Trends in the Treatment of Colorectal Cancer
Trends in the Treatment of Colorectal Cancer
US Oncology Review 2005
Published: October 2008
Published: October 2008
Colorectal cancer is the third most frequently diagnosed cancer in the US and the third most common cause of cancer deaths in men and women. In 2004, an estimated 146,940 new cases of colorectal cancer will be diagnosed and 56,730 deaths will occur.1 The stage of cancer at the time of diagnosis predicts overall survival. At presentation, 21% of patients will have stage IV disease, many pursuing chemotherapy to control disease and extend survival.
The 37% of patients diagnosed with stage III disease and some of the 28% of patients with stage II disease will be offered chemotherapy to eradicate micrometastatic disease for cure. Approximately 85,000 people yearly will receive chemotherapy for colorectal cancer.
5-fluorouracil (5FU) has been the cornerstone of therapy for the treatment of colorectal cancer for more than 50 years. Within the past six years, two other cytotoxic drugs, irinotecan and oxaliplatin, and two monoclonal antibodies that target specific cancer-related proteins, bevacizumab and cetuximab, have proven efficacious in the treatment of colorectal cancer. Recent results of randomized clinical trials have changed the approach to the treatment of colorectal cancer.
Irinotecan was first shown as a single agent to improve survival and quality of life for patients who progressed on 5FU-based therapy.2,3 Subsequently, two pivotal studies demonstrated a survival benefit of the combination of 5FU and leucovorin with irinotecan compared with 5FU and leucovorin alone. Different approaches in North America and Europe were pursued; in the North American study, 5FU, leucovorin, and irinotecan were administered on a weekly bolus schedule (IFL) and compared with bolus 5FU and leucovorin.4 A median survival benefit was demonstrated (14.8 months compared with 12.6 months, p=0.04) and established IFL as the standard of care in the US. The European study gave an infusion schedule of 5FU with leucovorin and irinotecan and also showed a survival advantage when compared with an infusion schedule of 5FU and leucovorin (17.4 months compared with 14.1 months, p=0.031).5 Subsequently, oxaliplatin with infusion 5FU and leucovorin (FOLFOX) was compared with infusion 5FU and leucovorin as first line treatment in a European study6 and as second line therapy in a North American study after progression on IFL.7 The European study again demonstrated an advantage to combination chemotherapy in the first line setting with an improvement in median progression-free survival (9.0 months versus 6.2 months, p=0.0003). The North American study demonstrated an advantage of the FOLFOX regimen compared with either infusion 5FU or single agent oxaliplatin in the second line setting in terms of response rate (9.9% versus 0% and 1.3%, respectively), time to tumor progression (4.6 months versus 2.7 months and 1.6 months, respectively), and improvement in tumor-related symptoms (33% versus 12% and 12%, respectively).
The randomized US Gastrointestinal Intergroup study was designed to determine the most effective therapy for the first-line treatment of advanced disease.8 At the time this study was designed, bolus 5FU and leucovorin were the standard arm and oxaliplatin was not available commercially. The study was amended to reflect increased toxicity in some of the bolus combination schedules and the inferiority of 5FU and leucovorin as first-line therapy. It ultimately compared IFL with FOLFOX and a combination of irinotecan and oxaliplatin (IrOx).The final results demonstrated an improved survival for FOLFOX compared with either IFL or IrOx. There are three major factors that may have contributed to these results. Patients who were randomized to receive oxaliplatin in a first-line regimen had an active second-line agent available to them at the time of progression – either irinotecan or 5FU. This was not the case for patients randomized to receive IFL, as oxaliplatin was not available except in the setting of a second-line clinical trial. The role of infusion 5FU used in the FOLFOX regimen compared with bolus 5FU in the IFL regimen may have contributed to the difference in two ways: 5FU, when given as an infusion, has shown an increase in response rate compared with 5FU as a bolus injection, although no survival benefit has previously been demonstrated.9,10 Furthermore, the incidence of treatment-related deaths was higher in the IFL regimen and is thought to be related to the use of bolus 5FU with irinotecan. This increase in mortality is not seen in infusion 5FU and irinotecan combinations.5 Finally, the use of oxaliplatin compared with irinotecan in the first-line setting may actually account for the difference. This has not been proven, however, as subsequent studies using 5FU, leucovorin, oxaliplatin, and irinotecan have led to a median survival of 20–21 months for patients who have received all agents, regardless of the sequence.8,11–13
The bolus IFL regimen has fallen out of favor as a result of associated toxicity demonstrated in two large randomized studies. In the Intergroup study for advanced disease, 14 patients died within 60 days of starting therapy compared with five patients on the FOLFOX arm and five patients on the IrOx arm.14 Meanwhile, an adjuvant study for patients with stage III colon cancer randomized patients to receive the bolus IFL regimen or the standard weekly bolus 5FU and leucovorin regimen following surgical resection. Again, an increased and unacceptable rate of treatment-related deaths was demonstrated in the IFL arm (14 compared with five).15 Subsequently, this regimen was not shown to offer a survival advantage compared with the standard 5FU and leucovorin in the final analysis recently reported.16
Prior to this toxicity being recognized, enrollment was progressing in a randomized study comparing IFL with IFL with the monoclonal antibody bevacizumab. Bevacizumab inhibits circulating vascular endothelial growth factor (VEGF), preventing its binding to the VEGF receptor tyrosine kinase. A median survival benefit was demonstrated for the combination of IFL with bevacizumab, compared with IFL (20.3 months compared with 15.6 months, p value less than 0.001).17 When added to 5FU and leucovorin alone, the addition of bevacizumab was also shown to improve survival.18 This led to the approval of bevacizumab for the firstline treatment of advanced colorectal cancer with 5FU-based chemotherapy.The actual median survival of IFL with bevacizumab was comparable with the median survival demonstrated in the Intergroup study for FOLFOX.8,17 Whether the addition of bevacizumab to FOLFOX will result in further prolongation of survival remains to be seen when the results of the Eastern Cooperative Oncology Group study of FOLFOX compared with FOFLOX with bevacizumab as second-line therapy becomes available. In these first studies demonstrating activity of one of the angiogenesis inhibitors, some unique toxicities were shown. The patients randomized to receive bevacizumab had a higher incidence of hypertension, asymptomatic proteinuria, and minor bleeding.Although infrequent, of greater concern was the increased incidence of arterial thrombosis and bowel perforation.With widespread use of this agent, the significance of these serious complications will become apparent.
References:
References
1 Jemal A et al., "Cancer statistics, 2004", CA Cancer J. Clin. (2004), 54 (1): pp. 8-29.
2. Cunningham D et al., "Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer", Lancet (1998), 352 (9138): pp. 1,413-1,418.
3. Rougier P et al.,"Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer", Lancet (1998), 352 (9138): pp. 1,407-1,412.
4. Saltz L B et al., "Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer", Irinotecan Study Group, N. Engl. J. Med. (2000), 343 (13): pp. 905-914.
5. Douillard J Y et al., "Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial", Lancet (2000), 355 (9209): pp. 1,041-1,047.
6. de Gramont A et al.,"Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer", J. Clin. Oncol. (2000), 18 (16): pp. 2,938-2,947.
7. Rothenberg M L et al.,"Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial", J. Clin. Oncol. (2003), 21 (11): pp. 2,059-2,069.
8. Goldberg R M 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 (1): pp. 23-30.
9. Leichman C G et al., "Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study", J. Clin. Oncol. (1995), 13 (6): pp. 1,303-1,311.
10. "Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Metaanalysis Group In Cancer", J. Clin. Oncol. (1998), 16 (1): pp. 301-308.
11. Grothey A et al., "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): pp. 1,209-1,214.
12. Giacchetti S et al.,"Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as firstline treatment of metastatic colorectal cancer", J. Clin. Oncol. (2000), 18 (1): pp. 136-147.
13. Tournigand C et al., "FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study", J. Clin. Oncol. (2004), 22 (2): pp. 229-237.
14. Rothenberg M L et al., "Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel", J. Clin. Oncol. (2001), 19 (18): pp. 3,801-3,807.
15. Burris H A 3rd et al., "Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial", J. Clin. Oncol. (1997), 15 (6): pp. 2,403-2,413.
16. L B Saltz, D N, Hollis D, Goldberg R M, Hantel A, Thomas J P, Fields A L A, Carver G, Mayer R J "Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803)", J. Clin. Oncol. (2004),ASCO Annual Meeting Proceedings (Post-Meeting Edition), 22 (14S).
17. Hurwitz H et al., "Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer", N. Engl. J. Med. (2004), 350 (23): pp. 2,335-2,342.
18. Kabbinavar F et al., "Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer", J. Clin. Oncol. (2003), 21 (1): pp. 60-65.
19. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A,Verslype C, Chau I and Van Cutsem E, "Cetuximab Monotherapy and Cetuximab Plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer", N. Eng. J. Med. (2004), 351 (4): pp. 337-345.
20. Saltz L B, et al.,"Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor", J. Clin. Oncol. (2004), 22 (7): pp. 1,201-1,208.
21. Saltz L B, R M, Hochster H,Tchekmeydian N S,Waksal H, Needle M and LoBuglio A, "Cetuximab (IMC-C225) Plus Irinotecan (CPT-11) is Active in CPT-11-Refractory Colorectal Cancer (CRC) that Expresses Epidermal Growth Factor Receptor (EGFR)", Am. Soc. Clin. Oncol. (2001), San Francisco, California.
22. H J Lenz, R J M, Gold P J, Mirtsching B, Stella P J, Cohn A L, Pippas A W, Azarnia N, Needle M N and Van Cutsem E, "Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin", J. Clin. Oncol. (2004), ASCO Annual Meeting Proceedings (Post-Meeting Edition), 22 (14S).
23. H X Chen, M M, Boron M, Grochow L, Zwiebel J,Vena D, Mosby K, Grandinetti C and Kaplan R S,"TRC Participating Investigators; NCI, Cancer Therapy Evaluation Program, Bethesda, MD; EMMES Corporation, Rockville, MD, Bevacizumab (BV) plus 5-FU/leucovorin (FU/LV) for advanced colorectal cancer (CRC) that progressed after standard chemotherapies: An NCI Treatment Referral Center trial (TRC-0301)", J. Clin. Oncol. (2004), ASCO Annual Meeting Proceedings (Post- Meeting Edition), 22(14S).
24. de Gramont A et al.,"Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose 4 leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study", J. Clin. Oncol. (1997), 15 (2): pp. 808-815.
25. Andre T et al.,"Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer", N. Engl. J. Med. (2004), 350 (23): pp. 2,343-2,351.
26. D J Sargent, S W, Benedetti J, Labianca R, Haller D G, Shepherd L E, Seitz J F, Francini G, De Gramont A and Goldberg R M, "Disease-free survival (DFS) vs. overall survival (OS) as a primary endpoint for adjuvant colon cancer studies: Individual patient data from 12,915 patients on 15 randomized trials", J. Clin. Oncol. (2004),ASCO Annual Meeting Proceedings (Post- Meeting Edition), 22 (14S).
27. Van Cutsem E et al., "Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study", J. Clin. Oncol. (2001), 19 (21): pp. 4,097-4,106.
28. Hoff P M et al., "Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study", J. Clin. Oncol. (2001), 19 (8): pp. 2,282-2,292.
29. N Wolmark, S W, Lembersky B, Colangelo L, Smith R and Pazdur R, "A phase III trial comparing oral UFT to FULV in stage II and III carcinoma of the colon: Results of NSABP Protocol C-06", J. Clin. Oncol. (2004), ASCO Annual Meeting Proceedings (Post-Meeting Edition), 2 (14S).
30. J Cassidy,W S, McKendrick J, Kröning H, Nowacki M P, Seitz J F,Twelves C,Van Hazel G,Wong A and Díaz-Rubio E,"On Behalf Of X-act Study Investigators;, Capecitabine (X) vs bolus 5-FU/leucovorin (LV) as adjuvant therapy for colon cancer (the X-ACT study): efficacy results of a phase III trial", J. Clin. Oncol. (2004),ASCO Annual Meeting Proceedings (Post-Meeting Edition), 22 (14S).
31. Schrag D,"The price tag on progress - chemotherapy for colorectal cancer", N. Engl. J. Med. (2004), 351 (4): pp. 317-319.
32. Benson A B 3rd et al.,"Recommended guidelines for the treatment of cancer treatment-induced diarrhea", J. Clin. Oncol. (2004), 22 (14): pp. 2,918-2,926.
1 Jemal A et al., "Cancer statistics, 2004", CA Cancer J. Clin. (2004), 54 (1): pp. 8-29.
2. Cunningham D et al., "Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer", Lancet (1998), 352 (9138): pp. 1,413-1,418.
3. Rougier P et al.,"Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer", Lancet (1998), 352 (9138): pp. 1,407-1,412.
4. Saltz L B et al., "Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer", Irinotecan Study Group, N. Engl. J. Med. (2000), 343 (13): pp. 905-914.
5. Douillard J Y et al., "Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial", Lancet (2000), 355 (9209): pp. 1,041-1,047.
6. de Gramont A et al.,"Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer", J. Clin. Oncol. (2000), 18 (16): pp. 2,938-2,947.
7. Rothenberg M L et al.,"Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial", J. Clin. Oncol. (2003), 21 (11): pp. 2,059-2,069.
8. Goldberg R M 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 (1): pp. 23-30.
9. Leichman C G et al., "Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study", J. Clin. Oncol. (1995), 13 (6): pp. 1,303-1,311.
10. "Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Metaanalysis Group In Cancer", J. Clin. Oncol. (1998), 16 (1): pp. 301-308.
11. Grothey A et al., "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): pp. 1,209-1,214.
12. Giacchetti S et al.,"Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as firstline treatment of metastatic colorectal cancer", J. Clin. Oncol. (2000), 18 (1): pp. 136-147.
13. Tournigand C et al., "FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study", J. Clin. Oncol. (2004), 22 (2): pp. 229-237.
14. Rothenberg M L et al., "Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel", J. Clin. Oncol. (2001), 19 (18): pp. 3,801-3,807.
15. Burris H A 3rd et al., "Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial", J. Clin. Oncol. (1997), 15 (6): pp. 2,403-2,413.
16. L B Saltz, D N, Hollis D, Goldberg R M, Hantel A, Thomas J P, Fields A L A, Carver G, Mayer R J "Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803)", J. Clin. Oncol. (2004),ASCO Annual Meeting Proceedings (Post-Meeting Edition), 22 (14S).
17. Hurwitz H et al., "Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer", N. Engl. J. Med. (2004), 350 (23): pp. 2,335-2,342.
18. Kabbinavar F et al., "Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer", J. Clin. Oncol. (2003), 21 (1): pp. 60-65.
19. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A,Verslype C, Chau I and Van Cutsem E, "Cetuximab Monotherapy and Cetuximab Plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer", N. Eng. J. Med. (2004), 351 (4): pp. 337-345.
20. Saltz L B, et al.,"Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor", J. Clin. Oncol. (2004), 22 (7): pp. 1,201-1,208.
21. Saltz L B, R M, Hochster H,Tchekmeydian N S,Waksal H, Needle M and LoBuglio A, "Cetuximab (IMC-C225) Plus Irinotecan (CPT-11) is Active in CPT-11-Refractory Colorectal Cancer (CRC) that Expresses Epidermal Growth Factor Receptor (EGFR)", Am. Soc. Clin. Oncol. (2001), San Francisco, California.
22. H J Lenz, R J M, Gold P J, Mirtsching B, Stella P J, Cohn A L, Pippas A W, Azarnia N, Needle M N and Van Cutsem E, "Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin", J. Clin. Oncol. (2004), ASCO Annual Meeting Proceedings (Post-Meeting Edition), 22 (14S).
23. H X Chen, M M, Boron M, Grochow L, Zwiebel J,Vena D, Mosby K, Grandinetti C and Kaplan R S,"TRC Participating Investigators; NCI, Cancer Therapy Evaluation Program, Bethesda, MD; EMMES Corporation, Rockville, MD, Bevacizumab (BV) plus 5-FU/leucovorin (FU/LV) for advanced colorectal cancer (CRC) that progressed after standard chemotherapies: An NCI Treatment Referral Center trial (TRC-0301)", J. Clin. Oncol. (2004), ASCO Annual Meeting Proceedings (Post- Meeting Edition), 22(14S).
24. de Gramont A et al.,"Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose 4 leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study", J. Clin. Oncol. (1997), 15 (2): pp. 808-815.
25. Andre T et al.,"Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer", N. Engl. J. Med. (2004), 350 (23): pp. 2,343-2,351.
26. D J Sargent, S W, Benedetti J, Labianca R, Haller D G, Shepherd L E, Seitz J F, Francini G, De Gramont A and Goldberg R M, "Disease-free survival (DFS) vs. overall survival (OS) as a primary endpoint for adjuvant colon cancer studies: Individual patient data from 12,915 patients on 15 randomized trials", J. Clin. Oncol. (2004),ASCO Annual Meeting Proceedings (Post- Meeting Edition), 22 (14S).
27. Van Cutsem E et al., "Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study", J. Clin. Oncol. (2001), 19 (21): pp. 4,097-4,106.
28. Hoff P M et al., "Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study", J. Clin. Oncol. (2001), 19 (8): pp. 2,282-2,292.
29. N Wolmark, S W, Lembersky B, Colangelo L, Smith R and Pazdur R, "A phase III trial comparing oral UFT to FULV in stage II and III carcinoma of the colon: Results of NSABP Protocol C-06", J. Clin. Oncol. (2004), ASCO Annual Meeting Proceedings (Post-Meeting Edition), 2 (14S).
30. J Cassidy,W S, McKendrick J, Kröning H, Nowacki M P, Seitz J F,Twelves C,Van Hazel G,Wong A and Díaz-Rubio E,"On Behalf Of X-act Study Investigators;, Capecitabine (X) vs bolus 5-FU/leucovorin (LV) as adjuvant therapy for colon cancer (the X-ACT study): efficacy results of a phase III trial", J. Clin. Oncol. (2004),ASCO Annual Meeting Proceedings (Post-Meeting Edition), 22 (14S).
31. Schrag D,"The price tag on progress - chemotherapy for colorectal cancer", N. Engl. J. Med. (2004), 351 (4): pp. 317-319.
32. Benson A B 3rd et al.,"Recommended guidelines for the treatment of cancer treatment-induced diarrhea", J. Clin. Oncol. (2004), 22 (14): pp. 2,918-2,926.
