Current Therapies for Advanced Colorectal Cancer

Colorectal cancer is a worldwide public health problem, with nearly 800,000 new cases diagnosed each year, resulting in approximately 500,000 deaths. In the United States, it is the second leading cause of cancer mortality; nearly 60,000 deaths will be attributed to this disease in 2005.[1] When diagnosed as advanced, metastatic disease, colorectal cancer is traditionally associated with a poor prognosis, with 5-year survival rates in the range of 5% to 8%. This survival rate has remained unchanged over the past 35 to 40 years. However, during the past 5 years, significant advances have been made in treatment options so that improvements in 2-year survival are now being reported, with median survival rates of 21 to 24 months in patients with metastatic disease. Chemotherapy has been the mainstay approach for patients with advanced colorectal cancer.[2,3] For nearly 40 years, the main drug used for this disease was the fluoropyrimidine fluorouracil(Drug information on fluorouracil) (5-FU). Since the late 1990s, there has been a marked increase in the number of agents that have been approved for colorectal cancer. The anticancer agents that have been approved by the US Food and Drug Administration (FDA) include the topoisomerase I inhibitor irinotecan (Camptosar), the third-generation platinum analog oxaliplatin (Eloxatin), and the oral fluoropyrimidine capecitabine(Drug information on capecitabine) (Xeloda). In February 2004, two novel biologic agents were approved by the FDA: the anti-epidermal growth factor receptor (EGFR) antibody cetuximab(Drug information on cetuximab) (Erbitux) and the anti-vascular endothelial growth factor (VEGF) bevacizumab(Drug information on bevacizumab) (Avastin). The general approach to treating patients with advanced colorectal cancer has been to use either monotherapy or combination therapy. In the United States, up to 25% to 30% of patients continue to be treated with monotherapy, which refers to the use of fluoropyrimidine chemotherapy- either with intravenous 5-FU or with the oral fluoropyrimidine capecitabine. Response rates are in the 15% to 30% range, with a median survival of 11 to 14 months. The appropriate setting for such an approach would include elderly patients as well as those with compromised performance status, comorbid illnesses, and impaired hepatic and/or renal function. Combination therapy has become the preferred approach for patients with advanced disease; it is used in up to 75% of cases in the first-line setting. Clinical efficacy is significantly improved with combination therapy, with response rates up to 35% to 50%, double that of monotherapy, and median overall survival approaching the 2-year mark in the 15 to 21 month range. Fluorouracil For nearly 40 years, 5-FU was the only active anticancer agent available to treat advanced colorectal cancer in the first-line setting.[4] However, response rates to 5-FU in patients with advanced disease are low, at only 10% to 15%. To improve the clinical efficacy of 5-FU, the addition of certain biomodulating agents such as the reduced folate leucovorin and/or a change in the schedule of administration of 5-FU from bolus to continuous infusion were investigated.[5,6] The most commonly used bolus schedules in the United States are the monthly regimen developed by the Mayo Clinic with 5-FU at a dose of 425 mg/m² and leucovorin at 20 mg/m² repeated every 4 weeks, and a weekly regimen developed by the Roswell Park Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project (NSABP) using 5-FU at 600 mg/m² and leucovorin at 500 mg/m². The three commonly used infusional schedules include the Lokich regimen of 5-FU at 300 mg/m² for 28 days; the AIO German regimen of 5- FU at 2,000 to 2,600 mg/m² over 24 hours and leucovorin at 500 mg/m2 once weekly for 6 weeks with a 1- week rest; and the LV5FU2 de Gramont regimen, a combination of bolus and infusional 5-FU/leucovorin administered on days 1 and 2 on a biweekly schedule. In general, while response rates are improved by up to twofold with these different strategies, overall survival has not been substantively altered. A recent meta-analysis incorporating 3,300 patients from 19 different clinical trials revealed that treatment with 5-FU/leucovorin yielded a significantly improved response rate of 21% compared with an 11% response rate for treatment with 5-FU alone (P < .0001). Of note, this analysis showed a statistically significant survival benefit for 5-FU/leucovorin compared with 5-FU alone, albeit of only 1 month (11.7 vs 10.5 months; P < .004). Capecitabine Capecitabine is an oral fluoropyrimidine carbamate prodrug of 5-FU that was rationally designed to closely simulate infusional administration of 5-FU.[7] In contrast to 5-FU, capecitabine is readily absorbed by the gastrointestinal tract. It is inactive in its parent form and requires conversion to 5-FU by three successive enzymatic steps. The third and final step is catalyzed by the enzyme thymidylate phosphorylase. Of note, the expression of thymidylate phosphorylase appears to be higher in tumor tissue when compared to corresponding normal tissue. This differential expression leads to enhanced selective activation of capecitabine in tumors, and in particular, in patients with colorectal cancer. Two randomized phase III trials were performed comparing capecitabine with bolus 5-FU/leucovorin (Mayo Clinic regimen).[8,9] An integrated analysis of the two studies showed that the overall response rate was significantly greater with capecitabine than with 5-FU/leucovorin (25.7% vs 16.7%; P < .0002), whereas secondary measures of time to tumor progression and survival were equivalent.[10] Moreover, patients treated with capecitabine displayed an improved safety profile and experienced a significantly lower incidence of effects in diarrhea, stomatitis, nausea, alopecia, and grade 3/4 neutropenia. The only side effect that was observed with higher incidence on the capecitabine arm was hand-foot syndrome. Of note, the improved safety profile associated with capecitabine resulted in a marked reduction of hospitalizations for adverse events when compared to treatment with bolus 5- FU/leucovorin. In the United Kingdom, it was shown that capecitabine treatment resulted in an improved use of the medical health-care system. Irinotecan Irinotecan(Drug information on irinotecan) is a semisynthetic derivative of camptothecin, a natural alkaloid first extracted from the Camptotheca acuminata tree, and it is a member of the topoisomerase I inhibitor class of anticancer agents.[11] Irinotecan is essentially inactive in its parent form and requires conversion to its active metabolite, SN-38, by a carboxylesterase enzyme in the liver. This metabolite forms a stable, covalent complex with DNA and topoisomerase I that then interrupts the breakage-reunion cycle associated with topoisomerase I activity- a process that eventually leads to cell death. Two randomized phase III studies in patients with metastatic colorectal cancer provided the initial evidence that first-line combination therapy with irinotecan plus 5-FU/leucovorin (IFL) resulted in improved clinical efficacy in terms of higher response rate and greater overall and progression- free survival when compared to 5-FU/leucovorin monotherapy. In Europe, Douillard et al investigated the clinical activity of infusional IFL, and reported a response rate of 35% in the IFL group and 22% in the 5-FU/leucovorin group for the intention- to-treat analysis (P = .005); overall survival was 17.4 and 14.2 months, respectively (P = .031).[12] Time to treatment failure or progression was 6.7 months with IFL and 4.4 months with 5-FU/leucovorin (P < .001). Saltz et al reported similar results in their North American trial, with response rates of 39% vs 21% (P < .001), overall survival times of 14.8 vs 12.6 months (P = .04), and median progression- free survival times of 7.0 vs 4.3 months (P = .004) for the bolus, weekly schedule of IFL and 5-FU/ leucovorin, respectively.[13] These studies demonstrated the clear superiority of IFL, whether it be administered via an infusional or bolus schedule, over 5-FU/leucovorin, and established IFL as a new standard in the first-line treatment of metastatic colorectal cancer. Kohne et al reported the results of a randomized phase III study comparing the AIO weekly infusional schedule of 5-FU/leucovorin vs the same weekly infusional schedule of 5-FU/leucovorin combined with weekly irinotecan.[14] This regimen was administered weekly for 6 weeks and repeated every 7 weeks. In terms of safety profile, the infusional IFL regimen was relatively well-tolerated with no significant increase in observed side effects. Patients treated with the infusional AIO IFL regimen experienced significantly improved response rates (54.2% vs 31.5%; P < .0001) and time to tumor progression (8.5 vs 6.4 months; P = .0001) when compared to patients treated with 5-FU/leucovorin. While patients on the IFL arm had improved overall survival (20.1 vs 16.9 months) when compared to 5-FU/leucovorin, this difference did not reach statistical significance (P = .2279 log-rank). Irinotecan in Combination With Capecitabine The combination of irinotecan/ capecitabine (XELIRI) is being actively investigated in an attempt to replace the more complicated and potentially more toxic 5-FU/leucovorin regimens with the oral fluoropyrimidine. Patt et al conducted a phase II study in the United States in which patients under age 65 received capecitabine at 1,000 mg/m² twice daily (days 1-14) plus irinotecan at 250 mg/m² (day 1) in a 21-day cycle, while those over age 65 received capecitabine at 750 mg/m² twice daily plus irinotecan at 200 mg/m².[15] Treatment with XELIRI yielded a 42% overall response rate and a median time to tumor progression of 7.1 months. Of interest, no apparent differences in clinical activity were observed between patients > 65 and < 65 years of age. Disease control (ie, complete response/partial response plus stable disease) was achieved in 71% of evaluable patients. The XELIRI regimen was relatively well tolerated, with the most common grade 3/4 toxicities being diarrhea (20%) and neutropenia (18%). However, patients older than 65 experienced a nearly twofold higher incidence of neutropenia and dehydration when compared to those < 65 years. In contrast, no significant differences were observed with respect to gastrointestinal toxicity. Bajetta et al conducted a multicenter, phase II trial of two different schedules of irinotecan combined with capecitabine in the first-line treatment of metastatic colorectal cancer.[16] A total of 140 patients received capecitabine at a dose of 1,250 mg/m² twice daily on days 2 through 15 and irinotecan at a dose of either 300 mg/m² on day 1 (arm A) or 150 mg/m² on days 1 and 8 (arm B), and cycles were given on an every-3-week schedule. The doses of capecitabine and irinotecan were subsequently reduced during the course of the trial to improve the safety profile of the combination. The dose of capecitabine was reduced to 1,000 mg/m², while the irinotecan dose was reduced to 240 mg/m² on arm A and 120 mg/m² on arm B. Overall response rates and median progression-free survival were similar in the treatment groups: 47% and 8.3 months for arm A and 44% and 7.6 months for arm B. In patients treated on arm A, the incidence of grade 3/ 4 gastrointestinal toxicity in the form of diarrhea was nearly 36%; however, upon dose reduction, the incidence of grade 3/4 diarrhea dropped to 25%, which was much lower than the nearly 38% incidence of grade 3/4 diarrhea observed in patients treated on arm B (days 1 and 8 schedule). Oxaliplatin Oxaliplatin(Drug information on oxaliplatin) is a third-generation platinum compound that exerts its cytotoxic effects through the formation of intrastrand and interstrand DNA crosslinks. It is the only platinum analog with activity against colorectal cancer, and it exhibits a different spectrum of toxicity when compared with other platinum compounds. In contrast to cisplatin(Drug information on cisplatin), it does not cause nephrotoxicity, nor does it give rise to the same degree of myelosuppression and alopecia commonly observed with carboplatin(Drug information on carboplatin) (Paraplatin).[3,17] The main dose-limiting toxicity is neurotoxicity, and this specific adverse event presents as both an acute and chronic sensory neuropathy. The acute form, exhibited by nearly all patients, typically presents as transient paresthesias that are exacerbated upon exposure to cold. In addition, about 3% to 4% of patients experience laryngopharyngeal spasms. In contrast, the chronic form is a cumulative sensory neuropathy that develops in up to 12% to 15% of patients. FOLFOX4 is now firmly established as an effective first-line treatment for patients with metastatic colorectal cancer. In a phase III study, de Gramont et al compared the FOLFOX4 regimen (oxaliplatin at a dose of 85 mg/m² as a 2-hour infusion on day 1, every 2 weeks, plus LV5FU2) with the de Gramont regimen of 5-FU/leucovorin (LV5FU2) alone in 420 patients with previously untreated advanced colorectal cancer.[18] FOLFOX4 was associated with significantly longer median progressionfree survival times (9 vs 6.2 months; P = .0003) and better response rates (50.7% vs 22.3%; P = .0001), although the two treatment groups did not differ significantly in regard to overall survival (16.2 vs 14.7 months; P = .12). Grade 3/4 neutropenia, diarrhea, and neurosensory toxicity were more frequent with FOLFOX4 than with 5-FU/leucovorin alone, although measures of quality of life did not differ between the groups. Intergroup trial N9741 was a randomized phase III trial in which the first-line therapy for metastatic colorectal cancer with the bolus, weekly IFL regimen as the control arm.[19] The two experimental arms of this trial included FOLFOX4 and a non-fluoropyrimidine-containing arm of irinotecan and oxaliplatin (IROX). This pivotal study showed that FOLFOX4 had significantly greater clinical efficacy than IFL in terms of response rate (45% vs 31%; P = .002), time to tumor progression (8.7 vs. 6.9 months; P = .0014), and median overall survival (19.5 vs 15 months; P = .0001). In addition, when compared to IFL or IROX, FOLFOX4 was associated with markedly lower incidence of febrile neutropenia and fewer gastrointestinal side effects in terms of nausea/vomiting, diarrhea, and dehydration. However, peripheral sensory neuropathy and myelosuppression were more common with both FOLFOX4 and IROX when compared to IFL. Based on the results from this large phase III clinical trial, FOLFOX4 was approved for use in the United States as first-line treatment of patients with advanced colorectal cancer in January 2004. The FOLFOX6 regimen incorporated a higher dose of oxaliplatin (100 mg/m²) on day 1 with a simplified 5-FU/leucovorin administration schedule in which a single dose of leucovorin and bolus 5-FU was given on day 1 followed by a single continuous 46-hour infusion of 5- FU every 2 weeks. Treatment with FOLFOX6 yielded overall response rates of 54% and 27%, respectively, in the first- and second-line settings, and yielded similar overall and progression-free survival when compared with previous FOLFOX regimens.[20,21] de Gramont and colleagues in France then developed the FOLFOX7 regimen in an effort to maximize the dose intensity of oxaliplatin. This regimen incorporated the same simplified infusion schedule of 5-FU as was delivered with FOLFOX6, but used a higher dose of oxaliplatin (130 mg/m²). In a phase II study in previously treated patients, FOLFOX7 resulted in a 42% response rate and a median overall survival of 16.1 months.[22] The FOLFOX7 regimen was subsequently selected for further testing in the first-line setting in the OPTIMOX trial, where it was compared directly to the FOLFOX4 regimen.[ 23] To reduce the incidence of oxaliplatin-associated neurotoxicity, patients enrolled in the FOLFOX7 arm of the OPTIMOX trial received intermittent exposure to oxaliplatin: 6 cycles of FOLFOX7, followed by 12 cycles of 5-FU/leucovorin, and then reintroduction of oxaliplatin for an additional 6 cycles of FOLFOX7. The safety profile appeared to be improved with FOLFOX7 as the incidence of grade 3/4 neutropenia was reduced significantly in patients treated with the FOLFOX7 regimen (21.9%) compared to FOLFOX4 (33.2%) (P = .013). There was, however, a higher incidence of grade 3/4 thrombocytopenia with the FOLFOX7 regimen (10.6%) than with FOLFOX4 (3.1%) (P = .0006). With respect to clinical efficacy, median overall survival, at the time of the original analysis, was not significantly different between the two treatment arms: 20.7 months for patients in the FOLFOX4 arm and 21.4 months for the patients in the FOLFOX7 arm. In addition, both the FOLFOX7 and FOLFOX4 regimens achieved comparable response and resection rates as well as similar total disease control rates. Oxaliplatin Combinations With Capecitabine The different FOLFOX regimens typically require infusional therapy over 2 days every 2 weeks, whereas oxaliplatin regimens in combination with capecitabine involve one 2-hour infusion every 3 weeks. There is growing evidence that the oral fluoropyrimidine capecitabine can effectively substitute for bolus or infusional schedules of 5-FU/leucovorin in combination with oxaliplatin in the metastatic setting. Scheithauer et al conducted a study in 89 patients with advanced colorectal cancer using a dose-intensified bimonthly schedule for capecitabine (3,500 mg/m² days 1-7 and 14-21) plus oxaliplatin (85 mg/m² days 1 and 14) every 4 weeks vs a conventional dose regimen.[24] Patients receiving high-dose therapy experienced a higher response rate (54.5% vs 42.2%) and a significantly longer median progression- free survival time than those receiving the conventional dose (10.5 vs 6.0 months; P = .0013). Quite surprisingly, the safety profile was similar to that observed with the lower-intensity regimen. While diarrhea was the most frequent side effect, in general it was well controlled. Cassidy et al performed a phase II multicenter international study investigating the XELOX regimen.[25] The dosing regimen of capecitabine 1,000 mg/m² twice daily (days 1-14) plus oxaliplatin at 130 mg/m2 IV (day 1) every 3 weeks yielded an overall response rate of 55%, similar to that observed with infusional 5-FU/leucovorin plus oxaliplatin, and a median overall survival of 19.5 months. The most common grade 3/4 adverse events observed in the study were gastrointestinal side effects, myelosuppression, and neurotoxicity. The incidence of grade 3/4 myelosuppression was less than 10%, which was significantly lower than the 40% to 45% incidence typically observed with the FOLFOX4 regimen. These findings suggest that the XELOX combination is an effective and welltolerated regimen in the first-line treatment of patients with metastatic colorectal cancer. Novel Targeted Agents The significant advances in molecular oncology have provided an enhanced understanding of the critical signaling pathways involved in tumor growth and proliferation. These insights have served as the rational basis for the development of novel targeted therapies for solid tumors. Such agents are designed to modulate, inhibit, and interfere with the function of specific molecular targets that are essential to the malignancy of tumors. The biologic agents that are currently approved for colorectal cancer are the monoclonal antibodies cetuximab and bevacizumab. Cetuximab
Cetuximab is a chimeric monoclonal antibody directed against the external cell surface of the EGFR.[26] The EGFR is overexpressed in up to 85% of colorectal tumors, and its expression has been correlated with metastatic disease and poor prognosis. The EGFR signaling pathway leads to activation of several key cellular events involved in cellular growth and proliferation, invasion and metastasis, and angiogenesis. In addition, this pathway inhibits the cytotoxic activity of various anticancer agents and radiation therapy, presumably through suppression of key apoptotic mechanisms, thereby leading to the development of cellular drug resistance. Saltz et al initially reported a 17% response rate in patients with irinotecan- refractory metastatic colorectal cancer who were treated with the combination of cetuximab and irinotecan.[ 27] A follow-up study evaluated the clinical activity of weekly cetuximab monotherapy in patients with refractory colorectal cancer whose tumors expressed EGFR.[28] In this trial, 57 patients were evaluated; the overall response rate was 9% with a median survival of 6.4 months. This therapy was generally well-tolerated. The most common side effects were acne-like skin rash presenting mainly on the face and upper torso as well as asthenia, fatigue, malaise, and/or lethargy. The BOND (Bowel Oncology With Cetuximab Antibody) trial was a randomized phase II study in heavily pretreated patients with advanced colorectal cancer. This study enrolled 329 patients with EGFR-positive metastatic colorectal cancer who had failed to respond to irinotecan (progressing on or within 30 days).[29] Patients were randomized in a 2:1 ratio to receive cetuximab as a 400-mg/m² infusion, followed by weekly cetuximab at 250 mg/m², plus irinotecan at the same dose and schedule on which they had been progressing, or cetuximab monotherapy. The objective response rate (22.9% vs 10.8; P = .0074), time to tumor progression (4.1 vs 1.5 months; P < .0001), and disease control rate (55.5% vs 32.4%; P = .0001) were significantly higher in the combination therapy group. Of note, cetuximab treatment did not worsen the toxicities normally associated with irinotecan chemotherapy. The most frequent grade 3/4 events in patients receiving combination therapy were diarrhea (21.2%), asthenia (13.7%), neutropenia (9.5%), acne-like rash (9.4%), and vomiting (6.1%). The results of this randomized study, along with supporting clinical data from the US phase II clinical studies, led to the approval of cetuximab for use in combination with irinotecan for the treatment of EGFRexpressing, metastatic colorectal cancer in patients who are refractory to irinotecan-based chemotherapy. This agent was also granted approval for use as a single agent for the treatment of EGFR-expressing, recurrent metastatic colorectal cancer in patients who are intolerant to irinotecan-based chemotherapy. At the American Society of Clinical Oncology (ASCO) 2004 annual meeting, Lenz and colleagues reported the results of a large (N = 346) phase II study of single-agent cetuximab in heavily pretreated patients who had previously failed both irinotecan and oxaliplatin.[30] The response rate in this trial was 12% and the median overall survival was 6.7 months. These results exactly paralleled those previously reported in irinotecan-refractory patients. Of note, nine patients with EGFR-negative disease were treated with cetuximab monotherapy, of which two showed a partial response. The fact that patients with EGFR-negative tumors were able to respond to cetuximab treatment suggests that EGFR testing may not be necessary for patient selection for cetuximab therapy. An important issue that is being actively investigated is whether cetuximab in combination with standard chemotherapy can be used in the firstline setting. Phase II studies have been performed with cetuximab in combination with either bolus or infusional IFL, and both combinations have demonstrated relatively promising clinical activity with response rates being 50% and 70%, respectively. In follow- up to these studies, Rougier and colleagues performed a phase II study where FOLFIRI was combined with cetuximab. The addition of cetuximab did not worsen the safety profile normally observed with FOLFIRI chemotherapy. With respect to clinical efficacy, the overall response rate was 43% with an overall tumor control rate approaching 80%. Tabernero and colleagues have studied the combination of cetuximab and FOLFOX4 in the first-line setting.[ 31] At the ASCO 2004 annual meeting, they reported that this combination was well tolerated with a manageable safety profile. The addition of cetuximab did not worsen the toxicities normally associated with oxaliplatin-based chemotherapy. Moreover, this combination showed significant clinical activity with an overall response rate of 81% and a total disease control rate of 98%. Bevacizumab
Vascular endothelial growth factor is considered to be one of the most important angiogenic growth factors known to regulate angiogenesis. The growth of both primary and metastatic tumors requires an intact vasculature; for this reason, VEGF and the VEGF-signaling pathway represents an attractive target for chemotherapy. Several approaches have been taken to inhibit VEGF signaling, and they include inhibition of VEGF/VEGF receptor interactions by targeting either the VEGF ligand with antibodies or soluble chimeric receptors or by direct inhibition of the VEGF receptor- associated tyrosine kinase activity by small molecule inhibitors. Bevacizumab is a recombinant humanized monoclonal antibody that targets all forms of VEGF-A. This antibody binds to and prevents VEGFA from interacting with the target VEGF receptors. In a pivotal randomized phase III study, previously untreated patients with metastatic colorectal cancer who received bevacizumab plus standard chemotherapy with the bolus weekly IFL regimen had longer progression-free survival (10.6 vs 6.2 months, P < .00001) and improved median overall survival (20.3 vs 15.6 months; P = .00003) compared to those receiving IFL chemotherapy plus placebo.[32] The only adverse event that occurred with greater frequency in patients treated with bevacizumab was grade 3 hypertension, which was managed effectively with oral medications. Six patients treated on the bevacizumab arm experienced a gastrointestinal perforation, although this number did not reach statistical significance. No increases in thromboembolic events, bleeding complications, and proteinuria were observed in patients treated with bevacizumab. Based on the strikingly positive clinical results of this phase III pivotal trial, bevacizumab was granted FDA approval in February 2004 as a firstline treatment for metastatic colorectal cancer in combination with any intravenous fluoropyrimidine-containing regimen. Trial AVF2192g was a randomized, double-blind, placebo-controlled, multicenter study of patients in the first-line setting who were deemed to be not optimal candidates for irinotecan-based chemotherapy.[ 33] The primary objective of the trial was survival. Secondary end points included response rate, progression free survival, response duration, quality-of-life assessment, and safety. Patients were randomized to one of two treatment arms. In arm 1, patients received the Roswell Park regimen of 5-FU/leucovorin and bevacizumab at 5 mg/kg, while in arm 2 patients received the Roswell Park regimen of 5-FU/leucovorin plus placebo. The overall median survival was 12.9 months on the placebo arm compared to 16.6 months on the bevacizumab arm (P = .159). Progressionfree survival in the placebo arm was 5.5 months compared to 9.2 months in the bevacizumab arm (P = .0002). The overall response rate was 15% in the placebo arm and 26% in the bevacizumab arm (P = .0552), with all responses being partial responses in both arms. Hypertension (4.8% vs 32%) and proteinuria (19.2% vs 38%) were observed more frequently in patients treated with bevacizumab, and as was observed in the pivotal registation trial, two patients in the bevacizumab arm experienced gastrointestinal perforations. In addition to being used in combination with either 5-FU/leucovorin or the bolus, weekly IFL schedule, bevacizumab has been studied with oxaliplatin-based chemotherapy in the second-line setting. A total of 829 patients with advanced colorectal cancer, previously treated with 5-FU- based therapy and irinotecan for advanced disease or relapsed disease following adjuvant chemotherapy, were randomized to one of three treatment arms, including FOLFOX4, FOLFOX4 and bevacizumab, and bevacizumab alone.[34] With respect to toxicity, the addition of bevacizumab to FOLFOX4 did not appear to increase the side effects normally associated with oxaliplatin. With respect to clinical efficacy, patients receiving bevacizumab in combination with FOLFOX4 had a 26% relative reduction in risk of death when compared to FOLFOX4 alone. Median overall survival was 12.5 months for FOLFOX4 plus bevacizumab vs 10.7 months for FOLFOX4 alone, which resulted in a significant 17% absolute improvement in median overall survival.[ 35] Summary Significant advances have been made in the treatment of advanced colorectal cancer over the past 5 years. This progress has been made possible with the introduction of three novel cytotoxic agents-capecitabine, irinotecan, and oxaliplatin-and with the recent approval of two biologic agents-bevacizumab and cetuximab. During this time period, the median survival of patients with advanced, metastatic disease has gone from 10 to 12 months to nearly 24 months. Intense efforts have focused on identifying novel targeted therapies which target specific growth factor receptors, critical signal transduction pathways, and/or key pathways that mediate the process of angiogenesis. The recent clinical results with the anti-VEGF antibody bevacizumab, in combination with the IFL bolus weekly regimen, the weekly Roswell Park schedule of 5-FU/leucovorin, and the FOLFOX4 regimen, validate the process of angiogenesis as being an important chemotherapeutic target for colorectal cancer and suggest that this antibody can be safely and effectively used in combination with each of the active anticancer agents used in colorectal cancer. Similarly, the randomized phase II BOND study validated the role of the EGFR-signaling pathway as a key target for chemotherapy, and recent studies now suggest that this agent can be safely and effectively developed in the front-line setting as well as in the salvage setting. Despite the development of active combination regimens, significant improvements in the actual cure rate have not yet been achieved. Combination regimens with activity in advanced disease are being evaluated in the adjuvant and neoadjuvant setting. Investigators continue to focus efforts on identifying novel therapies that target specific growth factor receptors, critical signal transduction pathways, and/or key pathways that mediate the process of angiogenesis. The goal is to integrate these targeted strategies into standard chemotherapy regimens so as to advance the therapeutic options for the treatment of advanced colorectal cancer. Finally, intense efforts are attempting to identify the critical molecular biomarkers that can be used to predict for either clinical response to chemotherapy and/or targeted therapies and/ or the drug-specific side effects. The goal of such studies is to facilitate the evolution of empiric chemotherapy to individually tailored treatments for patients with colorectal cancer.