Optimizing Palliative Treatment of Metastatic Colorectal Cancer in the Era of Biologic Therapy

Over the past decade, new cytotoxic and biologic therapies beyond the old standard-of-care, biomodulated fluorouracil (5-FU), have become available for the treatment of metastatic colorectal cancer (mCRC). The introductions of irinotecan (Camptosar), oxaliplatin (Eloxatin), and bevacizumab (Avastin) have prolonged survival, but the optimal use of these new therapies remains to be determined. Issues remain regarding management of toxicities, treatment of elderly patients or those with poor performance status, and the duration of treatment with front-line therapy. This article reviews recent and ongoing studies of newer therapies in an effort to determine the best use of these drugs in the treatment of mCRC. Current data support the front-line use of bevacizumab added to either 5-FU/leucovorin alone or 5-FU/leucovorin in combination with oxaliplatin (FOLFOX/bevacizumab) or irinotecan (FOLFIRI/bevacizumab). If oxaliplatin is used in first-line therapy, oxaliplatin should be discontinued before the development of severe neurotoxicity and be reintroduced or replaced with irinotecan on disease progression. Definitive conclusions on the sequence and duration of front-line therapy and the most effective strategy to ameliorate toxicity await results of ongoing prospective clinical trials.

The past decade has been a dynamic era in the treatment of metastatic colorectal cancer (mCRC). A host of new cytotoxic and biologic therapies have become available, some of which have completely changed our approach to treating mCRC. Still others are being investigated. The agents with the greatest impact in the first-line treatment of mCRC are bevacizumab (Avastin), oxaliplatin (Eloxatin), and irinotecan (Camptosar). In clinical studies, when combined with fluorouracil (5-FU) and leucovorin (LV), these agents have been shown to prolong time to disease progression (FOLFIRI[1]), progression-free survival (bevacizumab,[2] FOLFOX,[3] FUFOX[4]) and overall survival (bevacizumab,[2] FOLFIRI[1]), compared to 5-FU/LV alone. Agents that have been shown to be efficacious in second-line treatment are irinotecan, bevacizumab, cetuximab (Erbitux), and the newly approved drug panitumumab (Vectibix), which has shown promising activity as a single agent in clinical trials.

It is important that oncologists recognize that the optimal use of these new agents-in particular, their sequencing-remains to be determined. Several challenges are associated with using these new therapies, including (1) minimizing toxicity, especially with oxaliplatin-containing regimens, (2) determining the appropriate adjustments in elderly patients and patients with poor performance status, (3) deciding how long to administer front-line chemotherapy, and (4) understanding which is the most meaningful clinical endpoint-particularly with bevacizumab, which has a primarily cytostatic rather than cytotoxic mechanism of action. This article reviews the data that support the current standard of care, addresses these challenges, and, in the absence of conclusive clinical trials, suggests a treatment strategy based on the currently available data.

Current Standard of Care

A number of significant milestones in the past 2 decades have shaped the management of mCRC mainly through the introduction of new, active agents beyond 5-FU in this disease (Table 1). With regard to 5-FU, most clinicians have accepted that a protracted infusion plus biomodulation with LV is the preferred method of administration, especially in combination regimens with oxaliplatin (FOLFOX) and irinotecan (FOLFIRI).[5]

Oxaliplatin- and Irinotecan-Based Regimens

In the first few years of the 21st century, a total of six phase III trials clearly demonstrated that combination regimens using irinotecan or oxaliplatin plus 5-FU/LV (preferentially administered as infusional 5-FU) are superior to 5-FU/LV alone.[1,3,6-8] This superior efficacy manifested itself in increased response rate and prolonged progression-free survival, but did not necessarily translate into a significant improvement in overall survival, presumably due to the confounding effects of crossover therapies and subsequent second- and third-line therapies.

Although the ill-fated-and now obsolete-IFL regimen (weekly bolus 5-FU/LV/irinotecan) claimed the status of standard of care from April 2000 to April 2002, the results of Intergroup trial N9741 clearly showed that FOLFOX4 (bolus/infusional 5-FU/LV plus oxaliplatin) is superior to IFL in terms of toxicity and efficacy.[9] Inevitable imbalances in second-line therapies during this time when irinotecan, but not oxaliplatin, was readily available for patients on study conceivably contributed to the fact that the difference in overall survival was perhaps more pronounced than that expected from progression-free survival and response rate results. However, this does not negate the fact that FOLFOX established itself as superior to IFL.

Since IFL and FOLFOX use different 5-FU/LV backbones, a fairer comparison between optimized oxaliplatin- and irinotecan-based combination regimens can be seen in the trial conducted by Tournigand and colleagues.[10] In this relatively small trial, 220 evaluable patients with advanced colorectal cancer were randomized to either FOLFOX6 or FOLFIRI with a planned crossover option on progression. The key result of this trial was that all pertinent efficacy parameters (response rate, progression-free survival, and overall survival) revealed no appreciable difference between these two arms. These findings were recently confirmed by a slightly larger phase III trial conducted in Italy.[11] Thus, the key criterion in choosing between FOLFOX and FOLFIRI as the most suitable first-line therapy is the difference in expected toxicities associated with each regimen.

Notably, patients who are exposed to each of 5-FU/LV, oxaliplatin, and irinotecan at some time during treatment have the longest reported overall survival in trials evaluating cytotoxic agents. In trial populations where more than 50% of patients have been treated with all three treatments, median overall survival ranges from 17.4 to 21.5 months; in those with 50% or fewer who have been treated with all three agents, median overall survival ranges from 13.9 to 17.5 months.[12,13] In addition, overall survival appears to be influenced more by the percentage of patients treated with all the available drugs at some time in their treatment than by the sequence and combinations that were used.[12]

Furthermore, in multivariate analysis, the availability of all active agents was more important than the use of irinotecan- or oxaliplatin-based doublets as first-line therapy.[13] However, because patients who are treated with first-line chemotherapy doublets ultimately have a greater chance of receiving all three active agents, these data support using combination therapy as a first-line approach.

Capecitabine

The question of whether capecitabine (Xeloda) can serve as an equipotent and more convenient substitute for infusional 5-FU in combination regimens is currently being addressed in phase III trials. As a single agent, capecitabine is reportedly at least as active and better tolerated than bolus 5-FU/LV, except for a higher rate of hand-foot-syndrome.[14,15] The results from a phase III trial that compared capecitabine plus weekly oxaliplatin (CAPOX) with weekly 5-FU/LV/oxaliplatin (FUFOX) in 476 patients with advanced colorectal cancer showed no significant difference in overall response rates (48% and 54%, P = .70) or median overall survival (both ≥ 17.3 months, hazard ratio [HR] = 1.16) but slightly shorter median progression-free survival (7.1 vs 8.0 months, HR = 1.23) with CAPOX.[16] Toxicity was comparable, with the exception of more hand-foot syndrome associated with CAPOX.

The recently presented, Roche-sponsored NO16966 phase III trial did indeed show noninferiority of XELOX to FOLFOX4.[17] The trial was first designed as a direct comparison between XELOX and FOLFOX4 as palliative first-line treatment in advanced colorectal cancer. When bevacizumab was approved as a component of 5-FU-based first-line therapy, the trial was amended to a 2 × 2 design to test XELOX and FOLFOX plus bevacizumab or placebo. Eventually, 1,017 patients were randomized to a XELOX-based arm (XELOX or XELOX plus placebo or XELOX plus bevacizumab), and 1,018 patients received a FOLFOX-based treatment. In a pooled analysis, XELOX-based therapy was not inferior to FOLFOX4 in terms of the primary endpoint of the trial, progression-free survival (XELOX, 8.0 months; FOLFOX4, 8.5 months, HR = 1.04; 95% confidence interval = 0.93-1.16). On the basis of these data, XELOX and FOLFOX4 should be regarded as equally effective first-line combination regimens in this setting.

When compared to capecitabine/oxaliplatin or 5-FU/LV/irinotecan, the combination of capecitabine/irinotecan has led to a higher incidence of severe diarrhea.[7,18] When capecitabine is combined with either irinotecan or oxaliplatin, toxicity is related to the dose of capecitabine. Clearly, in studies conducted in the United States, dose reductions reduce the toxicity and, in the Three Regimens of Eloxatin Evaluation (TREE)-2 study, actually increased overall responses and outcomes. When using a capecitabine-based regimen, close attention must be paid to this issue of optimal dose.

Targeted Agents

•Bevacizumab-In the same year that the N9741 trial was reported, results from another landmark study were published, which evaluated bevacizumab, a humanized antibody to vascular endothelial growth factor (VEGF). This trial compared IFL/bevacizumab, weekly bolus 5-FU/LV/bevacizumab, and IFL/placebo, with treatment continuing until disease progression.[19,20] Compared to IFL/placebo, IFL/bevacizumab resulted in a higher response rate (45% vs 35%, P < .05), prolongation of median progression-free survival by 4.4 months (10.6 vs 6.2 months, P < .001) and median overall survival by 4.7 months (20.3 vs 15.6 months, P < .001).[19] It is important to note that patients who were treated with first-line IFL/placebo could not cross over to second-line bevacizumab; thus, the difference in progression-free survival was translated 1:1 into overall survival.

Once the safety of IFL/bevacizumab had been established in the phase III trial, the FU/LV/bevacizumab arm of the trial was discontinued with 110 patients enrolled. The results in this relatively small patient sample were later published, showing similar overall and progression-free survival for 5-FU/LV/bevacizumab and IFL/placebo with a trend in favor of the bevacizumab-containing arm.[20] The results of adding bevacizumab to 5-FU/LV alone (without irinotecan or oxaliplatin) are important for patients who cannot tolerate or do not wish to be treated with the newer cytotoxic agents. A combined analysis of three randomized trials (N = 500) of bevacizumab added to 5-FU/LV alone showed significantly greater overall survival and progression-free survival (more than 3.3 and 3.2 months), compared with the combined control group of chemotherapy without bevacizumab (5-FU/LV alone, 5-FU/LV/placebo, or IFL/placebo).[2] As the front-line use of IFL is (fortunately) diminishing, the efficacy and safety of bevacizumab had to be assessed in combination with oxaliplatin-containing regimens and with FOLFIRI.

For the TREE studies, two sequential randomized trials compared three oxaliplatin-based regimens with bevacizumab (TREE-2) or without bevacizumab (TREE-1).[21] In each trial, oxaliplatin was paired with either infusional 5-FU/LV (mFOLFOX6, Table 2), bolus 5-FU/LV (bFOL), or capecitabine (XELOX). Results of TREE-1 and TREE-2 were recently presented together at the American Society of Clinical Oncology (ASCO) annual meeting (Table 3). Comparisons across trials indicate that bevacizumab enhances the efficacy of each treatment in terms of response rate, time to progression, and overall survival (Table 2). At a median follow-up of 27 months, overall survival for all bevacizumab-containing regimens combined (TREE-2) was 24.4 months, compared with 18.2 months without bevacizumab (TREE-1). The addition of bevacizumab did not increase the median time to treatment failure, a composite endpoint of efficacy and toxicity.[21] The lack of effect of bevacizumab on this endpoint is conceivably due to the cumulative toxicity associated with oxaliplatin, which typically does not allow patients to remain on therapy for more than 6 months.

Most recently, a large randomized, placebo-controlled phase III trial (NO16966) investigated the addition of bevacizumab to XELOX or FOLFOX. This trial clearly demonstrated that bevacizumab increases progression-free survival when added to an oxaliplatin-based regimen in the first-line therapy of mCRC.[17] The results of this trial and its implications for current clinical practice are discussed further below.

In a design similar to that of the TREE trials, the Bolus, Infusion, or Capecitabine with Camptosar ± Celecoxib (BICC-C) studies investigated the optimal fluoropyrimidine backbone for the addition of irinotecan in first-line treatment of mCRC. When bevacizumab was approved, the trial was amended to eventually compare modified IFL/bevacizumab (n = 60) with FOLFIRI/bevacizumab (n = 57) at a phase II level. These data were most recently presented at the 2007 ASCO Gastrointestinal Cancers Symposium; the median overall survival (not yet reached vs 19.2 months, P = .007) and progression-free survival (11.2 vs 8.3 months, P = .28) were greater with FOLFIRI plus bevacizumab than with bevacizumab plus mIFL.[22] Of note, 1-year survival was markedly higher with FOLFIRI plus bevacizumab than with bevacizumab plus mIFL (87% vs 61%). Response rates were similar (54% and 53%) with the two regimens.

Bevacizumab has also been investigated in the second-line setting combined with oxaliplatin-based regimens. In the Eastern Cooperative Oncology Group (ECOG) E3200 phase III trial of FOLFOX4 plus bevacizumab (10 mg/kg) involving patients in whom irinotecan-based therapy had failed, FOLFOX4/bevacizumab significantly increased median progression-free survival (7.2 vs 4.8 months, P < .0001) and median overall survival (12.9 vs 10.8 months, P < .002) compared to FOLFOX4 alone.[23] This trial included a bevacizumab-only arm, in which progression-free survival was inferior to FOLFOX4 alone (2.7 vs 4.8 months, P < .0001). Based on these data, bevacizumab in combination with intravenous 5-FU-based therapies received US Food and Drug Administration (FDA) approval for use in the second-line setting. These results highlight the benefit of combining bevacizumab with a cytotoxic agent such as conventional chemotherapy or, alternatively, with cetuximab, as discussed below. In contrast, the single-agent activity of bevacizumab in mCRC appears to be marginal at best.

•EGFR Antibodies-The other biologic strategy with proof-of-efficacy in mCRC is to target the extracellular domain of the epidermal growth factor receptor (EGFR) with monoclonal antibodies.[24] The first antibody developed and eventually FDA-approved was cetuximab. The only currently published randomized trial of this agent for mCRC was conducted in the salvage setting of irinotecan-refractory disease. The addition of cetuximab to irinotecan compared to cetuximab alone in irinotecan-refractory patients significantly improved response (22.9% vs 10.8%) and time to progression (4.1 vs 1.5 months).[24] Bevacizumab appears to increase the therapeutic benefit in an irinotecan-refractory population as well. When the combination of bevacizumab/cetuximab/irinotecan was evaluated in the BOND-2 trial and compared to historical controls receiving cetuximab/irinotecan alone in this setting, time to progression and response rate were greater in those receiving bevacizumab.[24,25]

More recently, very promising results have been presented for the monoclonal anti-EGFR antibody panitumumab.[26] Unlike cetuximab, which is a chimeric IgG1 antibody, panitumumab is a fully human monoclonal IgG2 antibody. The pivotal trial was conducted in the third-line setting. Patients with mCRC who had failed oxaliplatin and irinotecan received either panitumumab plus best supportive care or best supportive care alone. Those receiving panitumumab experienced a 46% reduction in tumor progression compared to best supportive care alone (P < .000000001).[26] As of early 2007, only limited data exist on the combination of panitumumab with modern cytotoxic combination regimens such as FOLFIRI. Therefore, panitumumab was approved as a single-agent salvage therapy option in patients with mCRC refractory to 5-FU, irinotecan, and oxaliplatin.

Based on the available clinical data, FOLFIRI, FOLFOX, and XELOX are appropriate chemotherapy backbones in the first-line therapy of mCRC, to which bevacizumab should be added to maximize efficacy. 5-FU/LV plus bevacizumab is an alternative for patients not considered candidates for irinotecan- or oxaliplatin-based combination therapy.

Current Issues

In this review, we have focused on patients who do not have surgical options for their metastatic disease. However, whenever caring for stage IV colon cancer patients, we must reassess patients on a routine basis to determine if surgical or other local approaches could enter into the treatment scheme. If not, we then must bear in mind that with the introduction of new agents, our patients will most likely live for over 2 years. Certain issues are likely to arise during this time, such as managing toxicity, exploring the combination of biologic agents, treating elderly patients or those with poor performance status, identifying the appropriate endpoints, and choosing the optimal duration of first-line therapy.

Strategies to Minimize Oxaliplatin Toxicity

Oxaliplatin is associated with serious cumulative neurotoxicity that may limit long-term use of regimens such as FOLFOX. In the Intergroup N9741 trial comparing FOLFOX6 to IFL, the appearance of grade 3 or greater paresthesias was significantly higher in the FOLFOX group than in the IFL group (18% vs 3%, P < .001).[9] In a separate analysis of oxaliplatin-associated neurotoxicity from Intergroup N9741, 23% of patients discontinued treatment because of paresthesias. Overall, 63% of patients discontinued FOLFOX for reasons other than disease progression, primarily including paresthesia and neutropenia.[27]

This point has gained particular importance in view of the results of the first phase III trial (NO16966) investigating bevacizumab vs placebo added to an oxaliplatin-based first-line regimen (XELOX or FOLFOX4).[17] As one of the key results, XELOX was found not to be inferior to FOLFOX4 in terms of the primary endpoint of the trial (progression-free survival, see above). The addition of bevacizumab to both oxaliplatin arms combined did significantly prolong progression-free survival from 8.0 to 9.4 months, but the hazard ratio of 0.83 (P = .0023) showed a lower benefit than expected from the previous irinotecan- and 5-FU-based trials. In fact, in a subgroup analysis, only patients treated with XELOX enjoyed a significant increase in progression-free survival when bevacizumab was added (7.4 vs 9.3 months, HR = 0.77, P = .0026), but not patients on FOLFOX4 (8.6 vs 9.4 months, HR = 0.89, P = .187).

One explanation for the difference between the bevacizumab effect on XELOX and FOLFOX4 may be found in an apparent imbalance of patients with previous adjuvant chemotherapy between both arms. The overall rather moderate effect of bevacizumab on progression-free survival in both oxaliplatin-containing arms, however, is most likely caused by the fact that patients were likely to stop bevacizumab at the same time that oxaliplatin was discontinued due to cumulative neurotoxicity and other side effects. Thus, the postulated inhibitory effect of bevacizumab on tumor progression could not be fully utilized, since the drug was commonly discontinued before progression. The addition of bevacizumab did not significantly affect the side-effect profiles of XELOX and FOLFOX4, with only a slight increase in grade 3/4 hypertension and no effect on 60-day or overall mortality. The rate of gastrointestinal perforations was 0.6%.

The cumulative toxicity of oxaliplatin in these trials underscores the need to develop treatment strategies that reduce this toxicity and allow patients to remain on therapy longer, particularly in the era of bevacizumab, which significantly prolongs time to tumor progression in combination with chemotherapy. A series of trials, both completed and ongoing, are evaluating strategies to reduce cumulative exposure to oxaliplatin while maintaining efficacy.

•OPTIMOX Trials-Two completed trials, OPTIMOX-1[28] and OPTIMOX-2,[29] assessed an interrupted, or "stop-and-go," strategy of oxaliplatin administration. In OPTIMOX-1 (N = 620), patients were randomized to receive either FOLFOX4 conventionally until progression or treatment-limiting toxicity or FOLFOX7 using an interrupted strategy (Figure 1A).[28] Specifically, patients received FOLFOX4 every 2 weeks continuously or FOLFOX7 every 2 weeks for 6 cycles, then 12 cycles of 5-FU/LV alone, followed by a planned reintroduction of FOLFOX7. This strategy resulted in a lower median cumulative dose of oxaliplatin in the FOLFOX7 arm (780 mg/m²) than in the FOLFOX4 arm (935 mg/m²) before the reintroduction of oxaliplatin. However, the median dose intensity of oxaliplatin was 37% higher in the FOLFOX7 arm. Only 40% of patients on the FOLFOX7 arm received oxaliplatin reintroduction due to various reasons (death or progression and chemotherapy toxicity each accounted for 18% of failures to receive re-introduction).

The incidence of grade 3/4 neurotoxicity was lower with the interrupted strategy (13% vs 18%), but the difference was not significant, possibly because of the high oxaliplatin dose used in the FOLFOX7 regimen (130 mg/m² vs 85 mg/m² in FOLFOX4). Grade 3/4 neutropenia was significantly reduced in the FOLFOX7 arm, likely due to the omission of bolus 5-FU in the FOLFOX7 arm. However, more patients in the FOLFOX7 arm experienced thrombocytopenia, mucositis, nausea, and hand-foot syndrome. The interrupted administration of FOLFOX7 showed similar efficacy to the FOLFOX4 regimen in terms of response rate, progression-free survival, and overall survival. The primary endpoint was time of disease control, which is the sum of progression-free survival with the first FOLFOX administration and progression-free survival with the reintroduction of FOLFOX if partial remission or stable disease was achieved. Median time of disease control was 9.0 months with continuous FOLFOX4 and 10.6 months with interrupted FOLFOX7 (P = .89).

OPTIMOX 2 is a nonrandomized study to assess whether a chemotherapy holiday instead of a 5-FU interval would be a better strategy to reduce oxaliplatin exposure and associated toxicity (Figure 1B). Patients received FOLFOX7 for six cycles, followed by a chemotherapy-free interval until disease progression, at which time FOLFOX7 was reintroduced.[29] Of note, metastases were allowed to progress to baseline levels before FOLFOX7 was reintroduced. Results from this study were compared with those in the FOLFOX7 arm in OPTIMOX-1. Overall survival has not yet been reached; however, progression-free survival was longer with the maintenance protocol than with the chemotherapy holiday (8.7 vs 6.9 months, P = .009). Duration of disease control was similar between the two approaches (12.9 and 11.7 months, P = not statistically significant). Since both treatment arms omitted oxaliplatin after the induction phase of six cycles of FOLFOX7, no significant difference in neurotoxicity was observed.

The chemotherapy holiday may be a less appropriate strategy in patients with a poor prognosis (ie, ECOG performance status [PS] of 2, elevated lactate dehydrogenase (LDH), alkaline phosphatase greater than three times the upper limit of normal, and more than one metastatic site). Patients in this poor-prognosis group had significantly shorter chemotherapy-free intervals than those with a better prognosis (4.6 vs 8.0 months, P = .005). A full understanding of the differences in terms of survival and toxicity with these two approaches will be achieved when more data from the study are available.

Three additional trials, CONcePT, DREAM, and OASIS, were planned or are underway to assess strategies to reduce oxaliplatin toxicity by using bevacizumab and/or erlotinib (Tarceva).

•CONcePT Trial-The Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT), with a planned accrual of 270 patients in its recently revised form, will assess the role of front-line mFOLFOX7/bevacizumab-bevacizumab added to modified FOLFOX7 (Table 2)-and alternating with 5-FU/LV/bevacizumab, thus reducing oxaliplatin exposure within the first 8 months but increasing overall oxaliplatin exposure (Figure 1C).[30] This alternating regimen will be compared with continuous mFOLFOX7/bevacizumab, with a primary endpoint of time to treatment failure. CONcePT will also measure the effect of intravenous calcium and magnesium on the prevention of neurotoxicity. This trial will determine whether bevacizumab added to an alternating oxaliplatin-containing/nonoxaliplatin regimen will decrease toxicity without compromising efficacy. The trial may also show whether the use of an interrupted strategy with oxaliplatin can allow the patient to tolerate a higher cumulative dose of oxaliplatin.

•DREAM Trial-Another ongoing trial, DREAM (Double Reintroduction with Erlotinib and Avastin in Metastatic CRC), which has a planned accrual of 640 patients, will evaluate the role of bevacizumab with or without erlotinib as maintenance treatment in a stop-and-go strategy with oxaliplatin-containing regimens (Figure 1D).[31] Patients will be treated with FOLFOX/bevacizumab or XELOX4/bevacizumab, followed by maintenance bevacizumab, then reintroduction of the initial regimen. In addition, each arm will be treated with either erlotinib or placebo during maintenance bevacizumab treatment. This trial will assess the effect that VEGF inhibition by bevacizumab and EGFR inhibition by erlotinib will have on progression-free survival, overall survival, and time of disease control.

•OASIS Trial-Finally, the Oxaliplatin Avastin Sequence to Investigate Survival (OASIS) trial, with a planned accrual of 800 patients, attempted to evaluate initial therapy with FOLFOX/bevacizumab followed by either FOLFIRI/bevacizumab or 5-FU/LV/bevacizumab. After subsequent disease progression, FOLFOX/bevacizumab or FOLFIRI/bevacizumab was administered (Figure 1E).[32] This trial had the benefit of evaluating exposure of patients to all three active cytotoxic agents as well as to bevacizumab, the two strategies that independently have conferred the longest median survival advantage. In addition to the primary outcome of progression-free survival, this trial was designed to assess the tolerability of sequential treatment and the relative safety of FOLFIRI/bevacizumab and 5-FU/LV/bevacizumab. Unfortunately, the trial was closed in the spring of 2006 because of poor accrual and issues surrounding protocol adherence to the sequential treatment strategy.

Optimizing Biologic Therapies

In response to the positive results of the BOND-2 trial, several other ongoing trials are exploring the use of dual-targeted therapies in combination with chemotherapy to increase efficacy (Figure 3). The Intergroup trial, Cancer and Leukemia Group B (CALGB) C80405, is comparing bevacizumab, cetuximab, or both in combination with FOLFOX or FOLFIRI in the first-line treatment of advanced colorectal cancer (Figure 3A).[33] The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study is investigating the combination of bevacizumab and panitumumab in the first-line setting of mCRC and has recently completed accrual (Figure 3B).[34] In this trial, patients will be treated with bevacizumab plus oxaliplatin-based chemotherapy with or without panitumumab. The DREAM trial, described above (Figure 1D), is evaluating bevacizumab alone or in combination with erlotinib as maintenance therapy after initial treatment with bevacizumab plus XELOX (capecitabine/oxaliplatin) or bevacizumab plus a modified FOLFOX7 regimen.[31] Of note, at this stage, the goal of these studies is to enhance efficacy. Later iterations of these studies will likely be aimed at reducing toxicity, perhaps through sequencing strategies.

It is now rare to find a patient population similar to that treated in the BOND-1 and BOND-2 trials, because almost all patients are now treated with bevacizumab and cetuximab before third-line treatment. However, it is possible that dual targeting of VEGF and EGFR may retain clinical activity even in patients who have been treated with bevacizumab and cetuximab, but not yet in combination. The trial testing this (BOND 2.5) is ongoing and, if positive, will give us great insight into the synergy of these two cancer pathways.

Adjusting Chemotherapy for Age or Performance Status

•Impact of Age-Older patients may be treated less aggressively because of concerns about frailty, comorbidities, quality-of-life issues, and the ability to tolerate toxicity.[35,36] In fact, in some cases, age alone may be the sole factor in determining a treatment plan.[35,37] The frequency with which patients with colorectal cancer receive chemotherapy is related to age, with 45% of patients aged 65 to 69 years receiving chemotherapy but less than 5% of those older than 85 receiving chemotherapy. Since the incidence of colorectal cancer increases with age, clinicians should be aware of how age affects treatment.[35]

The influence of age on the usefulness of 5-FU chemotherapy with or without LV was assessed from a pooled analysis of four trials of the North Central Cancer Treatment Group (N = 1,748).[35] Four different age groups were identified: < 55, 55-65, 66-70, and > 70. Age was not a predictor of efficacy. When controlling for PS, age became a predictor of grade 3/4 diarrhea, stomatitis, and infection.[35]

A separate pooled analysis of four trials evaluating treatment with FOLFOX4 showed that patients aged 70 years or older had the same treatment benefit and similar toxicity rates as younger patients.[38] In the OPTIMOX-1 study, 37 patients over age 75 with good PS were included. Age did not affect response, progression-free survival, or overall survival.[39,40] When compared to those younger than 75 years old, the older patients appeared to have more neutropenia with FOLFOX4 and more grade 3 neurotoxicity with FOLFOX7, although a statistical analysis was not reported.[40] It should be noted that FOLFOX7 provides dose-intense oxaliplatin (130 mg/m² every 2 weeks), which is associated with more acute neuropathies.

In the pivotal trial of IFL/bevacizumab vs IFL/placebo, patients aged 65 or older showed a similar or better response to therapy in terms of overall survival, compared with the overall population. Patients aged 65 or older in the IFL/bevacizumab arm gained a median of 9.3 months in overall survival relative to patients in the IFL-alone arm.[41] This contrasts to a gain of 4.7 months between these treatment arms in the overall study population. Taken together, these data suggest that selected older patients with good PS are very likely to benefit from bevacizumab/chemotherapy combination therapy. However, these data are limited and sometimes conflicting, indicating that further study is warranted to understand the effect of age on efficacy and tolerability of therapy. Of note, bevacizumab-treated patients over age 65 with a history of arterial thrombotic events (ATEs) are at higher risk for a recurrence, although even these patients were shown to experience an overall survival benefit in the pivotal study.[42]

•Impact of Performance Status-Poor PS has been shown to have a negative effect on outcomes, being correlated with shorter survival in patients receiving 5-FU-based therapies, including regimens with oxaliplatin or irinotecan.[43] In the pooled analysis of the North Central Cancer Treatment Group, poor PS was predictive of poor response as measured by time to progression and overall survival. In addition, patients with poor PS had more grade 3/4 adverse events overall.[35]

In the pivotal bevacizumab trial, adding bevacizumab to front-line IFL increased survival in patients with PS ≥ 1 by 2.8 months (14.9 vs 12.1 months), resulting in a hazard ratio of 0.69.[41] The hazard ratio in the overall population was 0.65. In a study of 5-FU/LV/bevacizumab in patients considered poor candidates for irinotecan therapy primarily because of poor PS or age,[44] progression-free survival was significantly greater in the 5-FU/LV/bevacizumab group (9.2 vs 5.5 months, P = .002), and the safety profile was generally similar.

When a subgroup analysis was performed, patients with PS ≥ 1 or age ≥ 65 showed greater median survival in the 5-FU/LV/bevacizumab group than the 5-FU/LV group alone (PS ≥ 1: 15.3 vs 10.4 months; age ≥ 65: 13.7 vs 11.5 months), but the differences were not statistically significant. It is also important to note that a substantial number of patients in this study who were initially not considered optimal candidates for irinotecan in fact did receive irinotecan as second-line therapy. Since the proportion of the patients receiving irinotecan as second-line therapy was lower in the bevacizumab arm (34% vs 43%), this disparity did not account for the greater survival.

These studies suggest that a significant clinical benefit of bevacizumab-containing combination regimens is seen in patients with PS ≥ 1; however, the benefit could be less than that seen in patients with PS 0. The effect of PS on treatment tolerability is not clear and requires further investigation.

Two recently presented studies may give us further insights into the treatment of patients with poor performance status. In both studies, patients were randomized to FOLFOX alone or FOLFOX plus the oral VEGF inhibitor vatalanib (PTK 787). One trial was performed in the first-line setting and the other, second-line. Both studies were unfortunately negative. In preplanned analyses, however, both studies found that patients with high LDH and poor PS actually benefited from the addition of vatalanib. While interpretation of these results is far from resolved, the trials do suggest that there may be a subset of patients who will benefit from treatment with certain agents. Further trials are necessary to confirm these results.

How to Assess Therapeutic Benefit of Front-Line Therapy

Objective response is the most widely used criterion to assess the efficacy of a single drug or regimen. Using conventional chemotherapy with cytotoxic, apoptosis-inducing agents, objective response appears to correlate with time to progression and can be a surrogate marker for survival in certain settings with limited salvage therapy options. However, new regimens call for reevaluation of objective response as a primary clinical endpoint.

First, response may not be the best measure to evaluate agents whose mechanism of action is primarily cytostatic. This is likely the case with bevacizumab. While the absolute increase in tumor response rates with bevacizumab, when added to chemotherapy, is typically in the 10%-to-15% range, this drug is best characterized as a cytostatic agent that prevents tumor growth through a number of mechanisms. Two likely early effects of bevacizumab are normalization of tumor interstitial fluid pressure and blood flow, resulting in increased chemotherapy delivery, better tumor oxygenation, and greater cytotoxicity.[45] However, a likely later effect of bevacizumab is reduction of tumor vascular density, which, by impeding delivery of nutrients and oxygen, results in a cytostatic effect on tumors.[45]

Clinical data from the phase III trial support this theory. The addition of bevacizumab to IFL improved response rates over IFL/placebo (45% vs 35%, P = .004), presumably an acute-phase effect. However, the effect on progression-free survival was more pronounced (median: 10.6 vs 6.2 months, P < .001), presumably a late-phase effect.[19] This disconnect between the magnitude of effect on response vs progression-free survival is apparent in other bevacizumab trials as well, a discrepancy generally not observed in trials of cytotoxic agents alone (Figure 2). These data suggest that objective response is not an adequate marker for the efficacy of bevacizumab and that perhaps patients who are not responding according to Response Evaluation Criteria in Solid Tumors (RECIST criteria) still derive clinical benefit in the form of prolonged progression-free survival.

In the absence of prospective clinical data, a retrospective analysis was conducted to assess this relationship between objective response and clinical outcome in bevacizumab studies.[46] In this analysis, progression-free and overall survival were compared between "responding" and "nonresponding" groups from the pivotal phase III study[19] that compared IFL/bevacizumab and IFL/placebo. Responders were defined as patients with a complete or partial response, and nonresponders were defined as patients with stable disease, progressive disease, or nonevaluable disease. Regardless of whether patients showed a response according to RECIST criteria, patients treated with IFL/bevacizumab received a significant survival benefit compared to IFL/placebo. In nonresponders, the risk of death decreased by 24% and the risk of progression decreased by 37%. In responders, the risk of death decreased by 40% and the risk of progression decreased by 47%. This analysis suggests that the definition of objective response according to RECIST alone may not capture the full clinical benefit of bevacizumab; rather, progression-free and overall survival may be more appropriate criteria for measuring clinical benefit.

While it seems logical from the evidence presented thus far that objective response remains a valid endpoint in trials of cytotoxic chemotherapy, this issue has not yet been well studied in the current era of newer cytotoxic agents that have prolonged survival beyond that with 5-FU/LV alone. We have recently completed an analysis of the N9741 trial[9] that compared the influence of response to FOLFOX4 and IFL on progression-free and overall survival.[47] Patients in the FOLFOX4 arm who were classified as "nonresponders" according to World Health Organization criteria derived significant benefit in terms of progression-free and overall survival. In conjunction with the previous report on the response-independent clinical benefit associated with bevacizumab[46], this observation would suggest that use of objective response to evaluate first-line therapy in mCRC should be reevaluated and used cautiously, whether patients receive cytotoxic chemotherapy with or without bevacizumab.

Duration of Front-Line Chemotherapy

As objective response does not necessarily correlate with progression-free and overall survival, it would appear that a lack of objective response may not be an appropriate criterion for stopping treatment. While treatment failure with cytotoxic agents frequently occurs because of the drug's toxicity, the same has not been true with bevacizumab therapy. In the pivotal phase III trial, the proportion of patients discontinuing treatment because of an adverse event was 7.1% in the IFL/placebo arm and 8.4% in the IFL/bevacizumab arm (P = not statistically significant).[19] Therefore, while cytotoxic agents may be discontinued before disease progression, it seems reasonable to continue bevacizumab until progression regardless of the presence of an objective response. But the question remains as to how long to continue treatment once progression occurs.

With cytotoxic agents, it is well established that switching to an alternative agent (oxaliplatin to irinotecan or the reverse) or adding cetuximab to irinotecan in irinotecan-refractory disease are appropriate choices. However, the role of bevacizumab past progression is unclear. Whether the proposed cytostatic effect of bevacizumab results in clinical benefit past progression of mCRC is being evaluated in a phase III clinical trial (Figure 4). In this trial (the Intergroup Bevacizumab Continuation Trial, S0600/iBET), patients who progress on combination therapy with FOLFOX/bevacizumab (or XELOX/bevacizumab) will be randomized to (FOLF)IRI plus cetuximab or (FOLF)IRI plus cetuximab and 5 or 10 mg/kg of bevacizumab. The primary endpoint of the trial is overall survival.

Treatment Strategies

Before complete data are available from ongoing trials, what is a reasonable treatment approach in patients with mCRC? A number of factors influence the choice of therapy (Figure 5). Choosing the correct drugs and optimal sequence depends on the type and timing of previous therapy, and the toxicity profile of each drug.[48] A choice must be made regarding which drug or combination will produce the best potential benefit in balance with the patient's ability to tolerate therapy. Individual treatment goals for each patient should also be defined that are based on an assessment of potential resectability of metastases after downsizing. Patients who have potentially curable disease after use of a neoadjuvant approach should receive initial treatment focused on generating a high response rate. Patients who are not candidates for a curative approach should preferentially receive treatments that extend progression-free survival.[49]

Outside of clinical trials, a suggested treatment algorithm for patients with unresectable disease should include front-line therapy with FOLFOX/bevacizumab, then discontinuation of oxaliplatin before the appearance of severe neurotoxicity. At that time, either infusional 5-FU/LV or capecitabine plus bevacizumab should be administered until disease progression. Patients who are not considered optimal candidates for oxaliplatin in the first-line setting may benefit from a similar approach that substitutes FOLFIRI for the FOLFOX regimen. At primary progression, FOLFOX can then be reintroduced, or patients could be treated with FOLFIRI if neurotoxicity is a problem. Whether bevacizumab should then be continued remains unknown, but such an approach could be considered in the absence of any bevacizumab-related toxicity.

It must be highlighted, however, that the clinical benefit of continuing bevacizumab after documented tumor progression with bevacizumab-containing therapy is still an open question. Also outstanding is whether anti-EGFR antibodies should be added in the second line. Results of clinical trials that will answer these questions are eagerly awaited.

Conclusions

The treatment of mCRC has evolved substantially over the past decade, resulting in markedly greater survival. Bevacizumab-containing regimens using FOLFOX, FOLFIRI, and 5-FU/LV can be regarded as standard of care in the first-line treatment of advanced colorectal cancer. The greater overall survival achieved with modern systemic therapy and the numerous treatment options available create the challenge of developing optimized treatment strategies that maximize the benefit for each patient.

In this context, key questions remain to be answered: What is the best way to minimize oxaliplatin toxicity? How long should bevacizumab therapy be continued? What is the best measure of clinical efficacy? What are predictive markers that allow better selection of treatment approaches for individual patients? Ongoing studies continue to address these issues and underscore the critical need for patient enrollment in clinical trials so that treatment can be optimized.

Disclosures:

Dr. Grothey has received honoraria for consulting from Amgen, Bristol-Myers Squibb, Pfizer, Genentech, and Roche. Dr. Marshall has received research support and honoraria from Pfizer, Sanofi, Genentech, Roche, Bristol-Myers Squibb, Amgen, and Boehringer Ingelheim.

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