DOI:10.1093/jnci/djt442
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
Editorial
The Challenge to Optimize Medical Therapy for Advanced Colorectal Cancer Joleen M. Hubbard, Axel Grothey Correspondence to: Axel Grothey, MD, Division of Medical Oncology, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]).
jnci.oxfordjournals.org
The most commonly used first-line regimen in the United States is, not unexpectedly, a combination of FOLFOX and bevacizumab, with FOLFOX consistently accounting for approximately 70% of all chemotherapy regimens in this setting over the years. Bevacizumab was found to be a component of first-line therapy in slightly more than 50% of regimens from 2005 until 2010, with a notable drop in its use to 43% in 2011. In fact, 2011 was the first year since 2004 in which more patients received chemotherapy alone without biologic agents as first-line treatment. It can be speculated whether the negative trials of bevacizumab in adjuvant colon cancer and the FDA decision to revoke approval of bevacizumab in breast cancer had an influence on physicians’ prescribing pattern. Although cetuximab and bevacizumab gained FDA approval within 2 weeks from each other in early 2004, the uptake of bevacizumab in clinical practice appeared much more rapid than that of cetuximab. This was conceivably influenced by the fact that bevacizumab was approved as a component of first-line therapy whereas cetuximab was initially only approved as a salvage therapy option (3,4). Overall, the exposure to EGFR antibodies remained relatively low in the last decade, which is likely evidence that these agents are commonly used in later lines of therapy. Before KRAS testing became mandatory, their use had increased over time up to 44% of all patients, then dropped to 23%. However, in 2011, EGFR antibodies were offered to 33% of patients, which represents about 55% of the patients who would be considered candidates for EGFR antibodies based on their KRAS mutation status. Interestingly, about a third of patients received bevacizumab beyond progression even before data from randomized clinical trials that supported this strategy became available (5). The percentage of patients with bevacizumab continued into second-line therapy was relatively stable over time and not influenced by the presentation and publication of observational study data that suggested a large survival benefit for this treatment strategy (6). Of important concern is the finding that only 53% of patients received second-line therapies and only 28% received third-line therapies, so likely only a minority of patients were exposed to all active agents in the course of their therapy. Unfortunately, the very nature of the analysis did not allow the association between treatment patterns and outcome, so the impact of the limited exposure of patients to all active agents on survival is unclear. It is also concerning that even in academic centers only 50% of patients were tested for KRAS after 2009, which is the mandatory prerequisite to identify patients as appropriate candidates for EGFR antibody therapy (7). The study does not allow assessment JNCI | Editorial 1 of 2
Downloaded from http://jnci.oxfordjournals.org/ at Aston University on September 2, 2014
Outcomes of patients with metastatic colorectal cancer (mCRC) have shown remarkable improvements in the last 10 to 15 years, with median overall survival in clinical trials now approaching 3 years. These advances are closely linked to the introduction of multiple active agents and drug combinations into clinical practice. As of December 2013, nine drugs have received US Food and Drug Administration (FDA) approval for the treatment of mCRC: the cytotoxic agents 5-fluorouracil, capecitabine, irinotecan, and oxaliplatin; the EGFR antibodies cetuximab and panitumumab; the VEGF inhibitors bevacizumab and aflibercept; and the multikinase inhibitor regorafenib. Before the era of biologic agents, it was shown that access to all active agents in the course of therapy is associated with improved survival (1). Although no such analysis has yet been performed after the introduction of biologics, it is conceivable that the overall principle of optimizing outcome by exposing patients to all available active agents in a strategic manner is still valid today. An abundance of data from clinical trials has been generated in the last decade in advanced colorectal cancer. Evidence-based guidelines (National Comprehensive Cancer Network, European Society of Medical Oncology) try to synthesize and structure the complexity of these clinical trial data to guide practical treatment decisions. All guidelines emphasize the importance of exposing patients to all active agents in rational, sequential treatment steps. It has, however, been questioned whether the treatment principles outlined in guidelines are actually being implemented in clinical practice. In the absence of a comprehensive tumor registry in the United States, which includes information on medical therapy, observational studies are the best tools available to obtain an understanding of treatment algorithms in clinical practice. The study by Abrams and colleagues in this issue of the Journal (2) tried to analyze the treatment pattern of US oncologists for patients with mCRC from 2004 to 2011, the time when bevacizumab and the EGFR monoclonal antibodies cetuximab and panitumumab were integrated into clinical practice. It has to be pointed out that the very nature of the dataset, which was based on chemotherapy order entries provided by a commercial chemotherapy vendor, has certain shortcomings. No data on patient outcomes were recorded, the definition of line of therapy required extrapolation and modeling of treatment sequences based on chemotherapy prescriptions and time interval assumptions, and no data are available on the reason why therapies were changed. Nevertheless, the analysis provides valuable insights into the treatment preferences of oncologists in the United States.
2 of 2 Editorial | JNCI
The adherence to evidence-based guidelines needs to be implemented as a mandatory quality measure for the prescribing practice of oncologists with implications for reimbursement for medical care. In addition, the analysis by Abrams et al. (2) demonstrates the importance of outlining optimized treatment algorithms for patients with mCRC. Unfortunately, only a few prospective clinical trials have investigated treatment strategies in mCRC. With the overall low inclusion rate of patients in clinical trials [2.4% in the study by Abrams and colleagues (2)] and, particularly, the challenges the federally funded clinical trials system is facing in the United States, it is not likely that this situation will change. A solution could be to establish a national tumor registry in which treatment algorithms are documented and eventually associated with outcome. This registry could provide valuable information not obtainable from clinical trials and also serve as a tool to monitor guideline adherence to improve the care of patients with mCRC and other tumor entities. References 1. 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. 2004;22(7):1209–1214. 2. Abrams A, Meyer G, Schrag D, Meyerhardt JA. Chemotherapy usage patterns in a US-wide cohort of patients with metastatic colorectal cancer. JNCI J Natl Cancer Inst (2014) 106 (2):djt371 doi:10.1093/jnci/djt371 3. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–2342. 4. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–345. 5. 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. 2013;14(1):29–37. 6. Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol. 2008;26(33):5326–5334. 7. Blanke CD, Goldberg RM, Grothey A, et al. KRAS and colorectal cancer: ethical and pragmatic issues in effecting real-time change in oncology clinical trials and practice. Oncologist. 2011;16(8):1061–1068. 8. 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. 2004;22(2):229–237. 9. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343(13):905–914. 10. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355(9209):1041–1047. 11. Saltz LB, Clarke S, Diaz-Rubio E, 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. 2008;26(12):2013–2019. 12. Douillard JY, Oliner KS, Siena S, 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. 2010;28(31):4697–4705. 13. Loupakis F, Cremolini C, Salvatore L, et al. FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur J Cancer. 2014;50(1):57–63. Affiliation of authors: Division of Medical Oncology, Mayo Clinic Rochester, Rochester, MN (JMH, AG). Vol. 106, Issue 2 | djt442 | February 5, 2014
Downloaded from http://jnci.oxfordjournals.org/ at Aston University on September 2, 2014
of how many patients might have received EGFR antibodies without prior KRAS mutation testing, which could not only result in an ineffective therapy but also have a potential detrimental effect in patients with KRAS mutated mCRC. What are the main factors influencing these observed treatment patterns and the apparent lack of adherence to published guidelines? Certain prevalent treatment patterns can only be understood in the historic context in which they evolved. In the United States, irinotecan was initially developed in combination with bolus 5-fluorouracil/leucovorin (IFL), in contrast to Europe where an infusional 5-FU/LV regimen formed the backbone for FOLFIRI (8–10). When a US Intergroup phase III trial showed indisputable superiority for the oxaliplatin-based FOLFOX over IFL, FOLFOX was adopted as the standard first-line regimen by the majority of US oncologists in spite of the fact that European trials demonstrated identical efficacy for FOLFOX and FOLFIRI (8). When bevacizumab received FDA approval to be used in combination with “intravenous 5-fluorouracil–based chemotherapy,” it was simply added to FOLFOX, the perceived most effective firstline chemotherapy regimen. Thus, FOLFOX plus bevacizumab became the most widely used first-line therapy in the United States. Subsequent data from a large phase III trial (11) that questioned the magnitude of benefit patients derive from the addition of bevacizumab to FOLFOX in first-line therapy have not been able to affect the strong preference of oncologists for this combination, as documented in the analysis by Abrams et al. (2). It has to be pointed out that in Europe FOLFOX and FOLFIRI are used in similar frequency as first-line regimens with bevacizumab (5). Making appropriate treatment decisions in mCRC has become more challenging over the years with the availability of multiple active agents and combination regimens and prognostic and predictive biomarkers. The overwhelming amount of information from clinical trials could make oncologists preferably rely on one familiar, default therapeutic approach and resort to FOLFOX plus bevacizumab as standard first-line therapy. Although this treatment is likely appropriate for the majority of patients, a more individualized approach would be preferable to take more patient- and tumor-related factors into account. It is evident that oncologists will face a further increased complexity of treatment decisions in mCRC in the future with the development and validation of molecular prognostic and predictive markers. Even at this point in time, an expanded RAS analysis to include KRAS and NRAS mutations beyond standard KRAS exon 2 (codon 12/13) testing appears mandatory to appropriately select patients for EGFR antibody therapy (12). BRAF mutation testing for all patients with mCRC should also be considered because a differential, intensified upfront treatment approach with FOLFOXIRI plus bevacizumab is emerging as a new standard of care in this patient population (13). In addition, the poor prognosis of patients with BRAF mutated mCRC has made them the key target of various trials to improve outcome with combinations of targeted agents based on translational studies. These developments underscore the high educational need oncologists are facing to optimize treatment algorithms for individual patients. Improving access to high-quality, unbiased educational programs in the context of continued medical education seems pertinent to overcome the apparent failure to effectively disseminate and adopt practice-changing information, which ultimately affects the survival of patients.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
Editorial
The Challenge to Optimize Medical Therapy for Advanced Colorectal Cancer Joleen M. Hubbard, Axel Grothey Correspondence to: Axel Grothey, MD, Division of Medical Oncology, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]).
jnci.oxfordjournals.org
The most commonly used first-line regimen in the United States is, not unexpectedly, a combination of FOLFOX and bevacizumab, with FOLFOX consistently accounting for approximately 70% of all chemotherapy regimens in this setting over the years. Bevacizumab was found to be a component of first-line therapy in slightly more than 50% of regimens from 2005 until 2010, with a notable drop in its use to 43% in 2011. In fact, 2011 was the first year since 2004 in which more patients received chemotherapy alone without biologic agents as first-line treatment. It can be speculated whether the negative trials of bevacizumab in adjuvant colon cancer and the FDA decision to revoke approval of bevacizumab in breast cancer had an influence on physicians’ prescribing pattern. Although cetuximab and bevacizumab gained FDA approval within 2 weeks from each other in early 2004, the uptake of bevacizumab in clinical practice appeared much more rapid than that of cetuximab. This was conceivably influenced by the fact that bevacizumab was approved as a component of first-line therapy whereas cetuximab was initially only approved as a salvage therapy option (3,4). Overall, the exposure to EGFR antibodies remained relatively low in the last decade, which is likely evidence that these agents are commonly used in later lines of therapy. Before KRAS testing became mandatory, their use had increased over time up to 44% of all patients, then dropped to 23%. However, in 2011, EGFR antibodies were offered to 33% of patients, which represents about 55% of the patients who would be considered candidates for EGFR antibodies based on their KRAS mutation status. Interestingly, about a third of patients received bevacizumab beyond progression even before data from randomized clinical trials that supported this strategy became available (5). The percentage of patients with bevacizumab continued into second-line therapy was relatively stable over time and not influenced by the presentation and publication of observational study data that suggested a large survival benefit for this treatment strategy (6). Of important concern is the finding that only 53% of patients received second-line therapies and only 28% received third-line therapies, so likely only a minority of patients were exposed to all active agents in the course of their therapy. Unfortunately, the very nature of the analysis did not allow the association between treatment patterns and outcome, so the impact of the limited exposure of patients to all active agents on survival is unclear. It is also concerning that even in academic centers only 50% of patients were tested for KRAS after 2009, which is the mandatory prerequisite to identify patients as appropriate candidates for EGFR antibody therapy (7). The study does not allow assessment JNCI | Editorial 1 of 2
Downloaded from http://jnci.oxfordjournals.org/ at Aston University on September 2, 2014
Outcomes of patients with metastatic colorectal cancer (mCRC) have shown remarkable improvements in the last 10 to 15 years, with median overall survival in clinical trials now approaching 3 years. These advances are closely linked to the introduction of multiple active agents and drug combinations into clinical practice. As of December 2013, nine drugs have received US Food and Drug Administration (FDA) approval for the treatment of mCRC: the cytotoxic agents 5-fluorouracil, capecitabine, irinotecan, and oxaliplatin; the EGFR antibodies cetuximab and panitumumab; the VEGF inhibitors bevacizumab and aflibercept; and the multikinase inhibitor regorafenib. Before the era of biologic agents, it was shown that access to all active agents in the course of therapy is associated with improved survival (1). Although no such analysis has yet been performed after the introduction of biologics, it is conceivable that the overall principle of optimizing outcome by exposing patients to all available active agents in a strategic manner is still valid today. An abundance of data from clinical trials has been generated in the last decade in advanced colorectal cancer. Evidence-based guidelines (National Comprehensive Cancer Network, European Society of Medical Oncology) try to synthesize and structure the complexity of these clinical trial data to guide practical treatment decisions. All guidelines emphasize the importance of exposing patients to all active agents in rational, sequential treatment steps. It has, however, been questioned whether the treatment principles outlined in guidelines are actually being implemented in clinical practice. In the absence of a comprehensive tumor registry in the United States, which includes information on medical therapy, observational studies are the best tools available to obtain an understanding of treatment algorithms in clinical practice. The study by Abrams and colleagues in this issue of the Journal (2) tried to analyze the treatment pattern of US oncologists for patients with mCRC from 2004 to 2011, the time when bevacizumab and the EGFR monoclonal antibodies cetuximab and panitumumab were integrated into clinical practice. It has to be pointed out that the very nature of the dataset, which was based on chemotherapy order entries provided by a commercial chemotherapy vendor, has certain shortcomings. No data on patient outcomes were recorded, the definition of line of therapy required extrapolation and modeling of treatment sequences based on chemotherapy prescriptions and time interval assumptions, and no data are available on the reason why therapies were changed. Nevertheless, the analysis provides valuable insights into the treatment preferences of oncologists in the United States.
2 of 2 Editorial | JNCI
The adherence to evidence-based guidelines needs to be implemented as a mandatory quality measure for the prescribing practice of oncologists with implications for reimbursement for medical care. In addition, the analysis by Abrams et al. (2) demonstrates the importance of outlining optimized treatment algorithms for patients with mCRC. Unfortunately, only a few prospective clinical trials have investigated treatment strategies in mCRC. With the overall low inclusion rate of patients in clinical trials [2.4% in the study by Abrams and colleagues (2)] and, particularly, the challenges the federally funded clinical trials system is facing in the United States, it is not likely that this situation will change. A solution could be to establish a national tumor registry in which treatment algorithms are documented and eventually associated with outcome. This registry could provide valuable information not obtainable from clinical trials and also serve as a tool to monitor guideline adherence to improve the care of patients with mCRC and other tumor entities. References 1. 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. 2004;22(7):1209–1214. 2. Abrams A, Meyer G, Schrag D, Meyerhardt JA. Chemotherapy usage patterns in a US-wide cohort of patients with metastatic colorectal cancer. JNCI J Natl Cancer Inst (2014) 106 (2):djt371 doi:10.1093/jnci/djt371 3. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–2342. 4. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–345. 5. 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. 2013;14(1):29–37. 6. Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol. 2008;26(33):5326–5334. 7. Blanke CD, Goldberg RM, Grothey A, et al. KRAS and colorectal cancer: ethical and pragmatic issues in effecting real-time change in oncology clinical trials and practice. Oncologist. 2011;16(8):1061–1068. 8. 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. 2004;22(2):229–237. 9. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343(13):905–914. 10. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355(9209):1041–1047. 11. Saltz LB, Clarke S, Diaz-Rubio E, 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. 2008;26(12):2013–2019. 12. Douillard JY, Oliner KS, Siena S, 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. 2010;28(31):4697–4705. 13. Loupakis F, Cremolini C, Salvatore L, et al. FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. Eur J Cancer. 2014;50(1):57–63. Affiliation of authors: Division of Medical Oncology, Mayo Clinic Rochester, Rochester, MN (JMH, AG). Vol. 106, Issue 2 | djt442 | February 5, 2014
Downloaded from http://jnci.oxfordjournals.org/ at Aston University on September 2, 2014
of how many patients might have received EGFR antibodies without prior KRAS mutation testing, which could not only result in an ineffective therapy but also have a potential detrimental effect in patients with KRAS mutated mCRC. What are the main factors influencing these observed treatment patterns and the apparent lack of adherence to published guidelines? Certain prevalent treatment patterns can only be understood in the historic context in which they evolved. In the United States, irinotecan was initially developed in combination with bolus 5-fluorouracil/leucovorin (IFL), in contrast to Europe where an infusional 5-FU/LV regimen formed the backbone for FOLFIRI (8–10). When a US Intergroup phase III trial showed indisputable superiority for the oxaliplatin-based FOLFOX over IFL, FOLFOX was adopted as the standard first-line regimen by the majority of US oncologists in spite of the fact that European trials demonstrated identical efficacy for FOLFOX and FOLFIRI (8). When bevacizumab received FDA approval to be used in combination with “intravenous 5-fluorouracil–based chemotherapy,” it was simply added to FOLFOX, the perceived most effective firstline chemotherapy regimen. Thus, FOLFOX plus bevacizumab became the most widely used first-line therapy in the United States. Subsequent data from a large phase III trial (11) that questioned the magnitude of benefit patients derive from the addition of bevacizumab to FOLFOX in first-line therapy have not been able to affect the strong preference of oncologists for this combination, as documented in the analysis by Abrams et al. (2). It has to be pointed out that in Europe FOLFOX and FOLFIRI are used in similar frequency as first-line regimens with bevacizumab (5). Making appropriate treatment decisions in mCRC has become more challenging over the years with the availability of multiple active agents and combination regimens and prognostic and predictive biomarkers. The overwhelming amount of information from clinical trials could make oncologists preferably rely on one familiar, default therapeutic approach and resort to FOLFOX plus bevacizumab as standard first-line therapy. Although this treatment is likely appropriate for the majority of patients, a more individualized approach would be preferable to take more patient- and tumor-related factors into account. It is evident that oncologists will face a further increased complexity of treatment decisions in mCRC in the future with the development and validation of molecular prognostic and predictive markers. Even at this point in time, an expanded RAS analysis to include KRAS and NRAS mutations beyond standard KRAS exon 2 (codon 12/13) testing appears mandatory to appropriately select patients for EGFR antibody therapy (12). BRAF mutation testing for all patients with mCRC should also be considered because a differential, intensified upfront treatment approach with FOLFOXIRI plus bevacizumab is emerging as a new standard of care in this patient population (13). In addition, the poor prognosis of patients with BRAF mutated mCRC has made them the key target of various trials to improve outcome with combinations of targeted agents based on translational studies. These developments underscore the high educational need oncologists are facing to optimize treatment algorithms for individual patients. Improving access to high-quality, unbiased educational programs in the context of continued medical education seems pertinent to overcome the apparent failure to effectively disseminate and adopt practice-changing information, which ultimately affects the survival of patients.
