EDITORIAL For reprint orders, please contact: [email protected]
Tenth anniversary of bevacizumab in colorectal cancer: has it fulfilled its promise?
“While [bevacizumab] has definitely become a new option in many treatment combinations in the advanced disease setting, its strategic positioning is complex and controversial.”
Ramon Salazar*1, Julieta Grasselli1, Cristina Santos1 & Josep Tabernero2 The addition of bevacizumab to the treatment of metastatic colorectal cancer patients reaches its tenth anniversary this year accompanied by somewhat mixed feelings from our perspective and the lack of unanimity among oncologists dealing with this deadly disease. While it has definitely become a new option in many treatment combinations in the advanced disease setting, its strategic positioning is complex and controversial. While some advocate for its wider use in first- and second-line chemo therapy combinations, even continuing it beyond progression, others are more cautious and recommend a more restricted use. Its efficacy has been validated in multiple Phase III clinical trials with a number of chemotherapy backbone regimens, which provide solid evidence confirming its consistent biological activity and clinical relevance [1–6]. However, not all chemotherapy regimens are the same and bevacizumab has yielded its best, indisputable results in second-line therapy or in combination with chemotherapy backbones that could be viewed as suboptimal, alternative or even inappropriate. Furthermore, it has failed to
be of any additional benefit to current standard oxaliplatin-containing adjuvant chemotherapy [7,8] and there are also diverse views on its safety profile. While some physicians claim that it combines well with all chemotherapy regimens without cross toxicities, others emphasize its silent, yet life-threatening class effect cardiovascular adverse events [9]. A clear explanation of the gap between the promising preclinical findings and the limited efficacy of bevacizumab and other angiogenesis inhibitors in the clinic is lacking. Nevertheless, some hints derived from preclinical models regarding the induction of a more invasive phenotype can explain the absence of benefit in the adjuvant setting or, conversely, the higher clinical efficacy in the later advanced settings [10].
KEYWORDS
• bevacizumab • colon cancer • colonic neoplasms • therapeutics • therapy
“While some physicians claim [bevacizumab] combines well with all chemotherapy regimens without cross toxicities, others emphasize its silent, yet life-threatening class effect cardiovascular adverse events.”
Not all chemotherapeutic backbones are the same There is ample consensus and compelling evidence demonstrating that the three optimal chemotherapy backbone regimens for the advanced disease setting are
Medical Oncology Department, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain 2 Medical Oncology Department, Vall d’Hebron University Hospital & Institute of Oncology (VHIO), Barcelona, Spain *Author for correspondence: [email protected] 1
10.2217/FON.14.6 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(2), 149–152
part of
ISSN 1479-6694
149
EDITORIAL Salazar, Grasselli, Santos & Tabernero oxaliplatin plus 5-fluorouracil (5FU)/leucovorin (LV) infusion (FOLFOX), irinotecan plus 5FU/LV infusion (FOLFIRI) and capecitabine plus oxaliplatin (CAPOX). FOLFOX and FOLFIRI are interchangeable and prone to be sequenced between the first and the second line of chemotherapy [11,12]. The selection of one over the other is based on the differential toxicity profiles in relation to patients’ comorbidities and eventually on the evidence gathered for their optimal combination with the approved monoclonal antibodies bevacizumab, cetuximab or panitumumab, and their sequence of administration. It is important to note, especially for the discussion that follows, that both FOLFOX and FOLFIRI have proven to be more efficacious than 5FU/LV [13]. More importantly, FOLFOX has proven to be superior to and less toxic than irinotecan, weekly bolus 5FU and leucovorin (IFL), irinotecan and oxaliplatin (IROX) [14], and reduced-dose IFL (a less toxic version of IFL) [15], and FOLFIRI is more efficacious and less toxic than IFL or capecitabine plus irinotecan [16]. CAPOX has proven to be noninferior to FOLFOX in terms of efficacy and safety [17].
“There is ample consensus
and compelling evidence demonstrating that the three optimal chemotherapy backbone regimens for the advanced disease setting are oxaliplatin plus 5-fluorouracil/leucovorin infusion, irinotecan plus 5-fluorouracil/leucovorin infusion and capecitabine plus oxaliplatin.”
150
The addition of bevacizumab improves efficacy of first-line chemotherapy but its benefit is not homogeneous among distinct chemotherapy backbones Regarding first-line trials, bevacizumab has demonstrated unequivocally added value in combination with IFL [1], 5FU/LV [2] or capecitabine [3]. It has also provided a marginal improvement in progression-free survival in combination with FOLFOX or CAPOX in the complex 2 × 2 randomized NO16966 trial [4] but no randomized trial of the addition of bevacizumab to FOLFIRI in the first-line setting has been performed until now. The argument that the TREE [18] or BICCC [19] trials support the addition of bevacizumab to FOLFIRI or FOLFOX is flawed because these are nonrandomized comparisons. If anything, they speak against such an interpretation because the TREE trial shows that FOLFIRI is superior to irinotecan plus bolus 5-FU/LV and irinotecan plus oral capecitabine, and the BICC-C trial shows that FOLFOX is superior to bolus 5-FU plus low-dose LV with oxaliplatin, and CAPOX. Therefore, this defines FOLFOX and FOLFIRI as the toughest comparator arms, and the addition of bevacizumab has not demonstrated unambiguous improvement of efficacy in any randomized comparison with any of these
Future Oncol. (2014) 10(2)
arms. In the FOLFOX subgroup analysis of the NO16966 trial, the addition of bevacizumab provided a marginal yet statistically significant benefit in progression-free survival (hazard ratio [HR]: 0.89) [4]. Although thousands of patients have been treated with first-line FOLFIRI plus bevacizumab, and more than 20 trials with this combination have been reported, none have involved a randomization design [20]. Bevacizumab in second-line combinations & its strategic positioning in advanced colorectal cancer The second-line E3200 ECOG trial compared FOLFOX versus FOLFOX plus bevacizumab in patients that had received first-line chemotherapy with irinotecan and fluoropyrimidines. This was a clearly positive trial with a 2‑month improvement in median overall survival and a statistically significant HR for death of 0.75 [5]. The ML 18147 trial tested the continuation of bevacizumab beyond progression in patients who had received first-line treatments that contained standard fluoropyrimidine and irinotecan or oxaliplatin-containing chemotherapy regimens plus bevacizumab [6]. Upon progression, patients were randomized to receive or not to receive bevacizumab in combination with a switched oxaliplatin or irinotecan chemotherapy regimen. Those who had received irinotecan in the first-line setting were switched to an oxaliplatin-containing second-line regimen and vice versa. Patients had to have been on bevacizumab without progression for more than 3 months in the first-line regimen and progression had to be documented within 3 months from the last dose of bevacizumab. With this approach, rapid progressors, those intolerant to bevacizumab or chemotherapy, and patients that could reasonably still respond to the firstline combination were excluded. This was also a clearly positive trial with a 1.5-month improvement in median overall survival and a statistically significant HR for death of 0.81. Interestingly, the subgroup analysis showed that patients with a previous progression-free survival interval in the first-line setting longer than 9 months derived greater benefit (HR: 0.73; 95% CI: 0.58–0.92) than those with a shorter interval (HR: 0.89; 95% CI: 0.73–1.09). The interpretations of these results are challenged by the fact that the first-line therapy was uncontrolled and involved combinations for which there is no clear evidence of benefit in the first place, however
future science group
Tenth anniversary of bevacizumab in colorectal cancer: has it fulfilled its promise? there is little doubt that they again confirm the biological activity and clinical relevance of this compound in the advanced disease setting. How much they help in the strategic positioning in the global algorithm is a matter of further debate. They clearly confirm the positioning of bevacizumab in the second-line setting with either oxaliplatin or irinotecan combinations, and that it is beneficial to continue to administer bevacizumab beyond progression in those patients that have also received it in the firstline setting. Whether bevacizumab should be part of the first-line strategy in all patients with advanced colorectal cancer remains to be determined. First, this is because there is inconclusive evidence of its added value in combination with the optimal chemotherapy backbone regimens, which is particularly striking in the case of the FOLFIRI regimen, where there is a lack of randomized data, and second, because recent results of first-line combinations with EGFRinhibitors in patients selected with an extended panel of mutations both in K-RAS and N-RAS genes (hot spots in exons 2, 3 and 4) have been impressive [21,22]. This contrasts with the lack of validated predictive markers for bevacizumab [23,24] and raises the unresolved question of what the optimal sequence is between EGFR inhibitors and bevacizumab in combination with first, second and third lines of treatments. Finally, References 1
2
3
4
Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350(23), 2335–2342 (2004). Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J. Clin. Oncol. 23(16), 3706–3712 (2005). Cunningham D, Lang I, Marcuello E 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(11), 1077–1085 (2013). Saltz LB, Clarke S, Diaz-Rubio E et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line
future science group
bevacizumab-containing regimens remain the best option for the increasing number of patients ineligible for EGFR inhibitors or polychemotherapy regimens containing oxaliplatin or irinotecan. Hopefully, the large Phase III study CALGB 80405 will shed some light on this and elucidate which is the best treatment strategy in the first-line setting. Acknowledgements The authors would like to thank L Vecchione (KU Leuven, NKI Amsterdam) for critical reading of the manuscript and S Kelly for English editing.
Financial & competing interests disclosure R Salazar is a consultant and has a advisory role for Amgen, Merck KGaA, Novartis and Ipsen. He has also honoraria for presentations for Amgen, Merck KGaA, Novartis and Ipsen. J Tabernero is a consultant and has an advisory role for Amgen, Boehringer, Bristol-Myers Squibb, Genentech, Imclone, Lilly, Merck KGaA, Millennium, Novartis, Onyx, Pfizer, Roche, Sanofi and Celgene. He has also received honoraria for presentations for Amgen, Merck KGaA, Novartis, Roche and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
therapy in metastatic colorectal cancer: a randomized Phase III study. J. Clin. Oncol. 26(12), 2013–2019 (2008). 5
6
7
8
EDITORIAL
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(12), 1539–1544 (2007). Bennouna J, Sastre J, Arnold D et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised Phase 3 trial. Lancet Oncol. 14(1), 29–37 (2013). 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. 29(1), 11–16 (2013). de Gramont A, Van Cutsem E, Schmoll HJ et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a Phase 3 randomised
controlled trial. Lancet Oncol. 13(12), 1225–1233 (2012). 9
Ranpura V, Hapani S, Wu S. Treatmentrelated mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 305(5), 487–494 (2011).
10 Paez-Ribes M, Allen E, Hudock J et al.
Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15(3), 220–231 (2009). 11 Colucci G, Gebbia V, Paoletti 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(22), 4866–4875 (2005). 12 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(2), 229–237 (2004).
www.futuremedicine.com
151
EDITORIAL Salazar, Grasselli, Santos & Tabernero 13 Grothey A, Sargent D, Goldberg RM, Schmoll
HJ. 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(7), 1209–1214 (2004). 14 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(1), 23–30 (2004). 15 Goldberg RM, Sargent DJ, Morton RF et al.
Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: a North American Intergroup Trial. J. Clin. Oncol. 24(21), 3347–3353 (2006). 16 Fuchs CS, Marshall J, Mitchell E et al.
Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J. Clin. Oncol. 25(30), 4779–4786 (2007).
152
17 Cassidy J, Clarke S, Diaz-Rubio E et al.
Randomized Phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J. Clin. Oncol. 26(12), 2006–2012 (2008). 18 Hochster HS, Hart LL, Ramanathan RK
et al. 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. J. Clin. Oncol. 26(21), 3523–3529 (2008). 19 Fuchs CS, Marshall J, Barrueco J.
Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J. Clin. Oncol. 26(4), 689–690 (2008). 20 Petrelli F, Borgonovo K, Cabiddu M et al.
FOLFIRI-bevacizumab as first-line chemotherapy in 3500 patients with advanced colorectal cancer: a pooled analysis of 29 published trials. Clin. Colorectal Cancer 12(3), 145–151 (2013).
Future Oncol. (2014) 10(2)
21 Douillard JY, Oliner KS, Siena S et al.
Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N. Engl. J. Med. 369(11), 1023–1034 (2013). 22 Stintzing S, Jung A, Rossius L et al. Analysis of
KRAS/NRAS and BRAF mutations 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. Presented at: European Cancer Congress 2013. Amsterdam, The Netherlands, 28 September 2013 (Abstract LBA E17- 7073). 23 Hegde PS, Jubb AM, Chen D et al. Predictive
impact of circulating vascular endothelial growth factor in four Phase III trials evaluating bevacizumab. Clin. Cancer Res. 19(4), 929–937 (2013). 24 Hurwitz HI, Douglas PS, Middleton JP et al.
Analysis of early hypertension and clinical outcome with bevacizumab: results from seven Phase III studies. Oncologist 18(3), 273–280 (2013).
future science group
Tenth anniversary of bevacizumab in colorectal cancer: has it fulfilled its promise?
“While [bevacizumab] has definitely become a new option in many treatment combinations in the advanced disease setting, its strategic positioning is complex and controversial.”
Ramon Salazar*1, Julieta Grasselli1, Cristina Santos1 & Josep Tabernero2 The addition of bevacizumab to the treatment of metastatic colorectal cancer patients reaches its tenth anniversary this year accompanied by somewhat mixed feelings from our perspective and the lack of unanimity among oncologists dealing with this deadly disease. While it has definitely become a new option in many treatment combinations in the advanced disease setting, its strategic positioning is complex and controversial. While some advocate for its wider use in first- and second-line chemo therapy combinations, even continuing it beyond progression, others are more cautious and recommend a more restricted use. Its efficacy has been validated in multiple Phase III clinical trials with a number of chemotherapy backbone regimens, which provide solid evidence confirming its consistent biological activity and clinical relevance [1–6]. However, not all chemotherapy regimens are the same and bevacizumab has yielded its best, indisputable results in second-line therapy or in combination with chemotherapy backbones that could be viewed as suboptimal, alternative or even inappropriate. Furthermore, it has failed to
be of any additional benefit to current standard oxaliplatin-containing adjuvant chemotherapy [7,8] and there are also diverse views on its safety profile. While some physicians claim that it combines well with all chemotherapy regimens without cross toxicities, others emphasize its silent, yet life-threatening class effect cardiovascular adverse events [9]. A clear explanation of the gap between the promising preclinical findings and the limited efficacy of bevacizumab and other angiogenesis inhibitors in the clinic is lacking. Nevertheless, some hints derived from preclinical models regarding the induction of a more invasive phenotype can explain the absence of benefit in the adjuvant setting or, conversely, the higher clinical efficacy in the later advanced settings [10].
KEYWORDS
• bevacizumab • colon cancer • colonic neoplasms • therapeutics • therapy
“While some physicians claim [bevacizumab] combines well with all chemotherapy regimens without cross toxicities, others emphasize its silent, yet life-threatening class effect cardiovascular adverse events.”
Not all chemotherapeutic backbones are the same There is ample consensus and compelling evidence demonstrating that the three optimal chemotherapy backbone regimens for the advanced disease setting are
Medical Oncology Department, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain 2 Medical Oncology Department, Vall d’Hebron University Hospital & Institute of Oncology (VHIO), Barcelona, Spain *Author for correspondence: [email protected] 1
10.2217/FON.14.6 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(2), 149–152
part of
ISSN 1479-6694
149
EDITORIAL Salazar, Grasselli, Santos & Tabernero oxaliplatin plus 5-fluorouracil (5FU)/leucovorin (LV) infusion (FOLFOX), irinotecan plus 5FU/LV infusion (FOLFIRI) and capecitabine plus oxaliplatin (CAPOX). FOLFOX and FOLFIRI are interchangeable and prone to be sequenced between the first and the second line of chemotherapy [11,12]. The selection of one over the other is based on the differential toxicity profiles in relation to patients’ comorbidities and eventually on the evidence gathered for their optimal combination with the approved monoclonal antibodies bevacizumab, cetuximab or panitumumab, and their sequence of administration. It is important to note, especially for the discussion that follows, that both FOLFOX and FOLFIRI have proven to be more efficacious than 5FU/LV [13]. More importantly, FOLFOX has proven to be superior to and less toxic than irinotecan, weekly bolus 5FU and leucovorin (IFL), irinotecan and oxaliplatin (IROX) [14], and reduced-dose IFL (a less toxic version of IFL) [15], and FOLFIRI is more efficacious and less toxic than IFL or capecitabine plus irinotecan [16]. CAPOX has proven to be noninferior to FOLFOX in terms of efficacy and safety [17].
“There is ample consensus
and compelling evidence demonstrating that the three optimal chemotherapy backbone regimens for the advanced disease setting are oxaliplatin plus 5-fluorouracil/leucovorin infusion, irinotecan plus 5-fluorouracil/leucovorin infusion and capecitabine plus oxaliplatin.”
150
The addition of bevacizumab improves efficacy of first-line chemotherapy but its benefit is not homogeneous among distinct chemotherapy backbones Regarding first-line trials, bevacizumab has demonstrated unequivocally added value in combination with IFL [1], 5FU/LV [2] or capecitabine [3]. It has also provided a marginal improvement in progression-free survival in combination with FOLFOX or CAPOX in the complex 2 × 2 randomized NO16966 trial [4] but no randomized trial of the addition of bevacizumab to FOLFIRI in the first-line setting has been performed until now. The argument that the TREE [18] or BICCC [19] trials support the addition of bevacizumab to FOLFIRI or FOLFOX is flawed because these are nonrandomized comparisons. If anything, they speak against such an interpretation because the TREE trial shows that FOLFIRI is superior to irinotecan plus bolus 5-FU/LV and irinotecan plus oral capecitabine, and the BICC-C trial shows that FOLFOX is superior to bolus 5-FU plus low-dose LV with oxaliplatin, and CAPOX. Therefore, this defines FOLFOX and FOLFIRI as the toughest comparator arms, and the addition of bevacizumab has not demonstrated unambiguous improvement of efficacy in any randomized comparison with any of these
Future Oncol. (2014) 10(2)
arms. In the FOLFOX subgroup analysis of the NO16966 trial, the addition of bevacizumab provided a marginal yet statistically significant benefit in progression-free survival (hazard ratio [HR]: 0.89) [4]. Although thousands of patients have been treated with first-line FOLFIRI plus bevacizumab, and more than 20 trials with this combination have been reported, none have involved a randomization design [20]. Bevacizumab in second-line combinations & its strategic positioning in advanced colorectal cancer The second-line E3200 ECOG trial compared FOLFOX versus FOLFOX plus bevacizumab in patients that had received first-line chemotherapy with irinotecan and fluoropyrimidines. This was a clearly positive trial with a 2‑month improvement in median overall survival and a statistically significant HR for death of 0.75 [5]. The ML 18147 trial tested the continuation of bevacizumab beyond progression in patients who had received first-line treatments that contained standard fluoropyrimidine and irinotecan or oxaliplatin-containing chemotherapy regimens plus bevacizumab [6]. Upon progression, patients were randomized to receive or not to receive bevacizumab in combination with a switched oxaliplatin or irinotecan chemotherapy regimen. Those who had received irinotecan in the first-line setting were switched to an oxaliplatin-containing second-line regimen and vice versa. Patients had to have been on bevacizumab without progression for more than 3 months in the first-line regimen and progression had to be documented within 3 months from the last dose of bevacizumab. With this approach, rapid progressors, those intolerant to bevacizumab or chemotherapy, and patients that could reasonably still respond to the firstline combination were excluded. This was also a clearly positive trial with a 1.5-month improvement in median overall survival and a statistically significant HR for death of 0.81. Interestingly, the subgroup analysis showed that patients with a previous progression-free survival interval in the first-line setting longer than 9 months derived greater benefit (HR: 0.73; 95% CI: 0.58–0.92) than those with a shorter interval (HR: 0.89; 95% CI: 0.73–1.09). The interpretations of these results are challenged by the fact that the first-line therapy was uncontrolled and involved combinations for which there is no clear evidence of benefit in the first place, however
future science group
Tenth anniversary of bevacizumab in colorectal cancer: has it fulfilled its promise? there is little doubt that they again confirm the biological activity and clinical relevance of this compound in the advanced disease setting. How much they help in the strategic positioning in the global algorithm is a matter of further debate. They clearly confirm the positioning of bevacizumab in the second-line setting with either oxaliplatin or irinotecan combinations, and that it is beneficial to continue to administer bevacizumab beyond progression in those patients that have also received it in the firstline setting. Whether bevacizumab should be part of the first-line strategy in all patients with advanced colorectal cancer remains to be determined. First, this is because there is inconclusive evidence of its added value in combination with the optimal chemotherapy backbone regimens, which is particularly striking in the case of the FOLFIRI regimen, where there is a lack of randomized data, and second, because recent results of first-line combinations with EGFRinhibitors in patients selected with an extended panel of mutations both in K-RAS and N-RAS genes (hot spots in exons 2, 3 and 4) have been impressive [21,22]. This contrasts with the lack of validated predictive markers for bevacizumab [23,24] and raises the unresolved question of what the optimal sequence is between EGFR inhibitors and bevacizumab in combination with first, second and third lines of treatments. Finally, References 1
2
3
4
Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350(23), 2335–2342 (2004). Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J. Clin. Oncol. 23(16), 3706–3712 (2005). Cunningham D, Lang I, Marcuello E 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(11), 1077–1085 (2013). Saltz LB, Clarke S, Diaz-Rubio E et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line
future science group
bevacizumab-containing regimens remain the best option for the increasing number of patients ineligible for EGFR inhibitors or polychemotherapy regimens containing oxaliplatin or irinotecan. Hopefully, the large Phase III study CALGB 80405 will shed some light on this and elucidate which is the best treatment strategy in the first-line setting. Acknowledgements The authors would like to thank L Vecchione (KU Leuven, NKI Amsterdam) for critical reading of the manuscript and S Kelly for English editing.
Financial & competing interests disclosure R Salazar is a consultant and has a advisory role for Amgen, Merck KGaA, Novartis and Ipsen. He has also honoraria for presentations for Amgen, Merck KGaA, Novartis and Ipsen. J Tabernero is a consultant and has an advisory role for Amgen, Boehringer, Bristol-Myers Squibb, Genentech, Imclone, Lilly, Merck KGaA, Millennium, Novartis, Onyx, Pfizer, Roche, Sanofi and Celgene. He has also received honoraria for presentations for Amgen, Merck KGaA, Novartis, Roche and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
therapy in metastatic colorectal cancer: a randomized Phase III study. J. Clin. Oncol. 26(12), 2013–2019 (2008). 5
6
7
8
EDITORIAL
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(12), 1539–1544 (2007). Bennouna J, Sastre J, Arnold D et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised Phase 3 trial. Lancet Oncol. 14(1), 29–37 (2013). 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. 29(1), 11–16 (2013). de Gramont A, Van Cutsem E, Schmoll HJ et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a Phase 3 randomised
controlled trial. Lancet Oncol. 13(12), 1225–1233 (2012). 9
Ranpura V, Hapani S, Wu S. Treatmentrelated mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 305(5), 487–494 (2011).
10 Paez-Ribes M, Allen E, Hudock J et al.
Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15(3), 220–231 (2009). 11 Colucci G, Gebbia V, Paoletti 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(22), 4866–4875 (2005). 12 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(2), 229–237 (2004).
www.futuremedicine.com
151
EDITORIAL Salazar, Grasselli, Santos & Tabernero 13 Grothey A, Sargent D, Goldberg RM, Schmoll
HJ. 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(7), 1209–1214 (2004). 14 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(1), 23–30 (2004). 15 Goldberg RM, Sargent DJ, Morton RF et al.
Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: a North American Intergroup Trial. J. Clin. Oncol. 24(21), 3347–3353 (2006). 16 Fuchs CS, Marshall J, Mitchell E et al.
Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J. Clin. Oncol. 25(30), 4779–4786 (2007).
152
17 Cassidy J, Clarke S, Diaz-Rubio E et al.
Randomized Phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J. Clin. Oncol. 26(12), 2006–2012 (2008). 18 Hochster HS, Hart LL, Ramanathan RK
et al. 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. J. Clin. Oncol. 26(21), 3523–3529 (2008). 19 Fuchs CS, Marshall J, Barrueco J.
Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J. Clin. Oncol. 26(4), 689–690 (2008). 20 Petrelli F, Borgonovo K, Cabiddu M et al.
FOLFIRI-bevacizumab as first-line chemotherapy in 3500 patients with advanced colorectal cancer: a pooled analysis of 29 published trials. Clin. Colorectal Cancer 12(3), 145–151 (2013).
Future Oncol. (2014) 10(2)
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