Advances in the treatment ofmetastatic colorectal cancer inthe past several years havebeen expeditious and exciting-evenchaotic-but with the median survivaldoubled since the use of single-agentfluoropyrimidines alone. However, newquestions continue to arise, directly affectingour daily practice in the care ofpatients with colorectal cancer. One ofthese issues, the optimal therapy formetastatic colorectal cancer, is wonderfullyexplored by Dr. Saltz in thisissue of ONCOLOGY. To understandthis issue better, we may have to approachthe question a little differently:That is, is it possible to standardizetreatment options for metastatic colorectalcancer?
Advances in the treatment of metastatic colorectal cancer in the past several years have been expeditious and exciting-even chaotic-but with the median survival doubled since the use of single-agent fluoropyrimidines alone. However, new questions continue to arise, directly affecting our daily practice in the care of patients with colorectal cancer. One of these issues, the optimal therapy for metastatic colorectal cancer, is wonderfully explored by Dr. Saltz in this issue of ONCOLOGY. To understand this issue better, we may have to approach the question a little differently: That is, is it possible to standardize treatment options for metastatic colorectal cancer? Three Considerations
Before we try to answer this question, there are three facts we need to bear in mind. First, nearly 150,000 new cases of colorectal cancer are diagnosed each year in the United States, and nearly one-fourth of them are metastatic when the diagnosis is made. About one-third of those patients with initially localized disease may develop metastases, which means we are treating nearly 75,000 patients with metastatic colorectal cancer every year. It is surely a public health issue. Given these large numbers of patients, it is unlikely that there can be a single therapy or sequence of therapies that will be optimal. Second, our ultimate goal of treatment for most patients with metastatic colorectal cancer is to control their disease, to prolong their survival, and to improve their quality of life. However, in a small portion of highly selected patients, cure is possible, and that goal of treatment of metastatic colorectal cancer should be clearly defined at the outset of a patient's treatment program, and not as an afterthought. Third, but not least, the practice of modern medicine is guided ideally by evidence-based science. However, given the plethora of new treatments and the need to apply clinical trials information into the clinic population, it is unlikely that every question will, or should, be addressed by large-scale clinical trials. As Dr. Saltz points out, much of our current practice is based on leaps of faith; it is the job of the clinical trials mechanisms to make sure that leaps-when necessary-are made with as little guesswork and wishful thinking as possible. Novel Agents and Combinations
Irinotecan (Camptosar) and oxaliplatin (Eloxatin), two novel cytotoxic agents with different mechanisms of action, have significantly improved the treatment efficacy of metastatic colorectal cancer when administered with fluorouracil (5-FU).[2,3] Although the debates around the combination of irinotecan, 5-FU, and leucovorin (FOLFIRI, IFL) vs oxaliplatin, 5-FU, and leucovorin (FOLFOX) have continued for several years, the general consensus, based on clinical data, would suggest that oxaliplatin- and irinotecan- based regimens have roughly the same efficacy in first-line treatment. FOLFOX (infusional 5-FU with oxaliplatin) and FOLFIRI (infusional 5-FU and irinotecan) are considered equivalent in clinical efficacy but with different toxicity profiles. IFL (irinotecan with bolus 5-FU and leucovorin) is inferior in both efficacy and toxicity compared to FOLFIRI and FOLFOX.[3,4] The sequence of the application of these combinations may be considered not as important as the ability to administer all these medications to metastatic colorectal cancer patients, to gain the maximal benefits that chemotherapy may deliver. The study led by Tournigand showed identical median overall survival of about 21 months (P = .99) with either FOLFOX followed by FOLFIRI or vice versa. However, because of the different toxicity profiles of these two medications, oncologists may choose to prioritize one regimen over the other in a particular patient. Capecitabine (Xeloda), as an oral fluoropyrimidine carbamate derivative, has potential advantages over infusional 5-FU, which makes it attractive in combination with either oxaliplatin (XELOX) or irinotecan (XELIRI). Phase III data comparing infusional 5-FU to capecitabine with oxaliplatin are pending, and the routine use of the oral agent should likely await the results of these trials. The general concept of chemotherapy with cytotoxic agents is that all three agents-5-FU (or capecitabine), oxaliplatin, and irinotecan- should be given to patients with reasonable performance status in order to maximize the benefit. In his timely and comprehensive review, Dr. Saltz presents the preliminary data from the FOCUS trial, which appear to challenge the use of combination chemotherapy in first-line therapy for metastatic colorectal cancer patients. Further data from this study are eagerly awaited, but the overall conclusion may be confounded by the fact that a relatively small proportion of patients actually went on to second- line therapy-always a problem in trials with crossover study designs. New Era of Therapy
With advances in the understanding of molecular and biologic characteristics of cancer, new approaches of targeting angiogenesis and signal transduction in combination with cytotoxic chemotherapy have brought therapy for metastatic colorectal cancer to a new era. Significant advantages in overall survival, progression-free survival, and response rate have been shown when bevacizumab (Avastin), an anti-vascular endothelial growth factor monoclonal antibody, is combined with irinotecan, 5-FU, and leucovorin.[ 5] Survival benefit has also been demonstrated in the combination of bevacizumab with FOLFOX in secondline treatment in a large study conducted by Eastern Cooperative Oncology Group. Benefits have also been demonstrated when bevacizumab was added to 5-FU and leucovorin. As Dr. Saltz has noted, no therapy is without risks, and the side effects noted with this antiangiogenesis agent, such as hypertension, wound healing complications, gastrointestinal perforation, and proteinuria are risks that need to be taken into account when considering this agent in the clinic. A small but clinically significant increase in arterial thromboembolic events may be associated with bevacizumab, especially in patients with risk factors (age > 65 years and previous arterial thromboembolic events). Cetuximab (Erbitux), an anti-epidermal growth factor receptor monoclonal antibody, has been developed in a very different way from bevacizumab, so that the use of the drugs and their regulatory approvals are based not only on science or on their known optimal use, but on the data from the clinical trials that first showed benefit. In the case of bevacizumab, these are virtually all first-line data; for cetuximab, the data are primarily in heavily pretreated patients. For cetuximab, the activity in metastatic colorectal cancer has been persuasive, either as a single agent or combined with irinotecan. There is no reason to consider cetuximab ineffective as front-line treatment for metastatic colorectal cancer in conjunction with 5-FU, irinotecan, and oxaliplatin. However, large randomized studies of combination chemotherapy with or without cetuximab are under way, in first- and second-line metastatic colorectal cancer. These trials will help to further define the role of cetuximab. The US Intergroup will shortly activate a large trial in first-line treatment of metastatic colorectal cancer, in which patients and physicians can choose either FOLFIRI or FOLFOX, based on the attributes of the regimens outlined by Dr. Saltz, with randomization to bevacizumab, cetuximab, or both. Based on the activity of the combination of the two antibodies in the preliminary results of a small study reported by Dr. Saltz, each of these regimens stands a good chance of advancing the treatment of patients with metastatic colorectal cancer. Drug 'Holidays'
With the availability of all of these agents, is there a need to challenge the paradigm of "more is better"? The cumulative neurotoxicity has raised this issue, and the preliminary results of the OPTIMOX trial suggest that limited induction therapy with combination chemotherapy (plus a biologic), with drug "holidays" may be the optimal treatment for patients, saving toxicity and money, and allowing for the reintroduction of drugs. Whether the drug holiday should consist of no treatment, a fluoropyrimidine alone (or with a biologic such as bevazicumab) or a biologic alone, is uncertain at present. Based on the results of the OPTIMOX trial, we now consider limiting exposure of patients to six to eight cycles of combination therapy, with discussion at that time in stable or responding patients to either continuing their initial regimen, deleting the oxaliplatin or irinotecan, or discontinuing treatment, with close observation. The current DREAM trial may help to resolve the ideal maintenance program, and the CONCEPT trial in the United States will also retest the strategy of "stop-and-go" therapy compared to our previous standard approach of continuing until treatment failure. Conclusions
In summary, the optimal treatment for an individual metastatic colorectal cancer patient should be based on the most updated and emerging clinical data, with consideration of the benefit- risk ratio for each treatment option. At the moment, there is no absolutely standardized treatment strategy for all patients with metastatic colorectal cancer. For a disease in which nihilism and negative trials dominated the past quarter century, changing attitudes and improved treatment have brought the blessing of patient benefit and the curse of confusion. On the whole, we favor continued confusion over certain failure.
Dr. Haller is a consultant and receives research support from Pfizer, Sanofi-Aventis, and Roche, and is a consultant for Genetech.
1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005.
2. Saltz LB, Cox JV, Blanke CB, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905-914, 2000.
3. 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 22:23-30, 2004.
4. 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 22:229- 237, 2004.
5. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004.
6. Giantonio BJ, Catalano PJ, Meropol NJ, et al: High-dose bevacizumab in combination with FOLFOX4 in proves survival in patients with previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study 3200 (abstract A169). Proc Gastrointestinal Cancers Symposium, 2005, p 168.
7. Kabbinavar FF, Schulz J, McCleod M, et al: Bevacizumab (a monocolonal antibody to vascular endothelia growth factor) to prolong progression-free survival in first-line colorectal cancer (CRC) in subjects who are not suitable candidates for first-line CPT-11 (abstract 3516). Proc Am Soc Clin Oncol 23:249, 2004.
8. Avastin (bevacizumab) prescribing information- warning. December 2004.
9. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 35:337-345, 2004.
10. De Gramont A, Cervantes A, Andre T, et al: OPTIMOX study: FOLFOX7/LV5FU2 compared to FOLFOX4 in patients with advanced colorectal cancer (abstract 3525). Proc Am Soc Clin Oncol 23:251, 2004.