol. 25 (Suppl. 2), ii107-ii108 (2014).
59. Cremolini, C. et al. Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann. Oncol. 26, 1188-1194 (2015).
60. Gruenberger, T. et al. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann. Oncol. 26, 702-708 (2015).
61. Garufi, C. et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br. J. Cancer 103, 1542-1547 (2010).
62. Assenat, E. et al. Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial. Oncologist 16, 1557-1564 (2011).
63. Folprecht, G. et al. Dose escalating study of cetuximab and 5-FU/folinic acid (FA)/oxaliplatin/irinotecan (FOLFOXIRI) in first line therapy of patients with metastatic colorectal cancer. BMC Cancer 14, 521 (2014).
64. Saridaki, Z. et al. A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial. Br. J. Cancer 107, 1932-1937 (2012).
65. Fornaro, L. et al. FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO). Ann. Oncol. 24, 2062-2067 (2013).
66. Cremolini, C. et al. Modified FOLFOXIRI plus cetuximab (cet) as induction treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): preliminary results of the phase II randomized Macbeth trial by GONO group [abstract]. J. Clin. Oncol. 32 (5s Suppl.), a3596 (2014).
67. Seymour, M. T. et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 370, 143-152 (2007).
68. Koopman, M. et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 370, 135-142 (2007).
69. Ducreux, M. et al. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 12, 1032-1044 (2011).
70. O'Neil, B. H., Goldberg, R. M. Innovations in chemotherapy for metastatic colorectal cancer: an update of recent clinical trials. Oncologist 13, 1074-1083 (2008).
71. Kabbinavar, F. F. et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J. Clin. Oncol. 23, 3706-3712 (2005).
72. Aparicio, T. et al. Geriatric factors predict chemotherapy feasibility: ancillary results of FFCD 2001-02 phase III study in first-line chemotherapy for metastatic colorectal cancer in elderly patients. J. Clin. Oncol. 31, 1464-1470 (2013).
73. Sastre, J. et al. First-line cetuximab plus capecitabine in elderly patients with advanced colorectal cancer: clinical outcome and subgroup analysis according to KRAS status from a Spanish TTD Group study. Oncologist 17, 339-345 (2012).
74. Modest, D. P. et al. 2nd-line therapies after 1st-line therapy with FOLFIRI in combination with cetuximab or bevacizumab in patients with KRAS wild-type metastatic colorectal cancer (mCRC)-analysis of the AIO KRK 0306 (FIRE3)-trial [abstract 508PD]. Ann. Oncol. 25 (Suppl. 4), iv172 (2014).
75. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02339116?term=NCT02339116&rank=1 (2015).
76. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01910610?term=strategic1&rank=1 (2015).
77. Tveit, K. M. et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J. Clin. Oncol. 30, 1755-1762 (2012).
78. Maughan, T. S. et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 377, 2103-2114 (2011).
79. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT00940303 (2015).
80. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02246049?term=NCT02246049&rank=1 (2014).
81. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01321957?term=NCT01321957&rank=1 (2014).
82. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02271464?term=NCT02271464&rank=1 (2015).
83. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02295930?term=NCT02295930&rank=1 (2015).
84. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01328171?term=NCT01328171&rank=1 (2014).
85. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01442935?term=NCT01442935&rank=1 (2015).
86. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02162563?term=NCT02162563&rank=1 (2014).
87. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01802645?term=NCT01802645&rank=1 (2014).
88. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02063529?term=NCT02063529&rank=1 (2014).
89. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02350530 (2015).
90. Kabbinavar, F. 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).
91. Kabbinavar, F. F. et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J. Clin. Oncol. 23, 3697-3705 (2005).
92. Hurwitz, H. I. et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J. Clin. Oncol. 23, 3502-3508 (2005).