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Current Strategies in Previously Untreated Advanced Colorectal Cancer

Current Strategies in Previously Untreated Advanced Colorectal Cancer

ABSTRACT: Colorectal cancer is the second most common cause of cancerrelated death in the United States. Approximately 30% to 40% of patients with colorectal cancer have locoregionally advanced or metastatic disease on presentation and cannot be cured with surgical therapy. After many years without significant change, systemic therapy for colorectal cancer is rapidly evolving. The past decade has seen the introduction of new chemotherapeutic agents such as irinotecan (Camptosar), oxaliplatin (Eloxatin) and the oral 5-FU prodrug capecitabine (Xeloda). Combination studies of these new agents with the standard 5-FU/leucovorin have extended median survival in patients with advanced colorectal cancer for up to 21 months. In addition, targeted agents with activity in colorectal cancer have emerged and are promising. This article reviews the current treatment recommendations for patients who present with advanced colorectal cancer. Survival in patients with advanced colorectal cancer is on a positive trajectory. The hope that some patients with advanced disease will be long-term survivors (even without surgery) appears to be within the range of possibility.

In 2004, the American Cancer Society estimates that approximately 150,000 new cases of colorectal cancer will occur in the United States.[1] In spite of excellent screening techniques, colorectal cancer is the second most common cause of cancer-related death in the United States, and as such is a major public health problem. However, in the past 5 years, progress in the management of this disease has been rapid and very encouraging. Approximately 30% to 40% of patients with colorectal cancer have locoregionally advanced or metastatic disease on presentation and cannot be cured with surgical therapy.[2] Surgical resection is the only cure for localized colorectal cancer, yet despite optimal surgery, certain patients with resectable disease eventually die from metastatic recurrence. Patients with stage IV colorectal cancer have less than a 4% 5-year survival. The development of chemotherapies and effective regimens in the treatment of colorectal cancer has become a very active field, especially recently. In the late 1980s and early 1990s, several new agents with activityin colorectal cancers have emerged. These agents work through very different pathways than the standard fluorouracil (5-FU). Although 5-FU remains the backbone of most firstline regimens, irinotecan (Camptosar) and oxaliplatin (Eloxatin) are being rapidly integrated into first-line treatment of colorectal cancer. Overall median survival of up to 21 months has now been reported in patients with advanced colorectal cancer. Refinements in combination schedules with new agents are ongoing. With the rapidity of change, the developmentof new chemotherapeutics, and the appearance of new molecular targeted agents, choices have emerged. What is the best initial regimen, the best sequencing of drug administration, and the schedules of drug administration that can lead to a doubling of median survivals from the 12-month expectations of the 5-FU/ leucovorin days? Fluorouracil Fluorouracil, which belongs to a diverse class of agents known as thepyrimidine analogs, is a fluoropyrimidine. It impairs DNA synthesis through inhibition of the enzyme thymidylate synthase. This in turn leads to depletion of deoxythymidine triphosphate, a necessary constituent of DNA. With long-term infusion this is felt to be the primary mechanism of 5-FU cytotoxicity. In addition, there are data to suggest that the mechanism of 5-FU differs when given by different schedules.[3] When 5-FU is administered by bolus injection and not long-term infusion, it is felt that inhibition of RNA synthesis contributes to its antitumor effect. Fluorouracil has been combined with several agents in attempts to enhance its cytotoxic activity. The most common (and important) combination is the coupling of 5-FU with leucovorin. This combination has been shown to improve clinical outcomes.[ 3] Leucovorin enhances the efficacy of 5-FU by interacting with thymidylate synthase to form a stable ternary complex that permits prolonged inhibition of the enzyme by 5-FU. At 2003 American Society of Clinical Oncology (ASCO) annual meeting, Piedbois et al updated their 1992 meta-analysis comparing 5-FU to 5-FU/leucovorin. The 1992 metaanalysis analyzed nine trials comparing 5-FU to 5-FU/leucovorin in 1,381 patients with advanced colorectal cancer. They showed a doubling in tumor response in those patients treated with 5-FU/leucovorin, but did notshow a statistically significant survival difference between the two treatments.[ 4] The authors (now with longer patient follow-up and inclusion of nine more newly performed trials) have analyzed a total of 2,751 patients randomized in 18 trials. 1,224 patients were allocated to 5-FU alone and 1,527 allocated to 5-FU/leucovorin. Final analysis confirms a twofold increase in tumor response rates in favor of 5-FU/lecovorin (12% vs 23%, P = .0001), and a small but statistically significant survival benefit for 5-FU/leucovorin (5% absolute survival benefit at 1 year from 43% to 48%, P = .003).[5] Several different doses and administration schedules of 5-FU/leucovorin have been evaluated in patients with advanced colorectal cancer (see Table 1). In Europe it is more common to administer 5-FU via infusion, and in the United States via bolus injection. There is controversy as to the relative efficacies and toxicities of infusional compared to bolus regimens of 5-FU. In the United States, it has generally been felt that bolus 5-FU is no worse than continuous intravenous infusion of the drug. Bolus 5-FU for 5 consecutive days monthly (Mayo regimen) or weekly (Roswell Park regimen) are standard alternatives. Bolus 5-FU is clearly more convenient and avoids the complications of central venous catheter placement and use. There are, however, published data that show that 5-FU administered by continuous infusion has a better toxicityprofile. Evidence has also accumulated that a prolonged infusion of 5-FU may improve tumor response rate and survival time in association with the better toxicity profile when compared with 5-FU bolus regimens.[ 6,7] de Gramont and colleagues reported the results of a randomized study involving 448 patients with advanced colorectal cancer comparing highdose leucovorin in combination with bolus plus infusional 5-FU to the standard low-dose leucovorin/5-FU. A significantly higher response rate (32.6% vs 14.4%, P = .0004) and progression- free survival time (27.6 vs 22 weeks, P = .001) were observed in favor of the former regimen. It was also very well tolerated, with a low incidence of severe grade III/IV hematologic and nonhematologic toxicity. However, there was no evidence of increased survival (62 weeks vs 56.8 weeks, P = .067), perhaps because the trial was powered to discern a progression-free survival end point.[6] In addition, in a meta-analysis of controlled trials comparing bolus and continuous infusion of 5-FU in patients with advanced colorectal cancer that was published in 1998, the overall response rate was significantly higher in patients receiving continuous infusion than in those administered bolus 5-FU (22% vs 14%, P = .0002). Although none of the individual trials analyzed reported a significant survival difference between the groups, the survival hazard ratio for the combined studies demonstrated a small benefit in favor of continuous infusion (overall hazard ratio, 0.88; P = .04). The median survival was 12.1 months with continuous infusion and 11.3 months with bolus 5-FU. Grade 3/4 hematologic toxicity (neutropenia) was more common in patients treated with bolus 5-FU than in those receiving a continuous infusion of 5-FU (31% and 4%, respectively; P < .0001). Handfoot syndrome was more frequent with continuous than with bolus infusion (34% and 13%, P < .0001).[7] In a five-arm multicenter randomized trial conducted by the Eastern Cooperative Oncology Group(ECOG) and the Cancer and Leukemia Group B (CALGB), the authors found that infusional 5-FU was significantly less toxic than and as effective as 5-FU/leucovorin regimens. Arm A consisted of patients randomized to 5-FU (2,600 mg/m2 by 24- hour infusion, weekly), in arm C patients were randomized to bolus 5-FU/leucovorin (5-FU 600 mg/m2 with oral leucovorin 125 mg/m2, weekly), and in arm D bolus 5-FU/ leucovorin (5-FU 600 mg/m2 with IV leucovorin 600 mg/m2 weekly) was given. The toxicities observed in these three arms occurred in 11%, 30%, and 24% of patients, respectively, with diarrhea being the most common adverse effect. These toxicity patterns significantly favored the infusion arms (P < .001). However, the survival differences were not statistically significant, with median survival was reported as 14.8 months (arm A), 13.5 months (arm C), and 13.6 months (arm D).[8] Overall, in terms of efficacy, the differences between bolus and infusional 5-FU are not statistically significant; however, the differences in toxicity are statistically relevant. As discussed in the next section, the toxicity associated with bolus 5-FU has become an issue in the United States as a result of excessive toxicities when combined with the newer agent irinotecan. Capecitabine The development of oral chemotherapies is extremely attractive in oncology. The availability of such drugs obviates the need for indwelling catheters and their associated complications and is obviously more convenient for the patient. In the realm of colorectal cancer, an orally administered 5-FU prodrug-especially one with pharmacokinetics that mimic continuous infusion administration- is an extremely attractive potential replacement for 5-FU. Capecitabine (Xeloda) is a rationally designed oral fluoropyrimidine carbamate that is absorbed intact through the intestinal wall, and then converted to 5-FU in three sequential enzymatic reactions. The final enzyme- thymidine phosphorylase-ispresent at higher levels in the tumor compared to normal tissues, thereby providing the basis for enhanced selectivity in tumor cells.[9,10] Two trials have compared capecitabine to 5-FU/leucovorin for the firstline treatment of patients with metastatic colorectal cancer.[11,12] These trials were designed to demonstrate equivalency to 5-FU. In the first, published by Hoff et al, capecitabine (2,500 mg/m2 per day for 14 of every 21 days) was compared to 5-FU/leucovorin (Mayo regimen) in 605 patients with previously untreated metastatic colorectal cancer. Compared to 5-FU/leucovorin, capecitabine was associated with a significantly higher response rate (24.8% vs 15.5%), but a similar median time to progression (4.3 vs 4.7 months) and median survival (12.5 vs 13.3 months). The incidence of grade 3/4 diarrhea, stomatitis, nausea, and neutropenic sepsis was significantly less in the capecitabine group. Hand-foot syndrome was more common in those receiving the prodrug.[11] Similar results were noted in the second identically designed trial that included 602 patients. Once again, capecitabine was associated with a higher response rate (26.6% vs 17.9%) and a similar time to progression (5.2 vs 4.7 months) and median overall survival (13.2 vs 12.1 months). Grade 3 to 4 stomatitis and neutropenia were less frequent with capecitabine, whilehand-foot syndrome was more common (16% vs 0%).[12] Preliminary phase II data suggest that capecitibine may be as effective as 5-FU in combination with irinotecan and oxaliplatin.[13,14] Several phase III studies are under way to evaluate the potential of capecitabine/ irinotecan combinations as first-line treatment in metastatic colorectal cancer. Capecitibine is now approved in the United States for the first-line treatment of metastatic colorectal cancer in poor performance status patients or others who are not good candidates for combination therapy. Irinotecan Camptothecin is a natural product isolated from the Chinese camptotheca tree that works as a topoisomerase I inhibitor and a potent cytotoxin. It was initially abandoned in clinical practice secondary to idiosyncratic and excessive toxicity. Irinotecan, developed in Japan, is a synthetic analog of camptothecin.[15] It was first studied in the United States by Rothenberg et al as a single agent in patients with metastatic colorectal cancer refractory to 5-FU-based therapy.[16]In chemotherapy-naive patients, irinotecan produced response rates of 15% to 32%.[17,18] In 1998, two European randomized studies established the efficacy of irinotecan as second-line monotherapy in advanced colorectal cancer.[ 19,20] With irinotecan as a single agent, response rates were very similar to those observed with 5-FU, with little improvement in overall survival (irinotecan response rate 18%, survival ~12 months; 5-FU/leucovorin response rate 23%, survival ~12 months) (see Table 2). Because of this, the combination of irinotecan and 5-FU was explored as first-line therapy for metastatic colorectal cancer. Two studies published in 2000 showed a near doubling of response rate and a statistically significant improvement in both time to progression and overall survival.[21,22] The three-drug combination (irinotecan/5- FU/leucovorin) compared with 5-FU/ leucovorin (both when 5-FU is administered by a weekly bolus schedule or a biweekly infusional schedule) was superior in both trials. The value of irinotecan in the first-line treatment in colorectal cancer was established when the US Food and Drug Administration (FDA) approved irinotecan with either bolus or infused 5-FU as the reference regimens for the indication of treatment for advanced disease in the spring of 2000. The first of these landmark trials was conducted in the United States by Saltz et al and the second studywas done in Europe by Douillard et al. In the phase III North American trial, 683 stage IV patients were randomized to receive one of three treatment regimens: IFL (irinotecan plus 5-FU/leucovorin), 5-FU/leucovorin (Mayo bolus regimen), or single-agent irinotecan. The results of this study showed superiority of IFL for metastatic colorectal cancer in terms of progression-free survival (7 vs 4.3 months), response rate (39% vs 21%), and overall survival (14.4 vs 12 months) when compared directly with the standard 5-FU/leucovorin.[21] In the phase III trial conducted by Douillard et al, 387 stage IV patients were randomized to receive either 5-FU/leucovorin (AIO regimen or de Gramont regimen) or irinotecan plus 5-FU/leucovorin (AIO regimen or de Gramont regimen). Douillard's results confirmed those from the Saltz trial. The combination of irinotecan and 5-FU/leucovorin increased response rate (49% vs 31%), time to progression (6.7 vs 4.4 months), and median survival (17.4 vs 14.1 months); all differences were statistically significant. As in the Saltz trial, grade 3 and 4 diarrhea and neutropenia were more common in the irinotecan arm, but were felt to be manageable and did not affect overall quality of life.[22] Although the survival advantage was somewhat smaller in the Saltz study than in the Douillard study, both regimens were approved for firstline treatment of advanced colorectal cancer.[23] The combination known as IFL (Saltz regimen) was soon regarded as "standard of care" for first-line treatment of advanced colorectal cancer in North America. After the FDA's approval, however, controversy emerged about the safety of bolus IFL. In early 2001, among patients enrolled in US Intergroup study N9741 and CALGB 89803, a higher number of early deaths were noted in the IFL arms compared to either 5-FU/leucovorin or FOLFOX (5-FU/ leucovorin/oxaliplatin). In June 2001, Sargent and colleagues published a letter in the New England Journal of Medicine presenting data linking irinotecan use with a syndrome of nausea, vomiting, diarrhea, dehydration, and early death.[24] This report led to suspension of ongoing trials and reexamination of mortality data by an independent panel.[25] The principal toxicities of irinotecan (early and late diarrhea: median time to onset of late diarrhea is 11 days) and 5-FU (nausea, diarrhea, hematologic toxicity) overlap, and it appears that the combined toxicity of irinotecan and bolus 5-FU may be excessive. Extensive review of the available data has resulted in two conclusions. First, the toxicity profile of IFL seems to depend on the schedule of 5-FU administration. Second, the US view that bolus administration of 5-FU is preferable to continuous administration of 5-FU must be tempered by toxicity considerations. The European combination of irinotecan with an infusional schedule of 5-FU appears to produce a more acceptable toxicity profile, and should probably replace the IFL regimen as the standard of care for first-line therapy with irinotecan. Discussion of this point continues into the present. At ASCO 2003, Kohne et al presented results from the European Organization for Research and Treatment of Cancer (EORTC) study 40986. This study evaluated the addition of irinotecan to the AIO infusion regimen. The results of this study confirmed the superiority of irinotecan and short infusion of 5-FU/leucovorin in treating patients with advanced colorectal cancer (see Table 3).[26] Oxaliplatin Oxaliplatin is a diaminocyclohexane platinum that has undergone clinical investigation in Europe and in the United States. Unlike other platinumbased compounds, oxaliplatin does not cause nephrotoxicity; it is the only clinically available platinum compound to show preclinical activity in colorectal cancer. In patients with untreated metastatic colon cancer, response rates of 27% have been reported with oxaliplatin alone. Rates exceeding 50% have been noted when the drug is combined with 5-FU. Patients receiving oxaliplatin with infusional 5-FU/leucovorin have achieved overall median survivals of > 20 months in several recently reported trials. Oxaliplatin's toxicity profile includes a cumulative, reversible peripheral neuropathy, neutropenia, and nausea/vomiting. Neurotoxicity can be the dose-limiting toxicity. Patients may also develop a reversible, coldinduced, acute pharyngolaryngeal neuropathy commonly called laryngeal- pharyngeal dysesthesia.[27] In a paper published in 2000 in the Journal of Clinical Oncology, de Gramont et al investigated the combination of oxaliplatin and the LV5FU2 regimen (FOLFOX4) as first-line treatment in advanced colorectal cancer.[ 28] A total of 420 previously untreated patients were enrolled and randomized to receive a 2-hour infusion of leucovorin (200 mg/m2/d) followed by 5-FU bolus (400 mg/m2/d) and 22-hour infusion (600 mg/m2/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin (85 mg/m2) as an infusion on day 1. This phase III study found that patients treated on the oxaliplatin arm had a longer progression-free survival (9.0 vs 6.2 months, P = .0003) and better response rate (50.7% vs 22.3%, P = .0001). The observed improvement in overall survival (16.2 vs 14.7 months), however, did not reach statistical significance. Patients treated with oxaliplatin had higher frequencies of neutropenia (41.7% vs 5.3%), diarrhea (11.9% vs 5.3%), and neurosensory toxicity (18.2% vs 0%), but this did not affect their quality of life.[28] In Europe,this trial established oxaliplatin/5-FU combinations as a reasonable firstline alternatives to irinotecan/5-FU regimens. In the United States, the lack of overall survival benefit in the de Gramont study (powered to demonstrate a difference in time to disease progression) and the results of the Rothenberg trial led the FDA to approve the combination as secondline therapy for patients with disease progression after treatment with irinotecan and 5-FU/leucovorin. Grothey et al have reported the results of a phase III study that compared the Mayo regimen of 5-FU/leucovorin to FUFOX (5-FU/leucovorin/ oxaliplatin) in advanced colorectal cancer. Response rate was more than doubled in the FUFOX arm (48.3% vs 22.6%, P = .0001), progressionfree survival was improved (7.9 vs 5.3 months, P < .001), and median survival of the FUFOX arm was 20.4 months (see Table 4).[29] In an attempt to help define the optimal dose schedule of oxaliplatin and 5-FU/leucovorin, Andre et al conducted a study in which 623 stage IV patients were randomized between FOLFOX4 and FOLFOX7. Preliminary results were presented at ASCO 2003 and show a greater response (64% vs 58%) and time to progression (12.3 vs 10.3 months) in the FOLFOX7 arm. The results of this trial are still maturing and median overall survival statistics have not yet been released (see Table 4).[30] Comparing Doublets The doublet combinations of irinotecan or oxaliplatin and 5-FU/leucovorin have been definitely proven to be superior to 5-FU/leucovorin in the treatment of patients with advanced colorectal cancer. The superiority of oxaliplatin/5-FU/leucovorin compared to irinotecan/5-FU/leucovorin is less certain and appears to be dependent upon whether the 5-FU is delivered as a bolus or by infusion. In the first phase III trial (Intergroup trial 9741) to evaluate oxaliplatin and irinotecan in combination and compare oxaliplatin or irinotecan and 5-FU/leucovorin, the superiority of an oxaliplatin-based first-line therapy over IFL was demonstrated. The trial showed a statistically significant advantage in overall survival for FOLFOX compared with IFL, in terms of response rate (45% vs 31%), progression- free survival (8.7 vs 6.9 months), and overall survival (19.5 vs 15 months) and safety (see Table 4). A total of 795 patients with untreated advanced colorectal cancer were randomized to receive either IFL, FOLFOX4, or IROX (irinotecan/oxaliplatin). Grade 3 toxicities were the most favorable with FOLFOX4.[31] Based on the results of this trial, FDA approval for oxaliplatin in first-line therapy has recently been granted. In a phase III study conducted by Tournigand et al, previously untreated patients with advanced colorectalcancer received either FOLFIRI or FOLFOX with crossover to the other regimen after disease progression. Response rates (FOLFIRI 56% vs FOLFOX6 54%) and progression-free survival (FOLFIRI 8.5 months vs FOLFOX6 8.0 months) were similar. Second-line data was in favor of FOLFOX (FOLFIRI 4% response rate vs FOLFOX6 15% response rate) Overall, this trial demonstrated similar therapeutic efficacy between the two regimens. Toxicity profiles were different with grade 3/4 mucositis and nausea/ vomiting and grade 2 alopecia being the principle toxicities associated with FOLFIRI; grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6.[32] Likewise, early results presented at ASCO 2003 by Colucci et al revealed similar response rates between patients randomized to receive either FOLFOX or FOLFIRI. Preliminary data were reported on 287 of 360 patients.[33] In a soon to be published study, Grothey et al analyzed data from seven recently published phase III trials in advanced colorectal cancer. With the reported variations in median overallsurvival (14.8 to 21.5 months), the purpose of the study was to evaluate the influence of active salvage therapies on overall survival, and in particular, the availability of all three active agents (5-FU/leucovorin, irinotecan, oxaliplatin) in the course of treatment on overall survival. The authors found that studies in which patients received all three active drugs showed the longest overall survival and there was no significant correlation with the number of patients receiving second-line treatment (see Table 5).[34] Irinotecan/Oxaliplatin/5-FU Combinations Since the mechanism of action of 5-FU, oxaliplatin, and irinotecan differ, and doublet combinations have led to increased survival, the next logical step would be investigation of all three drugs in combination. The early administration of all three chemotherapeutics may be a viable strategy to avoid the development of resistant tumor cells. There is some evidence of synergism or additivity between irinotecan, oxaliplatin, and 5-FU in a ternary combination.[35] Preliminary data may also indicate that the combination has antitumor activity in those patients with advanced colorectal cancer who have been previously treated with irinotecan or oxaliplatin in doublet combination.[36] In a phase II trial conducted by Souglakos et al, the authors evaluated the triplet combination of irinotecan plus oxaliplatin plus continuous infusion 5-FU/leucovorin as first-line treatment in advanced colorectal cancer. Thirty-one patients with previously untreated advanced disease were enrolled. The overall response rate was 58.1%, the median duration of response was 9 months, and the median time to progression was 13 months. Predictable toxicities occurred and were grade 3/4 neutropenia in 45%, grade 3/4 diarrhea in 32%, and grade 3/4 neurotoxicity in 9%. The authors concluded that the triplet combination is highly active with manageable toxicities.[37] At ASCO 2002 Roth et al presented data from a phase I/II study evaluating oxaliplatin/irinotecan/5-FU/leucovorin (OCFL) in patients with advanced colorectal cancer not previously treated with oxaliplatin or irinotecan. Patients were treated every 5 weeks with drug doses escalated to toxicity (ie, grade 4 neutropenia with fever and/or grade 3 toxicity of any kind except alopecia). Thirty patients were evaluated for toxicity, with grade 3 and 4 neutropenia (17%/6%) and diarrhea (20%/3%) being the most common. Six patients underwent curative resection of their metastases. Overall, the authors concluded that OCFL is well tolerated with high efficacy.[ 38] As previously mentioned, there is evidence that the highest survival is in patients receiving all three active agents in the course of their treatment. Given that patients may not be able to receive second-line therapy, investigation of triple combination therapy as first line is being actively investigated.[39] Triple combination protocols have resulted in response rates of 57% to 78%. However, in order to assess improved outcomes, phase III trials must be done to evaluate doublet combinations against triplet therapy. Liver-Limited Disease This paper would not be complete without a brief mention of treatment of patients with liver-limited disease. These patients with advanced colorectal cancer represent an important subgroup. At time of diagnosis approximately 25% of patients present with hepatic metastasis. Of these 25%, only 20% are candidates for potentially curative surgical resection. The majority of these patients will go on to die of liver failure or other complications of advanced disease. Available regional treatments for isolated hepatic metastases include surgical resection, local tumor ablation with instillation of alcohol into the lesions, cryotherapy, radiofrequency ablation, and hepatic artery chemotherapy or chemoembolization. At present, the only curative option for patients with liver-isolated advanced colorectal cancer is surgical resection. In patients with four or fewer resectable hepatic lesions, 5-year survival rates rangefrom 24% to 3%.[40] Liver metastases receive the majority of blood supply from the hepatic artery, while the normal liver is supplied primarily by the portal circulation. As a result, the administration of chemotherapy into the hepatic artery allows the selective delivery of drug to the tumor while sparing normal hepatocytes. Regional chemotherapy by hepatic arterial infusion (HAI) has been a topic of interest for several decades, yet studies (although showing greater tumor response rates) have failed to show a survival advantage in comparison to systemic therapy. There have been several major prospective trials evaluating patients assigned to systemic chemotherapy or to HAI floxuridine. In each study, the response rate to HAI chemotherapy was superior to systemic treatment. However, this did not translate into a survival improvement in any study.[41] A meta-analysis of these trials included 654 patients with unresectable hepatic metastases enrolled in seven randomized trials comparing HAI to systemic 5-FU. Tumor response rates with HAI (41% vs 14%, P = .001) were improved. No significant survival advantage (16 vs 12.2 months, P = .14) was observed.[42] Most likely, this is because advanced colorectal cancer is a systemic disease. What is the role of neoadjuvant chemotherapy in unresectable patients? Bismuth et al pioneered the treatment of unresectable patients with adjuvant chemotherapy and surgical resection if successfully downstaged.[ 43] At ASCO 2003, Alberts et al presented data from their phase II North Central Cancer Treatment Group study evaluating the potential for liver resection after systemic 5-FU/leucovorin and oxaliplatin. A group of 42 patients with liveronly advanced colorectal cancer who were deemed initially not to be resectable were enrolled to receive FOLFOX4. Approximately 62% of patients had tumor reduction, and 41% of patients underwent surgery. Of those treated surgically, 59% recurred. Median survival was reported at 31.4 months.[44] Further studies employing the more active agents must beconducted. Given that surgical resection may offer hope of a cure in this group, further investigations are warranted. Future Directions It is an extremely exciting time in cancer research, and particularly in colorectal cancer. With the elucidation of molecular pathways that are involved in oncogenesis, therapies are becoming more specific. One of the principal goals of new chemotherapeutic drug design is to achieve specificity and selectivity in targeting cancer cells with the hopes of reducing toxicities to normal tissues and increasing tumor kill. There are hundreds of potential new pharmaceuticals in development that will be entering the clinical realm within the next decade. In 2003, for the first time in a wellperformed phase III trial, a targeted therapy was shown convincingly to prolong survival for patients with unresectable metastatic colorectal caner. Bevacizumab (Avastin) is a humanized monoclonal antibody directed against the circulating growth factor vascular endothelial growth factor. At ASCO 2003, Hurwitz et al reported the results from their phase III trial evaluating bevacizumab with bolus IFL as first-line therapy for metastatic colorectal cancer. Approximately 925 patients were enrolled and randomized to receive either IFL/bevacizumab placebo or IFL/bevacizumab. Initially a cohort of patients was assigned to FL/bevacizumab, but enrollment was discontinued once the safety of IFL/bevacizumab was assured. The authors found that the addition of bevacizumab resulted in statistically significant improvements in median survival (20.3 vs 15.6 months, P = .00003), progression-free survival (10.6 vs 6.24 months, P < .00001), duration of response (10.4 vs 7.1 months, P = .0014), and response rate (45% vs 35%, P = .0029). The only significant toxicity issue seen in the bevacizumab group was grade 3 hypertension, which was easily managed with oral antihypertensives.[45] Cetuximab (Erbitux) is a chimericanti-EGFR (epithelial growth factor receptor) monoclonal antibody. At ASCO 2003, Cunningham et al presented data that the antibody has activity in a heavily pretreated population of patients with advanced colorectal cancer. The study enrolled 329 patients with EGFR-positive advanced colorectal cancer with irinotecan- refractory disease. Patients were randomized in a 2:1 ratio to cetuximab at 400 mg/m2 infusion, followed by cetuximab at 250 mg/m2 weekly, plus irinotecan at the same dose and schedule on which they had been progressing, or cetuximab monotherapy with the option to switch to receive combination therapy at the time of disease progression. The objective response rate (22.9% vs 10.8%, P = .0074), time to 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 group. The lack of difference in survival between the arms may be attributable to crossover at disease progression.[46] Other targeted therapies being actively investigated involve COX-2 inhibitors, antiapoptotic therapies, EGFR-receptor inhibitors (small molecules and antibodies), and immunotherapies. Conclusions In the past decade, with the emergence of newer chemotherapeutics, overall survival for patients with advanced colorectal cancer has almost doubled. Administration of the three active drugs in series gives the potential for median survivals of almost 2 years. Triple therapy with 5-FU/irinotecan/ oxaliplatin is an attractive option for several reasons; first, it ensures that patients receive all three drugs, and second, synergism with ternary combinations may improve response rates. Phase III studies need to be conducted. Current data do not definitely suggest the superiority of one doublet sequence over the other. Initial therapy, therefore, in patients presenting with advanced colorectal cancer should involve a combination of either irinotecan or oxaliplatin with 5-FU, with crossover to the alternate regimen after disease progression. In patients with poor performance status or those unable to receive irinotecan or oxaliplatin, oral capecitabine is a reasonable first choice. The field of oncology is rapidly moving. The appearance of new chemotherapeutics and targeted therapies is beginning to revolutionize the way we practice oncology. Survival in patients with advanced colorectal cancer is on a positive trajectory. The hope that some patients with advanced disease will be long-term survivors (even without surgery) appears to be within the range of possibility.

Disclosures

Dr. Goldberg has received research support and honoraria from and given expert testimony for Sanofi-Synthelabo; he has done consulting for and received honoraria from Genentech and Bristol-Myers Squibb; and he has done consulting for and received research support from Pfizer.

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