Randomized Controlled Trial of Cetuximab Plus Chemother

Published Ahead of Print on April 8, 2013 as 10.1200/JCO.2012.44.8308
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.44.8308
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Randomized Controlled Trial of Cetuximab Plus Chemotherapy for Patients With KRAS Wild-Type Unresectable
Colorectal Liver-Limited Metastases
Le-Chi Ye, Tian-Shu Liu, Li Ren, Ye Wei, De-Xiang Zhu, Sheng-Yong Zai, Qing-Hai Ye, Yiyi Yu, Bo Xu,
Xin-Yu Qin, and Jianmin Xu
Processed as a Rapid Communication manuscript
All authors: Zhongshan Hospital, Fudan
University, Shanghai, People’s Republic
of China.
Published online ahead of print at
www.jco.org on April 8, 2013.
Supported by Key Projects of the Clinical Disciplines, administered by the
Ministry of Health.
L.-C.Y., T.-S.L., L.R., and Y.W. contributed equally to this work.
Presented orally at the 10th Annual
Meeting of the Japanese Society of
Medical Oncology, Osaka, Japan, July
26-28, 2012; at the 13th Korea-JapanChina Colorectal Cancer Symposium,
Seoul, Korea, September 8-9, 2012;
and in poster format at the 37th
Congress of the European Society for
Medical Oncology Vienna, Austria,
September 28-October 2, 2012.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Clinical trial information: NCT01564810.
Corresponding author: Jianmin Xu, MD,
PhD, Department of General Surgery,
Zhongshan Hospital, Fudan University,
180 Fenglin Rd, Shanghai, 200032,
People’s Republic of China; e-mail:
[email protected].
© 2013 by American Society of Clinical
Oncology
A
B
S
T
A
C
T
Purpose
To assess the effects of cetuximab plus chemotherapy as first-line treatment for unresectable
colorectal liver metastases (CLMs).
Patients and Methods
After resection of their primary tumors, patients with KRAS wild-type synchronous nonresectable
liver-limited metastases from colorectal cancer were randomly assigned to receive chemotherapy
(FOLFIRI [fluorouracil, leucovorin, and irinotecan] or mFOLFOX6 [modified fluorouracil, leucovorin,
and oxaliplatin]) plus cetuximab (arm A) or chemotherapy alone (arm B). The primary end point was
the rate of patients converted to resection for liver metastases. Secondary end points included
tumor response and survival.
Results
The intent-to-treat population comprised 138 patients; 70 patients were randomly assigned to arm
A and 68 to arm B. After a median of 25.0 months of follow-up, the 3-year overall survival (OS) rate
and median survival time (MST) for all patients were 30% and 24.4 months, respectively. The R0
resection rates for liver metastases were 25.7% (18 of 70 patients) in arm A and 7.4% (five of 68
patients) in arm B, which were significantly different (P Ͻ .01). Patients in arm A had improved
objective response rates (57.1% v 29.4%; P Ͻ .01), increased 3-year OS rate (41% v 18%;
P ϭ .013) and prolonged MST (30.9 v 21.0 months; P ϭ .013) compared with those in arm B. In
addition, in arm A, patients who had resection of liver metastases had a significantly improved
MST (46.4 v 25.7 months; P Ͻ .01) compared with those who did not undergo surgery.
Conclusion
For patients with initially unresectable KRAS wild-type CLMs, cetuximab combined with chemotherapy improved the resectability of liver metastases and improved response rates and survival
compared with chemotherapy alone.
J Clin Oncol 31. © 2013 by American Society of Clinical Oncology
INTRODUCTION
0732-183X/13/3199-1/$20.00
DOI: 10.1200/JCO.2012.44.8308
R
The liver is the most common site of metastasis in
patients with colorectal cancer (CRC). Approximately half of patients with CRC develop hepatic
metastases (LMs) during the course of disease,1 and
LM is responsible for death in at least two thirds of
those with CRC.2 In the absence of treatment, the
prognosis of patients with LMs is dismal, with a
5-year survival rate approaching zero.3,4
Over the past decade, with the introduction of
irinotecan- or oxaliplatin-based combination chemotherapy, the median survival among patients with
colorectal LMs (CLMs) has increased from 6 to 8
months to Ͼ 20 months.5In recent years, drug de-
velopment has focused on agents targeting molecular pathways that are expressed strongly or
exclusively by tumor cells. One of the most promising targets is the epidermal growth factor receptor
(EGFR), which is activated in colorectal tumors. As a
strong EGFR inhibitor,6 cetuximab (Erbitux; Merck
Serono, Darmstadt, Germany) has rapidly gained
attention for the treatment of CLM.
Although numerous publications have reported the efficacy of cetuximab in combination
treatment for patients with unselected metastatic
CRC (mCRC), most of these studies have focused
solely on addressing the impact of KRAS mutation
status or various combined chemotherapy regimens
on efficacy.7,8 In contrast, little work has concentrated
© 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on May 24, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
Copyright 2013 by American Society of Clinical Oncology
1
Ye et al
on exploring the impact of this approach on the conversion to secondary
resection of LM,9 which, if feasible, remains the only chance of cure for
patients with CLMs.10,11 In addition, the patients with mCRC enrolled
ontothesecetuximab-basedstudieswereprimarilyfromEuropeorNorth
America rather than from East Asian countries (especially China), which
might have led to trial bias in similar settings because of racial or genetic differences.
In this study, we compared first-line chemotherapy plus cetuximab with chemotherapy alone in Chinese patients with initially unresectable liver-limited KRAS wild-type synchronous mCRC. The
principal goal was to evaluate the effects of cetuximab-containing
treatment on the radical resectability of LM; however, tumor response
and patient survival were also comparatively analyzed.
PATIENTS AND METHODS
Patient Eligibility
Patients were eligible for inclusion if their primary tumors had been
resected and if they had histologically confirmed wild-type KRAS colorectal
adenocarcinoma with synchronous liver-confined metastases deemed nonresectable by a local multidisciplinary team, which included Ͼ three liver surgeons and one radiologist. Other criteria for eligibility were age Ն 18 and Յ 75
years, evidence of tumor EGFR expression, and one measurable tumor. Included patients also had Eastern Cooperative Oncology Group performance
status of 0 to 1, life expectancy Ն 3 months, and adequate hematologic,
hepatic, and renal function.
Patients were excluded if they had previously been exposed to any targeted therapy, chemotherapy, radiotherapy, or intervention therapy for
mCRC. Patients who had suspected brain metastases or other cancers (with
the exception of squamous cell carcinoma of the skin and cervical cancer in
situ) within the previous 5 years were also excluded.
In this controlled trial, patients who met these eligibility criteria were
randomly assigned to chemotherapy plus cetuximab (arm A) or chemotherapy alone (arm B). The choice of chemotherapy (mFOLFOX6 [modified fluorouracil, leucovorin, and oxaliplatin] or FOLFIRI [fluorouracil, leucovorin,
and irinotecan]) was decided before random assignment. All patients provided
written and oral informed consent.
Treatment
Treatment was planned to commence between 2 and 4 weeks after
primary surgery. For arm A, on day 1 of a 14-day treatment cycle, patients
received cetuximab once per week (with an initial loading dose of 400 mg/m2
and thereafter 250 mg/m2) or once every 2 weeks12 (performed after 2011; 500
mg/m2 on day 1 and once every 2 weeks thereafter) followed after 1 hour by
either mFOLFOX6 (day 1: oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, and
fluorouracil 400 mg/m2 intravenous bolus, then 2,400 mg/m2 over 46 hours
continuous infusion) or FOLFIRI (day 1: irinotecan 180 mg/m2 and folinic
acid and fluorouracil, administered as with mFOLFOX6). In arm B, patients
received the same regimen of mFOLFOX6 or FOLFIRI alone.
Treatment continued until tumor response indicated suitability for surgery for LM or until disease progression or unacceptable toxicity. In the event
of predefined toxicity related to chemotherapy or cetuximab, protocolspecified treatment modifications were permitted. Patients with progressive
disease were treated at the discretion of the investigators.
Trial Design
The primary end point was the conversion rate to radical resection for
LM, which was assessed by multidisciplinary team after four cycles and then
every other two cycles up to 12 cycles. LM resectability was determined using
four criteria13-15: one, ability to obtain a complete resection (negative margins); two, preservation of two contiguous hepatic segments; three, preservation of adequate vascular inflow and outflow as well as biliary drainage; and
four, ability to preserve adequate future liver remnant (Ͼ 20% in healthy
liver). Nonresectability was defined as not meeting any of these criteria. To
2
© 2013 by American Society of Clinical Oncology
provide an objective assessment of changes in resectability, radiologic images
were presented by a radiologist to Ͼ three liver surgeons, who were blinded to
the clinical data. Patients were considered to have resectable disease if Ն 50%
of surgeons voted for radical resection of LM. For patients whose LMs were
assessed resectable, resection was scheduled to be performed within 2 to 3
weeks of the last treatment cycle. After resection, patients were advised to
continue the same therapeutic regimen until treatment reached a total of 12
cycles. Disease-free survival was calculated from the date of liver surgery to date
of disease recurrence or last tumor assessment.
Secondary outcomes included tumor response, overall survival (OS),
and progression-free survival (PFS). OS and PFS were further analyzed separately by incidence of LM resection. A retrospective subgroup analysis was
used to investigate the associations between PFS, OS, or response rate and the
BRAF gene mutation status of tumors or whether the patient had undergone
hepatectomy. Adverse events were categorized according to the National Cancer Institute Common Toxicity Criteria, version 3.0.
In this trial, the assessable population was defined as patients who received
the first four cycles of study treatment beyond the first tumor assessment. Tumor
response was assessed by multidisciplinary team with the use of contrast-enhanced
computed tomography or magnetic resonance imaging (and optional positron emission tomography scan), according to RECIST criteria.16,17 When
a complete (CR) or partial remission (PR) was observed, a confirmatory
assessment was performed 4 weeks later. The total number of CRs and PRs
was reported as the overall response rate (ORR), whereas the disease control rate
included CRs, PRs, and stable disease. PFS was defined from date of random
assignment to date of disease progression or death. Patients without disease progression who discontinued the study for any reason were censored at the last
on-study tumor assessment date. OS was calculated from random assignment to
death resulting from any cause or date of last follow-up, at which point the data
were censored. The protocol was approved by the local ethic committees and was
registered with ClinicalTrials.gov.
Statistical Methods and Considerations
Patient baseline characteristics and disease factors were summarized
using descriptive statistics. The categorical parameters were compared using
two-sided Pearson’s ␹2 test or Fisher’s exact test, as appropriate. All summary
statistics on time-to-event variables were calculated according to the KaplanMeier method and were compared by means of the log-rank test. SPSS software (version 16.0; SPSS, Chicago, IL) was used for statistical analyses. A
P value Ͻ .05 was considered significant.
RESULTS
Baseline Patient Characteristics
From June 2008 to December 2011, 204 patients were enrolled at
Zhongshan Hospital. After screening, 138 patients were randomly
assigned (70 in arm A; 68 in arm B) and accordingly formed the
intent-to-treat (ITT) population. Of the ITT population, 22 patients
were considered early dropouts because they discontinued study treatment within the first four treatment cycles, and they were observed
every 2 to 3 months in the study. Thus, the assessable population
consisted of 116 patients (59 in arm A; 57 in arm B; Fig 1). There were
no major imbalances between the two groups in terms of baseline
characteristics18,19 (Table 1). The cutoff date for survival data was June
2012, with a median potential follow-up time for the entire cohort of
25.0 months.
Efficacy
For the ITT population, the median PFS, median survival time
(MST), and 3-year OS rate were 7.3 months, 24.4 months, and 30%,
respectively. After evaluation of resectability by multidisciplinary
team, 20 patients in arm A and nine in arm B were determined to be
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on May 24, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
Effect of Cetuximab Plus Chemotherapy on Unresectable CLMs
Patients enrolled
(N = 204)
Excluded patients
KRAS gene mutation
Extrahepatic metastases
Resectable liver metastases
Refused to participate
Other reasons
(n = 66)
(n = 41)
(n = 13)
(n = 6 )
(n = 4 )
(n = 2 )
Patients randomly assigned
(n = 138)
Arm A
Cetuximab + chemotherapy*
(n = 70)
Early dropout patients
Refused treatment with cetuximab
Allergic reaction
Symptomatic deterioration
Early death (< 3 months)
Lost to follow-up
Evaluated for first response
(arm A, n = 59)
Arm B
Chemotherapy* alone
(n = 68)
(n = 5)
(n = 2 )
(n = 2)
(n = 1)
(n = 1)
Early dropout patients
Asked for treatment with cetuximab
Refused treatment
Early death (< 3 months)
Lost to follow-up
Allergic reaction
Symptomatic deterioration
(n = 3)
(n = 2)
(n = 2)
(n = 2)
(n = 1)
(n = 1)
Evaluated for first response
(arm B, n = 57)
eligible for radical surgery for LM. However, three patients (one in
arm A; two in arm B) refused further surgical intervention, and for
another three patients (one in arm A; two in arm B), R0 resection
could not be obtained at exploration. Ultimately, 18 patients in arm A
and five in arm B achieved an R0 resection. None of the patients who
were early dropouts underwent liver surgery. Nevertheless, the rate of
resection with curative intent was significantly higher in the
cetuximab-containing treatment group than in the chemotherapyalone group (odds ratio, 4.37; P Ͻ .01).
All 18 patients who underwent radical resection for LM in arm A
had objective responses. The median number of treatment cycles
administered before surgery was six (range, four to 12). Of these 18
patients who underwent R0 hepatic resection, 11 (61.1% of all patients) had multiple wedge resections, four (22.2%) had right hepatectomies, and three (16.7%) had left hepatectomies. There were no
serious complications during the perioperative period except for mild
abnormalities of liver function in eight patients. At a median
follow-up of 37.0 months, the median DFS and MST were 10.7 and
46.4 months, respectively. A total of 12 patients (66.7%) experienced
relapse; recurrence primarily involved the hepatic remnant (eight
[66.7%] of 12 patients). Other sites of recurrence included lung (two
[16.7%] of 12 patients) and abdomen/peritoneum (two [16.7%] of 12
patients). Among those patients with liver- or lung-only recurrent
disease, three underwent another metastasectomy and continued
without recurrence. At the cutoff date, six of these 18 patients had died,
and the MST was 36.0 months.
Furthermore, patients in arm A experienced greater survival benefit than those in arm B in terms of OS (3-year survival, 41% v 18%;
www.jco.org
Fig 1. CONSORT diagram. (*) mFOLFOX6
(modified leucovorin, fluorouracil, and oxaliplatin) or FOLFIRI (leucovorin, fluorouracil, and irinotecan).
median, 30.9 v 21.0 months; hazard ratio, 0.54; P ϭ .013) and PFS
(median, 10.2 v 5.8 months; hazard ratio, 0.60; P ϭ .004; Fig 2).
Among patients who did not undergo liver surgery, those in arm A
also experienced increased survival benefit compared with those in
arm B, with regard to MST (P ϭ .050) and PFS (P ϭ .028). However,
among patients undergoing liver surgery, there were no statistically
significant differences between arm A (n ϭ 18) and arm B (n ϭ 5) in
terms of OS and PFS (Table 2).
Subgroup Analysis
Patients undergoing liver surgery had a significantly improved
MST compared with those who did not undergo surgery, whether in
arm A (46.4 v 25.7 months; P ϭ .007) or arm B (36.0 v 19.6 months;
P ϭ .016). For subsets of populations in arm A (Table 3), regardless of
whether the combined chemotherapy regimen was mFOLFOX6 or
FOLFIRI, neither treatment regimen yielded a significant survival
benefit. The association between BRAF mutation status and
cetuximab-based treatment, with regard to ORR and median PFS, was
not significant (P Ͼ .05). Ten patients in arm A harboring mutated
BRAF tended toward worse MST (P ϭ .043); this was not certified in
arm B (P ϭ .45).
Safety Analyses
Overall, the observed toxicity was mostly mild in both arms, and
no deaths were attributable to cetuximab. Grades 3 and 4 toxicities are
listed in Table 2, with no significant differences between the arms. For
patients who underwent secondary surgery, our study revealed no
serious liver toxicities from chemotherapy or cetuximab during the
© 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on May 24, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
3
Ye et al
Table 1. Baseline Patient Demographic and Clinical Characteristics (ITT population)
Arm A: Chemotherapy
Plus Cetuximab (n ϭ 70)
Characteristic
Age, years
Median
Range
Ͼ 65
Sex
Female
Male
ECOG PS
0
1
Clinical risk score†
0-2 (low)
3-4 (intermediate)
5-6 (high)
Primary tumor site
Colon
Rectum
Pathologic stage
I to II
III to IV
No. of liver metastases at diagnosis
1
2-4
Ͼ4
Maximum size of metastases, cm
Ͻ5
Ն5
Involved major vessel
Inferior vena cava
Portal or hepatic vein
None
Reason for unresectability
No.
Location
Size
Combination
Chemotherapy regimen
mFOLFOX6
FOLFIRI
Both (one after the other)
Time between primary surgery and start of treatment
2-4 weeks
Ͼ 4 weeks‡
Maximum length, days
No.
%
Arm B: Chemotherapy
Alone (n ϭ 68)
No.
57.0
26-75
%
59.0
35-75
P‫ء‬
.35
19
27.1
19
27.9
24
46
34.3
65.7
26
42
38.2
61.8
58
12
82.9
17.1
54
14
79.4
20.6
2
50
18
2.9
71.4
25.7
2
42
24
2.9
61.8
35.3
44
26
62.9
37.1
38
30
55.9
44.1
23
47
32.9
67.1
27
41
39.7
60.3
14
26
30
20.0
37.1
42.9
10
28
30
14.7
41.2
44.1
43
27
61.4
38.6
35
33
51.5
48.5
1
25
44
1.4
35.7
62.9
4
26
38
5.9
38.2
55.9
14
17
16
23
20.0
24.3
22.9
32.9
18
14
10
26
26.5
20.6
14.7
38.2
36
22
12
51.4
31.4
17.1
31
21
16
45.6
30.9
23.5
62
8
88.6
11.4
59
9
86.8
13.2
.92
.63
.61
.47
.40
.40
.70
.24
.33
.51
.63
.75
39
41
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFIRI, leucovorin, fluorouracil, and irinotecan; ITT, intent to treat;
mFOLFOX6, modified leucovorin, fluorouracil, and oxaliplatin.
‫ء‬
P values (arm A compared with arm B) were calculated using the ␹2 test for categorical variables and t test for continuous variables.
†Clinical risk score defined by Nordlinger et al.19 Risk factors include age Ն 60 years, extension into serosa of primary cancer, lymphatic spread of primary cancer,
interval Ͻ 2 years from primary tumor to metastasis, number of metastases Ն four, and largest size of liver metastasis Ն 5 cm. Each risk factor was assigned one
point, and total score was compared between patients in arms A and B.
‡Among ITT population, 17 patients delayed treatment because of delayed recovery (n ϭ 10) and delayed decision of choice of chemotherapy regimen (n ϭ 7).
perioperative period.20 With cetuximab plus chemotherapy, there was
a higher incidence of acne-like rash, but this effect was reversible in all
patients. Moreover, regarding the assessable population, patients with
grade 2 to 3 skin reactions experienced greater benefit than those with
grade 0 to 1 skin reactions in terms of ORR and MST, although the
latter was not significant (Table 3).
4
© 2013 by American Society of Clinical Oncology
DISCUSSION
For patients with CLMs, when complete removal of liver-limited
metastases can be achieved, reported 5-year OS rates can reach Ն 55%
under optimal conditions in specialized settings.10 However, Ͻ 20%
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on May 24, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
Effect of Cetuximab Plus Chemotherapy on Unresectable CLMs
B
1.0
Cetuximab + chemotherapy
Chemotherapy alone
0.8
Intent-to-treat population: n = 138
Progression-Free Survival
(probability)
Overall Survival
(probability)
A
0.6
0.4
0.2
HR = 0.54 (95% CI, 0.33 to 0.89); P = .013
0
10
20
30
40
50
1.0
Cetuximab + chemotherapy
Chemotherapy alone
0.8
Intent-to-treat population: n = 138
0.6
0.4
HR = 0.60 (95% CI, 0.41 to 0.87); P = .004
0.2
0
10
Time (months)
No. at risk
Cetuximab +
70
chemotherapy
Chemotherapy alone 68
20
30
40
50
Time (months)
51
26
14
4
0
50
20
6
1
0
No. at risk
Cetuximab +
70
chemotherapy
Chemotherapy alone 68
31
8
3
1
0
14
1
1
1
0
Fig 2. (A) Overall survival curves and (B) Kaplan-Meier progression-free survival for the intent-to-treat population in the cetuximab plus chemotherapy and
chemotherapy-alone treatment arms. HR, hazard ratio.
of patients with LMs are candidates for surgery.21 As such, the current
goal of medical treatment for initially unresectable CLM is to maximize the rate of potentially curative resection, as recommended by the
National Comprehensive Cancer Network (version 1.2012). To reach
this aim, over the past 10 years, one strategy has been to treat these
patients with neoadjuvant systemic chemotherapy, also referred to as
downsizing chemotherapy.21 Although traditional chemotherapeutic
agents (including irinotecan and oxaliplatin) for CLM have demonstrable capacity to reduce tumor burden in the neoadjuvant setting,21
the rate of secondary liver resection remains poor (3.3%).22 As our
data from arm B demonstrate, chemotherapy alone yielded a low rate
of metastasectomy (7.4%). With the introduction of cetuximab, a
higher rate of metastasectomy was achieved for CLM with this neoadjuvant strategy. For instance, in the CRYSTAL (Cetuximab Combined
With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial,8 the addition of cetuximab to FOLFIRI resulted in an increase in the resection rate from 4.5% to 9.8% in a subgroup of
patients with liver-only disease. Similarly, in the OPUS (Oxaliplatin
and Cetuximab in First-Line Treatment of mCRC) study,23 with
FOLFOX plus cetuximab, the resection rate for LM doubled from
2.4% to 4.7%. It must be noted that in both studies, decisions to offer
secondary liver resection were made in many cases by general oncologists, without the input of experienced liver surgeons, so it may be
that many resectable patient cases were missed.24 In our trial, where
entry and end points were determined by liver surgeons, the cetuximab combination yielded a high secondary resectable rate (25.7%)
compared with that in the chemotherapy-alone cohort (7.4%). These
results are in agreement with reported resection rates for patients in
similar settings.25
For 18 patients in arm A and five patients in arm B who reached
the goal of radical metastasectomy, there were few postoperative complications, a reflection of the multidisciplinary team and the experienced hepatic surgeons. The multidisciplinary team approach has
been mandatory for CLM since 2005 within the trial center and meets
weekly, providing objective assessments of changes in resectability.
The hepatic surgeons, members of this multidisciplinary team, perwww.jco.org
form more than 2,000 hepatic surgeries each year in their liver center
and have accumulated a wealth of experience in the resection of LM.
Several large studies have provided evidence that cetuximabbased anticancer agents can increase MST from 20.0 to 23.5 months or
from21.0to24.9monthsinpatientswithmCRC.7,8 Ourdataindicatethat
MST was significantly prolonged (from 21.0 to 30.9 months) with the
addition of cetuximab and improved more than in previous trials in
similar settings, which was partially because of the high converted metastasectomy rate in arm A. The patients who underwent liver surgery
achieved a longer MST (46.4 months). Regarding tumor response, the
ORR in arm A (57.1%) was consistent with previously reported data in
patients with wild-type KRAS mCRC, showing rates of 59% to 61%.7,23
Recently, the combination regimen of FOLFOX and cetuximab
was removed as a treatment option in the National Comprehensive
Cancer Network guideline (version 1.2012) for mCRC because of
recent European and US studies.26-28 One of these was the COIN
(Cetuximab Combined With Oxaliplatin-Based Chemotherapy in
First Therapy for Advanced CRC) trial,26 which reported no OS (17.9
v 17.0 months; P ϭ .67) or PFS benefit (8.6 months in both groups;
P ϭ .60) for patients with wild-type KRAS when cetuximab was added.
However, there are concerns that many patients in the COIN study
underwent significant dose reductions during treatment because of
adverse events, so the full therapeutic benefit of the study arm may not
have been realized. Our study indicated possibly improved MST and
PFS after adding cetuximab to mFOLFOX6 (Table 2); however, these
comparisons and conclusion should be interpreted with caution because of the small sample size.
Although tumor response to cetuximab is restricted to wild-type
KRAS tumors,8,29,30 whether patients with only a BRAF wild-type tumor
benefit from cetuximab remains ambiguous.31 According to our study,
patients with wild-type BRAF status in arm A (n ϭ 10) seemed to experience greater benefit in MST but not in PFS or ORR compared with those
with a BRAF mutation (n ϭ 60). Thus, BRAF mutation should not be
used to exclude patients from cetuximab therapy; however, the data
should be interpreted carefully because of the limited number of patients
in this study, which is by no means conclusive.
© 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on May 24, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
5
Ye et al
Table 2. Efficacy and Adverse Events (ITT population)
Arm A: Chemotherapy Plus
Cituximab (n ϭ 70)
Characteristic
Overall response†
CR
PR
SD
PD
Not assessable‡
ORR (CR plus PR)
DCR (CR plus PR plus SD)
PFS
Median
95% CI
OS, years
Median
95% CI
1
2
3
Surgery for liver metastases
Resection rate from MDT
Actual R0 resection rate§
Patients undergoing liver surgery
PFS
Median
95% CI
OS
Median
95% CI
Patients not undergoing liver surgery
PFS
Median
95% CI
OS
Median
95% CI
Chemotherapy regimenʈ
mFOLFOX6
PFS
Median
95% CI
OS
Median
95% CI
FOLFIRI
PFS
Median
95% CI
OS
Median
95% CI
Adverse events (grade 3 to 4)¶
Acne-like rash
Diarrhea
Leucopenia/neutropenia
Nausea/vomiting
Peripheral neuropathy
6
© 2013 by American Society of Clinical Oncology
Arm B: Chemotherapy Alone
(n ϭ 68)
P‫ء‬
No.
%
No.
%
1
39
16
12
2
40
56
1.4
55.7
22.9
17.1
2.9
57.1
80.0
0
20
23
21
4
20
43
0
29.4
33.8
30.9
5.9
29.4
63.2
.022
.001
.004
10.2
8.6 to 11.4
5.8
3.9 to 6.1
30.9
16.5 to 41.5
21.0
16.7 to 23.4
.013
85
62
41
20
18
18
28.6
25.7
25.7
80
40
18
9
5
5
13.2
7.4
7.4
.027
.004
.91
12.7
9.6 to 16.4
16.5
6.3 to 27.7
46.4
28.3 to 49.7
36.0
29.2 to 48.8
.94
52
74.3
63
92.6
.028
7.7
4.3 to 9.7
5.4
4.1 to 5.9
25.7
19.8 to 28.2
19.6
14.6 to 21.4
.050
36
51.4
31
45.6
.048
10.1
8.2 to 13.8
6.4
4.7 to 7.3
34.8
23.4 to 40.6
22.1
16.9 to 23.1
.041
22
31.4
21
30.9
.114
9.1
6.4 to 11.6
5.2
1.1 to 6.9
23.1
13.8 to 32.2
16.9
9.3 to 16.7
.028
9
4
8
3
3
12.9
5.7
11.4
4.3
4.3
(continued on following page)
2
3
6
3
4
2.9
4.4
8.8
4.4
5.9
.032
1.00
.61
1.00
.72
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on May 24, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
Effect of Cetuximab Plus Chemotherapy on Unresectable CLMs
Table 2. Efficacy and Adverse Events (ITT population) (continued)
Arm A: Chemotherapy Plus
Cituximab (n ϭ 70)
Characteristic
Allergic reaction
Other
Arm B: Chemotherapy Alone
(n ϭ 68)
No.
%
No.
%
P‫ء‬
2
4
2.9
5.7
1
3
1.5
4.4
1.00
1.00
Abbreviations: CR, complete response; DCR, disease control rate; FOLFIRI, leucovorin, fluorouracil, and irinotecan; ITT, intent to treat; MDT, multidisciplinary team;
mFOLFOX6, modified leucovorin, fluorouracil, and oxaliplatin; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free
survival; PR, partial response; SD, stable disease.
‫ء‬
P values were calculated using stratified log-rank test or, in the case of ORR, stratified ␹2 test.
†ORR was assessed after four cycles of treatment; it was not possible to confirm responses after RECIST-specified timeframe in six patients because of metastasectomy.
‡Patients who dropped out early, before first tumor assessment (three patients with early deaths; three lost to follow-up).
§Three patients refused surgery; for another three, R0 resection for liver metastases could not be achieved.
ʈPatients treated with mFOLFOX6 and FOLFIRI (one after the other) were excluded.
¶Adverse events were categorized according to National Cancer Institute Common Toxicity Criteria, version 3.0.
Our study has other limitations. First, the number of patients
analyzed was limited, and follow-up time was short. Therefore, certain
subgroup analyses are unconfirmed, and the 5-year OS rate has not yet
been reached. Second, cetuximab is a high-cost treatment not approved for reimbursement in China. On one hand, patients treated
with additional cetuximab mostly had better economic circumstances
than those treated with chemotherapy alone; on the other hand, the
financial burden led to treatment discontinuation (seven patients in
arm A abandoned the cetuximab-based regimen for economic
factors) and discouraged patients who wanted to receive cetuximab,
which might have resulted in minimal study bias.
There was no evidence to suggest that cetuximab increased the frequency or severity of the known toxicities of oxaliplatin, irinotecan, or
fluorouracil. One concern was that cetuximab-containing chemotherapy
might lead to inhibition of posthepatectomy hepatic regeneration.20 Although the results of our study did not substantiate this concern, it is
important to anticipate and minimize the potential liver toxicities of the
systemic treatment used for tumor shrinkage. Furthermore, in agreement
with previous studies,8,29 we found that higher-grade skin toxicities were
associated with an improved ORR. Although the mechanism of this relationship has not been fully clarified, skin toxicity may be currently regarded as a surrogate marker of therapeutic effectiveness for cetuximab.
Table 3. Subgroup Analysis
ORR‫ء‬
Total Patients
Factor
Arm A
Metastasectomy
Resected
Nonresected
BRAF status
Wild type
Mutated
Combined regimen‡
mFOLFOX6
FOLFIRI
Acne-like rash, grade§
0-1
Ͼ1
Arm B
Metastasectomy
Resected
Nonresected
BRAF status
Wild type
Mutated
No.
%
No.
%
18
52
25.7
74.3
18
22
100.0
42.3
60
10
85.7
14.3
36
4
60.0
40.0
36
22
62.1
37.9
19
13
52.8
59.1
40
19
67.8
32.2
23
16
57.5
84.2
5
63
7.4
92.6
5
15
100.0
23.8
61
7
89.7
10.3
17
3
27.9
42.9
Survival Time
(months)
PFS (months)
P†
Median
Ͻ .01
P†
Median
Ͻ .01
14.3
8.3
.31
.007
46.4
25.7
.30
10.2
8.1
.31
.043
34.3
17.9
.28
10.1
9.1
.043
.24
34.8
23.1
.90
11.1
9.6
.001
.13
29.1
38.8
.002
16.5
5.4
.41
.016
36.0
19.6
.26
5.80
5.25
P†
.45
21.5
18.6
Abbreviations: FOLFIRI, leucovorin, fluorouracil, and irinotecan; ITT, intent to treat; mFOLFOX6, modified leucovorin, fluorouracil, and oxaliplatin; ORR, overall
response rate; PFS, progression-free survival.
‫ء‬
ORR was assessed after four cycles of treatment; it was not possible to confirm responses after RECIST-specified timeframe in six patients because of
metastasectomy. Among ITT population, two patients in arm A and four in arm B were not assessable.
†P values were calculated using stratified log-rank test or, in the case of ORR, stratified ␹2 test.
‡Twelve patients changing from FOLFIRI to mFOLFOX6 (or vice versa) were excluded.
§Assessable population; adverse events were categorized according to National Cancer Institute Common Toxicity Criteria, version 3.0.
www.jco.org
© 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on May 24, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
7
Ye et al
In summary, despite these drawbacks, our study confirmed that
for Chinese patients with initially unresectable CLMs (wild-type
KRAS), the addition of cetuximab to FOLFIRI or mFOLFOX6 was
associated with facilitated radical resections of LMs with minimal
perioperative complications, providing improved long-term survival.
Further investigation in this group of patients, if possible, could shed
additional light on performing a multi-center clinical study in China.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Steele G Jr, Ravikumar TS: Resection of hepatic metastases from colorectal cancer: Biologic
perspective. Ann Surg 210:127-138, 1989
2. Foster JH: Treatment of metastatic disease of
the liver: A skeptic’s view. Semin Liver Dis 4:170179, 1984
3. Stangl R, Altendorf-Hofmann A, Charnley RM,
et al: Factors influencing the natural history of colorectal liver metastases. Lancet 343:1405-1410,
1994
4. Van Cutsem E, Nordlinger B, Adam R, et al:
Towards a pan-European consensus on the treatment of patients with colorectal liver metastases.
Eur J Cancer 42:2212-2221, 2006
5. Goldberg RM, Rothenberg ML, Van Cutsem
E, et al: The continuum of care: A paradigm for the
management of metastatic colorectal cancer. Oncologist 12:38-50, 2007
6. Ciardiello F, Tortora G: EGFR antagonists in
cancer treatment. N Engl J Med 358:1160-1174,
2008
7. Van Cutsem E, Ko¨hne CH, La´ng I, et al:
Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal
cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin
Oncol 29:2011-2019, 2011
8. Van Cutsem E, Ko¨hne CH, Hitre E, et al:
Cetuximab and chemotherapy as initial treatment
for metastatic colorectal cancer. N Engl J Med
360:1408-1417, 2009
9. Petrelli F, Barni S: Resectability and outcome
with anti-EGFR agents in patients with KRAS wildtype colorectal liver-limited metastases: A metaanalysis. Int J Colorectal Dis 27:997-1004, 2012
10. Abdalla EK, Vauthey JN, Ellis LM, et al: Recurrence and outcomes following hepatic resection,
radiofrequency ablation, and combined resection/
ablation for colorectal liver metastases. Ann Surg
239:818-825, 2004; discussion 825-827
11. Choti MA, Sitzmann JV, Tiburi MF, et al:
Trends in long-term survival following liver resection
for hepatic colorectal metastases. Ann Surg 235:
759-766, 2002
AUTHOR CONTRIBUTIONS
Conception and design: Li Ren, Jianmin Xu
Financial support: Jianmin Xu
Administrative support: De-Xiang Zhu, Jianmin Xu
Provision of study materials or patients: Li Ren, Ye Wei, Sheng-Yong
Zai, Bo Xu, Jianmin Xu
Collection and assembly of data: Le-Chi Ye, Tian-Shu Liu, Li Ren, Ye
Wei, De-Xiang Zhu, Sheng-Yong Zai, Yiyi Yu, Bo Xu, Jianmin Xu
Data analysis and interpretation: Le-Chi Ye, Tian-Shu Liu, Ye Wei,
De-Xiang Zhu, Qing-Hai Ye, Xin-Yu Qin, Jianmin Xu
Manuscript writing: All authors
Final approval of manuscript: All authors
12. Tabernero J, Ciardiello F, Rivera F, et al:
Cetuximab administered once every second week
to patients with metastatic colorectal cancer: A
two-part pharmacokinetic/pharmacodynamic phase
I dose-escalation study. Ann Oncol 21:1537-1545,
2010
13. Charnsangavej C, Clary B, Fong Y, et al:
Selection of patients for resection of hepatic colorectal metastases: Expert consensus statement.
Ann Surg Oncol 13:1261-1268, 2006
14. Pawlik TM, Schulick RD, Choti MA: Expanding
criteria for resectability of colorectal liver metastases. Oncologist 13:51-64, 2008
15. Garden OJ, Rees M, Poston GJ, et al: Guidelines for resection of colorectal cancer liver metastases. Gut 55:iii1-iii8, 2006 (suppl 3)
16. Therasse P, Arbuck SG, Eisenhauer EA, et al:
New guidelines to evaluate the response to treatment in solid tumors: European Organisation for
Research and Treatment of Cancer, National Cancer
Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000
17. Eisenhauer EA, Therasse P, Bogaerts J, et al:
New response evaluation criteria in solid tumours:
Revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009
18. Ayez N, Lalmahomed ZS, van der Pool AE, et
al: Is the clinical risk score for patients with colorectal liver metastases still useable in the era of effective neoadjuvant chemotherapy? Ann Surg Oncol
18:2757-2763, 2011
19. Nordlinger B, Guiguet M, Vaillant JC, et al:
Surgical resection of colorectal carcinoma metastases to the liver: A prognostic scoring system to
improve case selection, based on 1568 patients—
Association Franc¸aise de Chirurgie. Cancer 77:12541262, 1996
20. Choti MA: Chemotherapy-associated hepatotoxicity: Do we need to be concerned? Ann Surg
Oncol 16:2391-2394, 2009
21. Adam R: Chemotherapy and surgery: New
perspectives on the treatment of unresectable liver
metastases. Ann Oncol 14:ii13-ii16, 2003 (suppl 2)
22. Delaunoit T, Alberts SR, Sargent DJ, et al:
Chemotherapy permits resection of metastatic colorectal cancer: Experience from Intergroup N9741.
Ann Oncol 16:425-429, 2005
23. Bokemeyer C, Bondarenko I, Hartmann JT, et
al: Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: The OPUS study. Ann
Oncol 22:1535-1546, 2011
24. Jones RP, Vauthey JN, Adam R, et al: Effect
of specialist decision-making on treatment strategies for colorectal liver metastases. Br J Surg 99:
1263-1269, 2012
25. Folprecht G, Gruenberger T, Bechstein WO,
et al: Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: The CELIM
randomised phase 2 trial. Lancet Oncol 11:38-47,
2010
26. Maughan TS, Adams RA, Smith CG, et al:
Addition of cetuximab to oxaliplatin-based first-line
combination chemotherapy for treatment of advanced colorectal cancer: Results of the randomised
phase 3 MRC COIN trial. Lancet 377:2103-2114,
2011
27. Tveit K, Guren T, Glimelius B, et al: Phase III
trial of cetuximab with continuous or intermittent
fluorouracil, leucovorin, and oxaliplatin (Nordic
FLOX) versus FLOX alone in first-line treatment of
metastatic colorectal cancer: The NORDIC-VII study.
J Clin Oncol 30:1755-1762, 2012
28. Bokemeyer C, Bondarenko I, Hartmann JT, et
al: Biomarkers predictive for outcome in patients
with metastatic colorectal cancer (mCRC) treated
with first-line FOLFOX4 plus or minus cetuximab:
Updated data from the OPUS study. J Clin Oncol 28,
2010 (suppl; abstr 428)
29. Lie`vre A, Bachet JB, Boige V, et al: KRAS
mutations as an independent prognostic factor in
patients with advanced colorectal cancer treated
with cetuximab. J Clin Oncol 26:374-379, 2008
30. Karapetis CS, Khambata-Ford S, Jonker DJ, et
al: K-ras mutations and benefit from cetuximab in
advanced colorectal cancer. N Engl J Med 359:17571765, 2008
31. Di Nicolantonio F, Martini M, Molinari F, et al:
Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26:5705-5712, 2008
■ ■ ■
8
© 2013 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on May 24, 2014. For personal use only. No other uses without permission.
Copyright © 2013 American Society of Clinical Oncology. All rights reserved.

Download Report