Novel therapies and regimens have increased survival and the number of patients gaining from resection. Here, studies that have changed approaches and broadened treatment options are surveyed.
Department of Medical Oncology
University Hospital of Heraklion
Colorectal cancer (CRC) accounts for 8% of all malignant tumours in adults(1) and is considered a major cause of cancer morbidity and mortality worldwide.(2) Although macroscopically curative surgical resection is possible in 70-80% of patients at diagnosis, almost half of such patients will develop local and/or metastatic recurrence and die of the disease.(3)
Although chemotherapy has historically been used for palliation of symptoms, in recent years median overall survival of patients with advanced CRC has been substantially increased, from 12 to about 21-22 months when all the available chemotherapeutic agents are administered.(4) Therefore, in recent years treatment of metastatic colorectal cancer (mCRC) has changed considerably. Combinations of 5-fluorouracil/leucovorin (5-FU/LV) either as bolus (Roswell Park) or infusional administration (De Gramont schedule) combined with irinotecan(5) or oxaliplatin are accepted as the mainstay of first-line treatment, while the choice of a particular drug to combine with 5FU does not influence overall survival.6 A recent meta-analysis of seven phase III trials in advanced colorectal cancer showed that median overall survival correlated significantly with the proportion of patients receiving all active agents over the course of the disease, but not with the proportion of patients receiving second-line chemotherapy (see Table 1).(4)
In addition, resection for colorectal metastases (mainly of lung and liver) has become the standard of care for patients with limited metastatic disease and remains the only potentially curative therapy.(7) Several retrospective series have reported long-term survival. However, curative resection is possible in fewer than 25% of patients with disease limited to the liver or lungs, which translates into only 5-10% of the original group developing colorectal cancer.
The advent of targeted therapy further expanded treatment options for patients with mCRC. In particular, inhibition of epidermal growth factor receptor (EGFR) and of angiogenesis by blocking vascular endothelial growth factor (VEGF) using the monoclonal antibodies cetuximab and bevacizumab, respectively, led to further improvement in outcome for patients with mCRC.
Indeed, randomised studies demonstrated that adding bevacizumab to either 5FU/LV8-10 or to an irinotecan-5FU/LV combination (IFL)(11) as first-line treatment of mCRC was associated with improved objective response rate, time to tumour progression and overall survival. In addition, data from phase II studies suggests that adding bevacizumab to oxaliplatin-based chemotherapy further improved response rate(12) and resectability of primary unresectable metastatic lesions.(13) A recently reported phase III trial (NO 16966) demonstrated a relatively small but statistically significant (1.5 months, pâ€‰=â€‰0.0023) improvement for progression-free survival when bevacizumab was added to the oxaliplatin-based regimens XELOX (cepecitabine plus oxaliplatin) or FOLFOX4.(14) Moreover, the addition of bevacizumab improved the activity of the second-line oxaliplatin-containing combination in patients with mCRC.(15) However, in this study the effect of the combination on rate was modest, reflecting the more advanced stage of the disease in such patients.
On the other hand, cetuximab has shown its antitumour activity in patients with mCRC progressing under ï¿½irinotecan-based chemotherapy irrespective of the membrane expression of EGFR.(16,17) The results of the BOND trial also showed that in patients with mCRC who progress under CPT-11-based therapy, administration of CPT-11 and cetuximab has a higher efficacy than cetuximab alone, in terms of objective response rate, overall disease control rate and time to tumour progression.(18) In a phase II trial, we have reported that in patients who progressed or relapsed under oxaliplatin-based chemotherapy adding cetuximab to the same regimen led to response rates (20%), time to tumour progression (2.9 months) and overall survival (10.7 months).(19) These efficacy results were higher than those reported with cetuximab monotherapy (RR 9%, TTP 1.4 months and OS 6.4 months),(16,17) suggesting that adding cetuximab could also reverse resistance to oxaliplatin-based chemotherapy. In all the above-mentioned studies, the outcome for patients treated with cetuximab was unrelated to the level of EGFR protein expression. In fact, patients with EGFR-negative tumours seem to have the same probability of response to cetuximab as those with EGFR-positive tumours.(20)
Only preliminary data have been reported regarding the efficacy of cetuximab in the first-line setting. In a phase II trial the combination of FOLFOX-4 plus cetuximab achieved a response rate of 81%, with a disease control rate of more than 90% and a resectability rate of more than 15%.(21) In a similar study, the combination of FOLFIRI with cetuximab achieved a disease control rate of more than 90%.(22) The results of a phase III trial involving addition of cetuximab to first-line irinotecan-based chemotherapy were recently reported.(23) Patients who were treated with the combination of FOLFIRI plus cetuximab presented significantly higher response rates (pâ€‰=â€‰0.038) and progression-free survival (HR 0.85, pâ€‰=â€‰0.047). In addition, more patients treated with the combination underwent surgery with curative intent (4.3% vs 1.5%, pâ€‰=â€‰0.034). On the other hand, dermatological toxicity, a typical adverse event of all anti-EGFR clinical agents, appeared to be associated with an increased response and survival for patients treated with cetuximab in all the above trials.
These results are in line with efforts over the last decade to increase the number of patients who could benefit from resection of metastatic lesions. Regardless, the necessity for refining prognostic factors that would improve patient selection, advances in surgical technique and novel approaches to permit curative resection, the administration of effective systematic treatment could probably improve the outcome in patients who underwent resection of metastatic lesions from colorectal cancer. The results of a prospective trial for the perioperative treatment of patients with resectable cancer with FOLFOX further support this approach.(24) Patients treated with FOLFOX preoperatively presented significantly higher progression-free survival in comparison with those who underwent only metastasectomy (HR 0.77, pâ€‰=â€‰0.041 for all eligible patients; HR 0.73, pâ€‰=â€‰0.025 for all resected patients). Furthermore, treatment of selected patients with primarily unresectable disease treated using intensive first-line chemotherapy led to a higher resectability rate(25,26) and overall survival.(26) The addition of molecular targeted therapies could further improve the overall survival in this patient subgroup.(13)
Overall survival of patients with metastatic colorectal cancer has been substantially improved over the past decade (see Figure 1). The results of the recently reported studies emphasise the need for the design of a therapeutic algorithm at the time of initial diagnosis (see Figure 2).
Patients with primarily resectable metastatic lesions should be resected preferably with the addition of preoperative chemotherapy. Patients with unresectable metastatic disease should be treated according to the intent of treatment (curative or palliative). In any case, the published data support the treatment of patients with all available chemotherapeutic agents with the addition of molecular targeted treatment options in first- and second-line settings. â–
1. Parkin DM, et al. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
2. Jemal A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5-26.
3. Kuehne CH, et al. Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion. J Clin Oncol 1998;16:418-26.
4. 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: 1209-14.
5. Douillard JY, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041-7.
6. Tournigand C, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer. J Clin Oncol 2004;22:229-37.
7. Khatri VP, et al. Extending the frontiers of surgical therapy for hepatic colorectal metastases. J Clin Oncol 2005;23:8490-9.
8. Hurwitz HI, et al. Bevacizumab in combination with fluorouracil and leucovorin. J Clin Oncol 2005;23:3502-8.
9. Kabbinavar FF, et al. Combined analysis of efficacy. J Clin Oncol 2005;23:3706-12.
10. Kabbinavar FF, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer. J Clin Oncol 2005;23:3697-705.
11. Hurwitz H, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42.
12. Hochster HS, et al. Safety and efficacy of oxaliplatin/fluoropyrimidines regimens with or without bavacizumab as first-line treatment of metastatic colorectal cancer (mCRC). Proc ASCO 2006. Abstract.
13. Emmanouilides C, et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer. BMC Cancer 2007;7:91.
14. Saltz LB, et al. First efficacy and safety results from XELOX-1/NO16966, a randomised 2×2 factorial phase III trial of XELOX vs FOLFOX4 + bevacizumab or placebo in first-line metastatic colorectal cancer. Proc Gastrointestinal Cancer Symposium 2007. Abstract.
15. Giantonio BJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer. J Clin Oncol 2007;25:1539-44.
16. Saltz LB, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201-8.
17. Saltz LB, 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):1201-8.
18. Cunningham D, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351(4):337-45.
19. Souglakos J, et al. Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy. Ann Oncol 2007;18:305-10.
20. Choung KY, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005;23:1803-10.
21. Tabernero J, et al. An international phase II study of cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with metastatic colorectal cancer (CRC) expressing epidermal growth factor receptor (EGFR). Pr Am S Med Oncol 2004, Abst 3512.
22. Rougier P, et al. Cetuximab + FOLFIRI as first-line treatment for metastatic colorectal. Pr Am S Med Oncol 2004, Abst 3513.
23. Van Cutsem E, et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC). Pr Am S Med Oncol 2007, Abst 4000.
24. Nordlinger B, et al. Final results of the EORTC Intergroup randomized phase III study 40983 (EPOC) evaluating the benefit of peri-operative FOLFOX4 chemotherapy for patients with potentially resectable colorectal cancer liver metastases. Pr Am S Med Oncol 2007, Abst LBA5.
25. Souglakos J, et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC). Br J Cancer 2006;94(6):798-805.
26. Falcone A, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer. J Clin Oncol 2007;25:1670-76.
American Society of Clinical Oncology
American Chemical Society
European Organisation for Research and Treatment of Cancer
Clinical Care Options
2008 Gastrointestinal Cancers Symposium, 25-27 January 2008, Orlando, USA