Comment
In The Lancet Oncology, Hans-Joachim Schmoll and colleagues1 report an individual patient data pooled analysis from four randomised controlled trials of patients with stage III colon cancer, in which different treatment regimens were used. The authors directly compared chemotherapy regimens involving two different fluoropyrimidine chemotherapy backbones (fluorouracil and leucovorin vs capecitabine), with or without the addition of oxaliplatin. The authors report no relevant differences in disease-free survival (adjusted HR 1·02 [95% CI 0·93–1·11]; p=0·72), relapsefree survival (1·02 [0·93–1·12]; p=0·72), or overall survival (1·04 [0·93–1·15]; p=0·50), irrespective of the base chemotherapy regimen used. Post-relapse survival was also similar for capecitabine-based and fluorouracil and leucovorin-based regimens (p=0·26). These results show that there are two clear options for adjuvant chemotherapy in clinical practice: an infusional or orally administered fluoropyrimidine combined with oxaliplatin. Treatment after relapse in patients with colon cancer is an important issue because about a third of affected patients develop recurrence even after intensive adjuvant chemotherapy. Although two trials (MOSAIC2 and NSABP C-073) had suggested that adjuvant oxaliplatin had an adverse effect on postrelapse survival, this analysis shows that post-relapse survival was equivalent, irrespective of the use of oxaliplatin in the adjuvant chemotherapy. Although this analysis includes the largest number of patients so far, controversy still seems to persist about the adverse effect of oxaliplatin on post-relapse survival. Sensitivity to platinum-based drugs such as oxaliplatin reportedly resumes with a platinum-free interval.4 Irinotecanbased chemotherapy, such as FOLFIRI (leucovorin and fluorouracil plus irinotecan), combined with a molecularly-targeted drug is widely used as first-line chemotherapy, especially in cases of early recurrence after adjuvant chemotherapy with oxaliplatin. In this analysis, all three active chemotherapy agents (fluoropyrimidine, irinotecan, and oxaliplatin) were used in only 11–31% of patients as post-relapse treatment; however, it is important that treatment strategies make all active agents available.5 Therefore, the potential adverse effects of adjuvant oxaliplatin should be
discussed on the basis of best clinical practice after recurrence. Fluorouracil and oral fluoropyrimidine (eg, capecitabine) share the same mechanism of antitumour action—mainly through the inhibition of thymidilate synthase by 5-fluoro-2´-deoxyuridine-5´monophosphate, which is a fluorouracil metabolite. Orally administered capecitabine has shown equivalent efficacy for overall survival against colorectal cancer as fluorouracil in both the adjuvant treatment1 and palliative care6 settings. However, the mode of action of fluorouracil varies, depending on both the method of administration (ie, bolus or continuous infusion) and its modulation by leucovorin or other agents in the regimen. The FOLFOX chemotherapy regimen contains both bolus and continuous infusion of fluorouracil, whereas the pharmacokinetics of oral fluoropyrimidine such as S-1 resemble those of continuous infusion fluorouracil. Leucovorin is a precursor of 5,10-methylenetetrahydrofolate, which forms the ternary complex with thymidilate synthase and 5-fluoro-2´-deoxyuridine5´-monophosphate, leading to long-term thymidylate synthase inhibition. Capecitabine is a fluoropyrimidine carbamate that is ultimately converted to fluorouracil by thymidine phosphorylase in tumours,7 and it is not used with leucovorin. Although cross-resistance between fluorouracil and capecitabine has not been clarified clinically, the predictive factors for sensitivity to capecitabine and doxifluridine in xenograft models might differ from those for fluorouracil.8 Thus, switching use of capecitabine after fluorouracil and leucovorin or giving the agents in reverse order could offer some benefit. S-1 is another oral fluoropyrimidine, mainly used in Asian countries, which contains 5-chloro-2,4dihydroxypyridine—a dihydropyrimidine dehydrogenase inhibitor.9 Therefore, S-1 is judged to be effective against many tumours with high dihydropyrimidine dehydrogenase expression, which is one of the resistance mechanisms against fluorouracil. In the FIRIS trial that compared irinotecan plus S-1 (IRIS) versus FOLFIRI as second-line chemotherapy, IRIS and FOLFIRI showed similar progression-free and overall survival outcomes.10 Although previous chemotherapy with or without oxaliplatin was a stratifying factor, IRIS showed longer progression-free and overall survival
www.thelancet.com/oncology Published online November 12, 2014 http://dx.doi.org/10.1016/S1470-2045(14)71034-4
Biophoto Associates/Science Photo Library
How can we improve adjuvant chemotherapy for colon cancer?
Lancet Oncol 2014 Published Online November 12, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71034-4 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(14)70486-3
1
Comment
outcomes than FOLFIRI in the subgroup who had received previous chemotherapy with oxaliplatin, whereas IRIS was worse than FOLFIRI in the subgroup who had not received oxaliplatin. Many of the patients who had not received oxaliplatin had relapsed early after adjuvant chemotherapy with tagafur, uracil, and leucovorin or capecitabine. The resistance to fluorouracil and leucovorin that occurs in both FOLFOX and FOLFIRI might be partly overcome by dihydropyrimidine dehydrogenase inhibition. These results suggest that a treatment strategy that switches from fluorouracil and leucovorin to S-1 might offer some benefit. Sensitivity to fluorouracil could be restored by different modes of modulation; this approach could also be considered for the treatment of patients who have relapsed after adjuvant chemotherapy. No improvement in relapse-free or overall survival after adjuvant chemotherapy for stage III colon cancer has been made since neither bevacizumab nor cetuximab showed additional effects to those of to fluorouracil plus oxaliplatin. Although cancer stem cells are thought to have a key role in recurrence after surgery,11 stem cell markers of colon cancer such as CD133 and CD44 are also reported to be related to resistance to anti-tumour agents including fluorouracil and oxaliplatin.12 Therefore, new agents targeting stem cells might be the next step in progression of adjuvant chemotherapy for colon cancer.
I have received grants from Taiho, Chugai, and Yakult, and honoraria from Taiho, Chugai, Yakult, and Daiichi-Sankyo. 1
2
3
4
5
6
7
8
9
10
11
Narikazu Boku
12
Department of Clinical Oncology, St Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511 Japan [email protected]
2
Schmoll H-J, Twelves C, Sun W, et al. Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials. Lancet Oncol 2014; published online Nov 12. http://dx.doi.org/10.1016/ S1470-2045(14)70486-3. André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009; 27: 3109–16. Yothers GA, O’Connell MJ, Colangelo L, et al. 5-FU and leucovorin (Lv) with or without oxaliplatin (Ox) for adjuvant treatment of stage II and III colon cancer: Long-term follow-up of NSABP C-07 with survival analysis. American Society for Clinical Oncology Gastrointestinal Cancers Symposium; Orlando, FL, USA; Jan 22–24, 2010. Abstract 401. Chibaudel B, Tournigand C, Bonnetain F, et al. Platinum-sensitivity in metastatic colorectal cancer: towards a definition. Eur J Cancer 2013; 49: 3813–20. Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 2005; 23: 9441–42. Cassidy J, Clarke S, Díaz-Rubio E, et al. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer 2011; 105: 58–64 Miwa M, Ura M, Nishida M, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998; 34: 1274–81. Yasuno H, Kurasawa M, Yanagisawa M, et al. Predictive markers of capecitabine sensitivity identified from the expression profile of pyrimidine nucleoside-metabolizing enzymes. Oncol Rep 2013; 29: 451–58. Shirasaka T, Shimamato Y, Ohshimo H, et al. Development of a novel form of an oral 5-fl uorouracil derivative (S-1) directed to the potentiation of the tumour selective cytotoxicity of 5-fl uorouracil by two biochemical modulators. Anticancer Drugs 1996; 7: 548–57. Yasui H, Muro K, Shimada Y, et al. A phase 3 non-inferiority study of 5-FU/l-leucovorin/irinotecan (FOLFIRI) versus irinotecan/S-1 (IRIS) as second-line chemotherapy for metastatic colorectal cancer: updated results of the FIRIS study. J Cancer Res Clin Oncol 2014; published online Aug 9. DOI:10.1007/s00432-014-1783-3. Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–11. Kawahara S, Otsuji Y, Nakamura M, et al. Sphingosine kinase 1 plays a role in the upregulation of CD44 expression through extracellular signal-regulated kinase signaling in human colon cancer cells. Anticancer Drugs 2013; 24: 473–83.
www.thelancet.com/oncology Published online November 12, 2014 http://dx.doi.org/10.1016/S1470-2045(14)71034-4
In The Lancet Oncology, Hans-Joachim Schmoll and colleagues1 report an individual patient data pooled analysis from four randomised controlled trials of patients with stage III colon cancer, in which different treatment regimens were used. The authors directly compared chemotherapy regimens involving two different fluoropyrimidine chemotherapy backbones (fluorouracil and leucovorin vs capecitabine), with or without the addition of oxaliplatin. The authors report no relevant differences in disease-free survival (adjusted HR 1·02 [95% CI 0·93–1·11]; p=0·72), relapsefree survival (1·02 [0·93–1·12]; p=0·72), or overall survival (1·04 [0·93–1·15]; p=0·50), irrespective of the base chemotherapy regimen used. Post-relapse survival was also similar for capecitabine-based and fluorouracil and leucovorin-based regimens (p=0·26). These results show that there are two clear options for adjuvant chemotherapy in clinical practice: an infusional or orally administered fluoropyrimidine combined with oxaliplatin. Treatment after relapse in patients with colon cancer is an important issue because about a third of affected patients develop recurrence even after intensive adjuvant chemotherapy. Although two trials (MOSAIC2 and NSABP C-073) had suggested that adjuvant oxaliplatin had an adverse effect on postrelapse survival, this analysis shows that post-relapse survival was equivalent, irrespective of the use of oxaliplatin in the adjuvant chemotherapy. Although this analysis includes the largest number of patients so far, controversy still seems to persist about the adverse effect of oxaliplatin on post-relapse survival. Sensitivity to platinum-based drugs such as oxaliplatin reportedly resumes with a platinum-free interval.4 Irinotecanbased chemotherapy, such as FOLFIRI (leucovorin and fluorouracil plus irinotecan), combined with a molecularly-targeted drug is widely used as first-line chemotherapy, especially in cases of early recurrence after adjuvant chemotherapy with oxaliplatin. In this analysis, all three active chemotherapy agents (fluoropyrimidine, irinotecan, and oxaliplatin) were used in only 11–31% of patients as post-relapse treatment; however, it is important that treatment strategies make all active agents available.5 Therefore, the potential adverse effects of adjuvant oxaliplatin should be
discussed on the basis of best clinical practice after recurrence. Fluorouracil and oral fluoropyrimidine (eg, capecitabine) share the same mechanism of antitumour action—mainly through the inhibition of thymidilate synthase by 5-fluoro-2´-deoxyuridine-5´monophosphate, which is a fluorouracil metabolite. Orally administered capecitabine has shown equivalent efficacy for overall survival against colorectal cancer as fluorouracil in both the adjuvant treatment1 and palliative care6 settings. However, the mode of action of fluorouracil varies, depending on both the method of administration (ie, bolus or continuous infusion) and its modulation by leucovorin or other agents in the regimen. The FOLFOX chemotherapy regimen contains both bolus and continuous infusion of fluorouracil, whereas the pharmacokinetics of oral fluoropyrimidine such as S-1 resemble those of continuous infusion fluorouracil. Leucovorin is a precursor of 5,10-methylenetetrahydrofolate, which forms the ternary complex with thymidilate synthase and 5-fluoro-2´-deoxyuridine5´-monophosphate, leading to long-term thymidylate synthase inhibition. Capecitabine is a fluoropyrimidine carbamate that is ultimately converted to fluorouracil by thymidine phosphorylase in tumours,7 and it is not used with leucovorin. Although cross-resistance between fluorouracil and capecitabine has not been clarified clinically, the predictive factors for sensitivity to capecitabine and doxifluridine in xenograft models might differ from those for fluorouracil.8 Thus, switching use of capecitabine after fluorouracil and leucovorin or giving the agents in reverse order could offer some benefit. S-1 is another oral fluoropyrimidine, mainly used in Asian countries, which contains 5-chloro-2,4dihydroxypyridine—a dihydropyrimidine dehydrogenase inhibitor.9 Therefore, S-1 is judged to be effective against many tumours with high dihydropyrimidine dehydrogenase expression, which is one of the resistance mechanisms against fluorouracil. In the FIRIS trial that compared irinotecan plus S-1 (IRIS) versus FOLFIRI as second-line chemotherapy, IRIS and FOLFIRI showed similar progression-free and overall survival outcomes.10 Although previous chemotherapy with or without oxaliplatin was a stratifying factor, IRIS showed longer progression-free and overall survival
www.thelancet.com/oncology Published online November 12, 2014 http://dx.doi.org/10.1016/S1470-2045(14)71034-4
Biophoto Associates/Science Photo Library
How can we improve adjuvant chemotherapy for colon cancer?
Lancet Oncol 2014 Published Online November 12, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71034-4 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(14)70486-3
1
Comment
outcomes than FOLFIRI in the subgroup who had received previous chemotherapy with oxaliplatin, whereas IRIS was worse than FOLFIRI in the subgroup who had not received oxaliplatin. Many of the patients who had not received oxaliplatin had relapsed early after adjuvant chemotherapy with tagafur, uracil, and leucovorin or capecitabine. The resistance to fluorouracil and leucovorin that occurs in both FOLFOX and FOLFIRI might be partly overcome by dihydropyrimidine dehydrogenase inhibition. These results suggest that a treatment strategy that switches from fluorouracil and leucovorin to S-1 might offer some benefit. Sensitivity to fluorouracil could be restored by different modes of modulation; this approach could also be considered for the treatment of patients who have relapsed after adjuvant chemotherapy. No improvement in relapse-free or overall survival after adjuvant chemotherapy for stage III colon cancer has been made since neither bevacizumab nor cetuximab showed additional effects to those of to fluorouracil plus oxaliplatin. Although cancer stem cells are thought to have a key role in recurrence after surgery,11 stem cell markers of colon cancer such as CD133 and CD44 are also reported to be related to resistance to anti-tumour agents including fluorouracil and oxaliplatin.12 Therefore, new agents targeting stem cells might be the next step in progression of adjuvant chemotherapy for colon cancer.
I have received grants from Taiho, Chugai, and Yakult, and honoraria from Taiho, Chugai, Yakult, and Daiichi-Sankyo. 1
2
3
4
5
6
7
8
9
10
11
Narikazu Boku
12
Department of Clinical Oncology, St Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511 Japan [email protected]
2
Schmoll H-J, Twelves C, Sun W, et al. Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials. Lancet Oncol 2014; published online Nov 12. http://dx.doi.org/10.1016/ S1470-2045(14)70486-3. André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009; 27: 3109–16. Yothers GA, O’Connell MJ, Colangelo L, et al. 5-FU and leucovorin (Lv) with or without oxaliplatin (Ox) for adjuvant treatment of stage II and III colon cancer: Long-term follow-up of NSABP C-07 with survival analysis. American Society for Clinical Oncology Gastrointestinal Cancers Symposium; Orlando, FL, USA; Jan 22–24, 2010. Abstract 401. Chibaudel B, Tournigand C, Bonnetain F, et al. Platinum-sensitivity in metastatic colorectal cancer: towards a definition. Eur J Cancer 2013; 49: 3813–20. Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 2005; 23: 9441–42. Cassidy J, Clarke S, Díaz-Rubio E, et al. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer 2011; 105: 58–64 Miwa M, Ura M, Nishida M, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998; 34: 1274–81. Yasuno H, Kurasawa M, Yanagisawa M, et al. Predictive markers of capecitabine sensitivity identified from the expression profile of pyrimidine nucleoside-metabolizing enzymes. Oncol Rep 2013; 29: 451–58. Shirasaka T, Shimamato Y, Ohshimo H, et al. Development of a novel form of an oral 5-fl uorouracil derivative (S-1) directed to the potentiation of the tumour selective cytotoxicity of 5-fl uorouracil by two biochemical modulators. Anticancer Drugs 1996; 7: 548–57. Yasui H, Muro K, Shimada Y, et al. A phase 3 non-inferiority study of 5-FU/l-leucovorin/irinotecan (FOLFIRI) versus irinotecan/S-1 (IRIS) as second-line chemotherapy for metastatic colorectal cancer: updated results of the FIRIS study. J Cancer Res Clin Oncol 2014; published online Aug 9. DOI:10.1007/s00432-014-1783-3. Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–11. Kawahara S, Otsuji Y, Nakamura M, et al. Sphingosine kinase 1 plays a role in the upregulation of CD44 expression through extracellular signal-regulated kinase signaling in human colon cancer cells. Anticancer Drugs 2013; 24: 473–83.
www.thelancet.com/oncology Published online November 12, 2014 http://dx.doi.org/10.1016/S1470-2045(14)71034-4
