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First Published Online October 15, 2008
The Oncologist, Vol. 13, No. 10, 1074-1083, October 2008; doi:10.1634/theoncologist.2008-0083
© 2008 AlphaMed Press

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Gastrointestinal Cancer

Innovations in Chemotherapy for Metastatic Colorectal Cancer: An Update of Recent Clinical Trials

Bert H. O'Neil, Richard M. Goldberg

Division of Hematology and Oncology, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA

Key Words. Biologic therapy • Chemotherapy • Colorectal cancer • Metastatic

Correspondence: Bert H. O'Neil, M.D., UNC Lineberger Comprehensive Cancer Center, 101 Manning Drive, 3009 Old Clinic Building, Chapel Hill, North Carolina 27599-7305, USA. Telephone: 919-966-4431; Fax: 919-966-6735; e-mail: Bert_oneil{at}med.unc.edu

Received April 4, 2008; accepted for publication August 20, 2008; first published online in THE ONCOLOGIST Express on October 15, 2008.

Disclosure: Employment/leadership position: None; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: Richard A. Goldberg, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, ImClone, Myriad, Pfizer, Poniard, Sanofi-Aventis; Bert H. O'Neil, Sanofi-Aventis, Pfizer, Amgen, Bristol-Myers Squibb; Honoraria: None; Research funding: Richard A. Goldberg, Pfizer, Abbott; Ownership interest: None; Expert testimony: None; Other: None.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this articleáhave been disclosed by the authors, planners, independent peer reviewers, or staff managers.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Chemotherapy plus Biologics:...
 Chemotherapy plus Biologics:...
 Improving the Tolerability of...
 Surgical Resection and mCRC
 Conclusions
 Author Contributions
 References
 
After completing this course, the reader should be able to:

  1. Use the evolving treatment strategies in metastatic colorectal cancer, including key data from recent clinical trials.
  2. Prescribe biologic agents in combination with chemotherapy.
  3. Exploit strategies, such as "stop and go" dosing, that may help patients with metastatic colorectal cancer receive optimal therapy in terms of efficacy, with minimal toxicity.

This article is available for continuing medical education credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Chemotherapy plus Biologics:...
 Chemotherapy plus Biologics:...
 Improving the Tolerability of...
 Surgical Resection and mCRC
 Conclusions
 Author Contributions
 References
 
It has been estimated that cancer of the colon and rectum (CRC) would be diagnosed in 153,760 men and women in the U.S. alone in 2007. Approximately one in five patients has metastatic CRC (mCRC) at diagnosis, which, at best, is associated with a 5-year survival rate of just 10.3%. Oxaliplatin- and irinotecan-based combination regimens are standard first-line therapies for mCRC. Recent studies suggest that survival outcomes can possibly be further improved by adding biologic agents to chemotherapy. Novel treatment strategies are being investigated to optimize the opportunity for patients to receive and benefit from the increasing number of available active agents and to further improve the efficacy, safety, and tolerability of multiagent therapy. These include switching therapy before progression, maintenance therapy, and chemotherapy-free intervals. Recent innovations in chemotherapy for mCRC are reviewed, with a focus on emerging data that may significantly improve both survival and quality of life for patients with CRC in the future.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Chemotherapy plus Biologics:...
 Chemotherapy plus Biologics:...
 Improving the Tolerability of...
 Surgical Resection and mCRC
 Conclusions
 Author Contributions
 References
 
It was predicted that cancer of the colon and rectum (CRC) would be diagnosed in 153,760 men and women in the U.S. in 2007 according to the latest data from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry [1]. Furthermore, it was estimated that 52,180 men and women in the U.S. would die from CRC in 2007. The majority of patients are diagnosed with cancer that is no longer confined to the primary site: 36% of patients have locally advanced disease and 19% have metastatic disease. The 5-year survival rate is, at best, just 10.3% for patients with metastatic disease [1]; this review focuses on the treatment of this challenging patient population.

It is well established that multiagent regimens, including a combination of 5-fluorouracil (5-FU) plus leucovorin (LV) with oxaliplatin or irinotecan, are superior to 5-FU plus LV alone as therapy for metastatic colorectal cancer (mCRC) [2–6]. Both oxaliplatin combined with bolus and continuous infusion 5-FU plus LV (FOLFOX) and irinotecan combined with bolus and continuous infusion 5-FU plus LV (FOLFIRI) are recognized as standard first-line therapies for mCRC, with FOLFOX emerging as the preferred upfront treatment option in the U.S. [7]. FOLFOX superseded irinotecan and bolus 5-FU plus LV (IFL) as the first-line standard of care, with data from the three-arm N9741 trial showing that first-line FOLFOX resulted in a significantly greater overall response rate (ORR) and median overall survival (OS) time compared with IFL [8] (Table 1). A recent update of results from the N9741 trial showed that patients receiving FOLFOX were significantly more likely to survive for 5 years than patients receiving either irinotecan combined with oxaliplatin (IROX) or IFL [9] (Table 1). However, bolus administration of 5-FU, as in the IFL regimen, is no longer considered to be optimal. Tournigand et al. [10] compared FOLFOX and FOLFIRI directly—both regimens including bolus and continuous infusion IFL—with protocol-specified crossover to the other regimen as second-line therapy. The OS times were similar for the two regimens and impressive median OS durations of >20 months were achieved in both treatment arms.


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  		Table 1. Efficacy data from the phase III N9741 study

 
More recent studies have shown that survival outcomes can possibly be further improved by adding biologic agents to combination chemotherapy regimens in first and subsequent lines of therapy. The vascular endothelial growth factor inhibitor bevacizumab was approved by the U.S. Food and Drug Administration (FDA) in 2004 for use in combination with first-line i.v. 5-FU–based chemotherapy in patients with mCRC. This approval was based largely on the results of a pivotal study of bevacizumab in combination with IFL [11]. Subsequent to the approval of bevacizumab, many physicians began combining bevacizumab with first-line chemotherapy regimens that are superior to IFL (without randomized trial evidence), in particular FOLFOX and FOLFIRI [7, 12]. More recent data regarding these combinations are discussed below.

The availability of new, effective treatment options is driving a shift in conventional management strategies for advanced CRC. Historically, patients have received successive lines of chemotherapy, with treatment discontinuation or switching to alternative regimens in the event of disease progression. However, there are now more opportunities to tailor chemotherapy to the individual patient and clinical setting and novel treatment strategies are being investigated such as switching chemotherapy before progression, maintenance therapy, and chemotherapy-free intervals [13]. The unifying theme of these new approaches is to optimize the opportunity for patients to receive and benefit from all available active agents while minimizing treatment-associated toxicity, thereby improving both survival and quality of life (QoL).


   CHEMOTHERAPY PLUS BIOLOGICS: FIRST-LINE THERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 Chemotherapy plus Biologics:...
Chemotherapy plus Biologics:...
 Improving the Tolerability of...
 Surgical Resection and mCRC
 Conclusions
 Author Contributions
 References
 
The benefit of adding bevacizumab to second-line oxaliplatin-based therapy with FOLFOX has been established [14], and several studies have been designed to confirm these findings in the first-line setting. The phase II TREE study comprised two sequential cohorts and was conducted to assess the safety and efficacy of three different oxaliplatin-based regimens (modified FOLFOX, oxaliplatin plus bolus 5-FU and LV [bFOL], and oxaliplatin plus capecitabine [CapeOx]) without (TREE-1) or with (TREE-2) the addition of bevacizumab as first-line treatment for mCRC [12]. The primary endpoint was the incidence of grade 3 or 4 treatment-related toxicities during the first 12 weeks of therapy in the TREE-2 cohort; secondary endpoints included toxicity in the TREE-1 cohort and response rates, time to progression (TTP), time to treatment failure, and OS in both cohorts. Response rates, TTP, and OS were favorable in the TREE-2 cohort (Table 2). All three oxaliplatin-based regimens in combination with bevacizumab were associated with impressive median OS durations (20.7–27.0 months), with the longest observed in the FOLFOX plus bevacizumab (26 months) and CapeOx plus bevacizumab (27 months) arms. The addition of bevacizumab to chemotherapy was well tolerated, and did not appear to increase the incidence of chemotherapy-associated grade 3 or 4 events. In line with the known safety profile of bevacizumab, more grade 3 or 4 hypertension, impaired wound healing, and bowel perforation was observed in the TREE-2 cohort. Although the study was not powered to compare the two cohorts, the results (considering the fact that the two cohorts were enrolled sequentially and treated according to the same protocol) provided preliminary evidence that oxaliplatin-based chemotherapy can be further improved by the addition of bevacizumab in the first-line setting.


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  		Table 2. Efficacy results for selected studies of first-line chemotherapy plus biologic agents in patients with metastatic colorectal cancer

 
Building on the pivotal phase III data of bevacizumab in combination with 5-FU plus LV or IFL [11], results from the NO16966 trial, which evaluated the addition of bevacizumab to FOLFOX4 or XELOX as first-line therapy for mCRC, were recently presented [15] (Table 2). One of the two primary objectives was to investigate if oxaliplatin-based chemotherapy plus bevacizumab is superior to oxaliplatin-based chemotherapy plus placebo in terms of progression-free survival (PFS). In total, 1,401 patients were randomized to the 2 x 2 design of either FOLFOX4 plus bevacizumab (5 mg/kg) or XELOX plus bevacizumab (7.5 mg/kg), or FOLFOX or XELOX plus placebo. The PFS duration was significantly longer (p = .0023) among patients who received oxaliplatin-based chemotherapy plus bevacizumab than among those who received chemotherapy alone. However, the benefit of adding bevacizumab to chemotherapy observed in terms of PFS did not translate into a statistically significant difference in OS. Additionally, the PFS benefit of bevacizumab appeared to be limited to patients receiving capecitabine. This surprising and disappointing result may, at least in part, have been a result of the fact that many patients in the trial were not managed according to protocol. The protocol specified oxaliplatin cessation in the event of severe neuropathy but continuation of 5-FU with or without bevacizumab. Instead, patients with severe neuropathy were often given a chemotherapy holiday—a potentially suboptimal treatment strategy that may have prevented the true benefit of bevacizumab from appearing. The apparent differential interaction between bevacizumab and FOLFOX and bevacizumab and XELOX remains puzzling. An explanation could be that bevacizumab works best to optimize a regimen via vascular stabilization [16] but that the FOLFOX regimen is already optimized (in the first-line setting) so that bevacizumab adds little further benefit. This hypothesis is supported by the fact that ORRs were similar with or without bevacizumab [15] (Table 2). The results of this study cast some doubt on whether the routine use of bevacizumab with oxaliplatin-containing regimens is warranted given the overall cost of the combination. It is hoped that other ongoing studies will resolve the issue of whether bevacizumab adds meaningfully to first-line oxaliplatin combinations when bevacizumab and fluoropyrimidines are continued after oxaliplatin cessation.

Another significant question in the first-line treatment setting is whether an optimized irinotecan–fluoropyrimidine–bevacizumab regimen might improve results over the IFL–bevacizumab combination. Indeed, an irinotecan-based combination potentially avoids the one apparent pitfall of the N016966 study: the need to stop oxaliplatin because of cumulative toxicity. The randomized phase III BICC-C study partially addressed this question. The BICC-C study was initially designed to assess three irinotecan–fluoropyrimidine combinations (FOLFIRI, modified IFL [mIFL], and capecitabine plus irinotecan [CapIRI]) in patients with previously untreated mCRC along with the potential benefit of adding the cyclooxygenase-2 inhibitor celecoxib to chemotherapy [17]. Of note, neither efficacy nor safety outcomes appeared to be affected by the addition of celecoxib to chemotherapy compared with the addition of placebo.

After 430 patients had been enrolled into the original 3 x 2 factorial study, the protocol was modified (because of the approval of bevacizumab) and a further 117 patients were randomized to either FOLFIRI plus bevacizumab or mIFL plus bevacizumab. The CapIRI treatment arm was not continued in period II because of the rate of grade 3 or 4 diarrhea associated with the dose and schedule of the CapIRI regimen used. Before the introduction of bevacizumab (period I; median follow-up, 46 months), the median PFS time, but neither the OS time nor the ORR, was significantly longer in the FOLFIRI group than in the mIFL (p = .004) and CapIRI (p = .015) groups (Table 2). During period II (essentially a separate randomized phase II study), the median PFS time appeared to be longer with the addition of bevacizumab to both the mIFL and FOLFIRI regimens, with the longest PFS time observed in the FOLFIRI plus bevacizumab arm. This difference, however, did not reach statistical significance (p = .28). The 1-year survival rate favored FOLFIRI plus bevacizumab (87%) over mIFL plus bevacizumab (61%). Most strikingly, the median OS time for the FOLFIRI arm had not been reached after a median follow-up of 29 months, compared with a median survival duration of 19.4 months for the group treated with mIFL plus bevacizumab. Hence, the results of the BICC-C study show that FOLFIRI with or without bevacizumab is superior to the comparator regimens and confirm that mIFL is a suboptimal regimen that should not be used in the first-line treatment of mCRC. The data suggest that FOLFIRI plus bevacizumab may achieve a particularly long OS duration, but confirmatory phase III data are necessary to support this observation.

The epidermal growth factor receptor (EGFR) inhibitor cetuximab has also been investigated as an add-on to first-line chemotherapy for mCRC. In a phase II study of 62 patients with nonresectable EGFR-expressing mCRC, first-line FOLFOX4 plus cetuximab achieved an impressive ORR of 79% with stable disease in a further 16% of patients. With a median follow-up of 30.5 months, the median PFS time was 12.3 months and the median OS time was 30 months (Table 2). Notably, 10 patients (23%) who initially had unresectable metastases were able to undergo surgery with curative intent following study therapy, and nine of those patients achieved R0 resections (complete tumor resection). There were no unexpected toxicities; the main grade 3 or 4 adverse events were acne-like rash (28% grade 3), diarrhea (26%), neutropenia (23%), paresthesia (19%), and asthenia (9%) [18].

The phase III CRYSTAL study assessed the effect of adding cetuximab to FOLFIRI in the first-line treatment of 1,217 patients with EGFR-expressing mCRC. FOLFIRI plus cetuximab was associated with a significantly greater PFS time (p = .036) and ORR (p = .005) than with FOLFIRI alone (Table 2), but it also resulted in a higher incidence of grade 3 or 4 diarrhea (15.2% versus 10.5%, respectively) and skin reactions (18.7% versus 0.2%, respectively) [19]. OS data are not yet available for that trial.

Preliminary results from the phase III Cancer and Leukemia Group B (CALGB) 80203 trial—which closed because of the demand for biologic therapy in addition to chemotherapy after 238 of 2,200 planned patients were enrolled—showed a higher ORR for FOLFOX and FOLFIRI plus cetuximab than for chemotherapy alone (52% versus 38%; p = .029). In general, the incidence of grade 3 or 4 events was comparable between the study arms [20]. Although preliminary, these data support the further investigation of cetuximab in combination with chemotherapy as first-line treatment for mCRC. Following on from the CALGB 80203 trial, the Southwest Oncology Group (SWOG) and CALGB 80405 trial opened in November 2005 and will assess first-line chemotherapy using the physician's choice of FOLFOX or FOLFIRI, with the addition of bevacizumab, cetuximab, or both, in approximately 2,300 patients with mCRC [21] (Fig. 1). It is hoped that this study will finally confirm whether optimal chemotherapy plus a biologic agent is indeed the new standard of care for the first-line treatment of mCRC. Patient accrual for this study is now >50% complete, and no new safety signal has emerged, compared with the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial [22]. However, since recruitment began, the enrollment criteria have been amended, and only patients with wild type KRAS are now being enrolled based on an analysis of the EGFR antibody studies that are described below.


Figure 1
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  		Figure 1. The Southwest Oncology Group and Cancer and Leukemia Group B trial 80405 study design.

Abbreviations: FOLFIRI, irinotecan combined with bolus and continuous infusion 5-fluorouracil plus leucovorin; FOLFOX, oxaliplatin combined with bolus and continuous infusion 5-fluorouracil plus leucovorin.

 
Potentially providing a preview of the results of the CALGB/SWOG 80405 study, the randomized phase III PACCE study was designed to assess bevacizumab with or without panitumumab (a fully human anti-EGFR monoclonal antibody) in combination with the physician's choice of oxaliplatin- or irinotecan-based chemotherapy. The primary endpoint was PFS by central review in the oxaliplatin-based chemotherapy cohort. The study completed accrual of approximately 1,000 patients; however, panitumumab therapy was discontinued following a review of the data after the first 231 PFS events. Analysis of the data for the oxaliplatin-based chemotherapy cohort (data cutoff, October 2006) showed median PFS durations of 8.8 months among patients receiving chemotherapy plus bevacizumab with panitumumab and 10.5 months among patients receiving chemotherapy plus bevacizumab alone (hazard ratio [HR], 1.44; p = .004). OS events were most common in the bevacizumab–panitumumab arm (20% versus 14%; HR, 1.56). Additional toxicity was also observed in the bevacizumab–panitumumab arm, with grade 4 events in 28% and 18% of patients, grade 5 events in 4% and 3% of patients, and any serious event in 56% and 37% of patients, respectively. These results suggest a lack of synergy, and possibly even antagonism, between bevacizumab and panitumumab and that the toxicity of the individual agents may be increased in combination [23]. Whether this negative result is specific to panitumumab or applies to cetuximab plus bevacizumab as well will be answered by the CALGB/SWOG trial detailed earlier.


   CHEMOTHERAPY PLUS BIOLOGICS: SECOND-LINE THERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 Chemotherapy plus Biologics:...
 Chemotherapy plus Biologics:...
Improving the Tolerability of...
 Surgical Resection and mCRC
 Conclusions
 Author Contributions
 References
 
Bevacizumab, cetuximab, and the human anti-EGFR monoclonal antibody panitumumab have all received FDA approval for use in patients with mCRC who have failed first-line chemotherapy. Research is ongoing to extend the use of these biologics as second-line therapy in combination with various chemotherapy backbones, as well as to discover novel active agents.

The phase III EPIC trial compared cetuximab plus irinotecan with irinotecan alone in a total of 1,298 patients with previously treated EGFR-expressing mCRC. No significant difference was observed between the two treatment arms in terms of OS, the primary endpoint (p = .712) (Table 3). It is possible that crossover therapy may have obscured potential differences in efficacy, however, because 42% of the patients who were randomized to irinotecan monotherapy subsequently received cetuximab in combination with irinotecan. The secondary endpoints of PFS (p < .0001) and ORR (p < .0001) were significantly greater [24] and health-related QoL was better preserved in the combination therapy arm [25].


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  		Table 3. Efficacy results for selected studies of second-line chemotherapy plus biologic agents in patients with metastatic CRC

 
Data from the phase II BOND-2 study indicate that, in patients with CRC that has progressed on or within 3 months of irinotecan-based chemotherapy, adding bevacizumab and cetuximab to chemotherapy may be superior to switching treatment to bevacizumab and cetuximab alone (Table 3). In total, 76 patients were randomized to either a 400-mg/m2 cetuximab loading dose then cetuximab at 250 mg/m2 weekly plus bevacizumab at 5 mg/kg every 2 weeks, in addition to irinotecan at the same dose and schedule as used in the first-line setting, or the same biologic regimen without chemotherapy. Both response rates and the median TTP were higher with than without chemotherapy. The randomized phase II BOND study had previously shown that cetuximab–irinotecan resulted in a significantly greater ORR (p = .007) and PFS time (p < .001) than with cetuximab monotherapy; however, there was no significant difference for OS (Table 3) [26].

Although cetuximab has been proven to be effective in irinotecan-resistant mCRC expressing the EGFR by immunochemistry [26], the mechanisms underlying the clinical response remained unclear until recently. Cetuximab has now been found to bind to the EGFR with high specificity, blocking ligand-induced phosphorylation of the receptor, and hence preventing the activation of intracellular effectors involved in intracellular signaling pathways, such as the G protein K-Ras. KRAS gene mutations have subsequently been studied and an activating KRAS mutation was significantly associated with resistance to cetuximab and a shorter OS duration. Those patients without KRAS mutations had a higher disease control rate than those patients with mutations (76% versus 31%) [27]. A retrospective, larger, multicenter study found KRAS status to be an independent prognostic factor associated with OS and PFS, confirming the high prognostic value of such mutations in response to cetuximab and survival in patients with mCRC treated with cetuximab [28].

One of the major controversies in the treatment of mCRC is the continued use of bevacizumab after progression on first-line chemotherapy. The first-line Bevacizumab Regimens: Investigation of Treatment Effects (BRiTE) registry was initiated in 2004 to examine the safety and efficacy of first-line bevacizumab in patients with mCRC undergoing treatment in the community setting. Data were evaluated for 1,445 patients who had primary progressive disease and revealed markedly longer survival after primary progression among patients who received bevacizumab, compared with those who received therapy without bevacizumab or no further treatment (31.8, 19.9, and 12.6 months, respectively). In a multivariate analysis including pre- and post-treatment variables, postprogression bevacizumab was associated with a significantly longer survival time (p < .001) [29]. Because of the substantial potential for selection bias in this analysis, this phenomenon is the subject of further investigation in the Irinotecan Bevacizumab Continuation Trial (iBET) trial (SWOG 0600), in which patients who have progressed after treatment with an oxaliplatin plus bevacizumab regimen are randomized to irinotecan plus cetuximab with or without bevacizumab [29]. It is our opinion that the BRiTE registry data, while provocative, do not warrant the routine use of postprogression bevacizumab because of the nonrandomized and retrospective nature of these data.

Panitumumab is indicated for the treatment of EGFR-expressing mCRC with disease progression on or following fluoropyrimidine-, oxaliplatin-, or irinotecan-containing chemotherapy. Approval was on the basis of a randomized phase III study of panitumumab versus best supportive care in 463 patients with ≥1% of tumor cell membranes staining positive for EGFR and chemotherapy-refractory mCRC. The median PFS time was 8 weeks for patients who received panitumumab, compared with 7.3 weeks for patients who received best supportive care (p < .0001) [30]. In addition, an objective response was observed in 10% of patients receiving panitumumab but in no patients receiving best supportive care (p < .0001).


   IMPROVING THE TOLERABILITY OF CHEMOTHERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 Chemotherapy plus Biologics:...
 Chemotherapy plus Biologics:...
 Improving the Tolerability of...
Surgical Resection and mCRC
 Conclusions
 Author Contributions
 References
 
Intermittent Chemotherapy Dosing
Intermittent chemotherapy may be a feasible strategy to help reduce the burden of chemotherapy in terms of inconvenience and toxicity, with the potential to improve efficacy by allowing patients to remain on treatment for longer. Several intermittent dosing schedules have been investigated as a means to reduce oxaliplatin-associated neurotoxicity, with oxaliplatin discontinued either at a predetermined "time to best response" or at the development of neurotoxicity. Before oxaliplatin reintroduction, therapy may be continued without oxaliplatin or a complete chemotherapy-free interval may be observed.

The OPTIMOX1 study compared FOLFOX4 administered every 2 weeks until disease progression with a "stop and go" regimen comprising dose-intense oxaliplatin, LV, and 5-FU infusion (FOLFOX7) for six cycles, followed by maintenance without oxaliplatin for 12 cycles and then reintroduction of FOLFOX7 [31]. Stopping oxaliplatin after six cycles achieved the same efficacy results as continuing oxaliplatin until progression or toxicity. In the subsequent OPTIMOX2 study, patients were randomized to either the same treatment as in the "stop and go" arm of OPTIMOX1 or a similar regimen that included a complete chemotherapy-free window until FOLFOX7 was reintroduced at the time of progression (compared against the original baseline tumor measurements). This design element of the study was particularly controversial. Bevacizumab became commercially available during the study, and hence accrual was stopped early (after 202 of the planned 600 patients had been enrolled). The median PFS time (p = .04), OS time (p = .05), and ORR were greater among patients receiving maintenance therapy (Table 4). The survival difference between the two groups was particularly prominent among the subgroup of patients with a poor prognosis [32]. A complete chemotherapy-free window was considered to be feasible only in selected patients without poor prognostic factors [32]. Having established the feasibility of intermittent oxaliplatin-based chemotherapy with maintenance therapy, and the benefits in terms of less cumulative toxicity and equivalent efficacy, the OPTIMOX3 study (Dual Biologics to Increase Duration of Response with Erlotinib and Avastin Maintenance, DREAM) will evaluate the use of targeted therapy with bevacizumab and erlotinib during the maintenance phase.


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  		Table 4. Summary of efficacy results from studies of intermittent chemotherapy dosing

 
The phase IV Combined Oxaliplatin Neurotoxicity Prevention Trial was initiated to evaluate an intermittent regimen of FOLFOX plus bevacizumab in patients with previously untreated mCRC as well as the potential neuromodulatory effect of Ca2+/Mg2+ infusions [33]. An unplanned interim review of data for 174 patients by an independent data-monitoring committee showed a significantly lower response rate among patients receiving Ca2+/Mg2+ than among patients in the control group and the study was subsequently closed. However, following an independent radiologic review of imaging scans, performed to definitively evaluate the effect of Ca2+/Mg2+ on the activity of the study treatment, response rates for the combined treatment arms with Ca2+/Mg2+ and placebo were found to be 39% and 34%, respectively [34]. Thus, no apparent detrimental effect was observed with Ca2+/Mg2+ on the activity of FOLFOX plus bevacizumab. Additionally, even with curtailed enrolment, the primary endpoint of a longer time to treatment failure was actually achieved [35].

Intermittent irinotecan dosing has also been investigated with the objective of reducing irinotecan-associated toxicity. In total, 331 patients with previously untreated mCRC were randomized to continuous treatment with FOLFIRI for 6 months or intermittent treatment with FOLFIRI for 2 months followed by 2 months without treatment and then FOLFIRI for an additional 2 months. No significant differences were observed between the two groups in terms of efficacy (Table 4) or grade 3 or 4 adverse events [36]. The results of ongoing studies of intermittent chemotherapy plus biologics will provide further information on the role of this strategy.

Is Less More? Use of Single Agents Followed by Second-Line Combinations
While much of the preceding discussion is focused on combination therapy, two recently reported phase III studies—the Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer (CAIRO) trial and the Medical Research Council Fluorouracil, Oxaliplatin, and CPT11 [irinotecan]-Use and Sequencing (FOCUS) trial—suggest that sequential chemotherapy, rather than the upfront use of combination therapy, may be an effective alternative treatment option for some patients with mCRC. In the CAIRO trial, 820 patients were randomized to receive either sequential treatment with first-line capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin or combination treatment with first-line capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin. The median OS time—the primary endpoint—was not statistically different between the two treatment arms: 17.4 months for the combination treatment and 16.3 months for the sequential treatment (HR, 0.92; p = .3281). Toxicity was also comparable for the two regimens, although grade 3 hand–foot syndrome was more common with sequential therapy (13% versus 7%; p = .004) [37]. In the FOCUS study, 2,135 patients with untreated mCRC were randomized to receive one of three treatment regimens: first-line single-agent 5-FU administered with L-leucovorin (levofolinate) and second-line single-agent irinotecan (control group); first-line single-agent 5-FU and second-line combination therapy with 5-FU plus either irinotecan or oxaliplatin; or first-line combination chemotherapy with 5-FU plus either irinotecan or oxaliplatin. After a median follow-up of 26.5 months, all strategies achieved a longer OS time than the control regimen (13.9 months), although only the comparison for first-line combination therapy with 5-FU and irinotecan reached statistical significance (16.7 months; p = .01). First-line single-agent 5-FU followed by second-line combination therapy was not inferior to first-line combination therapy (HR, 1.06) [38].

As already discussed, previous studies have demonstrated that first-line combination therapy is superior to single-agent therapy [2–6], and the standard therapy for mCRC uses upfront oxaliplatin- or irinotecan-based combinations. Although the results of the CAIRO and FOCUS studies would appear to challenge this paradigm, there are issues with both that would prevent us from recommending a switch back to the use of upfront single-agent fluoropyrimidines for most patients. First, both studies actually showed a small benefit for upfront combination therapy, although the difference was not statistically significant. Second, the median OS durations for all treatment arms in both the CAIRO and FOCUS trials are poor compared with other recent randomized studies.


   SURGICAL RESECTION AND MCRC
Top
 Learning Objectives
 Abstract
 Introduction
 Chemotherapy plus Biologics:...
 Chemotherapy plus Biologics:...
 Improving the Tolerability of...
 Surgical Resection and mCRC
Conclusions
 Author Contributions
 References
 
In patients with potentially resectable liver-only metastases from CRC, a benefit has been reported for perioperative chemotherapy with FOLFOX4 compared with surgery alone. After a median follow-up of 3.9 years, data from the phase III European Organisation for Research and Treatment of Cancer 40983 study showed that perioperative FOLFOX4—comprising six cycles of FOLFOX4 both before and after surgery—resulted in a significantly longer PFS time than with surgery alone (HR, 0.73; p = .025, among patients who underwent surgery). Importantly, chemotherapy did not appear to reduce the likelihood of patients undergoing surgery [39].

An important subgroup of patients with mCRC have disease that is confined to the liver and that is not surgically resectable. This group is substantially larger than the subset of patients with initially resectable metastatic disease. One potentially important benefit of employing aggressive combination therapy upfront is the potential for secondary resection of liver metastases. Increasing evidence suggests that combination therapy regimens may increase the potential for long-term survival in patients with unresectable liver metastases by enabling high rates of secondary resection [31, 40–46]. FOLFOXIRI—a triplet regimen combining upfront oxaliplatin, irinotecan, 5-FU, and LV—was recently demonstrated to have promising efficacy in terms of the secondary resection rate and survival in patients with unresectable, previously untreated mCRC [46, 47]. Encouragingly, it was recently shown that patients with tumors refractory to first-line therapy may also become candidates for resection following treatment with cetuximab and irinotecan [48]; this observation extends the possibility of long-term survival to patients for whom this would have been considered impossible several years ago.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Chemotherapy plus Biologics:...
 Chemotherapy plus Biologics:...
 Improving the Tolerability of...
 Surgical Resection and mCRC
 Conclusions
Author Contributions
 References
 
Building on the therapeutic advances made with combination chemotherapy regimens, in particular FOLFOX and FOLFIRI, considerable research is ongoing to further optimize chemotherapy for patients with mCRC. Although phase III results are still awaited, the addition of bevacizumab to optimal first-line chemotherapy promises to improve the current survival outcomes by several months. Ongoing studies will help to better characterize the role of EGFR antibodies in the first-line setting as well. In addition to improving efficacy and prolonging survival with biologic agents, studies are ongoing to improve the safety and tolerability of established regimens and to ensure that patients can gain the full benefits of combination chemotherapy. Intermittent chemotherapy, with or without the use of biologic agents during a chemotherapy-free interval, is an interesting strategy currently under investigation in this setting. Regardless, new agents are desperately needed to continue the significant progress that has been made in this decade.

Lastly, research is ongoing to identify predictive markers of response and outcome, particularly for new biologic agents, and prospective clinical trials are required to validate these markers. The field of pharmacogenomics is widely heralded to represent the start of a new era in cancer care; it will be some time, however, before the benefits of this technology have a widespread impact on clinical practice. In the meantime, treatment decisions must be made on the basis of clinical trial data and under the guidance of current guidelines, balancing the clinical—as opposed to genetic—risks and benefits of treatment for each patient in order to customize therapy.

This review captures only a fraction of the immense research effort that continues to seek more effective, better tolerated, and more convenient treatment options for patients with mCRC. We can look forward to further evolution of drug therapy and further progress in CRC management as new data unfold.


   AUTHOR CONTRIBUTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Chemotherapy plus Biologics:...
 Chemotherapy plus Biologics:...
 Improving the Tolerability of...
 Surgical Resection and mCRC
 Conclusions
 Author Contributions
References
 
Conception/Design: Bert H. O'Neil, Richard M. Goldberg

Manuscript writing: Bert H. O'Neil, Richard M. Goldberg

Final approval of manuscript: Bert H. O'Neil, Richard M. Goldberg

The authors take full responsibility for the content of the paper but thank Samantha Richer, Ph.D., from Adelphi Communications, supported by Sanofi-Aventis, US, for her assistance in preparing the initial draft of the manuscript and collating the comments of authors.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Chemotherapy plus Biologics:...
 Chemotherapy plus Biologics:...
 Improving the Tolerability of...
 Surgical Resection and mCRC
 Conclusions
 Author Contributions
 References
 

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