Comment
The aim of palliative therapy in oncology is to prolong life and maintain quality of life for patients, with the least therapy necessary to control disease. The improvement in overall survival seen in metastatic colorectal cancer over the past decade is intrinsically associated with the increased number of active drugs in the management of disease, and a better understanding of how best to use these drugs.1 The availability of improved supportive care, less toxic regimens, and targeted drugs have led to a shift in the treatment paradigm. Previously, oncologists commonly used a fixed number of initial chemotherapy cycles or treatment to best response, followed by a complete treatment-free interval. Now, the emphasis has shifted toward prolonged duration of therapy to control cancer growth in the longer term. However, one of the most commonly used treatments in the first-line setting in metastatic colorectal cancer, a combination of oxaliplatin and fluoropyrimidine, does not lend itself to prolonged treatment because of cumulative neurotoxic effects of oxaliplatin. Results from trials with an oxaliplatin-based therapy have consistently shown that more patients come off therapy because of toxic effects than because of progressive disease.2,3 This issue is accentuated when a drug such as bevacizumab is added, which can further prolong time to tumour progression. Findings from a detailed analysis of one of the largest trials of first-line therapy with a combination of bevacizumab, fluoropyrimidine, and oxaliplatin in metastatic colorectal cancer showed that patients who received treatment until tumour progression obtained the greatest benefit of anti-VEGF treatment with bevacizumab.3 Additionally, findings from several phase 3 studies have confirmed that prolonged duration of anti-VEGF treatment, even beyond RECIST-defined tumour progression, is associated with improved outcomes in metastatic colorectal cancer.4,5 Thus, if an oxaliplatin-based first-line therapy is used, and one emphasis of first-line therapy is to optimise and maximise duration of treatment to provide prolonged tumour control, a strategy has to be developed to pre-emptively deal with the issue of oxaliplatin’s cumulative neurotoxic effects. Several trials have investigated the role of maintenance therapy in metastatic colorectal cancer using various designs, induction treatments, and maintenance
therapies. In The Lancet, Lieke Simkens and colleagues report on the CAIRO3 trial,6 which explored the activity of maintenance therapy with capecitabine plus bevacizumab, compared with observation, in patients who had achieved at least stable disease after six cycles (18 weeks) of induction therapy with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B). 558 patients were randomly assigned, 279 to observation and 279 to maintenance therapy. One of the interesting aspects of CAIRO3 is that capecitabine in the maintenance setting was given as continuous therapy at a dose of 625 mg/m² twice daily, with bevacizumab added every 3 weeks at 7·5 mg/kg. Capecitabine continuously given at a low dose could have a metronomic treatment effect, and might be associated with fewer side-effects and fewer interactions with other concomitant medications such as warfarin than intermittent treatment at higher doses, although the CAIRO3 investigators reported 64 (23%) grade 3 events of hand–foot skin reaction in the maintenance group with this approach. The complexity of such maintenance studies warrants the use of non-standard endpoints.7 Thus, CAIRO3 used PFS2 as its primary endpoint, the progression-free survival subsequent to reintroduction of CAPOX-B after the maintenance or observation phase. The primary endpoint was affected by the likelihood of patients to be re-exposed to the induction treatment. In spite of an imbalance of re-induction treatment (168 [60%] patients in the observation group vs 132 [47%] in the maintenance group), the primary endpoint of the study was reached: median PFS2 was 8·5 months in the observation group and 11·7 months in the maintenance group (HR 0·67, 95% CI 0·56–0·81). A better expression of the activity of maintenance therapy to delay tumour progression is PFS1, which directly compared the time to tumour progression on maintenance treatment versus observation, and was more than doubled with the use of maintenance therapy (4·1 months [95% CI 3·9–4·2] in the observation group vs 8·5 months [6·5–10·3] in the maintenance group, HR 0·43 [0·36−0·52]). Although no significant difference in overall survival, a secondary endpoint, was noted, a numerical difference in median overall survival of 3·5 months persisted in favour of maintenance therapy. The results of CAIRO36 have recently been confirmed by
www.thelancet.com Published online April 8, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62350-3
David M Martin MD/Science Photo Library
When less is more: maintenance therapy in colorectal cancer
Published Online April 8, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)62350-3 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)62004-3
1
Comment
other similar trials, most notably the German AIO KRK 0207 trial.8 The CAIRO3 study has several shortcomings, particularly the low rate of planned reintroduction of CAPOX-B in the trial and the short duration of overall survival compared with other recent trials, even when the induction phase of 4·5 months was added to the median survival. The low percentage of patients exposed to antibodies for EGFR (about 13%) could have a role here. What do the CAIRO3 results mean for clinical practice? For oncologists who have used an induction– maintenance strategy routinely in clinical practice, CAIRO3 will confirm this approach to be evidencebased and provide guidance on how to optimise the maintenance treatment phase. Oncologists who have been hesitant to embrace prolonged treatment durations might point to the absence of benefit in overall survival in this study, and cite patient preference for treatment breaks and the financial implications of maintenance treatment, particularly when biological drugs are used. Admittedly, no study has so far shown a significant effect of maintenance therapy on overall survival in this setting. However, this gap is probably a reflection of the fact that, in the era of multiple lines of post-first progression therapy in metastatic colorectal cancer, differences in overall survival based on first-line interventions are very difficult to achieve.9 The very fact that first-line progression-free survival has been largely unchanged since the introduction of combination chemotherapy and targeted drugs 10 years ago, but overall survival has increased from 20 months to over 30 months in recent trials, validates the effect of subsequent lines of therapy. If the goal of anti-tumour treatment is to delay tumour progression as long as possible, with as few treatment-related side-effects as possible, then induction–maintenance strategies need to be deemed one standard of care. However, not every patient will be deemed a candidate for maintenance treatment or require continuous therapy to control low-volume, smouldering disease. Thus, the treatment approach will need to be individualised on the basis of patient, tumour, and treatment characteristics, particularly toxic effects of previous therapy. The maintenance setting can, however, be used to develop novel drugs in metastatic colorectal cancer on the basis of molecular profiling, which can be done during the induction phase. Prospective studies in this
2
setting exploring the activity of novel interventions in molecularly defined subgroups have already been initiated, most notably the FOCUS410 and MODUL11 trials. CAIRO36 provides the best evidence so far for the magnitude of benefit that maintenance treatment can achieve in metastatic colorectal cancer. It does not set the one and only standard of care in the management of this disease, but provides very valuable guidance for how to optimise a treatment approach in clinical practice when a regimen of bevacizumab, fluoropyrimidine, and oxaliplatin is used as first-line therapy. Joleen M Hubbard, *Axel Grothey Division of Medical Oncology, Mayo Clinic Rochester, Rochester, MN 55905, USA [email protected] AG has received research funding via his institution from Genentech, Bayer, Eli Lilly, Pfizer, Eisai, and Boston Biomedicals. JMH has received research funding via her institution from Genentech, Bayer, Boston Biomedicals, PRISM Pharmaceuticals, and Senhwa Biosciences. 1
2
3
4
5
6
7 8
9
10 11
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: 1209–14. 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 2004; 22: 23–30. 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: 2013–19. 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: 29–37. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012; 30: 3499–506. Simkens LHJ, van Tinteren H, May A, 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 2015; published online April 8. http://dx.doi.org/10.1016/S01406736(14)62004-3. Allegra C, Blanke C, Buyse M, et al. End points in advanced colon cancer clinical trials: a review and proposal. J Clin Oncol 2007; 25: 3572–75. Hegewisch-Becker S, Graeven U, Lerchenmüller C, et al. Maintenance strategy with fluoropyrimidines (FP) plus bevacizumab (BEV), BEV alone or no treatment, following a 24-week first-line induction with FP, oxaliplatin (OX) and BEV for patients with metastatic colorectal cancer: mature data and subgroup analysis of the AIO KRK 0207 phase III study. Ann Oncol 2014; 25 (suppl 4): iv167. Shi Q, de Gramont A, Grothey A, et al. Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database. J Clin Oncol 2015; 33: 22–28. Kaplan R, Maughan T, Crook A, et al. Evaluating many treatments and biomarkers in oncology: a new design. J Clin Oncol 2013; 31: 4562–68. Schmoll H, Arnold D, De Gramont A, et al. MODUL—a multicentre randomised clinical trial of biomarker-driven therapy for the 1st-line maintenance treatment of metastatic colorectal cancer (mCRC): a signal-seeking approach. Ann Oncol 2014; 25 (suppl 4): iv209.
www.thelancet.com Published online April 8, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62350-3
The aim of palliative therapy in oncology is to prolong life and maintain quality of life for patients, with the least therapy necessary to control disease. The improvement in overall survival seen in metastatic colorectal cancer over the past decade is intrinsically associated with the increased number of active drugs in the management of disease, and a better understanding of how best to use these drugs.1 The availability of improved supportive care, less toxic regimens, and targeted drugs have led to a shift in the treatment paradigm. Previously, oncologists commonly used a fixed number of initial chemotherapy cycles or treatment to best response, followed by a complete treatment-free interval. Now, the emphasis has shifted toward prolonged duration of therapy to control cancer growth in the longer term. However, one of the most commonly used treatments in the first-line setting in metastatic colorectal cancer, a combination of oxaliplatin and fluoropyrimidine, does not lend itself to prolonged treatment because of cumulative neurotoxic effects of oxaliplatin. Results from trials with an oxaliplatin-based therapy have consistently shown that more patients come off therapy because of toxic effects than because of progressive disease.2,3 This issue is accentuated when a drug such as bevacizumab is added, which can further prolong time to tumour progression. Findings from a detailed analysis of one of the largest trials of first-line therapy with a combination of bevacizumab, fluoropyrimidine, and oxaliplatin in metastatic colorectal cancer showed that patients who received treatment until tumour progression obtained the greatest benefit of anti-VEGF treatment with bevacizumab.3 Additionally, findings from several phase 3 studies have confirmed that prolonged duration of anti-VEGF treatment, even beyond RECIST-defined tumour progression, is associated with improved outcomes in metastatic colorectal cancer.4,5 Thus, if an oxaliplatin-based first-line therapy is used, and one emphasis of first-line therapy is to optimise and maximise duration of treatment to provide prolonged tumour control, a strategy has to be developed to pre-emptively deal with the issue of oxaliplatin’s cumulative neurotoxic effects. Several trials have investigated the role of maintenance therapy in metastatic colorectal cancer using various designs, induction treatments, and maintenance
therapies. In The Lancet, Lieke Simkens and colleagues report on the CAIRO3 trial,6 which explored the activity of maintenance therapy with capecitabine plus bevacizumab, compared with observation, in patients who had achieved at least stable disease after six cycles (18 weeks) of induction therapy with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B). 558 patients were randomly assigned, 279 to observation and 279 to maintenance therapy. One of the interesting aspects of CAIRO3 is that capecitabine in the maintenance setting was given as continuous therapy at a dose of 625 mg/m² twice daily, with bevacizumab added every 3 weeks at 7·5 mg/kg. Capecitabine continuously given at a low dose could have a metronomic treatment effect, and might be associated with fewer side-effects and fewer interactions with other concomitant medications such as warfarin than intermittent treatment at higher doses, although the CAIRO3 investigators reported 64 (23%) grade 3 events of hand–foot skin reaction in the maintenance group with this approach. The complexity of such maintenance studies warrants the use of non-standard endpoints.7 Thus, CAIRO3 used PFS2 as its primary endpoint, the progression-free survival subsequent to reintroduction of CAPOX-B after the maintenance or observation phase. The primary endpoint was affected by the likelihood of patients to be re-exposed to the induction treatment. In spite of an imbalance of re-induction treatment (168 [60%] patients in the observation group vs 132 [47%] in the maintenance group), the primary endpoint of the study was reached: median PFS2 was 8·5 months in the observation group and 11·7 months in the maintenance group (HR 0·67, 95% CI 0·56–0·81). A better expression of the activity of maintenance therapy to delay tumour progression is PFS1, which directly compared the time to tumour progression on maintenance treatment versus observation, and was more than doubled with the use of maintenance therapy (4·1 months [95% CI 3·9–4·2] in the observation group vs 8·5 months [6·5–10·3] in the maintenance group, HR 0·43 [0·36−0·52]). Although no significant difference in overall survival, a secondary endpoint, was noted, a numerical difference in median overall survival of 3·5 months persisted in favour of maintenance therapy. The results of CAIRO36 have recently been confirmed by
www.thelancet.com Published online April 8, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62350-3
David M Martin MD/Science Photo Library
When less is more: maintenance therapy in colorectal cancer
Published Online April 8, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)62350-3 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)62004-3
1
Comment
other similar trials, most notably the German AIO KRK 0207 trial.8 The CAIRO3 study has several shortcomings, particularly the low rate of planned reintroduction of CAPOX-B in the trial and the short duration of overall survival compared with other recent trials, even when the induction phase of 4·5 months was added to the median survival. The low percentage of patients exposed to antibodies for EGFR (about 13%) could have a role here. What do the CAIRO3 results mean for clinical practice? For oncologists who have used an induction– maintenance strategy routinely in clinical practice, CAIRO3 will confirm this approach to be evidencebased and provide guidance on how to optimise the maintenance treatment phase. Oncologists who have been hesitant to embrace prolonged treatment durations might point to the absence of benefit in overall survival in this study, and cite patient preference for treatment breaks and the financial implications of maintenance treatment, particularly when biological drugs are used. Admittedly, no study has so far shown a significant effect of maintenance therapy on overall survival in this setting. However, this gap is probably a reflection of the fact that, in the era of multiple lines of post-first progression therapy in metastatic colorectal cancer, differences in overall survival based on first-line interventions are very difficult to achieve.9 The very fact that first-line progression-free survival has been largely unchanged since the introduction of combination chemotherapy and targeted drugs 10 years ago, but overall survival has increased from 20 months to over 30 months in recent trials, validates the effect of subsequent lines of therapy. If the goal of anti-tumour treatment is to delay tumour progression as long as possible, with as few treatment-related side-effects as possible, then induction–maintenance strategies need to be deemed one standard of care. However, not every patient will be deemed a candidate for maintenance treatment or require continuous therapy to control low-volume, smouldering disease. Thus, the treatment approach will need to be individualised on the basis of patient, tumour, and treatment characteristics, particularly toxic effects of previous therapy. The maintenance setting can, however, be used to develop novel drugs in metastatic colorectal cancer on the basis of molecular profiling, which can be done during the induction phase. Prospective studies in this
2
setting exploring the activity of novel interventions in molecularly defined subgroups have already been initiated, most notably the FOCUS410 and MODUL11 trials. CAIRO36 provides the best evidence so far for the magnitude of benefit that maintenance treatment can achieve in metastatic colorectal cancer. It does not set the one and only standard of care in the management of this disease, but provides very valuable guidance for how to optimise a treatment approach in clinical practice when a regimen of bevacizumab, fluoropyrimidine, and oxaliplatin is used as first-line therapy. Joleen M Hubbard, *Axel Grothey Division of Medical Oncology, Mayo Clinic Rochester, Rochester, MN 55905, USA [email protected] AG has received research funding via his institution from Genentech, Bayer, Eli Lilly, Pfizer, Eisai, and Boston Biomedicals. JMH has received research funding via her institution from Genentech, Bayer, Boston Biomedicals, PRISM Pharmaceuticals, and Senhwa Biosciences. 1
2
3
4
5
6
7 8
9
10 11
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: 1209–14. 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 2004; 22: 23–30. 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: 2013–19. 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: 29–37. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012; 30: 3499–506. Simkens LHJ, van Tinteren H, May A, 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 2015; published online April 8. http://dx.doi.org/10.1016/S01406736(14)62004-3. Allegra C, Blanke C, Buyse M, et al. End points in advanced colon cancer clinical trials: a review and proposal. J Clin Oncol 2007; 25: 3572–75. Hegewisch-Becker S, Graeven U, Lerchenmüller C, et al. Maintenance strategy with fluoropyrimidines (FP) plus bevacizumab (BEV), BEV alone or no treatment, following a 24-week first-line induction with FP, oxaliplatin (OX) and BEV for patients with metastatic colorectal cancer: mature data and subgroup analysis of the AIO KRK 0207 phase III study. Ann Oncol 2014; 25 (suppl 4): iv167. Shi Q, de Gramont A, Grothey A, et al. Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database. J Clin Oncol 2015; 33: 22–28. Kaplan R, Maughan T, Crook A, et al. Evaluating many treatments and biomarkers in oncology: a new design. J Clin Oncol 2013; 31: 4562–68. Schmoll H, Arnold D, De Gramont A, et al. MODUL—a multicentre randomised clinical trial of biomarker-driven therapy for the 1st-line maintenance treatment of metastatic colorectal cancer (mCRC): a signal-seeking approach. Ann Oncol 2014; 25 (suppl 4): iv209.
www.thelancet.com Published online April 8, 2015 http://dx.doi.org/10.1016/S0140-6736(14)62350-3
