First-Line Therapeutic Strategies in Metastatic Colorectal Cancer

Janine M. Davies, MD
Senior Fellow

Richard M. Goldberg, MD
Professor and Chief
Division of Hematology
and Oncology
University of North Carolina
at Chapel Hill
Chapel Hill, North Carolina


Financial Disclosure
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

The treatment of metastatic colorectal cancer (mCRC) has changed dramatically from the 1980s, when only fluorouracil (5-FU) was available for treatment and the median survival was at best 12 months, to a time when mCRC is considered more of a chronic disease in which the median survival is now reported in excess of 2 years. This review traces the evolution of treatment in this setting, including studies of single-agent vs combination treatment with 5-FU/leucovorin, irinotecan, oxaliplatin, and capecitabine, comparisons of simultaenous and sequential regimens, and the role of targeted agents such as bevacizumab, cetuximab, and panitumumab.

Colorectal cancer is the third most common cancer in the United States.[1] In 2008, an estimated 148,810 new cases of colorectal cancer will be diagnosed and nearly 50,000 people will die of the disease.[1] In the past 20 years, great advances have been made in the treatment of advanced colorectal cancer, increasing survival from 6 months to over 2 years. However, among patients diagnosed with metastatic colorectal cancer (mCRC), the 5-year survival rate is, on average, only 8%.[2] This paper will outline the progression of treatment advances in mCRC, including single and combination chemotherapeutic agents and the addition of targeted agents.

Evolution of Combination Chemotherapy

Single vs Combination Chemotherapy

• Fluorouracil/Leucovorin—Prior to the integration of fluoropyrimidines in the management of mCRC, the median survival with best supportive care alone was a mere 6 months.[3] This improved to 10 to 12 months with the use of fluorouracil (5-FU) with or without leucovorin (LV).[3,4] 5-FU is thought to inhibit thymidylate synthase which then blocks DNA synthesis. Introduced more than 50 years ago, it was the first major breakthrough in the treatment of mCRC. The addition of LV, a reduced folate, was found preclinically to increase the intracellular concentration of reduced folates, resulting in increased binding of 5-FU to thymidylate synthase and therefore producing increased inhibition of DNA synthesis and enhanced antitumor effects.[3]

Numerous phase II and III trials assessing the dose, schedule, and method of administration of 5-FU–based chemotherapy were completed by the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) trials group. The GERCOR trials culminated in the French Intergroup Study comparing monthly bolus 5-FU/ LV (North Central Cancer Treatment Group [NCCTG]-Mayo regimen) with bimonthly bolus and continuous-infusion 5-FU/LV (modified LV5FU2 regimen).[5] The dose of chemotherapy given with the LV5FU2 regimen was twice that of the Mayo regimen. While there was no statistically significant difference in overall survival (OS), both response rate and progression-free survival (PFS) were improved with the modified LV5FU2 regimen. The LV5FU2 regimen also was associated with fewer grade 3/4 toxicities than were seen with the monthly regimen.[5]

Both regimens had inconveniences related to delivery. The Mayo regimen required daily bolus administration of 5-FU for 5 consecutive days on a monthly basis. By comparison, the LV5FU2 regimen consisted of a 5-FU bolus followed by a continuous infusion of 5-FU for 48 hours every 2 weeks, which involved the need for long-term venous access and an administration pump.

Subsequently, two key meta-analyses assessed the impact of the modes of delivery of 5-FU/LV on survival[6] and the relative contribution of LV to 5-FU–based chemotherapy,[7] respectively. First, a meta-analysis was performed that compared infusional vs bolus 5-FU/LV from seven phase III clinical trials, representing 1,219 patients.[6] The meta-analysis showed that infusional 5-FU was associated with an improved tumor response (22% vs 14%, P = .0002) but without a corresponding improvement in median survival (12.1 vs 11.3 months, P = .039).[6] A companion paper described the toxicity profiles and showed that bolus 5-FU was associated with increased grade 3/4 hematologic toxicity, particularly neutropenia (4% vs 31%) and mucositis, whereas higher rates of hand-foot syndrome (34% vs 13%) were observed with infusional 5-FU.[8]

Another meta-analysis assessed the impact of modulation of 5-FU by LV.[7] The tumor response rate improved from 11% to 21% with the use of 5-FU/LV vs 5-FU alone (P < .0001). Median OS improved from 10.5 to 11.7 months (P = .004). The 1-year survival rate was 43% vs 49%, but 2-year survival was identical in both groups at 17%. Prognostic factors of a good tumor response included good performance status, metastases confined to the liver, and treatment with 5-FU/LV. One-year survival was clearly worse with increasing performance status (63% vs 45% vs 20% for PS 0, 1, and 2, respectively) and was influenced by the site of metastatic disease (liver only, 50%; lung only, 57%; and other sites, 44%).[7] Overall, this analysis demonstrated a small but discernable benefit for the addition of LV to bolus 5-FU.

• Irinotecan—Irinotecan (CPT-11) was then added to the armamentarium, receiving US Food and Drug Administration (FDA) approval in 2002. Irinotecan inhibits the topoisomerase 1 enzyme. Normally, topoisomerase 1 catalyzes DNA breakage, repair, and rejoining of DNA strands, all necessary for DNA replication. Irinotecan-induced inhibition stabilizes these breaks, leaving fragmented DNA and resulting in cell death.[3]

Douillard et al[9] authored the first phase III study in which irinotecan was added to infusional 5-FU/calcium folinate compared to 5-FU/calcium folinate alone. This study demonstrated a benefit in response rate (35% vs 22%, P = .005) and median time to progression (7 vs 4 months, P = .001). The survival benefit was 3 months (17 vs 14 months, P = .031), with a 1-year survival of 69% vs 59%. Grade 3/4 toxicities were mostly limited to the irinotecan group, and consisted of diarrhea (44% vs 26%), vomiting, and leukopenia. Grade 3/4 neutropenia affected 29% of patients on irinotecan, but only 2% of all patients developed infection.[9]

At the same time, Saltz et al[10] compared three regimens: (1) weekly bolus irinotecan and 5-FU/LV (IFL); (2) 5-FU/LV (Mayo protocol); and (3) weekly single-agent irinotecan. The IFL regimen demonstrated a superior PFS compared to 5-FU/LV, increasing PFS from 4.3 to 7.0 months (P = .004) and enhanced survival from 12.6 to 14.8 months (P = .04). Survival and PFS for weekly irinotecan were similar to the 5-FU/LV regimen. However, additional toxicities of IFL included grade 3/4 diarrhea, vomiting, and infection. Mucositis was substantially increased (16.9% vs 2.2%) in the 5-FU/LV group and higher than expected by the meta-analysis data.[8]

• Oxaliplatin—Oxaliplatin (Eloxatin), a third-generation platinum derivative, demonstrated activity in mCRC in synergy with 5-FU/LV.[3] Oxaliplatin induces apoptosis by forming DNA adducts.[3] The first major study demonstrating the effectiveness of oxaliplatin when compared with the Mayo protocol (FOLFOX4 [leucovorin (folinic acid), 5-FU, oxaliplatin]) found a significant improvement in PFS from 6.2 to 9 months (P = .0001) and response rate over 5-FU/LV alone.[11] Overall survival improved from 14.7 to 16.2 months but was not statistically different between the two treatment arms, although this may have been obscured by crossover for salvage chemotherapy. Toxicity of oxaliplatin was predominantly neurosensory, overall affecting 68% of patients with grade 1 to 3 toxicity, including pharyngolaryngeal dysesthesia in almost one-quarter of the patients.[11]

• Capecitabine—Another advance in the management of mCRC was the demonstration of equivalence of 5-FU/LV and capecitabine (Xeloda). Capecitabine is an oral fluoropyrimidine that is converted enzymatically to fluorouracil, with a toxicity profile similar to infusional 5-FU [3]. Two simultaneous and identical phase III clinical trials were performed to compare the 5-FU/LV Mayo protocol with capecitabine.[12,13] One study demonstrated at least equivalence,[13] and the other demonstrated superiority of capecitabine[12] in terms of response rate. Otherwise, secondary endpoints were equivalent, including a median survival of 12 to 13 months. The toxicity profile of capecitabine demonstrated expected rates of diarrhea but more frequent hand-foot syndrome. Alopecia was less frequent and stomatitis was both less frequent and less severe with capecitabine than 5-FU.[12,13] These studies confirmed the interchangeability of 5-FU/LV and capecitabine.

Combination Comparisons and the Role of Sequential Therapies

By 2000, the optimal use of the available agents in first-line therapy, 5-FU/LV, irinotecan, and oxaliplatin, had not been determined, and capecitabine would shortly become a treatment option. Evidence was mounting for combination treatment to improve the objective response rate and time to disease progression. Irinotecan in combination with 5-FU/LV had demonstrated a benefit over 5-FU/LV or irinotecan alone,[9,10] as had oxaliplatin.[11] Second-line options were emerging, although not prespecified in trials, and the treatment options outside a clinical trial were limited. At this point, the combinations of treatments and sequencing of these agents became the focus of attention.

• N9741 Trial—In the phase III N9741 trial comparing IFL to FOLFOX and IROX (irinotecan/oxaliplatin), the superiority of FOLFOX was demonstrated in terms of improved time to progression and response rates, and an OS of 19.5 months compared to 15 months for IFL and 17.4 months for IROX (P = .0001).[14] Aside from sensory neuropathy (grade 3/4 in 18% vs 3%, P = .001), fewer and less severe toxicities were observed with FOLFOX compared to the toxicities seen with the IFL regimen. More severe vomiting and paresthesias, however, were observed with IROX as compared to IFL.[14] Based on response and survival rates, and toxicity profiles, FOLFOX was judged to be the superior regimen for mCRC, and in 2004, the FDA approved the use of FOLFOX for previously untreated mCRC.

• BICC-C Trial—The Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C) trial was developed as a 3×2 factorial design comparing three chemotherapy options (FOLFIRI [leucovorin, 5-FU, irinotecan], modified [m]IFL, and CapeIRI [capecitabine, irinotecan]). A second randomization was performed to compare the use of celecoxib (Celebrex) or placebo with each of the chemotherapeutic regimens evaluated.[15] Due to the excessive number and severity of toxicities, the CapeIRI arm was subsequently dropped. As data emerged regarding its efficacy in CRC, bevacizumab (Avastin) was included in the trial. Patients in both the FOLFIRI and mIFL arms were subsequently randomized to receive chemotherapy plus bevacizumab or chemotherapy only. The final study design involved FOLFIRI vs mIFL with or without celecoxib, and with or without bevacizumab.

First, celecoxib did not influence therapeutic outcomes, and the randomization of celecoxib was not considered relevant to the analysis of the chemotherapeutic regimens administered either alone or in combination with bevacizumab.

Second, FOLFIRI was found to be superior to mIFL in PFS (7.6 vs 5.9 months, P = .004). Overall survival was similarly improved (23.1 vs 17.6 months, P = .09), with 1-year survival rates of 75% and 65%, respectively. CapeIRI and mIFL produced similar results for OS and PFS, but excessive toxicity was observed from CapeIRI compared to either FOLFIRI or mIFL. FOLFIRI still maintained a superior PFS over CapeIRI, even when the analysis excluded patients on the CapeIRI arm who discontinued treatment early due to significant toxicity.[15]

• XELOX vs FOLFOX—Subsequently, the NO16966 (XELOX-1) trial was designed to combine oxaliplatin with either capecitabine or 5-FU/LV.[16] Later in the trial, patients were randomized to receive XELOX and FOLFOX4 alone or with bevacizumab. The first objective of the amended protocol was to show the noninferiority of XELOX and FOLFOX4 for PFS, with or without bevacizumab. The investigators found no difference in PFS in the eligible patient population (7.9 vs 8.5 months; hazard ratio [HR] = 1.05; 97.5% confidence interval [CI] = 0.94–1.18, the upper limit being below the predefined 1.23 noninferiority margin). The median OS was also similar at 19.8 and 19.6 months, respectively. Toxicities were also similar aside from increased grade 3/4 diarrhea in the XELOX group and the increased rate of neutropenia in the FOLFOX group.[16] The interchangeability of XELOX and FOLFOX was then established.

• FOLFIRI vs FOLFOX—Colucci et al [17] reported a direct comparison of an irinotecan 5-FU combination (Douillard regimen) with FOLFOX4 (de Gramont regimen). The authors found no differences in response rate, time to progression, or survival. Almost two-thirds of patients had previously received second-line chemotherapy, mostly oxaliplatin in the FOLFIRI group and irinotecan in the FOLFOX4 group. The analysis of those patients previously treated with second-line chemotherapy demonstrated a median survival of 17 months, compared to a median survival of 10 months among patients who did not get second-line chemotherapy.[17] This confirmed the similarity in activity between the FOLFOX and the Douillard 5-FU plus irinotecan regimens in first-line chemotherapy for mCRC. The choice of an initial regimen for mCRC then became a matter of patient and physician preference and toxicity profiles rather than differential efficacy. FOLFOX caused more neutropenia and sensory neuropathy, whereas the Douillard regimen was associated with hair loss and more gastrointestinal (GI) toxicity.

• Refining the Regimens—With no new chemotherapeutic agents on the horizon, the next issue was to determine the most appropriate delivery of the agents. This was done retrospectively by Grothey et al[18] and prospectively in the FOCUS (Fluorouracil, Oxaliplatin, and CPT-11 [irinotecan] Use and Sequencing) and CAIRO (CApecitabine, IRinotecan, Oxaliplatin) trials. The variation in median survival in studies using combination chemotherapy, which ranged from 14.8 to 21.5 months, was thought to be influenced more by the choice of salvage therapies following first-line treatment, rather than explained on the basis of patient selection or other factors unrelated to the treatments.

Grothey et al[18] analyzed the impact of receiving all three active treatments (5-FU, irinotecan, and oxaliplatin) during the course of disease in a pooled analysis. Median survival was strongly correlated with the percentage of patients who received all three drugs (P = .0008). No correlation was found, however, with survival and percentage of patients who received second-line treatment (P = .19). Administration of all three drugs (combination therapy) was associated with a 3.5-month increase in median survival compared to the initial administration of only one of the three agents (monotherapy, P = .01).

This analysis brought up two important points. First, in these studies between 58% and 77% of the patients who initially received monotherapy later received second-line chemotherapy on progression. This would make a case for the early initiation of combination therapy, although the potential influence of performance status at the time of progression affecting the second-line treatment choice cannot be excluded. These patients likely had a poorer performance status at the time of initial therapy and at the time of progression that affected the administration of second-line chemotherapy. Second, because of the survival benefit gained from second-line chemotherapy, other endpoints, such as PFS and time to treatment failure, might better assess the benefit of the initial chemotherapy regimen.[18]

Subsequently, Grothey and Sargent[19] presented an updated analysis with patients from four additional trials that validated this concept. They found that the median survival correlated with the percentage of patients receiving all three chemotherapy regimens. In multivariate analyses, only first-line exposure to all three treatments was correlated with survival.[19]

• FOCUS and CAIRO Studies—The FOCUS and CAIRO trials investigated whether combination treatment was indeed required to improve overall survival, as opposed to a sequential approach that used single agents. One obvious advantage of the sequential approach would be to minimize side effects. The Medical Research Council’s FOCUS trial compared three treatment options: 5-FU/LV followed by irinotecan at treatment failure, single-agent 5-FU/LV followed by combination chemotherapy, and combination chemotherapy at the outset.[20] In the combination chemotherapy arms, patients were further randomized to 5-FU/irinotecan or 5-FU/oxaliplatin. After second-line chemotherapy, salvage chemotherapy or supportive care was instituted. Initially, salvage with 5-FU and mitomycin was the treatment of choice, but with evidence supporting the sequential use of irinotecan and oxaliplatin, these agents were later recommended (although only received by 23% of patients).[20]

Compared with single-agent 5-FU/LV, only the initial combination arm with irinotecan demonstrated an improved overall survival by 2.6 months (P = .02, adjusting for multiple comparisons). However, no differences were reported between the three groups in 2-year OS (22% vs 25% vs 28%, respectively, adjusted for multiple comparisons). A further analysis found noninferiority between the two combination strategies. Additionally, no differences in quality of life or by performance status were noted.[20] The advantage of such a study is that it demonstrates that toxicities can be balanced with the treatment options, and that treatment can be individualized without compromising survival in patients for whom curative options are not available.

A similarly aimed study, CAIRO, was published simultaneously by the Dutch Colorectal Cancer Group.[21] It used a simple two-arm study design, comparing sequential treatment (capecitabine followed by irinotecan on progression followed by CapeOX [capecitabine, oxaliplatin]) with combination treatment (CapeIRI followed by CapeOX on progression). Overall survival was not statistically different between the sequential and combination therapy groups (16.3 and 17.4 months, respectively). The 1-year survival rates were 64% and 67%, respectively (P = .38). However, multivariate analyses showed that worse survival was associated with a performance status of 2 and an abnormal lactate dehydrogenase (LDH).

Adverse effects were generally similar in the sequential and combination treatment arms except for grade 3 hand-foot syndrome, which was worse in the sequential group. Of note, both treatments were associated with grade 3/4 diarrhea (25%), nausea, vomiting, and febrile neutropenia. Quality of life was not significantly different in the two groups, aside from the incidence of diarrhea, which was worse in the combination group.[21] The diarrhea from CapeIRI, however, was less severe in this trial than in either the BICC-C or the European Organisation for Research and Treatment of Cancer (EORTC) 40015 trial, where toxicities resulted in the closure of the BICC-C trial’s CapeIRI arm and the premature closure of the EORTC 40015 trial. While possible explanations have been offered, these differences have yet to be explained.

While neither the FOCUS nor CAIRO studies used monoclonal antibody treatments, these studies were the first to determine that sequential treatment could produce similar survival as combination therapy among patients with unresectable or only potentially resectable disease. The increased median survival in the CAIRO study may be attributed to the use of all available treatments (5-FU, irinotecan, and oxaliplatin) in 36% of the sequential and 53% of the combination patients. By comparison, only 25% of the patients in the FOCUS trial received all three treatments. Clearly toxicity increased with combination treatment.

An accompanying editorial suggested that combination therapy may be most important for patients with potentially resectable disease to give the best possible chance of resection as well as for those with aggressive disease who have or are anticipated to have tumor-related symptoms or poor performance status related to disease.[22] Otherwise, the results of the FOCUS and CAIRO studies may be most appropriate for patients who do not fit into either of these two groups.[22]

• Timing—Another question relates to the sequencing of FOLFOX and FOLFIRI regimens. The C97 study by the GERCOR group compared FOLFIRI followed by FOLFOX6 at progression with the reverse sequence of regimens.[23] Performance status improved with both sequences, and the sequence of therapy had no impact on either PFS or OS. However, the sequence did influence toxicities. Grade 3/4 nausea, vomiting, and mucositis were more common with FOLFIRI, whereas neurotoxicity and neutropenia were more common with FOLFOX. Only grade 3 neurotoxicity with FOLFOX was increased when FOLFOX was used as second-line chemotherapy. Elderly patients did not experience more toxicities than younger patients.[23]

• Lower-Intensity Regimens—A previous pooled analysis in mCRC demonstrated that survival correlated with the proportion of patients receiving all three chemotherapy agents, yet did not correlate with the proportion of patients who receive second-line chemotherapy.[18] This prior analysis formed the basis of trials conducted separately by Falcone et al[24] and Souglakos et al,[25] who examined the efficacy of a modified, lower-intensity variation of the FOLFIRI regimen vs FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, irinotecan) as first-line therapy. Previously, a phase II study reported a median survival of 28.4 months and a response rate of 72% with administration of FOLFOXIRI.[26]

The study by Souglakos et al[25] found that survival was not different between the groups (19.5 vs 21.5 months, P = .337), nor was time to progression (6.9 vs 8.4 months, P = .17). The dose intensity, which was only marginally higher in the mFOLFIRI group, did not explain the lack of difference. FOLFOXIRI was associated with increased diarrhea, neurosensory disorders, and severe alopecia.

In contrast, the study by Falcone et al[24] was positive. The primary endpoint was response rate, which the authors justified by the strong correlations in meta-analyses between response rate and survival, and between response rate and rate of secondary surgery on metastases. When compared with mFOLFOX, FOLFOXIRI produced an impressive response rate (66% vs 41%, P = .002), for which treatment with FOLFOXIRI was the only independent predictor in multivariate analyses. PFS improved and overall survival increased from 16.7 to 22.5 months (P = .032). As expected, FOLFOXIRI was more toxic with regard to neurotoxicity and neutropenia, although the rates of febrile neutropenia were not different. The data were insufficient for quality-of-life analyses.[24]

So how do we evaluate these discrepant results? The study by Souglakos et al used a bolus 5-FU/LV regimen, which by virtue of its side-effect profile, may have limited the dosing of irinotecan and oxaliplatin. However, both studies demonstrated significant rates of grade 3/4 diarrhea. Additionally, the patients in the Souglakos study were older and had a higher performance status. Regardless, the FOLFOXIRI regimen is not a commonly used treatment option given the alternate available regimens that include monoclonal antibodies.

• ‘Stop and Go’ Strategies—The benefits of irinotecan and oxaliplatin in overall survival for patients with mCRC have been accompanied by added toxicity. The dose-limiting factor with oxaliplatin is the neurotoxicity. Tournigand et al[27] evaluated the concept of treatment breaks (“stop and go”) by comparing continuous FOLFOX4 until progression with a regimen of higher-dose oxaliplatin (FOLFOX7) for 6 cycles, followed by 5-FU/LV for 12 cycles, followed by FOLFOX7 for 6 cycles, in the OPTIMOX1 study. With this design, duration of disease control was the primary endpoint. This was defined as PFS for the continuous group, and for the stop-and-go arm, it combined the first PFS interval with the second PFS interval if a response or stable disease was achieved with the second regimen.

Both regimens produced a similar duration of disease control (9 vs 10.6 months, P = .89), as well as overall survival (19.3 vs 21.2 months, P = .49) and PFS. In both groups, approximately 15% of patients underwent metastectomy with no difference in survival. The benefit of the stop-and-go arm was the reduced oxaliplatin-related neurotoxicity. The absolute benefit of oxaliplatin reintroduction on PFS and OS was ultimately difficult to discern because of the number of patients who never had reintroduction of oxaliplatin upon progression and the diverse reasons that the protocol-designated treatment plan was not followed.[27] For patients who experience toxicity or require breaks for various reasons, this information will help to guide clinicians in “real world” situations.

The OPTIMOX2 randomized phase II exploratory study assessed the stop-and-go strategy with oxaliplatin-based regimens, introducing the concept of chemotherapy-free intervals.[28] Randomization between the OPTIMOX1 regimen (mFOLFOX7 until progression, with adjusted oxaliplatin and 5-FU doses) vs mFOLFOX7 for six cycles and then no maintenance until progression, at which time FOLFOX7 was reintroduced. The duration of disease control was 12 and 9 months (P = .39), and PFS was 8.3 and 6.7 months in the two groups, respectively (P = .08), favoring the no-break arm. Response rates were similar in both arms. OS was 26 and 19 months (P = .0549) in favor of the no-break arm. The median chemotherapy-free interval was 17 weeks. The stop-and-go arm was better tolerated than the control arm. Although this study was underpowered to find statistically significant differences in survival unless such differences were large in magnitude, the data suggest that the OPTIMOX1 strategy (with 5-FU maintenanceis better than incorporating a chemotherapy-free interval.[28]