This Review refers to the following Article: First-Line Therapeutic Strategies in Metastatic Colorectal Cancer
The past decade has seen exciting developments in the field of colorectal cancer, particularly in the setting of advanced disease. The developments of new treatment options have translated into impressive gains in response rates, progression-free survival, overall survival, and, in certain situations, potential cure. In this issue of ONCOLOGY, Drs. Davies and Goldberg have provided an excellent review of the history of the development of newer therapies for metastatic colorectal cancer (mCRC), presenting the data and rationale behind each new therapeutic approach.
The article eloquently details how multiple studies have investigated the use of cytotoxic chemotherapeutic agents (fluorouracil [5-FU], oxaliplatin [Eloxatin], and irinotecan) in attempts to determine the best combination and the ideal order in which to administer them. Doublet chemotherapy regimens (FOLFOX [leucovorin (folinic acid), 5-FU, oxaliplatin] and FOLFIRI [leucovorin, 5-FU, irinotecan]) have improved efficacy over 5-FU/leucovorin alone.[1,2] It does not appear to change outcomes whether FOLFOX or FOLFIRI are used as first- or second-line therapy, and ultimately it was shown that survival is improved with exposure to all three drugs. Capecitabine (Xeloda) appears to be an acceptable alternative for 5-FU,[5,6] although this agent has not gained the popularity in the United States that it has in Europe.
Targeted therapies have provided an additional mechanism with which to attack advanced colorectal cancer. Bevacizumab (Avastin), a vascular endothelial growth factor (VEGF) inhibitor, and epidermal growth factor receptor (EGFR) inhibitors (cetuximab [Erbitux] and panitumumab [Vectibix]) can lead to increased response rates, progression-free survival, and—in the case of bevacizumab—overall survival, particularly when used in combination with cytotoxic chemotherapy.[7-11] Ongoing trials are aimed at determining the optimal combinations of cytotoxic and targeted therapies.
With the treatment options we have available, the challenge is the following: How do we best utilize these therapies to provide the greatest benefit to our patients with advanced colorectal cancer? The focus now should be to tailor each therapeutic option to the individual, minimizing toxicity while obtaining the maximum efficacy our treatments can provide.
Biomarker-Driven Treatment Decisions
The latest breakthrough in the individualization of therapy for mCRC involves determining whether the patient’s tumor has a mutation in K-ras. As outlined by Drs. Davies and Goldberg, a large body of evidence shows that only individuals with K-ras wild-type status stand to benefit from the use of EGFR inhibitors. These agents provide no survival advantage to patients with K-ras mutant tumors and, in fact, have the potential to harm this subset of patients.[12,13]
To determine whether a given patient might benefit from the use of an EGFR inhibitor, tumors should be tested for K-ras mutation status. Ideally, this should be done at the time of diagnosis for all patients with colorectal cancer. Testing can also be performed on tissue from previously resected lesions or biopsies. Recurrent and metastatic lesions retain their K-ras status; therefore, knowledge of K-ras status initially, even in patients without advanced disease, will indicate whether EGFR inhibitors will be an option for treatment in the event of recurrence.
Beyond K-ras, further biomarkers such as B-raf (V600E) mutations, intact expression of PTEN, and expression levels of EGFR ligands (amphiregulin, epiregulin) will conceivably allow us to more specifically identify patients who will benefit from EGFR-targeted therapies.[15-17] The ideal patient for cetuximab or panitumumab therapy would have a K-ras wild-type colorectal cancer without B-raf mutations, intact PTEN, and high expression levels of amphiregulin and/or epiregulin.
Curative vs Palliative Approach
Another question to ask when considering treatment for advanced colorectal cancer is: What is the goal of treatment? Is the hope to downsize metastatic lesions with chemotherapy to convert previously unresectable metastatic disease to resectable status with the intention of cure—so-called conversion therapy? Or, is the situation palliative, to help the patient live with the best quality of life for as long as possible? This decision can be made as part of a multidisciplinary approach, including surgical and medical oncology teams.
Surgical resection of metastatic disease can lead to significantly improved survival times and offers the patient potential for cure. Traditionally, based on prior criteria for resection, only 10% to 20% of patients with mCRC were eligible to have surgery at the time of presentation. Now, based on data showing that outcomes are not dependent on tumor size or number of lesions, surgeons focus on the amount of functioning organ that remains after resection to determine feasibility.[18,19]
Whether metastatic lesions are resected upfront or after downsizing with chemotherapy, patients gain a survival benefit. Two prospective trials suggest improved resection rates with oxaliplatin-based regimens.[3,21] The addition of a biologic agent appears to improve resection rates as well. Data from two phase II trials support the use of bevacizumab in combination with an oxaliplatin-based regimen.[13,22] The CRYSTAL trial showed improved resection rates when cetuximab was added to FOLFIRI. Due to concerns about postoperative complications, a 6- to 8-week interval is recommended between bevacizumab use and surgery. Cetuximab does not appear to increase the surgical complication risk.
The duration of neoadjuvant chemotherapy in this setting is dependent on the responsiveness of the disease. Treating until best response may make lesions undetectable, and the exact location of the tumor becomes difficult to detect. It is currently recommended that patients be treated until the point when their disease becomes resectable.
Minimizing Toxicity n the Palliative Setting
In the United States, first-line therapy for unresectable mCRC most commonly includes FOLFOX plus bevacizumab. The majority of patients discontinue oxaliplatin-based chemotherapy due to neurotoxicity, not because of disease progression. As mentioned in the review article, several trials provide guidance for extending duration of treatment and disease control while minimizing toxicity.
The stop-and-go strategy used in an OPTIMOX1 fashion, does not compromise efficacy, and reduces the incidence of grade 3/4 neurotoxicity. With disease stability, six cycles of FOLFOX plus bevacizumab can be followed by maintenance 5-FU and bevacizumab. Upon progression, FOLFOX can be reintroduced, and bevacizumab can be continued as well. Continuing bevacizumab beyond progression can potentially improve survival and does not add significant toxicity. Giving patients a break from oxaliplatin during the maintenance phase, with reintroduction at a future point, allows us to gain the maximum benefit from oxaliplatin therapy while hopefully providing improved quality of life for patients. The use of targeted agents as maintenance therapy is currently being evaluated in phase III clinical trials. The DREAM-OPTIMOX3 study randomizes patients to receive bevacizumab with or without erlotinib (Tarceva) during a chemotherapy-free interval after six cycles of FOLFOX7 or XELOX4 (capecitabine, oxaliplatin) plus bevacizumab.
Another study from the Spanish Cooperative Group for Gastrointestinal Tumour Therapy is comparing XELOX plus bevacizumab until disease progression or toxicity vs XELOX plus bevacizumab for six cycles followed by bevacizumab alone until disease progression. These trials will hopefully provide more information regarding the incorporation of biologic agents as maintenance therapy.
Acceptable Regimens in the Elderly
A pooled analysis of adjuvant, first-line, and second-line trials showed that individuals over 70 years old benefit from oxaliplatin-based chemotherapy as much as younger patients. Efficacy was comparable, and with the exception of more hematologic toxicity (including neutropenia and thrombocytopenia), the safety/toxicity profile did not differ by age. Similar findings of efficacy and safety in patients over 70 years have been reported in a pooled analysis of trials using irinotecan-based chemotherapy. Keeping in mind that these trials include patients with good performance status, both irinotecan- and oxaliplatin-based therapy can be utilized in elderly patients.
However, caution must be used when considering the addition of antiangiogenesis agents to cytotoxic chemotherapy in the elderly. Patients over 65 years old do have a 1.8-fold increased risk of arterial thrombotic events (ATE) with the use of bevacizumab. This effect was substantially increased in patients with a prior history of ATEs. Analysis of the BRiTE (Bevacizumab Regimens: Investigation of Treatment Effects and Safety) registry confirmed this risk in patients older than age 75. No increased risk of gastrointestinal bleeding/perforation or hypertension was seen in the elderly. When considering bevacizumab in the elderly, an increased risk of ATEs needs to be recognized, and for those who have experienced prior ATEs, bevacizumab is contraindicated.
Treatment options for mCRC have significantly expanded over the past 10 years, providing oncologists with the opportunity to choose therapies that are more closely tailored to the individual. The plethora of potential treatment sequences can be focused on the individual need of specific patients by using biomarkers, establishing treatment goals a priori, and employing treatment algorithms that prevent excess toxicity in order to administer optimal care while minimizing harm to patients. Ongoing research will continue to investigate how to appropriately utilize targeted therapies in the era of individualized medicine.
1. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000.
2. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905-914, 2000.
3. 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.
4. Grothey A, Sargent D, Goldberg RM, 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 22:1209-1214, 2004.
5. Cassidy J, Clarke S, Diaz-Rubio E, et al: Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26:2006-2012, 2008.
6. Hochster HS, Hart LL, Ramanathan RK, et al: Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: Results of the TREE Study. J Clin Oncol 26:3523-3529, 2008.
7. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004.
8. 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.
9. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539-1544, 2007.
10. Fuchs CS, Marshall J, Mitchell E, et al: Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the BICC-C Study. J Clin Oncol 25:4779-4786, 2007.
11. Tabernero J, Van Cutsem E, Diaz-Rubio E, et al: Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 25:5225-5232, 2007.
12. Van Cutsem E, Lang I, D’haens G, et al: KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience (abstract 2). J Clin Oncol 26(15S):5s, 2008.
13. Bokemeyer C, I. Bondarenko, Hartmann JT, et al: KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience (abstract 4000). J Clin Oncol 26(15S):178s, 2008.
14. Loupakis F, Pollina L, Stasi I, et al: Evaluation of PTEN expression in colorectal cancer (CRC) metastases (mets) and in primary tumors as predictors of activity of cetuximab plus irinotecan treatment (abstract 4003). J Clin Oncol 26(15S):178s, 2008.
15. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67:2643-2648, 2007.
16. Cappuzzo F, Varella-Garcia M, Finocchiaro G, et al: Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer 99:83-89, 2008.
17. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230-3237, 2007.
18. Hamady ZZ, Malik HZ, Finch R, et al: Hepatic resection for colorectal metastasis: impact of tumour size. Ann Surg Oncol 13:1493-1499, 2006.
19. Minagawa M, Makuuchi M, Torzilli G, et al: Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: long-term results. Ann Surg 231:487-499, 2000.
20. Adam R, Avisar E, Ariche A, et al: Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 8:347-353, 2001.
21. Delaunoit T, Alberts SR, Sargent DJ, et al: Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741. Ann Oncol 16:425-429, 2005.
22. Gruenberger T, Kaczirek K, Bergmann M, et al: Progression-free survival in a phase II study of perioperative bevacizumab plus XELOX in patients with potentially curable metastatic colorectal cancer (abstract 4073). J Clin Oncol 26(15S):196s, 2008.
23. Tournigand C, Cervantes A, Figer A, et al: OPTIMOX1: A randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol 24:394-400, 2006.
24. Grothey A, Sugrue MM, Purdie DM, et al: Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: Results from a large observational cohort study (BRiTE). J Clin Oncol Oct 14, 2008 (Epub ahead of print).
25. US National Institutes of Health: Combination chemotherapy and bevacizumab with or without erlotinib in treating patients with metastatic colorectal cancer that cannot be removed by surgery. Available at http://clinicaltrials.gov/ct/show/NCT00265824?order=2. Accessed Nov 7, 2008.
26. US National Institutes of Health: Study of bevacizumab alone or combined with capecitabine and oxaliplatin as support therapy in metastatic colorectal cancer patients. Available at http://clinicaltrials.gov/ct/show/NCT00335595. Accessed Nov 7, 2008.
27. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al: Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 24:4085-4091, 2006.
28. Folprecht G, Seymour MT, Saltz L, et al: Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer: Combined analysis of 2,691 patients in randomized controlled trials. J Clin Oncol 26:1443-1451, 2008.
29. Scappaticci FA, Skillings JR, Holden SN, et al: Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 99:1232-1239, 2007.
30. Kozloff M, Sugrue M, Berlin J, et al: Safety and effectiveness of bevacizumab (BV) and chemotherapy (CT) in elderly patients (pts) with metastatic colorectal cancer (mCRC): Results from the BRiTE Prospective Cohort Study (abstract 454). Presented at the 2008 Gastrointestinal Cancers Symposium; Orlando, Fla; Jan 25–27, 2008.