Colorectal cancer (CRC) is the third most common cancer worldwide, and the fourth most common cause of death from cancer.1,2 It is estimated that in 2009, 146,970 men and women will have been diagnosed with cancer of the colon and rectum in the United States, and that 49,920 will have died from the disease.3 From 2002 to 2006 the median age of diagnosis was 71 years.3
Stage at diagnosis is the most important determinant of 5-year survival. Data from 2002 show that 39% of patients with CRC were diagnosed at the localized stage (tumor, node, metastasis [TNM] stage I and II), 37% were diagnosed as “regional disease” or involving lymph nodes (TNM stage III), and 19% were diagnosed with metastatic disease (TNM stage IV), leaving 5% unstaged at diagnosis.3 The 5-year survival rates were 90.8% for localized disease, 69.5% for regional disease, and 11.3% for metastatic disease, and 38.4% for unstaged disease.3
The treatment options for metastatic CRC (mCRC) have greatly increased in the past decade, and the therapeutic efficacy of multiple-drug regimens has improved. This, in turn, has made treatment choices for first, second, and subsequent lines of therapy a complex decision. Further, issues not yet fully elucidated remain at the crux of this complexity. This review will focus on the treatment of metastatic/advanced disease and these issues.
Irinotecan or oxaliplatin: Is there a best first-line choice?
Most patients will receive some combination of oxaliplatin or irinotecan plus fluorouracil in the first line. Oxaliplatin plus infusional fluorouracil (as in leucovorin/fluorouracil/oxaliplatin [FOLFOX] 4) has been shown to be superior to irinotecan plus bolus fluorouracil (IFL) and is equivalent to irinotecan plus infusional fluorouracil (as in leucovorin/ fluorouracil/irinotecan [FOLFIRI]).4,5 Further, FOLFOX6, which, for practical reasons, has largely taken the place of FOLFOX4, was studied as first-line therapy followed by FOLFIRI versus FOLFIRI followed by FOLFOX6.6 This study revealed no significant differences in overall survival (OS; 21.5 vs 20.6 months), initial response rates (54% vs 56%), or progression-free survival (PFS; 8 vs 8.5 months) when either an oxaliplatin- based or an irinotecan-based regimen was used as first-line therapy. The question of whether there is a better first-line regimen, it seemed, could be put to rest. With the approval of bevacizumab and its rise to the standard of care in first-line treatment, this question has again resurfaced.
Bevacizumab was first studied in combination with bolus fluorouracil/ leucovorin and with IFL, and was shown to improve OS in combination with IFL compared with IFL alone by just more than 3 months (18.3 vs 15.1 months).7 This study resulted in the approval of bevacizumab in the United States in March 2004. At the time of approval, IFL was beginning to lose favor, largely due to higher toxicities and less efficacy when compared with infusional fluorouracil regimens (ie, FOLFOX6 or FOLFIRI). The question then became: Would bevacizumab add efficacy to these other, more common first-line regimens?
In a small phase 2 study with oxaliplatin- based therapy, bevacizumab did appear to improve OS when added to FOLFOX4; however, that comparison was to historical controls.8 A secondline, phase 3 trial was published in 2007, which showed that bevacizumab combined with FOLFOX4 improved survival over FOLFOX4 alone.9 Patients in this trial had to have progressed on irinotecan and could not have received bevacizumab as first-line therapy. However, validation in phase 3 studies of bevacizumab’s ability to improve survival in combination with either FOLFOX6 or FOLFIRI in the first line did not come until almost 4 years after its initial approval.10,11
In one trial, bevacizumab or placebo was combined with three different oxaliplatin- based regimens (one using bolus fluorouracil, one with infusional fluorouracil, and one with capecitabine).10 The results were contrary to the earlier phase 2 trials. Bevacizumab had no significant impact on OS or PFS. Critics will cite that the stopping rules of the trial may have resulted in undue bias, because only 29% of patients were taken off therapy because of disease progression. The remaining patients had their therapy discontinued because of toxicity (largely oxaliplatin-induced neurotoxicity). It should also be noted, however, that response rates measured at 3 months (when most patients were still on therapy) were also not significantly impacted by the addition of bevacizumab (49% vs 47%). Another issue that may have contributed to these results is the dose of bevacizumab. In the secondline trial previously mentioned, the dose of bevacizumab was 10 mg/kg combined with FOLFOX4. This is double the conventional 5-mg/kg dose used in CRC regimens and in the first-line trial. The question of whether bevacizumab in combination with oxaliplatin-based therapy in the first line adds any benefit or only significant cost is an ongoing debate, given the results of this phase 3 trial. To date, however, the only positive phase 3 data to support this combination is with bevacizumab dosed at 10 mg/kg in patients who have failed irinotecan and who are bevacizumab-naïve.
In contrast, another phase 3 trial evaluated the addition of bevacizumab to irinotecan-containing regimens. The trial was initially designed to compare three different irinotecan-containing regimens: IFL versus FOLFIRI versus capecitabine/irinotecan (CAPIRI). However, during the accrual period (February 2003 to December 2004) bevacizumab gained approval. The CAPIRI arm was discontinued, and a second study period was initiated in which bevacizumab was added to the IFL and the FOLFIRI arms. The results showed that patients treated with bevacizumab plus FOLFIRI had greater OS and PFS (28 and 11.2 months) when compared with patients treated with FOLFIRI alone (23.1 and 7.6 months).11-13 Further, the investigators concluded that bevacizumab plus FOLFIRI was superior to bevacizumab plus IFL.11 It should be noted that the former comparison cannot be statistically validated because of the different accrual periods. However, given the current data from phase 3 trials, bevacizumab, when added to irinotecan-containing regimens in the first line, does seem to provide a consistent benefit in both prolonged PFS and OS.
Should bevacizumab be continued after progression?
Since bevacizumab’s approval, it has become standard to add it to first-line therapy in mCRC. The question that has yet to be answered is whether there is any benefit in continuing bevacizumab after a patient has progressed on it within the first-line regimen. It has been theorized that not only does bevacizumab, as a vascular endothelial growth factor inhibitor, impair a tumor’s ability to secure a blood supply via antiangiogenesis, but that it also stabilizes the existing vasculature by inhibiting formation of collateral vessels that are too small to deliver cytotoxics to the tumor bed. Should this be the case, it would make sense to change cytotoxic regimens, but to continue the bevacizumab to add synergy via continued enhancement of drug delivery. However, this theorized benefit has yet to be tested in a randomized controlled trial. In an observational study, Grothey and colleagues compared one cohort in which patients received bevacizumab beyond first progression with two matched cohorts, one in which the patients were treated beyond progression without bevacizumab and another in which patients were not treated after progression.13 The results seem to indicate that there is, indeed, benefit to continuing bevacizumab into secondline treatment. When compared with the cohort treated beyond progression without bevacizumab, the cohort that received bevacizumab beyond progression had a longer OS (31.8 vs 19.9 months) and longer beyond-first-progression survival (19.2 vs 9.5 months).It should be noted, however, that this was an observational study. There is concern regarding selection bias, specifically which patients were prescribed bevacizumab in the second line versus which were not. The bevacizumabbeyond- first-progression group not only had a higher percentage of patients with better performance status (reported as Eastern Cooperative Oncology Group 0), but also 45% of the group were not receiving bevacizumab at the time of first progression.13 In addition, progression was assessed by the treating physician with no control over the measure used (ie, response evaluation criteria in solid tumors vs other clinical evaluation) to standardize what progression actually meant.13 In other words, we cannot conclude from this study that the patients in the bevacizumab-beyondfirst- progression cohort actually progressed by RECIST definition on bevacizumab in the first line. Therefore, until a randomized controlled study can answer this question, there are no data to support continued bevacizumab use after progression on bevacizumab in mCRC.
Can patients with mCRC take a break from treatment?
Although there has been great improvement in OS for patients with metastatic disease, the thought of being treated with some form of intravenous chemotherapy every 2 weeks for the rest of one’s life can be daunting. So, the question of breaks from therapy has been an interesting one, keeping in mind that the goal for these patients is palliative care. Three studies have attempted to answer this question. Labianca and colleagues looked at a stop-and-go version of FOLFIRI in which previously untreated patients received either FOLFIRI in a stop-and-go pattern involving 2-month rotations of “on therapy” followed by “chemotherapy-free intervals” (arm A, n = 163) or continuously until progression (arm B, n = 168). OS benefit was comparable in arm A and arm B (16.9 vs 17.6 months).14 Two other studies employed the same idea using FOLFOX. In the OPTIMOX1 study, patients received either FOLFOX until tumor progression (arm A, n = 309) or FOLFOX with a higher dose of oxaliplatin (FOLFOX7) for 3 months followed by 6 months of fluorouracil/leucovorin only. FOLFOX7 was then restarted at 6 months or at progression, whichever came first (arm B, n = 303).15 In OPTIMOX2, FOLFOX was given either as in arm B of the OPTIMOX1 study with a “maintenance phase” of only leucovorin/fluorouracil (n = 100) or with a chemotherapy-free interval (n = 102).16 In evaluating the latter two trials, it appears that a maintenance phase of leucovorin/fluorouracil did not impact the OS benefit of oxaliplatin- based therapy in the first line (19.3 months for FOLFOX4 vs 21.2 months for FOLFOX7 with maintenance phase).15 In the second trial, however, the investigators used an end point called duration of disease control (DDC), which is the first PFS (time to progression back to baseline tumor size) plus the second PFS (time to progression after reinitiating FOLFOX7).16 In this trial, DDC was better with a maintenance approach rather than a chemotherapy-free interval (12.9 vs 11.7 months, P = .41), as was PFS (8.7 vs 6.9 months, P = .009).
From these trials, and with the goal of palliation in mind, it is feasible to propose a break in treatment to patients who have achieved a response to first-line therapy. Further, it seems that this break may favor more of a maintenance approach with infusional fluorouracil than a complete chemotherapy-free interval. However, a patient’s clinical symptoms, toxicities to chemotherapy, and quality of life play a major role in determining how and when this break should be executed.
EGFR inhibition: When, how, and with what other agents
With two inhibitors of the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, on the market and given the cost of these therapies, EGFR inhibition is an important topic to discuss in mCRC. It is well documented that both of these agents have no benefit in patients with a mutated KRAS gene.17,18 The mutated gene encodes for a “gain-in-function” for the KRAS protein, which is downstream from the EGFR signal transduction pathway. With the commercial availability of KRAS testing, it has become the standard of care to test for the mutation before initiating therapy with EGFR inhibitors to spare those who would not respond to therapy the toxicities and expense of these agents.
Both EGFR inhibitors are currently indicated after failure of oxaliplatinand irinotecan-containing regimens. Panitumumab is currently labeled only for monotherapy by the US Food and Drug Administration and cetuximab’s labeling is for either monotherapy or in combination with irinotecan only. How - ever, both these agents are currently being studied in combination with more agents, and both have been studied with bevacizumab. Studies looking at combination cytotoxics in patients with nonmutated KRAS have had encouraging results, although studies indicate that EGFR inhibition with bevacizumab may have a negative impact.19-21
Panitumumab has been studied in a phase 3 trial in combination with FOLFIRI in patients who had progressed on oxaliplatin and/or bevacizumab.22 This trial reported an in crease of 2 months for both PFS and OS when panitumumab was added to FOLFIRI; however, the increase in OS was not statistically significant. Panitumumb has also been studied in the first line with FOLFOX therapy. Although OS in the panitumumab arm had not yet been reached at 20.3 months, panitumumab did increase PFS in patients without the KRAS mutation by 1.5 months compared with FOLFOX alone.23
Cetuximab has been studied in the first line with both FOLFIRI and with oxaliplatin combined with either fluor ouracil or capecitabine. In patients with out the KRAS mutation, OS was increased from 21 months with FOLFIRI alone to 24.9 months with the addition of cetuximab (P = .022).24,25 In contrast, cetuximab, when combined with oxaliplatin-based therapy, failed to show significant survival benefit in the first line in patients with nonmutated KRAS (17 months with cetuximab vs 17.9 months without cetuximab, P = ns).26
Both agents have utility beyond firstline therapy and may have benefit in the first line, although the gold standard first-line biologic remains bevacizumab. Currently, neither of the EGFR inhibitors should be used in combination with bevacizumab or in patients with the KRAS mutation. Further, cetuximab in combination with oxaliplatin-containing regimens appears to have no impact on OS.
Management of the patient with mCRC is complex, with many cytotoxic regimens to choose from. We can draw from multiple phase 3 studies regarding choice of therapy, but with data being constantly generated, it seems that “standard of care” is a moving target. Healthcare providers need to balance efficacy data with toxicity management and with cost. All members of the multidisciplinary team can use the data presented to raise these questions in an attempt to get patients the most effective treatments in terms of clinical efficacy, toxicity, and cost.
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26. Maughan T, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based combination chemotherapy (CT) in patients with KRAS wild-type advanced colorectal cancer (ACRC): a randomised superiority trial (MRC COIN). Eur J Cancer. 2009;7(suppl): Abstract 6LBA.