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Cetuximab plus XELIRI or XELOX for First-Line Therapy of Metastatic Colorectal Cancer
Comprehensive
Review
Cetuximab plus XELIRI or XELOX for First-Line Therapy of Metastatic Colorectal Cancer Nicolas Moosmann, Volker Heinemann Abstract Modern chemotherapy combinations for metastatic colorectal cancer (mCRC) comprise infusional 5-fluorouracil (5-FU), leucovorin, and irinotecan or oxaliplatin. The fluoropyrimidine derivative capecitabine is at least as effective as 5-FU plus leucovorin bolus regimens. It displays a favorable toxicity profile and offers the advantages of oral administration. The epidermal growth factor receptor antibody cetuximab induces synergistic antitumor activity when combined with chemotherapy. In pretreated patients, cetuximab can restore the sensitivity to irinotecan and, therefore, has been registered in this setting. Several phase I/II trials have investigated the combination of cetuximab with irinotecan-based or oxaliplatin-based chemotherapy for the first-line treatment of mCRC. These combinations have been proven to be safe and have provided promising efficacy data. A recent phase III trial confirmed improved progression-free survival, response rates, and a particularly significant increase of secondary resection rates for the combination of FOLFIRI (infusional 5-FU/leucovorin/irinotecan) plus cetuximab compared with FOLFIRI alone. In this review, we discuss the background of combining XELIRI (capecitabine/irinotecan) or XELOX (capecit-abine/oxaliplatin) with cetuximab for the first-line treatment of mCRC and present available data of these combined cytotoxic and targeted treatment approaches. Clinical Colorectal Cancer, Vol. 7, No. 2, 110-117, 2008 Key words: Capecitabine, Epidermal growth factor receptor, Irinotecan, Leucovorin, Oxaliplatin
Introduction Colorectal cancer (CRC) is the third most common malignant disease in the United States, with > 150,000 estimated new cases in 2007.1 Approximately 50% of patients with CRC develop metastases and eventually die from disease. Until recently, chemotherapy was based on 5-fluorouracil (5-FU), inducing response rates of 11%-14% as a single agent. Cytotoxic activity of 5-FU can be improved by bimodulation with leucovorin and infusional application of 5-FU. However, response rates of 21%-23% and overall survival times of approximately 12 months still remain modest.2-4 In the past decade, the median survival times have improved significantly to 16-21 months, mainly because of the introduction of the topoisomerase-I inhibitor irinotecan and the third-generation platinum compound oxaliplatin.5-8 University of Munich, Medical Department III, Klinikum MuenchenGrosshadern, Germany Submitted: Jun 27, 2007; Revised: Dec 7, 2007; Accepted: Dec 7, 2007 Address for correspondence: Nicolas Moosmann, MD, Medizinische Klinik III, Klinikum Muenchen-Grosshadern, Marchioninistrasse 15, D-81377 München, Germany Fax: 49-89-7095-5256; e-mail: [email protected]
Modern chemotherapy regimens combine infusional 5-FU and leucovorin with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX). A further landmark in the cytostatic treatment of CRC was the development of oral fluoropyrimidine derivatives. Capecitabine is a rationally designed prodrug that is converted to 5-FU predominantly in tumor cells because of the high activity of thymidine phosphorylase in tumor tissue. In turn, this catalyzes the last enzymatic step required for capecitabine activation. In 2 randomized phase III trials, capecitabine proved at least equivalent to an intravenous 5-FU/leucovorin bolus regimen in terms of response rate and survival.9,10 In addition, capecitabine displays a favorable toxicity profile. The incidence of diarrhea, stomatitis, nausea, alopecia, neutropenia, and febrile neutropenia is significantly lower compared with the 5-FU/leucovorin bolus protocols. There is a later onset of treatment-related grade 3/4 adverse events leading to fewer patients requiring hospitalization. These advantages give rise to a high patient acceptance of the oral capecitabine treatment. The most frequent side effect of capecitabine is plantar-palmar erythrodysesthesia (PPE). Patients who develop this cutaneous syndrome respond well to dose interruption or reduction and treatment with topical emollients.9,10
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110 • Clinical Colorectal Cancer March 2008
The chimeric epidermal growth facTable 1 Capecitabine plus Oxaliplatin in the First-Line Treatment of Metastatic tor receptor (EGFR) antibody cetuxColorectal Cancer: Results from Phase II Trials imab has clinically significant activity DCR Overall when applied alone or in combination Failure/PFS CR + PR SD (CR+ Survival Study N Treatment (Months) (%) (%) with irinotecan in irinotecan-refracPR + SD) (Months) tory metastatic CRC (mCRC). It was 18 Borner et al 43 XELOX 49 19 68% TTF, 5.9 17.1 approved in this setting in 2004.11,12 19 Cassidy et al 96 XELOX 55 31 86% TTP, 7.7 19.5 A variety of phase I/II trials provide 20 + Grothey et al 71 CAPOX 49 42 91% PFS, 6.6 15.8+ encouraging efficacy parameters for the combination of cetuximab with Shields et al21 35 XELOX 37 – – PFS, 6.9 – irinotecan-based or oxaliplatin-based 22 Zeuli et al 43 XELOX 44 23 67% TTF, 8.2 20 first-line treatment. The CRYSTAL 2 2 CAPOX: capecitabine 1000 mg/m twice daily on days 1-14 plus oxaliplatin 70 mg/m on days 1 and 8, repeated every 22 days. study, a large phase III trial evaluatXELOX: capecitabine 1000 mg/m2 twice daily on days 1-14 plus oxaliplatin 130 mg/m2 on day 1, repeated every 22 days. ing 1217 patients receiving FOLFIRI Abbreviations: DCR = disease control rate; PFS = progression-free survival; TTF = time to treatment failure; TTP = time to progression with or without cetuximab in the 13 first-line setting, recently confirmed these results. In this review, we will elaborate on the rationale Because toxicity profiles showed that CAPOX and XELOX of combining the EGFR antibody cetuximab with XELOX were feasible and safe, further evaluation in phase III trials (capecitabine/oxaliplatin) or XELIRI (capecitabine/irinotewas warranted. can) for the first-line treatment of mCRC.
Phase III Trials
Capecitabine plus Oxaliplatin Two different schedules combine capecitabine and oxaliplatin. The XELOX regimens include oxaliplatin 130 mg/m2 on days 1 and 22, whereas CAPOX regimens split the oxaliplatin dose to 70 mg/m2 on days 1 and 8. Capecitabine 1000 mg/m2 is given orally twice daily on days 1-14, with a 1 week rest period on days 15-21. CAPOX and XELOX have comparable efficacy and safety profiles. They are both used in current phase III trials.14-17
Phase II Trials Early phase II trials of CAPOX and XELOX achieved promising response rates of 37%-55%, median time to progression of approximately 6-8 months, and median overall survival of approximately 16-20 months (Table 1).18-22
Table 2
Four phase III trials investigating capecitabine/oxaliplatin versus infusional 5-FU plus oxaliplatin have recently been published or were presented at the 2007 American Society of Clinical Oncology (ASCO) Annual Meeting. The German AIO (Association of Medical Oncology of the German Cancer Society) trial evaluated 474 patients (CAPOX vs. FUFOX [5-FU/leucovorin/oxaliplatin])17; the Spanish trial, 348 patients (XELOX vs. FUOX [5-FU/oxaliplatin])16; and the French trial, 306 patients (XELOX vs. FOLFOX6).14 The largest trial in this setting to date is XELOX-1/NO16966, presented by Cassidy et al at the 2007 ASCO meeting. This study randomized 634 patients with mCRC to first-line treatment with XELOX versus FOLFOX4. After data on increased efficacy of first-line chemotherapy by the addition of the vascular endothelial growth factor (VEGF) antibody
Phase III Studies Comparing Capecitabine plus Oxaliplatin Versus Infusional 5-FU/Leucovorin/Oxaliplatin Combinations
Study Porschen et al17
Diaz-Rubio et al16
Ducreux et al14
Cassidy et al15
Treatment
N
RR (%)
DCR (CR + PR + SD)
PFS (Months)
Overall Survival (Months)
CAPOX
241
48
76%
7.1
16.8
FUFOX
233
54
77%
8
18.8
XELOX
171
37
66%
TTP, 8.9
18.1
FUOX
171
46
71%
TTP, 9.5
20.8
XELOX
156
42
84%
8.8
19.9
FOLFOX6
150
46
87%
9.3
20.5
XELOX
317 (1017*)
37*
74%
7.3
17.7
FOLFOX4
317 (1018*)
39*
77%
7.7
18.8
These studies provide consistent evidence that the capecitabine-based treatment options are noninferior to standard infusional 5-FU–based regimens. CAPOX: capecitabine 1000 mg/m2 twice daily on days 1-14 plus oxaliplatin 70 mg/m2 on days 1 and 8, repeated every 22 days. XELOX: capecitabine 1000 mg/m2 twice daily on days 1-14 plus oxaliplatin 130 mg/m2 on day 1, repeated every 22 days. FUFOX: oxaliplatin 50 mg/m2, followed by leucovorin 500 mg/m2 and 5-FU 2000 mg/m2 as 22-hour continuous infusion on days 1, 8, 15, and 22, repeated every 36 days. FUOX: oxaliplatin 85 mg/m2 on days 1, 15, 29 and 5-FU 2250 mg/m2 as 48-hour continuous infusion on days 1, 8, 15, 22, 29, and 36, repeated every 6 weeks. FOLFOX6: oxaliplatin 100 mg/m2 plus folinic acid 400 mg/m2, followed by a 5-FU 400 mg/m2 bolus and 5-FU 2400-3000 mg/m2 as 46-hour continuous infusion on day 1, repeated on day 15. FOLFOX4: oxaliplatin 85 mg/m2 day 1 plus folinic acid 200 mg/m2, followed by a 5-FU 400 mg/m2 bolus and 5-FU 600 mg/m2 as 22-hour continuous infusion on days 1 and 2, repeated on day 15. *Combined analysis: n = 1017 and n = 1018; chemotherapy alone, chemotherapy plus placebo, and chemotherapy plus bevacizumab. Abbreviation: DCR = disease control rate
Clinical Colorectal Cancer March 2008 • 111
Cetuximab plus XELIRI or XELOX for mCRC Table 3
Capecitabine and Irinotecan in the First-Line Treatment of Metastatic Colorectal Cancer: Results from Phase II/III Trials DCR PFS (CR + PR + SD) (Months)
OS (Months)
Grade 3/4 Diarrhea (%)
CAPIRI: 7.6 XELIRI: 8.3
–
CAPIRI: 17* XELIRI: 36*
CAPIRI: 60 XELIRI: 69
CAPIRI: 6.9 XELIRI: 9.2
CAPIRI: 17.4 XELIRI: 24.7
CAPIRI: 34 XELIRI: 19
93
6.2
13.4
20*
Phase
Treatment
N
CR + PR (%)
SD (%)
Bajeta et al26
II
CAPIRI vs. XELIRI
140
CAPIRI: 44 XELIRI: 47
CAPIRI: 21 XELIRI: 34
CAPIRI: 65 XELIRI: 81
Borner et al25
II
CAPIRI vs. XELIRI
75
CAPIRI: 34 XELIRI: 35
CAPIRI: 26 XELIRI: 34
Cartwright et al27
II
XELIRI
49
45
48
Study
Grothey et
al20
Patt et al28 Rea et
al29
+
II
XELIRI
64
38
42
80
8.2
15.8
12*
II
CAPIRI
52
46
–
–
TTP, 7.1
15.6
20*
II
XELIRI
57
42
26
68
TTP, 8.3
–
19
III (Suspended)
XELIRI ± Celecoxib
43
22-48
24-52
72-74
TTP, 5.9
14.8
37*
Fuchs et al31
III
XELIRI ± Celecoxib
145
38
29
67
5.5
18.9
48
Punt et al32
III
XELIRI
398
41
46
87
7.8
17.4
26
De Grève et al30
CAPIRI: regimens with the application of irinotecan on days 1 and 8 every 3 weeks or weekly regimens. XELIRI: regimens with application of irinotecan on day 1 every 3 weeks. *Dose reduction recommended by the author. Abbreviations: DCR = disease control rate; OS = overall survival; TTP = time to progression
bevacizumab became available,23,24 XELOX-1/NO16966 randomized another 1400 patients in a 2 × 2 factorial design to receive XELOX versus FOLFOX4 plus bevacizumab versus placebo.15 Data across all 4 trials were very consistent (Table 2).14-17 Efficacy data of the capecitabine-based versus the infusional 5-FU–based treatment arms revealed response rates of 37%48% versus 39%-54%, disease control rates of 66%-84% versus 71%-87%, progression-free survival (PFS) of 7.1-8.9 months versus 7.7-9.3 months, and overall survival (OS) of 16.8-19.9 months versus 18.8-20.8 months, respectively. In all 4 trials, XELOX or CAPOX resulted in slightly inferior efficacy than the FUOX, FUFOX, or FOLFOX regimens. However, this difference was clinically irrelevant and did not reach statistical significance in any of the trials. The safety profiles were well balanced, with a trend for FUOX, FUFOX, and FOLFOX inducing higher rates of diarrhea, mucositis, neuropathy, and neutropenia/febrile neutropenia in single trials, whereas CAPOX and XELOX expectedly caused more PPE and hyperbilirubinemia. Thus, it can be concluded that XELOX (and CAPOX) are alternative first-line regimens to standard infusional 5-FU, leucovorin, and oxaliplatin protocols. They offer the advantage of more convenient oral fluoropyrimidine administration. This might be of particular interest for working as well as younger and active patients, because the XELOX regimen requires only 1 hospital visit every 3 weeks. However, patients need to be well informed about possible side effects because surveillance by their oncologist might be less frequent. In particular, patients should be informed of PPE and gastrointestinal toxicities as well as measures to prevent or cope with such side effects.
Capecitabine plus Irinotecan Because data on the combination of capecitabine and irinotecan are less consistent across different trials, they must be discussed in more detail.
112 • Clinical Colorectal Cancer March 2008
Phase II Trials Different schedules were evaluated in phase II trials. Applications of irinotecan 100-150 mg/m2 on days 1 and 8 or weekly irinotecan 70 mg/m2 (most commonly called “CAPIRI”) were compared with regimens with the application of irinotecan at higher doses only at day 1 every 3 weeks (most commonly called “XELIRI”). The 3-weekly regimens seemed to be slightly advantageous in terms of grade 3/4 diarrhea, time to progression (TTP), OS, and patient convenience (Table 3).20,25-32 Efficacy data of these phase II trials were encouraging. Response rates of XELIRI or CAPIRI of 34%47%, TTP of approximately 6-9 months, and OS of approximately 13-25 months, respectively, were achieved.20,25-29 However, irinotecan and capecitabine displayed partly overlapping adverse effects, particularly with respect to gastrointestinal toxicity. Up to 36% of patients in these phase II trials developed grade 3/4 diarrhea and considerable incidences of grade 3/4 nausea (3%-13%), emesis (6%-7%), dehydration (up to 10%), and neutropenia (5%-25%). Therefore, many patients required dose modification. Some of the authors suggested lower irinotecan and capecitabine doses for further evaluation in phase III trials.
Phase III Trials The European Organization for Research and Treatment of Cancer (EORTC) 40015 study was the first phase III trial aiming to randomize 692 patients in a 2 × 2 factorial design to receive XELIRI (irinotecan 250 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily on days 1-14, every 3 weeks) versus FOLFIRI with or without the cyclooxygenase2 inhibitor celecoxib. This trial had to be suspended after the accrual of 85 patients (n = 43 for XELIRI) because of 8 fatal events unrelated to disease progression. Six patients died in the XELIRI arm (3 patients of thromboembolic events and 3 of severe diarrhea) and 2 in the FOLFIRI arm. Furthermore,
Nicolas Moosmann, Volker Heinemann Table 4
Cetuximab plus Oxaliplatin-Based Regimens in the First-Line Treatment of Metastatic Colorectal Cancer: Results from Phase I/II Trials
Study Andre et
al45
Treatment
N CR + PR (%) SD (%) DCR (CR + PR + SD) PFS (Months) OS (Months) Resection Rate (%)
FOLFOX4 + Cetuximab 43
77
18
95
12.3
30
23
Bokemeyer et al47 FOLFOX4 + Cetuximab 169
46
39
85
–
–
–
al42
FUFOX + Cetuximab
49
57
20
77
8.1
30.6
–
Colucci et al44
FOLFOX + Cetuximab
67
63
–
–
–
–
10
Venook et al41
FOLFOX + Cetuximab
35
60
–
–
8.2
–
–
Dakhil et al43
FOLFOX + Cetuximab
57
61
28
89
8.1
–
–
al46
XELOX + Cetuximab
37
57
30
87
–
–
–
XELOX + Cetuximab
25
68
24
92
–
–
–
Dittrich et
Borner et
Heinemann et al48
Abbreviation: DCR = disease control rate
37% of patients receiving XELIRI experienced grade 3/4 diarrhea, and 61% required dose reduction, mainly because of nonhematologic toxicity. The authors concluded that celecoxib might reduce, rather than improve, chemotherapy efficacy and that XELIRI should be evaluated at a 20% reduced dose in a future EORTC phase III study.30,33 A second randomized phase III trial (BICC-C) investigated FOLFIRI versus modified IFL (mIFL; irinotecan in combination with 5-FU/leucovorin bolus regimen) versus XELIRI (dosed as above) with or without celecoxib and randomized 145 patients into the XELIRI arm. Efficacy data are shown in Table 3. There was a trend toward higher response rates and improved OS for FOLFIRI compared with the mIFL and XELIRI arms. Progression-free survival was significantly in favor of FOLFIRI. The frequency of grade 3/4 diarrhea (48%) was higher than in any of the previous phase II trials in patients receiving XELIRI. Contrary to the EORTC trial, there were neither increased 60-day mortality rates (XELIRI: 3.5%; FOLFIRI: 2.9%; mIFL: 5.8%), nor increased incidences of thromboembolic events (myocardial infarction/stroke: XELIRI: 0; FOLFIRI: 0.7%; mIFL: 4.4%).31
The CAIRO Trial Currently, the largest cohort of patients (n = 398) with XELIRI first-line treatment for mCRC was investigated by the Dutch Colorectal Cancer Group testing sequential versus combination chemotherapy in a phase III setting (arm A: first-line single-agent capecitabine, second-line single-agent irinotecan, and third-line XELOX; arm B: first-line XELIRI and second-line XELOX).32,34 Patients in arm B received irinotecan 250 mg/m2 and capecitabine 1000 mg/m2, the same doses used in the EORTC 40015 and BICC-C trials. The Dutch trial revealed the following grade 3/4 toxicities: 26% diarrhea, 10% nausea, 9% emesis, 7% febrile neutropenia, and 6% PPE. The frequency of thromboembolic events of all grades was 10% for XELIRI compared with 7% for the capecitabine alone arm and, thus, did not reach a statistically significant difference between the 2 treatment arms (P = .2). Because of the unexpected occurrence of fatal events in the EORTC 40015 trial, the investigators of the CAIRO
trial focused on treatment-related fatal events in their study. The 60-day mortality rate was 4.5% for the XELIRI arm and 3% for the capecitabine treatment arm. Three deaths in the XELIRI and 8 deaths in the capecitabine arm were considered “probably” related to treatment. The most frequent complication leading to death was sepsis on the background of neutropenia. Reviewing the charts of the deceased patients, the authors revealed major protocol violations in 9 of these 11 cases. These violations included application of irinotecan despite hyperbilirubinemia and continued full-dose capecitabine despite grade 3/4 diarrhea. Five more patients in the XELIRI arm and 1 patient in the capecitabine arm died suddenly. Four of these 6 patients were known to have a history of cardiovascular risk factors. The investigators of the Dutch trial concluded that the overall incidence of ischemic and thromboembolic events were comparable and low in both arms. They did not exceed the incidences observed in recent phase III trials investigating fluoropyrimidine and irinotecan combinations.23,35 As a result, the negative results of the EORTC 40015 and the BICC-C trials were not confirmed in this much larger cohort of patients receiving XELIRI. Efficacy data of the CAIRO trial could underline the positive results of earlier phase II trials with a response rate of 41%, a disease control rate of 87%, PFS of 7.8 months, and an OS reaching 17.4 months for patients treated with XELIRI as first-line treatment.32
Recommendations Regarding XELIRI The gastrointestinal toxicity of XELIRI needs to be addressed with caution. The incidence of grade 3/4 diarrhea varies considerably across different trials. Treatment efficacy appears to be compromised in the trials with the highest incidences of diarrhea (eg, EORTC 40015 and BICC-C; Table 3). However, it reached an acceptable rate of 26% in the CAIRO trial. Grade 3/4 diarrhea seems to be less frequent with regimens combining irinotecan in a biweekly schedule with infusional 5-FU and leucovorin (13%),8 while higher incidence rates were observed with weekly FOLFIRI regimens (29%44%).5,35 Patients need to be informed in detail about the possibility of delayed diarrhea and measures to be taken, such as Clinical Colorectal Cancer March 2008 • 113
Cetuximab plus XELIRI or XELOX for mCRC Table 5
Cetuximab plus Irinotecan-Based Regimens in the First-Line Treatment of Metastatic Colorectal Cancer: Results from Phase I/II Trials and the Phase III CRYSTAL Study
Study Rosenberg et
al49
Treatment
N
CR + PR (%) DCR (CR + PR + SD) TTP (Months) OS (Months) Resection Rate (%)
IFL + Cetuximab
29
48
89
–
–
–
FUFIRI (AIO) + Cetuximab
21
67
96
9.9
33
19
Peeters et al51
FOLFIRI + Cetuximab
42
45
83
Response duration, 10
23
24
Venook et al41
FOLFIRI + Cetuximab
55
44
76
10.6
–
–
Heinemann et al48
XELIRI + Cetuximab
27
41
89
–
–
–
Van Cutsem et al13
FOLFIRI + Cetuximab
599 (Phase III)
47
84
PFS, 8.9
–
6
Folprecht et al50
Abbreviation: DCR = disease control rate
immediate antidiarrheic medication and sufficient fluid intake at home, presentation at a hospital in case of diarrhea associated with fever or neutropenia, or hospitalization because of insufficient oral compensation of fluid loss. Furthermore, it is mandatory to comply with specified protocol guidelines in order to prevent severe toxicities. Doses of irinotecan and capecitabine need to be adjusted in case of liver or renal dysfunction, and doses must be reduced if patients present significant gastrointestinal toxicity. Provided these measures apply, the combination of capecitabine and irinotecan is a highly effective option for first-line treatment of patients with mCRC. Further investigation in phase III trials as well as combinations with biologic agents is warranted.
The EGFR Antibody Cetuximab and Its Role in the First-Line Treatment of Metastatic Colorectal Cancer Epidermal Growth Factor Receptor and Cetuximab The epidermal growth factor receptor is a protein tyrosine kinase and a member of the ErbB receptor family. In resting nontransformed cells, EGFR and its intracellular downstream signaling cascade are tightly controlled, and the cells have very low levels of tyrosyl phosphorylated proteins. This makes EGFR an excellent target for directed cancer therapy since EGFR is known to be overexpressed in many human tumors, including CRC. This overexpression correlates with poor prognosis. Activation of EGFR by its natural ligands initiates a variety of important steps during malignant transformation, such as cell proliferation and protection from apoptosis, dedifferentiation, angiogenesis, and increased cell migration and invasion favoring the metastatic potential of tumor cells.36-39 Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody that binds EGFR with approximately 10 times higher affinity than its natural ligands. Competitive binding of cetuximab to EGFR prevents ligand-induced phosphorylation of the intracellular tyrosine kinase domain, thus inhibiting activation of the further downstream signaling cascade.40 Cetuximab is known to have synergistic activity with irinotecan. The biologic agent was approved for the treatment of
114 • Clinical Colorectal Cancer March 2008
patients with mCRC after failure of previous irinotecan-based chemotherapy in the United States and in Europe in 2004.11
Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer A number of phase I/II trials could provide consistent data that combinations of the EGFR antibody with the modern chemotherapy regimens FOLFOX, FUFOX (infusional 5-FU/ leucovorin plus oxaliplatin in a weekly schedule), FOLFIRI, FUFIRI (infusional 5-FU/leucovorin plus irinotecan in a weekly schedule), and IFL are feasible and safe. Even though patient numbers of these early trials were limited, response rates from 44% to 77% and disease control rates ranging between 76% and 96% were very encouraging and among the highest ever observed in the systemic therapy of mCRC (Tables 4 and 5).13,41-51
The CRYSTAL Study The CRYSTAL study is a multinational, randomized, phase III trial investigating FOLFIRI with or without cetuximab in the first-line treatment of 1217 patients with mCRC. Van Cutsem et al presented first efficacy results at the 2007 ASCO Annual Meeting13: The primary endpoint of the CRYSTAL study, which was PFS, was met. The combination of FOLFIRI plus cetuximab achieved a PFS of 8.9 months compared with 8 months for the chemotherapy alone arm (P = .0479). Response rates reached 46.9% versus 38.7% in favor of the combination arm (P = .0038). Furthermore, the results on secondary resection rates in this large phase III trial were of particular interest: In the FOLFIRI plus cetuximab arm, 6% of patients were able to undergo secondary resection of their residual tumors, whereas only 2.5% of patients were rendered operable by FOLFIRI alone. In 4.3% versus 1.5% of patients, the secondary surgical approach achieved an R0 resection. This difference was statistically significant (P = .0034). One hundred thirty-four patients in the FOLFIRI alone arm and 122 patients in the FOLFIRI plus cetuximab arm entered the study with inoperable metastases confined to the liver. The secondary resection rates of this subgroup of patients more than doubled (9.8% vs. 4.5%) by the combination of FOLFIRI plus the EGFR antibody. Because surgical resection of residual liver metastases offers a chance of
Nicolas Moosmann, Volker Heinemann long-term survival, these results are clinically important. Adam et al showed that a 5-year survival rate of 34% and a 10-year survival rate on the order of 20% can be achieved in patients whose liver metastases become resectable after chemotherapy.52,53 These survival data are clearly superior to long-term survival data of systemic treatment alone, even when modern chemotherapy is combined with targeted agents.
Cetuximab plus XELIRI or XELOX for the First-Line Treatment of Metastatic Colorectal Cancer To date, only preliminary data of 3 clinical trials are available for the combination of XELIRI or XELOX with the EGFR antibody cetuximab: The British COIN trial, the Swiss SAKK 41/04 trial, and the German CIOX trial.46,48,54 The COIN trial is a 3-arm phase III trial investigating continuous oxaliplatin-based chemotherapy versus continuous oxaliplatin-based chemotherapy plus cetuximab versus intermittent oxaliplatin-based chemotherapy. Because the chemotherapy backbone in the COIN trial can be chosen between a modified FOLFOX regimen or XELOX by the treating doctor, this trial will provide important data on XELOX plus cetuximab and help to answer the question of whether XELOX will be able to replace FOLFOX in combination with cetuximab. Preliminary safety results of the first 804 patients, including 152 patients receiving XELOX plus cetuximab, were reported at the 2007 ASCO meeting.54 Maughan et al concluded that the addition of cetuximab to FOLFOX or XELOX results in an overall increase of grade 3/4 toxicities of approximately 20% (XELOX: 30%; FOLFOX: 32%; XELOX plus cetuximab: 51%; and FOLFOX plus cetuximab: 54%). These additional adverse effects comprise higher rates of rash, nausea/ vomiting, diarrhea, and lethargy. In the COIN trial, XELOX plus cetuximab was associated with an increased incidence of diarrhea compared with FOLFOX plus cetuximab (26% vs. 13%), whereas neutropenia occurred significantly less frequently (1% vs. 26%). All-cause mortality and treatmentrelated deaths within 60 days showed no significant differences across the 4 regimens, and the COIN trial is currently continuing accrual to a planned number of 2421 patients. SAKK 41/04 and the CIOX trial are the only 2 trials that can provide preliminary efficacy results (Tables 4 and 5).46,48 SAKK 41/04 is a randomized phase II trial investigating XELOX versus XELOX plus cetuximab. The addition of the EGFR antibody resulted in a 30% increase in response rates (XELOX plus cetuximab: 57%; XELOX: 27%) without compromising safety data. The rate of grade 3/4 diarrhea for XELOX plus cetuximab in this trial was only 8%, and there were no patients showing grade 3/4 neutropenia. The CIOX trial is a randomized phase II trial of the German AIO (Association of Medical Oncology of the German Cancer Society) investigating XELIRI plus cetuximab versus XELOX plus cetuximab. It addresses the currently unanswered question of whether oxaliplatin- or irinotecan-based chemotherapy is the most effective combination partner for the EGFR antibody. A planned interim analysis was presented at the 2006 ASCO
meeting. The very preliminary evaluation indicates an overall response rate of 41% for XELIRI plus cetuximab and 68% for XELOX plus cetuximab, accompanied by high disease control rates of 89% and 92% for the 2 treatment arms, respectively. In the CIOX trial, 19% of patients experienced grade 3/4 diarrhea and 11% grade 3/4 neutropenia in the XELIRI plus cetuximab arm compared with 22% grade 3/4 diarrhea and 3% grade 3/4 neutropenia in the XELOX plus cetuximab arm. This trial has completed recruitment (n = 185), and final evaluation will be available at the 2008 ASCO Annual Meeting. The question of why the aforementioned toxicity data for XELOX or XELIRI plus cetuximab are not consistent across the 3 trials is currently unclear. It might be a result of the very preliminary character of available results. This question will hopefully be answered in the near future with more mature data to be presented.
Conclusion The introduction of the oral fluoropyrimidine capecitabine in the treatment of mCRC was an important step toward offering patients an easier application of therapy requiring fewer admissions to hospital and leading to a higher quality of life for many patients. The combination of capecitabine with oxaliplatin (XELOX) is an equally effective treatment alter-native to standard infusional 5-FU plus oxaliplatin regimens. Combining capecitabine with irinotecan (XELIRI) also achieves promising efficacy data. Owing to the partly overlapping gastrointestinal toxicities of the 2 chemotherapeutic substances, patients must be aware of measures to be taken if delayed diarrhea occurs. Furthermore, the doses of both agents must be adjusted to the patients’ renal and liver function. Dose reduction or treatment delay is mandatory in case of preexisting gastrointestinal toxicity. The EGFR antibody cetuximab achieves impressive results when combined with modern irinotecan-based or oxaliplatinbased chemotherapy regimens. The response rates are among the highest ever observed in the first-line treatment of mCRC, leading to secondary resection in approximately 10%-24% of patients in a number of early trials.44,45,48,50,51,55 These data could recently be confirmed by the CRYSTAL study, a large phase III trial. The combination of FOLFIRI plus cetuximab leads to significantly improved PFS, response rates, and secondary resection rates compared with FOLFIRI alone.13 The increased resection rates are particularly important because a curative surgical approach of liver metastases can provide a chance for long-term survival for a considerable proportion of these patients.52,53 The rationale of combining XELOX or XELIRI with cetuximab is offering patients a simplified and highly effective combined cytotoxic and targeted treatment regimen. Preliminary data of the British COIN trial, the Swiss SAKK 41/04 trial, and the German CIOX trial show that these combinations are feasible and achieve promising efficacy data.46,48,54 Provided these results will be confirmed by more mature data in the near future, these combined cytotoxic and targeted treatment approaches will hopefully add to the growing arsenal of highly effective regimens in the treatment of mCRC. Clinical Colorectal Cancer March 2008 • 115
Cetuximab plus XELIRI or XELOX for mCRC References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin 2007; 57:43-66. 2. Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 1992; 10:896903. 3. Meta-analysis Group In Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16:301-8. 4. Thirion P, Michiels S, Pignon JP, et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol 2004; 22:3766-75. 5. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355:1041-7. 6. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22:23-30. 7. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18:2938-47. 8. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22:229-37. 9. Hoff PM, Ansari R, Batist G, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001; 19:2282-92. 10. Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001; 19:4097-106. 11. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351:337-45. 12. Wilke H, Glynne-Jones R, Thaler J, et al. MABEL - a large multinational study of cetuximab plus irinotecan in metastatic colorectal cancer progressing on irinotecan. J Clin Oncol 2006; 24(18 suppl):158s (Abstract 3549). 13. Van Cutsem E, Nowacki M, Lang I, et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer: The CRYSTAL trial. J Clin Oncol 2007; 25(18 suppl):164s (Abstract 4000). 14. Ducreux M, Bennouna J, Hebbar M, et al. Efficacy and safety findings from a randomized phase III study of capecitabine plus oxaliplatin (XELOX) versus infusional 5-FU/LV plus oxaliplatin (FOLFOX-6) for metastatic colorectal cancer. J Clin Oncol 2007; 25(18 suppl):170s (Abstract 4029). 15. Cassidy J, Clarke S, Diaz-Rubio E, et al. XELOX compared to FOLFOX4: Survival and response results from XELOX-1/NO16966, a randomized phase III trial of first-line treatment for patients with metastatic colorectal cancer. J Clin Oncol 2007; 25(18 suppl):171s (Abstract 4030). 16. Diaz-Rubio E, Tabernero J, Gomez-Espana A, et al. Phase III study of capecitabine plus oxaliplatin versus continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors trial. J Clin Oncol 2007; 25:4224-30. 17. Porschen R, Arkenau HT, Kubicka S, et al. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol 2007; 25:4217-23. 18. Borner MM, Dietrich D, Stupp R, et al. Phase II study of capecitabine and oxaliplatin in first- and second-line treatment of advanced or metastatic colorectal cancer. J Clin Oncol 2002; 20:1759-66. 19. Cassidy J, Tabernero J, Twelves C, et al. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 2004; 22:2084-91. 20. Grothey A, Jordan K, Kellner O, et al. Randomized phase II trial of
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Nicolas Moosmann, Volker Heinemann Eur J Cancer 2001; 37(suppl 4):S9-15. 40. Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995; 1:1311-8. 41. Venook A, Niedzwiecki D, Hollis D, et al. Phase III study of irinotecan/5-FU/LV (FOLFIRI) or oxaliplatin/5-FU/LV (FOLFOX) +/- cetuximab (C225) for patients (pts) with untreated metastatic adeno carcinoma of the colon or rectum (mCRC): CALGB 80203 preliminary results. J Clin Oncol 2006; 24(18 suppl):148s (Abstract 3509). 42. Dittrich C, Hoehler T, Lordick F, et al. A phase I/II study of cetuximab in combination with 5-fluorouracil/folinic acid plus weekly oxaliplatin (FUFOX) in the first-line treatment of patients with metastatic colorectal cancer expressing epidermal growth factor receptor (EGFR). Preliminary results. Presented at: the World Congress on Gastrointestinal Cancer; June 28-July 1, 2006; Barcelona, Spain. Abstract O-019. 43. Dakhil S, Cosgriff T, Headley D, Boccia R, Badarinath S. Cetuximab plus FOLFOX6 as first-line therapy for metastatic colorectal cancer (an International Oncology Network study, I-03-002). J Clin Oncol 2006; 24(18 suppl):160s (Abstract 3557). 44. Colucci G, Giuliani F, Mattioli R, et al. FOLFOX-4 plus cetuximab in untreated patients with advanced colorectal cancer. A phase II study of the Gruppo Oncologico dell´Italia Meridionale (prot. GOIM 2402). J Clin Oncol 2006; 24(18 suppl):160s (Abstract 3559). 45. Andre T, Tabernero J, Van Cutsem E, et al. Phase II study with cetuximab plus FOLFOX-4 in first-line setting for epidermal growth factor receptor-expressing metastatic colorectal cancer: final results. Presented at: the 2007 ASCO Gastrointestinal Cancers Symposium; January 19-21, 2007; Orlando, FL. Abstract 334. 46. Borner M, Mingrone W, Koeberle D, et al. The impact of cetuximab on the capecitabine plus oxaliplatin (XELOX) combination in firstline treatment of metastatic colorectal cancer: A randomized phase II trial of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol 2006; 24(18 suppl):158s (Abstract 3551). 47. Bokemeyer C, Bondarenko I, Makhson A, et al. Cetuximab plus 5FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the first-line treatment of metastatic colorectal cancer: OPUS, a randomized phase
II study. J Clin Oncol 2007; 25(18 suppl):172s (Abstract 4035). 48. Heinemann V, Fischer von Weikersthal L, Moosmann N, et al. Cetuximab plus capecitabine plus irinotecan versus cetuximab plus capecitabine plus oxaliplatin as first-line therapy for patients with metastatic colorectal cancer: Preliminary results of a randomized phase II trial of the AIO study group. J Clin Oncol 2006; 24(18 suppl):158s (Abstract 3550). 49. Rosenberg AH, Loehrer PJ, Needle MN, et al. Erbitux (IMC-C225) plus weekly irinotecan (CPT-11), fluorouracil (5-FU) and leucovorin (LV) in colorectal cancer (CRC) that expresses the epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 2002; 21:135a (Abstract 536). 50. Folprecht G, Lutz MP, Schoffski P, et al. Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol 2006; 17:450-6. 51. Peeters M, Raoul J, Van Laethem J, et al. Cetuximab in combination with irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFIRI) in the first-line treatment of metastatic colorectal cancer (mCRC). Presented at: the 2005 European Cancer Conference; October 30Noveber 3, 2005; Paris, France. Abstract 664. 52. Adam R. Chemotherapy and surgery: new perspectives on the treatment of unresectable liver metastases. Ann Oncol 2003; 14(suppl 2): ii13-6. 53. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004; 240:644-57; discussion 657-8. 54. Maughan T, on behalf of the COIN Trial Management Group and Investigators. Cetuximab, oxaliplatin and fluoropyrimidine: Toxicity during the first 12 weeks of treatment for the first 804 patients entered into the MRC COIN (CR10) trial. J Clin Oncol 2007; 25(18 suppl):181s (Abstract 4070). 55. Diaz-Rubio E, Tabernero J, Van Cutsem E, et al. Cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC): An international phase II study. J Clin Oncol 2005; 23(16 suppl):254s (Abstract 3535).
Clinical Colorectal Cancer March 2008 • 117
Review
Cetuximab plus XELIRI or XELOX for First-Line Therapy of Metastatic Colorectal Cancer Nicolas Moosmann, Volker Heinemann Abstract Modern chemotherapy combinations for metastatic colorectal cancer (mCRC) comprise infusional 5-fluorouracil (5-FU), leucovorin, and irinotecan or oxaliplatin. The fluoropyrimidine derivative capecitabine is at least as effective as 5-FU plus leucovorin bolus regimens. It displays a favorable toxicity profile and offers the advantages of oral administration. The epidermal growth factor receptor antibody cetuximab induces synergistic antitumor activity when combined with chemotherapy. In pretreated patients, cetuximab can restore the sensitivity to irinotecan and, therefore, has been registered in this setting. Several phase I/II trials have investigated the combination of cetuximab with irinotecan-based or oxaliplatin-based chemotherapy for the first-line treatment of mCRC. These combinations have been proven to be safe and have provided promising efficacy data. A recent phase III trial confirmed improved progression-free survival, response rates, and a particularly significant increase of secondary resection rates for the combination of FOLFIRI (infusional 5-FU/leucovorin/irinotecan) plus cetuximab compared with FOLFIRI alone. In this review, we discuss the background of combining XELIRI (capecitabine/irinotecan) or XELOX (capecit-abine/oxaliplatin) with cetuximab for the first-line treatment of mCRC and present available data of these combined cytotoxic and targeted treatment approaches. Clinical Colorectal Cancer, Vol. 7, No. 2, 110-117, 2008 Key words: Capecitabine, Epidermal growth factor receptor, Irinotecan, Leucovorin, Oxaliplatin
Introduction Colorectal cancer (CRC) is the third most common malignant disease in the United States, with > 150,000 estimated new cases in 2007.1 Approximately 50% of patients with CRC develop metastases and eventually die from disease. Until recently, chemotherapy was based on 5-fluorouracil (5-FU), inducing response rates of 11%-14% as a single agent. Cytotoxic activity of 5-FU can be improved by bimodulation with leucovorin and infusional application of 5-FU. However, response rates of 21%-23% and overall survival times of approximately 12 months still remain modest.2-4 In the past decade, the median survival times have improved significantly to 16-21 months, mainly because of the introduction of the topoisomerase-I inhibitor irinotecan and the third-generation platinum compound oxaliplatin.5-8 University of Munich, Medical Department III, Klinikum MuenchenGrosshadern, Germany Submitted: Jun 27, 2007; Revised: Dec 7, 2007; Accepted: Dec 7, 2007 Address for correspondence: Nicolas Moosmann, MD, Medizinische Klinik III, Klinikum Muenchen-Grosshadern, Marchioninistrasse 15, D-81377 München, Germany Fax: 49-89-7095-5256; e-mail: [email protected]
Modern chemotherapy regimens combine infusional 5-FU and leucovorin with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX). A further landmark in the cytostatic treatment of CRC was the development of oral fluoropyrimidine derivatives. Capecitabine is a rationally designed prodrug that is converted to 5-FU predominantly in tumor cells because of the high activity of thymidine phosphorylase in tumor tissue. In turn, this catalyzes the last enzymatic step required for capecitabine activation. In 2 randomized phase III trials, capecitabine proved at least equivalent to an intravenous 5-FU/leucovorin bolus regimen in terms of response rate and survival.9,10 In addition, capecitabine displays a favorable toxicity profile. The incidence of diarrhea, stomatitis, nausea, alopecia, neutropenia, and febrile neutropenia is significantly lower compared with the 5-FU/leucovorin bolus protocols. There is a later onset of treatment-related grade 3/4 adverse events leading to fewer patients requiring hospitalization. These advantages give rise to a high patient acceptance of the oral capecitabine treatment. The most frequent side effect of capecitabine is plantar-palmar erythrodysesthesia (PPE). Patients who develop this cutaneous syndrome respond well to dose interruption or reduction and treatment with topical emollients.9,10
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110 • Clinical Colorectal Cancer March 2008
The chimeric epidermal growth facTable 1 Capecitabine plus Oxaliplatin in the First-Line Treatment of Metastatic tor receptor (EGFR) antibody cetuxColorectal Cancer: Results from Phase II Trials imab has clinically significant activity DCR Overall when applied alone or in combination Failure/PFS CR + PR SD (CR+ Survival Study N Treatment (Months) (%) (%) with irinotecan in irinotecan-refracPR + SD) (Months) tory metastatic CRC (mCRC). It was 18 Borner et al 43 XELOX 49 19 68% TTF, 5.9 17.1 approved in this setting in 2004.11,12 19 Cassidy et al 96 XELOX 55 31 86% TTP, 7.7 19.5 A variety of phase I/II trials provide 20 + Grothey et al 71 CAPOX 49 42 91% PFS, 6.6 15.8+ encouraging efficacy parameters for the combination of cetuximab with Shields et al21 35 XELOX 37 – – PFS, 6.9 – irinotecan-based or oxaliplatin-based 22 Zeuli et al 43 XELOX 44 23 67% TTF, 8.2 20 first-line treatment. The CRYSTAL 2 2 CAPOX: capecitabine 1000 mg/m twice daily on days 1-14 plus oxaliplatin 70 mg/m on days 1 and 8, repeated every 22 days. study, a large phase III trial evaluatXELOX: capecitabine 1000 mg/m2 twice daily on days 1-14 plus oxaliplatin 130 mg/m2 on day 1, repeated every 22 days. ing 1217 patients receiving FOLFIRI Abbreviations: DCR = disease control rate; PFS = progression-free survival; TTF = time to treatment failure; TTP = time to progression with or without cetuximab in the 13 first-line setting, recently confirmed these results. In this review, we will elaborate on the rationale Because toxicity profiles showed that CAPOX and XELOX of combining the EGFR antibody cetuximab with XELOX were feasible and safe, further evaluation in phase III trials (capecitabine/oxaliplatin) or XELIRI (capecitabine/irinotewas warranted. can) for the first-line treatment of mCRC.
Phase III Trials
Capecitabine plus Oxaliplatin Two different schedules combine capecitabine and oxaliplatin. The XELOX regimens include oxaliplatin 130 mg/m2 on days 1 and 22, whereas CAPOX regimens split the oxaliplatin dose to 70 mg/m2 on days 1 and 8. Capecitabine 1000 mg/m2 is given orally twice daily on days 1-14, with a 1 week rest period on days 15-21. CAPOX and XELOX have comparable efficacy and safety profiles. They are both used in current phase III trials.14-17
Phase II Trials Early phase II trials of CAPOX and XELOX achieved promising response rates of 37%-55%, median time to progression of approximately 6-8 months, and median overall survival of approximately 16-20 months (Table 1).18-22
Table 2
Four phase III trials investigating capecitabine/oxaliplatin versus infusional 5-FU plus oxaliplatin have recently been published or were presented at the 2007 American Society of Clinical Oncology (ASCO) Annual Meeting. The German AIO (Association of Medical Oncology of the German Cancer Society) trial evaluated 474 patients (CAPOX vs. FUFOX [5-FU/leucovorin/oxaliplatin])17; the Spanish trial, 348 patients (XELOX vs. FUOX [5-FU/oxaliplatin])16; and the French trial, 306 patients (XELOX vs. FOLFOX6).14 The largest trial in this setting to date is XELOX-1/NO16966, presented by Cassidy et al at the 2007 ASCO meeting. This study randomized 634 patients with mCRC to first-line treatment with XELOX versus FOLFOX4. After data on increased efficacy of first-line chemotherapy by the addition of the vascular endothelial growth factor (VEGF) antibody
Phase III Studies Comparing Capecitabine plus Oxaliplatin Versus Infusional 5-FU/Leucovorin/Oxaliplatin Combinations
Study Porschen et al17
Diaz-Rubio et al16
Ducreux et al14
Cassidy et al15
Treatment
N
RR (%)
DCR (CR + PR + SD)
PFS (Months)
Overall Survival (Months)
CAPOX
241
48
76%
7.1
16.8
FUFOX
233
54
77%
8
18.8
XELOX
171
37
66%
TTP, 8.9
18.1
FUOX
171
46
71%
TTP, 9.5
20.8
XELOX
156
42
84%
8.8
19.9
FOLFOX6
150
46
87%
9.3
20.5
XELOX
317 (1017*)
37*
74%
7.3
17.7
FOLFOX4
317 (1018*)
39*
77%
7.7
18.8
These studies provide consistent evidence that the capecitabine-based treatment options are noninferior to standard infusional 5-FU–based regimens. CAPOX: capecitabine 1000 mg/m2 twice daily on days 1-14 plus oxaliplatin 70 mg/m2 on days 1 and 8, repeated every 22 days. XELOX: capecitabine 1000 mg/m2 twice daily on days 1-14 plus oxaliplatin 130 mg/m2 on day 1, repeated every 22 days. FUFOX: oxaliplatin 50 mg/m2, followed by leucovorin 500 mg/m2 and 5-FU 2000 mg/m2 as 22-hour continuous infusion on days 1, 8, 15, and 22, repeated every 36 days. FUOX: oxaliplatin 85 mg/m2 on days 1, 15, 29 and 5-FU 2250 mg/m2 as 48-hour continuous infusion on days 1, 8, 15, 22, 29, and 36, repeated every 6 weeks. FOLFOX6: oxaliplatin 100 mg/m2 plus folinic acid 400 mg/m2, followed by a 5-FU 400 mg/m2 bolus and 5-FU 2400-3000 mg/m2 as 46-hour continuous infusion on day 1, repeated on day 15. FOLFOX4: oxaliplatin 85 mg/m2 day 1 plus folinic acid 200 mg/m2, followed by a 5-FU 400 mg/m2 bolus and 5-FU 600 mg/m2 as 22-hour continuous infusion on days 1 and 2, repeated on day 15. *Combined analysis: n = 1017 and n = 1018; chemotherapy alone, chemotherapy plus placebo, and chemotherapy plus bevacizumab. Abbreviation: DCR = disease control rate
Clinical Colorectal Cancer March 2008 • 111
Cetuximab plus XELIRI or XELOX for mCRC Table 3
Capecitabine and Irinotecan in the First-Line Treatment of Metastatic Colorectal Cancer: Results from Phase II/III Trials DCR PFS (CR + PR + SD) (Months)
OS (Months)
Grade 3/4 Diarrhea (%)
CAPIRI: 7.6 XELIRI: 8.3
–
CAPIRI: 17* XELIRI: 36*
CAPIRI: 60 XELIRI: 69
CAPIRI: 6.9 XELIRI: 9.2
CAPIRI: 17.4 XELIRI: 24.7
CAPIRI: 34 XELIRI: 19
93
6.2
13.4
20*
Phase
Treatment
N
CR + PR (%)
SD (%)
Bajeta et al26
II
CAPIRI vs. XELIRI
140
CAPIRI: 44 XELIRI: 47
CAPIRI: 21 XELIRI: 34
CAPIRI: 65 XELIRI: 81
Borner et al25
II
CAPIRI vs. XELIRI
75
CAPIRI: 34 XELIRI: 35
CAPIRI: 26 XELIRI: 34
Cartwright et al27
II
XELIRI
49
45
48
Study
Grothey et
al20
Patt et al28 Rea et
al29
+
II
XELIRI
64
38
42
80
8.2
15.8
12*
II
CAPIRI
52
46
–
–
TTP, 7.1
15.6
20*
II
XELIRI
57
42
26
68
TTP, 8.3
–
19
III (Suspended)
XELIRI ± Celecoxib
43
22-48
24-52
72-74
TTP, 5.9
14.8
37*
Fuchs et al31
III
XELIRI ± Celecoxib
145
38
29
67
5.5
18.9
48
Punt et al32
III
XELIRI
398
41
46
87
7.8
17.4
26
De Grève et al30
CAPIRI: regimens with the application of irinotecan on days 1 and 8 every 3 weeks or weekly regimens. XELIRI: regimens with application of irinotecan on day 1 every 3 weeks. *Dose reduction recommended by the author. Abbreviations: DCR = disease control rate; OS = overall survival; TTP = time to progression
bevacizumab became available,23,24 XELOX-1/NO16966 randomized another 1400 patients in a 2 × 2 factorial design to receive XELOX versus FOLFOX4 plus bevacizumab versus placebo.15 Data across all 4 trials were very consistent (Table 2).14-17 Efficacy data of the capecitabine-based versus the infusional 5-FU–based treatment arms revealed response rates of 37%48% versus 39%-54%, disease control rates of 66%-84% versus 71%-87%, progression-free survival (PFS) of 7.1-8.9 months versus 7.7-9.3 months, and overall survival (OS) of 16.8-19.9 months versus 18.8-20.8 months, respectively. In all 4 trials, XELOX or CAPOX resulted in slightly inferior efficacy than the FUOX, FUFOX, or FOLFOX regimens. However, this difference was clinically irrelevant and did not reach statistical significance in any of the trials. The safety profiles were well balanced, with a trend for FUOX, FUFOX, and FOLFOX inducing higher rates of diarrhea, mucositis, neuropathy, and neutropenia/febrile neutropenia in single trials, whereas CAPOX and XELOX expectedly caused more PPE and hyperbilirubinemia. Thus, it can be concluded that XELOX (and CAPOX) are alternative first-line regimens to standard infusional 5-FU, leucovorin, and oxaliplatin protocols. They offer the advantage of more convenient oral fluoropyrimidine administration. This might be of particular interest for working as well as younger and active patients, because the XELOX regimen requires only 1 hospital visit every 3 weeks. However, patients need to be well informed about possible side effects because surveillance by their oncologist might be less frequent. In particular, patients should be informed of PPE and gastrointestinal toxicities as well as measures to prevent or cope with such side effects.
Capecitabine plus Irinotecan Because data on the combination of capecitabine and irinotecan are less consistent across different trials, they must be discussed in more detail.
112 • Clinical Colorectal Cancer March 2008
Phase II Trials Different schedules were evaluated in phase II trials. Applications of irinotecan 100-150 mg/m2 on days 1 and 8 or weekly irinotecan 70 mg/m2 (most commonly called “CAPIRI”) were compared with regimens with the application of irinotecan at higher doses only at day 1 every 3 weeks (most commonly called “XELIRI”). The 3-weekly regimens seemed to be slightly advantageous in terms of grade 3/4 diarrhea, time to progression (TTP), OS, and patient convenience (Table 3).20,25-32 Efficacy data of these phase II trials were encouraging. Response rates of XELIRI or CAPIRI of 34%47%, TTP of approximately 6-9 months, and OS of approximately 13-25 months, respectively, were achieved.20,25-29 However, irinotecan and capecitabine displayed partly overlapping adverse effects, particularly with respect to gastrointestinal toxicity. Up to 36% of patients in these phase II trials developed grade 3/4 diarrhea and considerable incidences of grade 3/4 nausea (3%-13%), emesis (6%-7%), dehydration (up to 10%), and neutropenia (5%-25%). Therefore, many patients required dose modification. Some of the authors suggested lower irinotecan and capecitabine doses for further evaluation in phase III trials.
Phase III Trials The European Organization for Research and Treatment of Cancer (EORTC) 40015 study was the first phase III trial aiming to randomize 692 patients in a 2 × 2 factorial design to receive XELIRI (irinotecan 250 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily on days 1-14, every 3 weeks) versus FOLFIRI with or without the cyclooxygenase2 inhibitor celecoxib. This trial had to be suspended after the accrual of 85 patients (n = 43 for XELIRI) because of 8 fatal events unrelated to disease progression. Six patients died in the XELIRI arm (3 patients of thromboembolic events and 3 of severe diarrhea) and 2 in the FOLFIRI arm. Furthermore,
Nicolas Moosmann, Volker Heinemann Table 4
Cetuximab plus Oxaliplatin-Based Regimens in the First-Line Treatment of Metastatic Colorectal Cancer: Results from Phase I/II Trials
Study Andre et
al45
Treatment
N CR + PR (%) SD (%) DCR (CR + PR + SD) PFS (Months) OS (Months) Resection Rate (%)
FOLFOX4 + Cetuximab 43
77
18
95
12.3
30
23
Bokemeyer et al47 FOLFOX4 + Cetuximab 169
46
39
85
–
–
–
al42
FUFOX + Cetuximab
49
57
20
77
8.1
30.6
–
Colucci et al44
FOLFOX + Cetuximab
67
63
–
–
–
–
10
Venook et al41
FOLFOX + Cetuximab
35
60
–
–
8.2
–
–
Dakhil et al43
FOLFOX + Cetuximab
57
61
28
89
8.1
–
–
al46
XELOX + Cetuximab
37
57
30
87
–
–
–
XELOX + Cetuximab
25
68
24
92
–
–
–
Dittrich et
Borner et
Heinemann et al48
Abbreviation: DCR = disease control rate
37% of patients receiving XELIRI experienced grade 3/4 diarrhea, and 61% required dose reduction, mainly because of nonhematologic toxicity. The authors concluded that celecoxib might reduce, rather than improve, chemotherapy efficacy and that XELIRI should be evaluated at a 20% reduced dose in a future EORTC phase III study.30,33 A second randomized phase III trial (BICC-C) investigated FOLFIRI versus modified IFL (mIFL; irinotecan in combination with 5-FU/leucovorin bolus regimen) versus XELIRI (dosed as above) with or without celecoxib and randomized 145 patients into the XELIRI arm. Efficacy data are shown in Table 3. There was a trend toward higher response rates and improved OS for FOLFIRI compared with the mIFL and XELIRI arms. Progression-free survival was significantly in favor of FOLFIRI. The frequency of grade 3/4 diarrhea (48%) was higher than in any of the previous phase II trials in patients receiving XELIRI. Contrary to the EORTC trial, there were neither increased 60-day mortality rates (XELIRI: 3.5%; FOLFIRI: 2.9%; mIFL: 5.8%), nor increased incidences of thromboembolic events (myocardial infarction/stroke: XELIRI: 0; FOLFIRI: 0.7%; mIFL: 4.4%).31
The CAIRO Trial Currently, the largest cohort of patients (n = 398) with XELIRI first-line treatment for mCRC was investigated by the Dutch Colorectal Cancer Group testing sequential versus combination chemotherapy in a phase III setting (arm A: first-line single-agent capecitabine, second-line single-agent irinotecan, and third-line XELOX; arm B: first-line XELIRI and second-line XELOX).32,34 Patients in arm B received irinotecan 250 mg/m2 and capecitabine 1000 mg/m2, the same doses used in the EORTC 40015 and BICC-C trials. The Dutch trial revealed the following grade 3/4 toxicities: 26% diarrhea, 10% nausea, 9% emesis, 7% febrile neutropenia, and 6% PPE. The frequency of thromboembolic events of all grades was 10% for XELIRI compared with 7% for the capecitabine alone arm and, thus, did not reach a statistically significant difference between the 2 treatment arms (P = .2). Because of the unexpected occurrence of fatal events in the EORTC 40015 trial, the investigators of the CAIRO
trial focused on treatment-related fatal events in their study. The 60-day mortality rate was 4.5% for the XELIRI arm and 3% for the capecitabine treatment arm. Three deaths in the XELIRI and 8 deaths in the capecitabine arm were considered “probably” related to treatment. The most frequent complication leading to death was sepsis on the background of neutropenia. Reviewing the charts of the deceased patients, the authors revealed major protocol violations in 9 of these 11 cases. These violations included application of irinotecan despite hyperbilirubinemia and continued full-dose capecitabine despite grade 3/4 diarrhea. Five more patients in the XELIRI arm and 1 patient in the capecitabine arm died suddenly. Four of these 6 patients were known to have a history of cardiovascular risk factors. The investigators of the Dutch trial concluded that the overall incidence of ischemic and thromboembolic events were comparable and low in both arms. They did not exceed the incidences observed in recent phase III trials investigating fluoropyrimidine and irinotecan combinations.23,35 As a result, the negative results of the EORTC 40015 and the BICC-C trials were not confirmed in this much larger cohort of patients receiving XELIRI. Efficacy data of the CAIRO trial could underline the positive results of earlier phase II trials with a response rate of 41%, a disease control rate of 87%, PFS of 7.8 months, and an OS reaching 17.4 months for patients treated with XELIRI as first-line treatment.32
Recommendations Regarding XELIRI The gastrointestinal toxicity of XELIRI needs to be addressed with caution. The incidence of grade 3/4 diarrhea varies considerably across different trials. Treatment efficacy appears to be compromised in the trials with the highest incidences of diarrhea (eg, EORTC 40015 and BICC-C; Table 3). However, it reached an acceptable rate of 26% in the CAIRO trial. Grade 3/4 diarrhea seems to be less frequent with regimens combining irinotecan in a biweekly schedule with infusional 5-FU and leucovorin (13%),8 while higher incidence rates were observed with weekly FOLFIRI regimens (29%44%).5,35 Patients need to be informed in detail about the possibility of delayed diarrhea and measures to be taken, such as Clinical Colorectal Cancer March 2008 • 113
Cetuximab plus XELIRI or XELOX for mCRC Table 5
Cetuximab plus Irinotecan-Based Regimens in the First-Line Treatment of Metastatic Colorectal Cancer: Results from Phase I/II Trials and the Phase III CRYSTAL Study
Study Rosenberg et
al49
Treatment
N
CR + PR (%) DCR (CR + PR + SD) TTP (Months) OS (Months) Resection Rate (%)
IFL + Cetuximab
29
48
89
–
–
–
FUFIRI (AIO) + Cetuximab
21
67
96
9.9
33
19
Peeters et al51
FOLFIRI + Cetuximab
42
45
83
Response duration, 10
23
24
Venook et al41
FOLFIRI + Cetuximab
55
44
76
10.6
–
–
Heinemann et al48
XELIRI + Cetuximab
27
41
89
–
–
–
Van Cutsem et al13
FOLFIRI + Cetuximab
599 (Phase III)
47
84
PFS, 8.9
–
6
Folprecht et al50
Abbreviation: DCR = disease control rate
immediate antidiarrheic medication and sufficient fluid intake at home, presentation at a hospital in case of diarrhea associated with fever or neutropenia, or hospitalization because of insufficient oral compensation of fluid loss. Furthermore, it is mandatory to comply with specified protocol guidelines in order to prevent severe toxicities. Doses of irinotecan and capecitabine need to be adjusted in case of liver or renal dysfunction, and doses must be reduced if patients present significant gastrointestinal toxicity. Provided these measures apply, the combination of capecitabine and irinotecan is a highly effective option for first-line treatment of patients with mCRC. Further investigation in phase III trials as well as combinations with biologic agents is warranted.
The EGFR Antibody Cetuximab and Its Role in the First-Line Treatment of Metastatic Colorectal Cancer Epidermal Growth Factor Receptor and Cetuximab The epidermal growth factor receptor is a protein tyrosine kinase and a member of the ErbB receptor family. In resting nontransformed cells, EGFR and its intracellular downstream signaling cascade are tightly controlled, and the cells have very low levels of tyrosyl phosphorylated proteins. This makes EGFR an excellent target for directed cancer therapy since EGFR is known to be overexpressed in many human tumors, including CRC. This overexpression correlates with poor prognosis. Activation of EGFR by its natural ligands initiates a variety of important steps during malignant transformation, such as cell proliferation and protection from apoptosis, dedifferentiation, angiogenesis, and increased cell migration and invasion favoring the metastatic potential of tumor cells.36-39 Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody that binds EGFR with approximately 10 times higher affinity than its natural ligands. Competitive binding of cetuximab to EGFR prevents ligand-induced phosphorylation of the intracellular tyrosine kinase domain, thus inhibiting activation of the further downstream signaling cascade.40 Cetuximab is known to have synergistic activity with irinotecan. The biologic agent was approved for the treatment of
114 • Clinical Colorectal Cancer March 2008
patients with mCRC after failure of previous irinotecan-based chemotherapy in the United States and in Europe in 2004.11
Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer A number of phase I/II trials could provide consistent data that combinations of the EGFR antibody with the modern chemotherapy regimens FOLFOX, FUFOX (infusional 5-FU/ leucovorin plus oxaliplatin in a weekly schedule), FOLFIRI, FUFIRI (infusional 5-FU/leucovorin plus irinotecan in a weekly schedule), and IFL are feasible and safe. Even though patient numbers of these early trials were limited, response rates from 44% to 77% and disease control rates ranging between 76% and 96% were very encouraging and among the highest ever observed in the systemic therapy of mCRC (Tables 4 and 5).13,41-51
The CRYSTAL Study The CRYSTAL study is a multinational, randomized, phase III trial investigating FOLFIRI with or without cetuximab in the first-line treatment of 1217 patients with mCRC. Van Cutsem et al presented first efficacy results at the 2007 ASCO Annual Meeting13: The primary endpoint of the CRYSTAL study, which was PFS, was met. The combination of FOLFIRI plus cetuximab achieved a PFS of 8.9 months compared with 8 months for the chemotherapy alone arm (P = .0479). Response rates reached 46.9% versus 38.7% in favor of the combination arm (P = .0038). Furthermore, the results on secondary resection rates in this large phase III trial were of particular interest: In the FOLFIRI plus cetuximab arm, 6% of patients were able to undergo secondary resection of their residual tumors, whereas only 2.5% of patients were rendered operable by FOLFIRI alone. In 4.3% versus 1.5% of patients, the secondary surgical approach achieved an R0 resection. This difference was statistically significant (P = .0034). One hundred thirty-four patients in the FOLFIRI alone arm and 122 patients in the FOLFIRI plus cetuximab arm entered the study with inoperable metastases confined to the liver. The secondary resection rates of this subgroup of patients more than doubled (9.8% vs. 4.5%) by the combination of FOLFIRI plus the EGFR antibody. Because surgical resection of residual liver metastases offers a chance of
Nicolas Moosmann, Volker Heinemann long-term survival, these results are clinically important. Adam et al showed that a 5-year survival rate of 34% and a 10-year survival rate on the order of 20% can be achieved in patients whose liver metastases become resectable after chemotherapy.52,53 These survival data are clearly superior to long-term survival data of systemic treatment alone, even when modern chemotherapy is combined with targeted agents.
Cetuximab plus XELIRI or XELOX for the First-Line Treatment of Metastatic Colorectal Cancer To date, only preliminary data of 3 clinical trials are available for the combination of XELIRI or XELOX with the EGFR antibody cetuximab: The British COIN trial, the Swiss SAKK 41/04 trial, and the German CIOX trial.46,48,54 The COIN trial is a 3-arm phase III trial investigating continuous oxaliplatin-based chemotherapy versus continuous oxaliplatin-based chemotherapy plus cetuximab versus intermittent oxaliplatin-based chemotherapy. Because the chemotherapy backbone in the COIN trial can be chosen between a modified FOLFOX regimen or XELOX by the treating doctor, this trial will provide important data on XELOX plus cetuximab and help to answer the question of whether XELOX will be able to replace FOLFOX in combination with cetuximab. Preliminary safety results of the first 804 patients, including 152 patients receiving XELOX plus cetuximab, were reported at the 2007 ASCO meeting.54 Maughan et al concluded that the addition of cetuximab to FOLFOX or XELOX results in an overall increase of grade 3/4 toxicities of approximately 20% (XELOX: 30%; FOLFOX: 32%; XELOX plus cetuximab: 51%; and FOLFOX plus cetuximab: 54%). These additional adverse effects comprise higher rates of rash, nausea/ vomiting, diarrhea, and lethargy. In the COIN trial, XELOX plus cetuximab was associated with an increased incidence of diarrhea compared with FOLFOX plus cetuximab (26% vs. 13%), whereas neutropenia occurred significantly less frequently (1% vs. 26%). All-cause mortality and treatmentrelated deaths within 60 days showed no significant differences across the 4 regimens, and the COIN trial is currently continuing accrual to a planned number of 2421 patients. SAKK 41/04 and the CIOX trial are the only 2 trials that can provide preliminary efficacy results (Tables 4 and 5).46,48 SAKK 41/04 is a randomized phase II trial investigating XELOX versus XELOX plus cetuximab. The addition of the EGFR antibody resulted in a 30% increase in response rates (XELOX plus cetuximab: 57%; XELOX: 27%) without compromising safety data. The rate of grade 3/4 diarrhea for XELOX plus cetuximab in this trial was only 8%, and there were no patients showing grade 3/4 neutropenia. The CIOX trial is a randomized phase II trial of the German AIO (Association of Medical Oncology of the German Cancer Society) investigating XELIRI plus cetuximab versus XELOX plus cetuximab. It addresses the currently unanswered question of whether oxaliplatin- or irinotecan-based chemotherapy is the most effective combination partner for the EGFR antibody. A planned interim analysis was presented at the 2006 ASCO
meeting. The very preliminary evaluation indicates an overall response rate of 41% for XELIRI plus cetuximab and 68% for XELOX plus cetuximab, accompanied by high disease control rates of 89% and 92% for the 2 treatment arms, respectively. In the CIOX trial, 19% of patients experienced grade 3/4 diarrhea and 11% grade 3/4 neutropenia in the XELIRI plus cetuximab arm compared with 22% grade 3/4 diarrhea and 3% grade 3/4 neutropenia in the XELOX plus cetuximab arm. This trial has completed recruitment (n = 185), and final evaluation will be available at the 2008 ASCO Annual Meeting. The question of why the aforementioned toxicity data for XELOX or XELIRI plus cetuximab are not consistent across the 3 trials is currently unclear. It might be a result of the very preliminary character of available results. This question will hopefully be answered in the near future with more mature data to be presented.
Conclusion The introduction of the oral fluoropyrimidine capecitabine in the treatment of mCRC was an important step toward offering patients an easier application of therapy requiring fewer admissions to hospital and leading to a higher quality of life for many patients. The combination of capecitabine with oxaliplatin (XELOX) is an equally effective treatment alter-native to standard infusional 5-FU plus oxaliplatin regimens. Combining capecitabine with irinotecan (XELIRI) also achieves promising efficacy data. Owing to the partly overlapping gastrointestinal toxicities of the 2 chemotherapeutic substances, patients must be aware of measures to be taken if delayed diarrhea occurs. Furthermore, the doses of both agents must be adjusted to the patients’ renal and liver function. Dose reduction or treatment delay is mandatory in case of preexisting gastrointestinal toxicity. The EGFR antibody cetuximab achieves impressive results when combined with modern irinotecan-based or oxaliplatinbased chemotherapy regimens. The response rates are among the highest ever observed in the first-line treatment of mCRC, leading to secondary resection in approximately 10%-24% of patients in a number of early trials.44,45,48,50,51,55 These data could recently be confirmed by the CRYSTAL study, a large phase III trial. The combination of FOLFIRI plus cetuximab leads to significantly improved PFS, response rates, and secondary resection rates compared with FOLFIRI alone.13 The increased resection rates are particularly important because a curative surgical approach of liver metastases can provide a chance for long-term survival for a considerable proportion of these patients.52,53 The rationale of combining XELOX or XELIRI with cetuximab is offering patients a simplified and highly effective combined cytotoxic and targeted treatment regimen. Preliminary data of the British COIN trial, the Swiss SAKK 41/04 trial, and the German CIOX trial show that these combinations are feasible and achieve promising efficacy data.46,48,54 Provided these results will be confirmed by more mature data in the near future, these combined cytotoxic and targeted treatment approaches will hopefully add to the growing arsenal of highly effective regimens in the treatment of mCRC. Clinical Colorectal Cancer March 2008 • 115
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116 • Clinical Colorectal Cancer March 2008
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