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- Patients and Methods
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The goal of the present study was to compare the efficacy of the combination of cetuximab and irinotecan to the combination of oxaliplatin and fluoropyrimidines as second-line chemotherapy in patients with irinotecan-refractory and oxaliplatin-naïve metastatic colorectal cancer (mCRC) harboring wild-type KRAS. The study included 120 patients with mCRC who had progressed after irinotecan-containing first-line chemotherapy and were never treated with oxaliplatin; 40 patients with wild-type KRAS were accrued prospectively in the experimental arm (arm A), and 80 patients accrued retrospectively were divided into control arms B (n = 46) and C (n = 34) according to KRAS genotype. Second-line treatments consisted of cetuximab plus irinotecan for arm A, and oxaliplatin plus either 5-fluorouracil (FOLFOX) or capecitabine (CapeOX) for the control arms. The median progression-free survival (PFS) was 8.3, 5.8 and 3.9 months, for arms A, B and C, respectively, with statistical significance favoring arm A (P = 0.007). Differences in overall survival did not reach statistical significance (18.3 vs 12.6 vs 12.9, P = 0.138), although there was a trend toward longer overall survival in arm A. In terms of benefit from oxaliplatin-containing regimens either as second-line or third-line therapy, the median PFS was 5.0 months in arms B and C as second-line therapy, and 4.0 months in arm A as third-line therapy, with no statistical significance (P = 0.385). Second-line cetuximab plus irinotecan is a valid treatment strategy for mCRC patients with irinotecan-refractory and oxaliplatin-naïve tumors harboring wild-type KRAS. Oxaliplatin-containing chemotherapy resulted in equivalent PFS both as a second-line and a third-line therapy, enabling delay of the administration of FOLFOX and CapeOX until subsequent treatment cycles.
At present, a limited number of active drugs are available for the treatment of metastatic colorectal cancer (mCRC), and the upfront doublet combination of fluoropyrimidines plus either oxaliplatin or irinotecan is regarded as the reference strategy for patients for whom intensive therapy is appropriate.[1-3] Before the era of targeted agents, treatment strategies in terms of the combination or sequence of cytotoxic agents were rather simple; survival outcomes did not differ according to either the administration sequence of oxaliplatin or irinotecan, and whether sequential or combination chemotherapy was applied in the treatment continuum was inconsequential.[4-7] Treatment strategies have become more complicated in the era of targeted agents.
Bevacizumab plus chemotherapy as initial chemotherapy improved efficacy without significant adverse events and was proven effective as second-line continuation beyond progression;[8-12] however, limited overall survival (OS) benefit was observed when bevacizumab was combined with optimal doublet chemotherapy.
As a first-line treatment, cetuximab has shown OS benefit when combined with irinotecan plus infusional 5-fluorouracil and leucovorin (FOLFIRI), and improved OS even in mCRC patients who failed all standard treatments.[14-16] However, only patients whose tumors harbor wild-type KRAS benefit from cetuximab, and no survival benefit was observed upon combination with oxaliplatin-containing chemotherapy in large, randomized trials conducted recently.[17, 18]
Second-line chemotherapy with oxaliplatin plus fluoropyrimidines is generally accepted as a strategy following first progression with irinotecan-based chemotherapy in mCRC patients; however, the survival benefit from second-line oxaliplatin-based chemotherapy has not been satisfactory. Indeed, the use of cetuximab is appropriate with irinotecan-based chemotherapy, and has an advantage in terms of overcoming irinotecan-refractoriness; cetuximab plus irinotecan in patients who progressed after irinotecan-containing chemotherapy has been proven more effective than cetuximab alone.[19, 20] We recently reported promising efficacy in a prospective phase II study of second-line cetuximab plus irinotecan in mCRC patients whose tumors were irinotecan-refractory, oxaliplatin-naïve and harboring wild-type KRAS. Based on these results, the present study was designed to: (i) compare two different second-line treatment strategies, cetuximab plus irinotecan versus oxaliplatin plus fluoropyrimidines, in patients with irinotecan-refractory mCRC and oxaliplatin-naïve mCRC patients; and (ii) to investigate whether the oxaliplatin plus fluoropyrimidines regimen could be delayed to third-line therapy in the treatment continuum of these patients.
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- Patients and Methods
- Disclosure Statement
Second-line cetuximab plus irinotecan showed longer PFS (8.3 vs 5.8 months, HR 1.41 [0.88–2.26], P = 0.007) than FOLFOX or CapeOX in patients with oxaliplatin-naïve, wild-type KRAS mCRC who progressed after first-line irinotecan plus fluoropyrimidines. There was a trend toward higher ORR (45.0% vs 28.8%) and longer OS (18.3 vs 12.7 months) upon administration of second-line cetuximab plus irinotecan, although without statistical significance. The PFS of FOLFOX and CapeOX were similar whether these regimens were administered as second-line or third-line treatments.
The addition of targeted agents to the doublet combination chemotherapy of fluoropyrimidines with either irinotecan or oxaliplatin is now regarded as standard of care in mCRC. In the first-line setting, the targeted agents can easily be selected: bevacizumab improves efficacy regardless of the cytotoxic agent with which it is combined,[9-11, 13] and cetuximab improves overall efficacy, including OS, when combined with first-line FOLFIRI.[14, 15] Panitumumab plus FOLFOX also improves PFS in these patients. However, the selection of targeted agents is more difficult in second-line therapy.
Cetuximab with or without irinotecan-based chemotherapy is frequently considered in the second-line setting or later in the treatment continuum,[19, 24] and recent studies demonstrate that the addition of aflibercept or panitumumab to second-line FOLFIRI is reasonable in mCRC that has progressed after first-line oxaliplatin plus fluoropyrimidines. On the basis of the present results, patients who have progressed after first-line FOLFOX or CapeOX with or without bevacizumab still have reasonable choices of targeted agents as a second-line treatment.
However, the selection of targeted agents, especially for patients who have progressed after FOLFIRI with or without targeted agents and for patients for whom second-line FOLFOX or CapeOX was planned, is now difficult because cetuximab is no longer recommended in combination with oxaliplatin-based chemotherapy[17, 18] and because aflibercept and panitumumab have been proven effective as a second-line therapy only when combined with FOLFIRI.[25, 26]
The present study involved patients who became refractory to first-line irinotecan plus fluoropyrimidines. Second-line treatment strategies were compared according to KRAS genotype: patients with mutant KRAS followed crossover cytotoxic doublet regimens of FOLFOX or CapeOX, and those with wild-type KRAS followed second-line cetuximab plus irinotecan or FOLFOX or CapeOX regimens. Second-line cetuximab plus irinotecan improved efficacy compared to crossover FOLFOX or CapeOX, even in patients who progressed after irinotecan-based regimens, and the efficacy of third-line FOLFOX or CapeOX was comparable to that of second-line FOLFOX or CapeOX. Furthermore, the efficacy of second-line cetuximab plus irinotecan in the present study (ORR 45.0%, PFS 8.3 months) was very promising compared to that in previous studies involving second-line aflibercept (RR 19.8%, PFS 6.9 months) or panitumumab (RR 35%, PFS 5.9 months).
In the present study, the median OS from the second-line treatments was 18.3 months for arm A, 12.6 months for arm B and 12.9 months for arm C, respectively, and there was a trend favoring arm A without statistical significance (P = 0.138, Fig. 2C,D). The different proportions between arms of patients who could be treated with third-line treatments might act as one of the confounding factors for the longer OS favoring arm A; of note, more patients in arm A (82.5%) entered into the third-line treatments with compared to those in arm B (34.8%). A recent trial of first-line chemotherapy in Korean patients showed that the proportion of patients who could receive subsequent treatments was relatively limited; approximately 60% of patients could enter into second-line treatments, and only around 18% of patients could enter into third-line treatments. The ML18147 study, which studied bevacizumab continuation as second-line chemotherapy, also demonstrated that only 39.8% of patients could receive third-line treatment with either cetuximab or panitumumab, regardless of KRAS status. Therefore, the proportion of patients (34.8%) who could receive third-line treatment with cetuximab-based chemotherapy in arm B is comparable with results reported in previous publications. In fact, the OS from the third-line treatment was 11.7 months for arm A and 6.0 months for arm B, and these differences might contribute to the trend favoring arm A in terms of OS.
Anti-EGFR agents offer survival benefits in patients with wild-type KRAS later in the treatment continuum,[16, 28] and some authors point out that the absolute benefit of OS is not different between first-line and subsequent administrations of cetuximab. Recently, another targeted agent, regorafenib, was approved by US FDA on September 27, 2012 for mCRC patients who have failed all standard treatments. Because regorafenib improved PFS and OS in these heavily-treated patients, earlier administration of cetuximab may be a reasonable strategy in the treatment continuum.
The present study has limitations, including a small patient population and the retrospective design of the control arms, in which patients were treated with FOLFOX or CapeOX, although the experimental arm, in which patients were treated with cetuximab plus irinotecan, was accrued prospectively. In addition, only a few patients could be treated with bevacizumab either as a first-line therapy in the experimental arm or as a second-line therapy in the control arm, representing another limitation of the study in terms of comparison of survival outcome after optimized treatment continuum. Due to cost, only a small number of patients were treated with bevacizumab; bevacizumab (and other targeted agents) is yet to be covered by National Insurance; thus, most mCRC patients cannot afford to include targeted agents in their treatment. Of note, the number of patients in arm B who were treated with anti-EGFR agents as their third-line treatment was rather small; only 34.8% (16/46) of patients received cetuximab-based chemotherapy and this might be the main reason for similar OS between arms B and C.
In conclusion, cetuximab plus irinotecan as second-line chemotherapy could be an alternative treatment option for irinotecan-refractory and oxaliplatin-naïve mCRC with wild-type KRAS. Delayed administration of crossover oxaliplatin-based chemotherapy as a third-line treatment did not impair efficacy. KRAS status should be considered when selecting treatment with targeted agents or when deciding on a sequence of cytotoxic agents.