During the past eight years, there have been significant advances in the treatment and outcome of patients with metastatic colorectal cancer. This is likely the result of improved imaging, staging, chemotherapy, and surgery. After conducting a standardized MEDLINE literature search, this article reviews the prospective randomized controlled trials in advanced colorectal cancer published between May 2001 and October 2008. There are a total of 96 studies, all chemotherapy-related trials, divided into five categories based on trial focus: (1) types of chemotherapy; (2) administration of adjuvant or neoadjuvant chemotherapy for resectable liver metastases; (3) regional chemotherapy with hepatic arterial infusion; (4) molecular markers of chemotherapy efficacy; and (5) duration, dosing, and sequencing of chemotherapy.
It is estimated that approximately 150,000 new colorectal cancers are diagnosed each year in the United States and approximately 50% of patients eventually develop liver metastases. During the past 8 years, there have been significant advances in the treatment and outcome of patients with metastatic colorectal cancer (MCRC). This is likely the result of improved imaging, staging, chemotherapy, and surgery. After conducting a standardized MEDLINE literature search, this article reviews the prospective randomized controlled trials in advanced colorectal cancer published between May 2001 and October 2008. There are a total of 96 studies and all are chemotherapy-related trials. They are divided into five categories based on each trial’s focus: (1) types of chemotherapy (N = 55); (2) Administration of adjuvant or neoadjuvant chemotherapy for resectable liver metastases (N = 5); (3) regional chemotherapy with hepatic arterial infusion (HAI) (N = 11); (4) molecular markers of chemotherapy efficacy (N = 2); and (5) duration, dosing, and sequencing of chemotherapy (N = 23).
Trials using different types of chemotherapy
The time period of the previous report primarily included trials that focused on 5-fluorouracil (5-FU) as the primary chemotherapeutic agent. Many of these trials investigated whether infusional 5-FU had any oncologic advantage over bolus administration and if comodulation with leucovorin (LV) was beneficial. The results of these previous trials resulted in infusional 5-FU administered with LV being the standard regimen offered to patients.
After multiple failed attempts to improve on the results of 5-FU–LV, the addition of irinotecan demonstrated superior response rates and survival for patients with MCRC and became the new standard first-line therapy. It should be noted, however, that this regimen (irinotecan, bolus 5-FU, LV[ IFL], Saltz regimen) used bolus 5-FU as opposed to infusional 5-FU, the latter of which had demonstrated superiority to the bolus preparation. As oxaliplatin emerged as an effective agent for MCRC, numerous trials examined the comparative affects of oxaliplatin versus irinotecan-based chemotherapeutic regimens. However, initial trials compared FOLFOX with the IFL regimen, which used the bolus preparation of 5-FU. Although some studies have reported FOLFOX to be superior to irinotecan-based regimens, these studies may have failed to accurately compare the efficacy of oxaliplatin with irinotecan because different administrations of 5-FU were used. Level Ia trials that do compare FOLFOX with irinotecan, infusional 5-FU, LV (FOLFIRI), however, report equivalent tumor response and patient outcomes with an approximate median survival of 21 months. Most oncologists today choose first-line treatment based on the toxicity profile of the regimen as it applies to each individual patient given equivalent oncologic efficacy.
For those patients not able to receive 5-FU chemotherapy because of toxicity, the combination of oxaliplatin with irinotecan has demonstrated manageable toxicity and oncologic efficacy as well with a median survival of 20.4 months when used as first-line therapy in advanced colorectal cancer. Irinotecan administered alone also demonstrated similar response rates as 5-FU–LV, but the use of oxaliplatin as a monotherapy seems to have minimal effect and should be discouraged as first-line therapy. Most recently, new targeted antibody therapies, such as bevacizumab (Avastin) and cetuximab (Erbitux), have been added to the armamentarium of agents to combat advanced colorectal cancer. Although the data in support are not that convincing (discussed in detail later), bevacizumab is frequently added to either FOLFOX or FOLFIRI as first-line therapy. Cetuximab has mainly been used as third-line therapy for those patients who have progressed through standard cytotoxic chemotherapy (ie, FOLFOX and FOLFIRI).
Studies have also investigated the efficacy of an oral 5-FU analog (capecitabine, Xeloda), and they suggest that the oral preparation has similar oncologic benefit as the intravenous form and may actually be preferred by some patients. This finding has led to the widespread use of capecitabine for the treatment of MCRC (discussed in more detail in the level Ia evidence section).
Lastly, multiple trials have investigated the use of coadministering immunotherapy and other agents, such as mitomycin C, celecoxib, methotrexate, and carbamazepine, with standard chemotherapeutic regimens to improve survival outcomes and reduce patient toxicity. None of these trials have demonstrated improved outcomes and have not changed standard management. There is some suggestion that Marimastat, a metalloproteinase inhibitor, may offer a survival advantage in a select group of patients that demonstrate musculoskeletal side effects from the drug and warrants further study.
Trials on neoadjuvant and adjuvant chemotherapy for resectable liver metastases
There have been few randomized studies assessing the use of administering chemotherapy either before or after complete resection of liver metastases. Portier and colleagues investigated the use of adjuvant 5-FU–LV after complete resection of liver metastases and reported an increased 5-year disease-free survival in patients receiving chemotherapy compared with those patients who did not (33.5% versus 26.7%; P = .028). There was no significant difference in overall survival (OS) between the two groups. This trial, however, was closed prematurely because of slow accrual. A pooled analysis of two trials addressing this issue of administering adjuvant 5-FU–LV after hepatic resection, one of which includes the Portier and colleagues study, found that adjuvant 5-FU–LV was independently associated with both prolonged progression-free survival (PFS) and OS in multivariable analysis (median OS: chemotherapy group, 62.2 months; surgery alone, 47.3 months). Kemeny and colleagues investigated the use of adjuvant combined regional (FUDR) and systemic chemotherapy (infusional 5-FU) after complete resection of limited hepatic metastases (≤3 lesions) compared with surgery alone and found that patients receiving chemotherapy had a significantly improved 4-year recurrence-free survival (46% versus 25%; P = .04) and 4-year liver recurrence-free rate (67% versus 43%; P = .03). Finally, Kemeny and colleagues have previously reported an improvement in PFS and OS at 2 years when HAI therapy is combined with systemic chemotherapy after resection compared with systemic therapy alone. It should be noted, however, that all of these studies were conducted before the era of modern chemotherapy and did not incorporate oxaliplatin- or irinotecan-based regimens. The EORTC Intergroup trial that addressed perioperative FOLFOX chemotherapy for resectable liver metastases is discussed in detail in the level Ia evidence section.
Trials on neoadjuvant and adjuvant chemotherapy for resectable liver metastases
There have been few randomized studies assessing the use of administering chemotherapy either before or after complete resection of liver metastases. Portier and colleagues investigated the use of adjuvant 5-FU–LV after complete resection of liver metastases and reported an increased 5-year disease-free survival in patients receiving chemotherapy compared with those patients who did not (33.5% versus 26.7%; P = .028). There was no significant difference in overall survival (OS) between the two groups. This trial, however, was closed prematurely because of slow accrual. A pooled analysis of two trials addressing this issue of administering adjuvant 5-FU–LV after hepatic resection, one of which includes the Portier and colleagues study, found that adjuvant 5-FU–LV was independently associated with both prolonged progression-free survival (PFS) and OS in multivariable analysis (median OS: chemotherapy group, 62.2 months; surgery alone, 47.3 months). Kemeny and colleagues investigated the use of adjuvant combined regional (FUDR) and systemic chemotherapy (infusional 5-FU) after complete resection of limited hepatic metastases (≤3 lesions) compared with surgery alone and found that patients receiving chemotherapy had a significantly improved 4-year recurrence-free survival (46% versus 25%; P = .04) and 4-year liver recurrence-free rate (67% versus 43%; P = .03). Finally, Kemeny and colleagues have previously reported an improvement in PFS and OS at 2 years when HAI therapy is combined with systemic chemotherapy after resection compared with systemic therapy alone. It should be noted, however, that all of these studies were conducted before the era of modern chemotherapy and did not incorporate oxaliplatin- or irinotecan-based regimens. The EORTC Intergroup trial that addressed perioperative FOLFOX chemotherapy for resectable liver metastases is discussed in detail in the level Ia evidence section.
Trials for HAI regional chemotherapy
The rationale for delivering HAI chemotherapy for liver metastases is based on the fact that metastases derive their blood supply from the hepatic artery and chemotherapy can be delivered in higher doses. Trials that have investigated the use of HAI have differed in the chemotherapeutic agent used for regional infusion ranging from FUDR (90% hepatic extraction rate) to 5-FU (variable hepatic extraction rate ranging from 19%–90%) so that the delivery of chemotherapy has not been standardized among trials. The second problem is that some studies have concurrently administered systemic therapy along with regional therapy, whereas others have compared regional therapy in isolation. Regional therapy to the liver with a high extraction rate has minimal impact on the progression of extrahepatic disease. Trials have been conflicting and difficult to compare because eight previous trials using HAI for unresectable hepatic metastases yielded mixed results. There are two trials during the more recent time period included in this article that were ranked as Ia trials (discussed in detail later).
Trials on molecular markers of chemotherapy efficacy
In this generation of new chemotherapeutic agents and novel monoclonal antibodies directed at specific membrane receptors, it seems logical that the initiative has been to shift from a one-size-fits-all disease-based chemotherapy to individual tumor-directed therapy. The literature is populated with many retrospective studies that describe associations of chemotherapeutic response and patient survival outcomes with certain tumor genetic signatures, protein expression levels, or molecular markers. There is only a single study by Karapetis and colleagues that has investigated such an association in a prospective randomized fashion, however, and it has defined the use of cetuximab and other epidermal growth factor receptor (EGFR) receptor inhibitors for patients with tumors that possess K-ras wild-type genotype. This study is discussed in detail in the level Ia evidence section.
Trials on the duration, dosing, and sequencing of chemotherapy
Studies in this subject area have focused on using different dosages, durations, and schedules of delivering chemotherapy. There is not one single recipe for dosage, sequence, and duration that defines the standard administration of chemotherapy for all patients. Tournigand and colleagues demonstrated similar results when FOLFOX and FOLFIRI are interchanged as first-line and second-line therapy, suggesting that either order can be used. This trial also provided further support for the notion that FOLFOX and FOLFIRI have equivalent efficacy in advanced colorectal cancer. Two large trials recently published in 2007 (CAIRO study and MRC FOCUS study) reported that a sequential treatment strategy of 5-FU followed by either oxaliplatin- or irinotecan-based regimens after failure yielded similar patient survival outcomes as initiating treatment with a combination regimen as first-line therapy. This strategy has not permeated into most oncologists’ clinical practice today, however, because most patients are offered either FOLFOX or FOLFIRI as first-line therapy barring any toxicity contraindications.
Level Ia evidence randomized clinical trials
Trials Using Different Types of Chemotherapy
1. Oral capecitabine versus intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomized, phase III trials. Van Cutsem E, Hoff PM, Harper P, et al. Br J Cancer 2004 Mar 22;90(6):1190–7 .
Hypothesis: Oral capecitabine has similar efficacy as IV 5-FU for advanced colorectal cancer.
| No. Patients Randomized | Study Groups | Stratification | Significance Demonstrated | % Change Identified in Trial |
|---|---|---|---|---|
| 1207 | Capecitabine N = 603 Bolus 5-FU–LV N = 604 | None | No difference in OS | Median OS: 12.9 versus 12.8 mo |
Published abstract: This study evaluates the efficacy of capecitabine using data from a large, well-characterized population of patients with MCRC treated in two identically designed phase III studies. A total of 1207 patients with previously untreated MCRC were randomized to either oral capecitabine (1250 mg m[-2] twice daily, days 1–14 every 21 days; N = 603) or IV bolus 5-FU–LV (Mayo Clinic regimen; N = 604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU–LV (26% versus 17%; P <.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates ( P <.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio [HR] 0.997; 95% confidence interval [CI], 0.885–1.123; P = .95; median 4.6 versus 4.7 months with capecitabine and 5-FU–LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases, and poor Karnofsky performance status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95; 95% CI, 0.84–1.06; P = .48; median 12.9 versus 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and OS, an improved safety profile, and improved convenience compared with IV 5-FU–LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomized trials are evaluating capecitabine in combination with irinotecan, oxaliplatin, and radiotherapy. Capecitabine is a suitable replacement for IV 5-FU as the backbone of colorectal cancer therapy. (Copyright 2004 Nature Publishing Group; reprinted with permission.)
Editor’s summary and comments: Although this is a pooled analysis of two identically designed studies, it secured a spot for oral capecitabine in the treatment of advanced colorectal cancer. It seems that the oral preparation has similar efficacy, less toxicity, and increased ease for patients. This trial must be interpreted in the context of the control group, however, consisting of bolus 5-FU as opposed to infusional 5-FU, of which the latter is the standard of care today.
2. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. Cassidy J, Clarke S, Díaz-Rubio E, et al. J Clin Oncol 2008 Apr 20;26(12):2006–12 .
Hypothesis: Capecitabine plus oxaliplatin (XELOX) is not inferior to FOLFOX4 as first-line therapy in MCRC colorectal cancer.
| No. Patients Randomized | Study Groups | Stratification | Significance Demonstrated | % Change Identified in Trial |
|---|---|---|---|---|
| 2035 | XELOX N = 1017 FOLFOX4 N = 1018 | None | No difference in PFS or OS | Median PFS: 8 versus 8.5 mo Median OS: 19.8 versus 19.6 mo |
Published abstract: The purpose is to evaluate whether XELOX is noninferior to FOLFOX4 as first-line therapy in MCRC. Patients and methods: The initial design of this trial was a randomized, two-arm, noninferiority, phase III comparison of XELOX with FOLFOX4. After patient accrual had begun, the trial design was amended in 2003 after bevacizumab phase III data became available. The resulting 2 × 2 factorial design randomly assigned patients to XELOX versus FOLFOX4, and then to also receive either bevacizumab or placebo. The results of the analysis of the XELOX versus FOLFOX4 arms are reported here. The analysis of bevacizumab versus placebo with oxaliplatin-based chemotherapy is reported separately. The prespecified primary end point for the noninferiority analysis was PFS. Results: The intent-to-treat population comprised 634 patients from the original two-arm portion of the study, plus an additional 1400 patients after the start of the amended 2 × 2 design, for a total of 2034 patients. The median PFS was 8 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX4-containing arms (HR, 1.04; 97.5% CI, 0.93–1.16). The median OS was 19.8 months with XELOX versus 19.6 months with FOLFOX4 (HR, 0.99; 97.5% CI, 0.88–1.12). FOLFOX4 was associated with more grade 3 to 4 neutropenia-granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhea and grade 3 hand-foot syndrome than FOLFOX4. Conclusion: XELOX is noninferior to FOLFOX4 as a first-line treatment for MCRC, and may be considered as a routine treatment option for appropriate patients. (Copyright 2008 American Society of Clinical Oncology; reprinted with permission.)
Editor’s summary and comments: This multicenter trial compared the efficacy of oral capecitabine with infusional 5-FU in combination with oxaliplatin chemotherapy. The trial was amended in 2003, however, to include the addition of bevacizumab as a 2 × 2 factorial design. The XELOX and FOLFOX groups each contain three subgroups of patients: those who received (1) the assigned chemotherapy, (2) chemotherapy plus placebo, and (3) chemotherapy plus bevacizumab. Although the authors state that treatment interaction was ruled out to assess for the effect of bevacizumab, the results of this trial are based on a pooled analysis of these groups. Nevertheless, assuming that the effect of bevacizumab was equal in both groups, capecitabine demonstrated oncologic noninferiority compared with standard infusional 5-FU.
3. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. Goldberg RM, Sargent DJ, Morton RF, et al. J Clin Oncol 2004 Jan 1;22(1):23–30 .
Hypothesis: Oxaliplatin-based chemotherapy is superior to the IFL regimen.
| No. Patients Randomized | Study Groups | Stratification | Significance Demonstrated | % Change Identified in Trial |
|---|---|---|---|---|
| 795 | FOLFOX N = 267 IFL N = 264 IROX N = 264 | Performance status, prior chemotherapy, prior immunotherapy, age, randomizing location | FOLFOX improved PFS, tumor response rate, and OS compared with IFL and IROX | Median PFS: 8.7 versus 6.9 versus 6.5 mo Tumor response rate: 45% versus 31% versus 35% Median OS: 19.5 versus 15 versus 17.4 mo |
Published abstract: Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: (1) FU, (2) irinotecan, and (3) oxaliplatin. This study compares the activity and toxicity of three different two-drug combinations in patients with MCRC who had not been treated previously for advanced disease. Patients and methods: Patients were concurrently randomly assigned to receive IFL (control combination); FOLFOX; or irinotecan and oxaliplatin (IROX). The primary end point was TTP, with secondary end points of response rate, survival time, and toxicity. Results: A total of 795 patients were randomly assigned between May 1999 and April 2001. A median TTP of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for TTP and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. Conclusion: The FOLFOX regimen was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer. (Copyright 2004 American Society of Clinical Oncology; reprinted with permission.)
Editor’s summary and comments: In the year 2000, the IFL regimen became the standard of care chemotherapeutic regimen in the United States for MCRC. The multicenter trial reported previously (N9741) compared FOLFOX with IROX and IFL regimens in terms of PFS, tumor response, and OS. Although the median follow-up was only 20.4 months, the FOLFOX regimen performed better in all three end points. To the authors’ credit, a recent update after 5-year follow-up reported consistent findings. The authors concluded that FOLFOX should replace irinotecan-based regimens as the standard therapy for advanced colorectal cancer. It must be stressed, however, that not all irinotecan regimens are the same; IFL, which uses bolus-FU, is distinct from FOLFIRI, which includes infusional 5-FU.
4. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. Colucci G, Gebbia V, Paoletti G, et al. J Clin Oncol 2005 Aug 1;23(22):4866–75 .
Hypothesis: FOLFOX and FOLFIRI have equivalent tumor response rates.
| No. Patients Randomized | Study Groups | Stratification | Significance Demonstrated | % Change Identified in Trial |
|---|---|---|---|---|
| 360 | FOLFIRI N = 178 FOLFOX4 N = 182 | None | Similar overall response rate, TTP, and OS | Overall response rates: 31% versus 34% Median PFS: 7 versus 7 mo Median OS: 14 versus 15 mo |
Published abstract: This phase III study was performed to compare the FOLFIRI with the FOLFOX4 in previously untreated patients with advanced colorectal cancer. Patients and methods: A total of 360 chemotherapy-naive patients were randomly assigned to receive, every 2 weeks, either arm A (FOLFIRI: irinotecan, 180 mg/m 2 , on day 1 with LV, 100 mg/m 2 , administered as a 2-hour infusion before FU, 400 mg/m 2 , administered as an IV bolus injection, and FU, 600 mg/m 2 , as a 22-hour infusion immediately after FU bolus injection on days 1 and 2 [LV5FU2]) or arm B (FOLFOX4: oxaliplatin, 85 mg/m 2 , on day 1 with LV5FU2 regimen). Results: One hundred sixty-four and 172 patients were assessable in arm A and B, respectively. Overall response rates were 31% in arm A (95% CI, 24.6–38.3) and 34% in arm B (95% CI, 27.2–41.5; P = .60). In both arms A and B, median TTP (7 versus 7 months, respectively), duration of response (9 versus 10 months, respectively), and OS (14 versus 15 months, respectively) were similar, without any statistically significant difference. Toxicity was mild in both groups: alopecia and gastrointestinal disturbances were the most common toxicities in arm A; thrombocytopenia and neurosensorial were the most common toxicities in arm B. Grade 3 to 4 toxicities were uncommon in both arms, and no statistical significant difference was observed. Conclusion: There is no difference in overall response rates, TTP, and OS for patients treated with the FOLFIRI or FOLFOX4 regimen. Both therapies seemed effective as first-line treatment in these patients. The difference between these two combination therapies is mainly in the toxicity profile. (Copyright 2005 American Society of Clinical Oncology; reprinted with permission.)
Editor’s summary and comments: This Italian study describes equivalent efficacy of oxaliplatin and irinotecan, namely that FOLFIRI and FOLFOX have similar tumor response rates, PFS, and OS. It is worth highlighting that this trial used irinotecan in combination with infusional 5-FU and reported its equivalent efficacy to FOLFOX as opposed to what has been previously reported for the IFL regimen (bolus 5-FU). Most oncologists today choose first-line treatment based on the toxicity profile of the regimen as it applies to each individual patient rather than a superior oncologic efficacy of one regimen over the other.
5. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med 2004 Jun 3;350(23):2335–42 .
Hypothesis: Bevacizumab improves the efficacy of IFL.
| No. Patients Randomized | Study Groups | Stratification | Significance Demonstrated | % Change Identified in Trial |
|---|---|---|---|---|
| 813 | IFL/Bev N = 402 IFL/placebo N = 411 | None | Improved PFS and OS | Median PFS: 10.6 versus 6.2 mo Median OS: 20.3 versus 15.6 mo |
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