Original Article
Is Resection of Colorectal Liver Metastases
After a Second-Line Chemotherapy
Regimen Justified?
Antoine Brouquet, MD1; Michael J. Overman, MD2; Scott Kopetz, MD, PhD2; Dipen M. Maru, MD, PhD3;
Evelyne M. Loyer, MD4; Andreas Andreou, MD1; Amanda Cooper, MS1; Steven A. Curley, MD1; Christopher R. Garrett, MD2;
Eddie K. Abdalla, MD1; and Jean-Nicolas Vauthey, MD1
BACKGROUND: Patient outcomes following resection of colorectal liver metastases (CLM) after second-line chemotherapy regimen is unknown. METHODS: From August 1998 to June 2009, data from 1099 patients with CLM were
collected prospectively. We retrospectively analyzed outcomes of patients who underwent resection of CLM after
second-line (2 or more) chemotherapy regimens. RESULTS: Sixty patients underwent resection of CLM after 2 or
more chemotherapy regimens. Patients had advanced CLM (mean number of CLM standard deviation, 4 3.5;
mean maximum size of CLM, 5 3.2 cm) and had received 17 8 cycles of preoperative chemotherapy. In 54 (90%)
patients, the switch from the first regimen to another regimen was motivated by tumor progression or suboptimal radiographic response. All patients received irinotecan or oxaliplatin, and the majority (42/60 [70%]) received a monoclonal antibody (bevacizumab or cetuximab) as part of the last preoperative regimen. Postoperative morbidity and
mortality rates were 33% and 3%, respectively. At a median follow-up of 32 months, 1-year, 3-year, and 5-year overall
survival rates were 83%, 41%, and 22%, respectively. Median chemotherapy-free survival after resection or completion
of additional chemotherapy administered after resection was 9 months (95% confidence interval, 4-14 months). Synchronous (vs metachronous) CLM and minor (vs major) pathologic response were independently associated with
worse survival. CONCLUSIONS: Resection of CLM after a second-line chemotherapy regimen was found to be safe
and was associated with a modest hope for definitive cure. This approach represents a viable option in patients with
C 2011 American Cancer Society.
advanced CLM. Cancer 2011;117:4484–92. V
KEYWORDS: colorectal liver metastases, liver resection, second-line chemotherapy, outcome.
Colorectal cancer is one of the leading causes of cancer death worldwide and was responsible for an estimated
49,920 deaths in 2009 in the United States.1 In most cases, death occurs at the end of the evolution of metastatic disease,
and in the majority of patients, the liver is the first site of metastasis. In patients with colorectal liver metastases (CLM),
liver resection is the only treatment associated with long-term survival. In patients with unresectable CLM, chemotherapy
is the only therapy with a proven survival benefit, and resection may be possible in case of good response to chemotherapy.2 In patients with resectable CLM, preoperative systemic chemotherapy has been used as part of the treatment strategy
to decrease the risk of recurrence after resection.3 Disease progression during preoperative chemotherapy predicts poor
outcome after resection.4 For patients with advanced disease and progression during preoperative chemotherapy, a change
to an alternate chemotherapy regimen is usually recommended, and liver resection may be reconsidered if there is disease
response or stabilization in response to the alternative chemotherapy.5 However, objective response rates to second-line
preoperative chemotherapy are only 4%-28%, hence surgery is rarely an option after failure of first-line chemotherapy.6-10
Furthermore, the safety, efficacy, and outcome of hepatic surgery in patients who received multiple lines of chemotherapy
have been evaluated only in small series of patients who received cetuximab or intra-arterial hepatic artery chemotherapy
infusion as a ‘‘rescue’’ regimen.11-13
Corresponding author: Jean-Nicolas Vauthey, MD, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe
Boulevard, Unit 444, Houston, TX 77030; Fax: (713) 745-1921; [email protected]
1
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 2Department of Gastrointestinal Medical Oncology, The
University of Texas MD Anderson Cancer Center, Houston, Texas; 3Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas;
4
Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
We thank Stephanie P. Deming and Ruth J. Haynes for editing the manuscript.
DOI: 10.1002/cncr.26036, Received: September 13, 2010; Revised: November 22, 2010; Accepted: January 3, 2011, Published online March 28, 2011 in Wiley
Online Library (wileyonlinelibrary.com)
4484
Cancer
October 1, 2011
CLM Resection After Second-Line Chemotherapy/Brouquet et al
In this study, we analyzed the feasibility and outcomes of resection of CLM after a second-line chemotherapy regimen. We aimed to determine the role of liver
surgery in patients with advanced metastatic disease who
received multiple lines of chemotherapy because of suboptimal response or toxicity after first-line chemotherapy.
MATERIALS AND METHODS
Patient Population and Definitions
Between August 13, 1998, and June, 17, 2009, data from
1099 consecutive patients who underwent surgical resection for CLM at 1 institution were collected prospectively.
Inclusion criteria for this study were resection of CLM following second-line (2 or more) chemotherapy regimens
and at least 1 year of follow-up after surgery. The study
was approved by the institutional review board of The
University of Texas MD Anderson Cancer Center
(RCR01-116).
Preoperative Chemotherapy
At The University of Texas MD Anderson Cancer Center,
the institutional guidelines for patients with CLM include
preoperative chemotherapy in almost all patients.5 Exceptions to this practice are patients who develop CLM less
than 1 year after adjuvant chemotherapy for the primary
tumor and patients with small volume CLM at risk of disappearing during chemotherapy and that cannot have
their position radiographically labeled by a fiducial
marker.14,15 In patients with initially resectable CLM,
preoperative short-course chemotherapy (8-12 weeks) is
used. Patients with advanced CLM initially unsuitable for
resection are seen by the surgeon prior to initiation of
chemotherapy to determine whether the patient may be a
surgical candidate with a chemosensitive tumor (radiographic response to chemotherapy). In patients with initially unresectable disease, surgical resection is considered
as soon as the lesions become resectable.5 During treatment, restaging is performed every 3 to 4 cycles on the basis of clinical assessment and imaging. For this study,
imaging studies were retrospectively reviewed for each
patient to measure response according to the Response
Evaluation Criteria in Solid Tumors (RECIST)16
(response defined as complete response, partial response,
stable, or progressive disease) and morphologic criteria17
(response defined as none, incomplete, or optimal
response). Second-line chemotherapy was defined as any
change in chemotherapy regimen administered for CLM
except for the discontinuation of bevacizumab 6-8 weeks
Cancer
October 1, 2011
before surgery. Adjuvant chemotherapy administered for
the primary tumor was not considered first-line chemotherapy for CLM except in patients with CLM detected at
the same time as the primary tumor (synchronous CLM)
and patients who developed CLM during adjuvant chemotherapy for the primary tumor. Reasons for receiving second-line chemotherapy were classified into the following
categories: (1) progression during first-line chemotherapy,
(2) advanced metastases with suboptimal response to the
first-line chemotherapy regimen, or (3) intolerable toxicity of the first-line chemotherapy regimen. A suboptimal
response was defined as a response insufficient to allow
safe resection based on volumetric assessment.
Surgical Procedure, Postoperative
Complications, and Pathologic Findings
Liver resections were performed only with curative
intent—that is, only if it was believed that a complete
tumor resection could be achieved. During laparotomy,
the peritoneal cavity was inspected to rule out extrahepatic
spread of disease. Hepatic palpation and intraoperative
ultrasonography were performed in all cases to better
define the location of the CLM in the liver and their relationship to portal pedicles and hepatic veins. Major hepatectomy was defined as hepatic resection including 3 or
more contiguous liver segments. Radiofrequency ablation
was used in combination with liver resection and only for
small tumors in selected patients when a complete resection with staged resections and portal vein embolization
were not otherwise possible. Data on postoperative morbidity and 90-day mortality were collected prospectively.
The severity of postoperative complications was graded
using the classification of Dindo et al.18 Complete pathologic response was defined as 0% of tumor cells viable,
major pathologic response as 1%-49% of tumor cells viable, and minor pathologic response as 50% or more of tumor cells viable.19 Changes of the nontumorous liver
parenchyma, including nonalcoholic fatty liver disease
(steatosis and steatohepatitis) and sinusoidal dilation,
were assessed semiquantitatively as described previously.20-22 Hepatic injury was defined as steatosis in more
than 30% of the hepatocytes and/or the presence of steatohepatitis (Kleiner score >4) and/or moderate or severe
sinusoidal dilation.
Long-Term Outcome
The decision whether to deliver additional chemotherapy
after resection was made at the time of the follow-up postoperative visit on an individualized basis, based on the
4485
Original Article
presence of possible residual disease, response to preoperative chemotherapy on imaging,16,17 tolerance and number
of cycles of preoperative chemotherapy, and pathologic
response. The policy was to avoid chemotherapy after resection when possible, because most patients who undergo
resection of CLM have already received prolonged chemotherapy. Patients were reassessed via physical examination,
carcinoembryonic antigen serum measurement, and multiphase (liver protocol) computed tomography examination
every 3-4 months after resection, and decisions about
further treatment were made according to the findings on
follow-up workup.
Statistical Analysis
Quantitative and qualitative variables were expressed as
mean standard deviation, median (range), and frequency.
Overall and disease-free survival were calculated using the
Kaplan-Meier method from the date of resection of CLM
and compared using a log-rank test. Chemotherapy-free survival was calculated from the date of resection of CLM in
patients who did not receive postoperative chemotherapy
and from the date of last dose of postoperative chemotherapy in those who did receive postoperative chemotherapy.
For the detection of factors associated with survival
after resection of CLM following second-line chemotherapy regimen, univariate analysis was used to examine the
relationship between overall survival and the following
clinicopathologic variables: rectal (vs other) location of
the primary tumor, presence of regional lymph node metastases (v absence), synchronous (vs metachronous)
CLM, multiple (vs single) CLM (greater than 2), size of
CLM measured at the time of diagnosis (greater or less
than 5 cm), presence of extrahepatic disease, preoperative
serum CEA level >5 ng/dL, progression of disease during
first-line chemotherapy, intolerable toxic effects during
first-line chemotherapy, total number of cycles of chemotherapy, number of cycles of the last chemotherapy regimen, partial or stable disease after last chemotherapy
regimen according to RECIST criteria, morphologic
response after last chemotherapy regimen, occurrence of
major postoperative complications, pathologic response
(complete or major vs minor), and postoperative chemotherapy. All variables associated with survival with P < .2
in univariate proportional hazards model were subsequently entered into a Cox multivariate regression model
with backward elimination. P < .05 was considered statistically significant. Comparisons between groups were analyzed via chi-squared or Fisher’s exact test for proportions,
Mann-Whitney U test for medians, and Student t test for
4486
Figure 1. The number of patients undergoing resection of
colorectal liver metastases after second-line chemotherapy
over time is shown.
means, as appropriate. Statistical analysis was performed
using SPSS version 17.2 (SPSS, Chicago, IL).
RESULTS
Patient Characteristics
Among the 1099 patients who underwent resection of
CLM during the study period, 230 did not receive any preoperative chemotherapy, and 809 received only 1 line of
preoperative chemotherapy before surgery. The remaining
60 (5%) patients received 2 or more lines of preoperative
chemotherapy and were the subjects of our study. The
number of patients who underwent resection of CLM after
a second-line chemotherapy increased over time (Figure 1).
The patient characteristics are summarized in Table 1.
The majority (38/60 [63%]) of patients had synchronous
and multiple CLM. Twelve (20%) patients had at least 5
CLM, and 25 (42%) patients had CLM measuring at least
5 cm in diameter. The 13 patients who had metachronous
CLM had previously received adjuvant chemotherapy for
node-positive primary tumors (5-fluorouracil and levamisole in 8 patients, 5-fluorouracil and oxaliplatin in 5
patients). The median time between the last cycle of adjuvant chemotherapy and the detection of CLM in these 13
patients was 28 months (range, 4-90 months). Fourteen
(23%) patients had extrahepatic disease, including 8
patients with resectable lung metastases, 5 patients with
portal node involvement, and 1 patient with pelvic local
recurrence of rectal cancer.
Preoperative Chemotherapy
Characteristics of preoperative chemotherapy are detailed
in Table 2. Most patients received oxaliplatin- or irinotecan-based chemotherapy as first-line treatment. In most
Cancer
October 1, 2011
CLM Resection After Second-Line Chemotherapy/Brouquet et al
Table 1. Clinicopathologic Characteristics, Operative Details,
and Postoperative Mortality and Morbidity
Table 2. Preoperative Chemotherapy: Regimens, Numbers of
Cycles, and Response Rates
Characteristic
Value
Characteristic
Age, y, meanSD
Sex, women:men
Rectal primary tumor
Positive lymph nodes
Synchronous liver metastases
No. of CLM, meanSD
Size of CLM at diagnosis, cm, meanSD
Bilateral liver metastases
Extrahepatic metastases
Preoperative plasma CEA level, ng/dL,
median (range)
Preoperative portal vein embolization
Two-stage liver resection
59 11
20:40
17 (28)
43 (72)
47 (78)
4 3.5
5 3.2
24 (40)
14 (23)
7 (1-1192)
First chemotherapy regimen
6 (10)
5 (8)
Type of liver resection
Extended hepatectomy
Major hepatectomy
Minor liver resection
Resection combined with radiofrequency ablation
Estimated blood loss, mL, median (range)
Transfusion of packed red blood cells
Positive surgical margins
Major or complete pathologic response
Death within 90 days after surgery
Postoperative morbidity
Major postoperative complication
(25)
(42)
(33)
(25)
(25-3100)
(17)
(20)
(32)
(3)
(33)
(17)
cases, the reason for a switch to a different chemotherapy
regimen was tumor progression or advanced disease with
insufficient response. In all patients, the last chemotherapy regimen before resection included irinotecan or oxaliplatin, and in the majority, it was associated with either
cetuximab or bevacizumab. Most patients (39/60 [60%])
had prolonged chemotherapy (more than 6 months or
12 cycles). Twenty-two (37%) patients had objective
response (complete or partial tumor response) with the
last preoperative chemotherapy regimen according to the
RECIST criteria, and 16 (27%) patients had an optimal
morphologic response to the last preoperative chemotherapy regimen.
Feasibility of Resection of CLM After
Second-Line Chemotherapy Regimen
Operative details and postoperative morbidity and mortality are summarized in Table 1. The majority (40/60
[67%]) of patients underwent major liver resection. Two
(3%) patients died within 90 days postoperatively. One
patient developed postoperative bleeding after right hepatectomy that necessitated reoperation; this patient subsequently developed irreversible hepatic failure. The other
October 1, 2011
First chemotherapy regimen included bevacizumab
12
11
37
26
(20)
(18)
(62)
(43)
Indication for switch to second
chemotherapy regimen
Progression during first regimen
Advanced metastases with insufficient
response with or without toxicity
Intolerable toxicity
Empiric or unknown
30 (50)
24 (40)
4 (6)
2 (4)
No. of chemotherapy regimens received
15
25
20
15
337
10
12
19
2
20
10
SD indicates standard deviation; CLM, colorectal liver metastases; CEA,
carcinoembryonic antigen.
Data are presented as no. of patients (%) unless indicated otherwise.
Cancer
5-FU-based
5-FU- and oxaliplatin-based
5-FU- and irinotecan-based
Value
2
>2
57 (95)
3 (5)
Last chemotherapy regimen
555555-
FU
FU
FU
FU
FU
FU
1
1
1
1
1
1
irinotecan
irinotecan 1 bevacizumab
irinotecan 1 cetuximab
oxaliplatin
oxaliplatin 1 bevacizumab
oxaliplatin 1 cetuximab
No. of cycles of last chemotherapy regimen,
meanSD
Total no. of cycles of preoperative
chemotherapy, meanSD
14 (23)
17 (28)
10 (17)
4 (7)
12 (20)
3 (5)
7.5 4.6
17 7.8
Radiographic response to last
chemotherapy regimen according to RECIST
Complete response
Partial response
Stable disease
Progressive disease
Optimal morphologic response to last chemotherapy regimen
1
21
22
16
16
(2)
(35)
(37)
(27)
(27)
5-FU indicates 5-fluorouracil; RECIST, Response Evaluation Criteria for
Solid Tumors; SD, standard deviation.
Data are presented as no. of patients (%) unless indicated otherwise.
patient had a bile leakage with multiple infectious complications after segmental resection and lymphadenectomy.
Ten (17%) patients developed major postoperative complications necessitating a surgical, endoscopic, or radiologic procedure. On pathologic examination, 48 (80%)
patients had a complete resection, and 19 (32%) patients
had major or complete pathologic response to systemic
therapy. Upon histopathologic review of the nontumorous liver, 15 (25%) patients had substantial hepatic
injury. Four patients had moderate or severe sinusoidal
injuries, 12 patients had steatosis >30%, and 4 patients
had steatohepatitis. Five (8%) patients had overlapping
injuries (steatosis >30% associated with steatohepatitis in
4 patients, steatosis >30% associated with moderate sinusoidal dilation in 1 patient).
4487
Original Article
Figure 2. Overall and disease-free survival are shown.
Long-Term Outcomes and Postoperative
Chemotherapy
After a median follow-up time of 32 months, 1-year, 3-year,
and 5-year overall survival rates were 83%, 41%, and 22%,
respectively, and 1-year, 3-year, and 5-year disease-free survival were 37%, 11%, and 11%, respectively (Figure 2).
Twenty-six (43%) patients received postoperative
chemotherapy. Forty-nine (81%) patients experienced recurrence, and palliative chemotherapy was restarted in all
of them. Among these patients, 8 underwent surgery
(resection of lung metastases in 5 patients; repeat liver
resection in 2 patients; resection of local recurrence of
rectal cancer in 1 patient). Median chemotherapy-free survival time was 9.2 months (95% confidence interval, 4-14
months) after surgery or after the end of postoperative
chemotherapy (Figure 3). In the 34 patients who did not
receive postoperative chemotherapy, the median chemotherapy-free survival time was 12 months (95% confidence
interval, 6-18 months). Eight patients were alive and free of
disease 12 months after resection (Figure 4).
Predictors of Survival After Resection of CLM
After Second-Line Chemotherapy Regimen
Results of univariate and multivariate analysis for factors
associated with survival after resection of CLM after secondline chemotherapy regimen are summarized in Table 3.
Univariate analysis showed that synchronous CLM, multiple CLM, absence of radiographic response or stability
of CLM by RECIST, and minor pathologic response were
associated with worse survival. On multivariate analysis,
only synchronous CLM and minor pathologic response
4488
Figure 3. Chemotherapy-free survivals in patients who
received postoperative chemotherapy after resection of colorectal liver metastases are shown. Chemotherapy-free survival
was calculated from the end of postoperative chemotherapy.
were independent factors of worse survival (Figure 5).
The 5-year survival rate was 10% in patients with both
factors, compared with 32% in patients with neither factor (P < .001).
DISCUSSION
Our study shows that hepatectomy for CLM after a second-line chemotherapy regimen is feasible and associated
with a modest survival benefit in patients who present
with advanced CLM and have a suboptimal response to
systemic therapy. Although oncologic outcomes seen in
this series are not as good as previously reported after
resection of CLM after first-line chemotherapy, resection
of CLM after second-line chemotherapy regimen can be
associated with prolonged survival and a chemotherapyfree interval and therefore represents a reasonable alternative in patients with advanced CLM.
To our knowledge, this is the largest series evaluating outcome of patients undergoing resection of CLM
after second-line chemotherapy regimen. We found
1-year and 3-year overall survival rates of 83% and 41%,
respectively, and 1-year and 3-year disease-free survival
rates of 37% and 11%, respectively. The 1-year overall
survival rate reported in this study compares favorably to
the 1-year survival rates of 28%-40% reported previously
in small series of patients treated with cetuximab or intraarterial hepatic artery chemotherapy infusion as secondline therapy.11,13,23 This approach was associated with a
median chemotherapy-free interval of 9 months after liver
resection or after completion of additional chemotherapy
Cancer
October 1, 2011
CLM Resection After Second-Line Chemotherapy/Brouquet et al
Figure 4. Contrast-enhanced computed tomography images of a 52-year-old man with diffuse multiple bilateral synchronous
colorectal liver metastases are shown. The images depict scans taken (A) at diagnosis, (B) after 4 cycles of FOLFOX and bevacizumab, (C) after 6 cycles of FOLFIRI and bevacizumab followed by first stage resection of left liver metastases, and (D) after
second-stage right hepatectomy resection of liver metastases. Indication for second-line chemotherapy was advanced disease
with suboptimal response to therapy. The patient was alive and free of disease at last follow-up, 3 years after resection.
administered after resection. We believe this represents an alternative to maintenance chemotherapy in patients with
advanced disease in addition to modest possible survival
benefit.
Over the past decade, the oncosurgical strategy of
combining effective preoperative chemotherapy with an
aggressive surgical approach has received wide acceptance
for the treatment of CLM.2,3,19 In addition to lowering
recurrence rates after resection,3 preoperative chemotherapy guides the treatment strategy, because tumor response
to preoperative chemotherapy represents a powerful prognostic factor in patients undergoing resection.17,19 Tumor
progression during chemotherapy is considered a contraindication to resection of CLM by most oncologic teams.4
In patients who experience disease progression or develop
severe toxic effects during first-line chemotherapy, a second-line regimen is usually introduced. Although this
Cancer
October 1, 2011
approach has been shown to improve survival, reported
radiographic response rates after second-line chemotherapy are only 4%-28%.6-10 Our finding of a 37% objective
radiographic response rate is consistent with rates reported
by others, illustrating the difficulty in obtaining a tumor
response with second-line chemotherapy. The extent of
the disease probably contributes to the 20% positive margins after resection in our population. However, this rate
remains acceptable with regard to previously reported
data in patients with advanced colorectal liver metastases
that can be up to 46%.24 Recently, yttrium 90 microsphere hepatic artery radioembolization has been proposed as an alternative to second-line chemotherapy as it
has been shown to improve survival compared to intravenous fluorouracil in patients with unresectable CLM
refractory to therapy.25 However, with yttrium 90 radioembolization, the radiographic tumor response rate rarely
4489
Original Article
Table 3. Univariate and Multivariate Analysis of Predictors of Survival
Predictor
Univariate
Analysis
P
Rectal primary tumor
Positive lymph nodes
Synchronous liver metastases
Multiple CLM
Maximum size of CLM 5 cm
Extrahepatic disease
CEA level >5 ng/dL
Progression during first chemotherapy regimen
Toxic effects during first chemotherapy regimen
Six or more cycles of second-line chemotherapy regimen
Sixteen or more cycles of total chemotherapy
Radiographic response or stability after last
chemotherapy regimen
Morphologic response
Major postoperative complication
Positive surgical margins
Minor pathologic response
Postoperative chemotherapy
.26
.98
.02
.02
.6
.28
.47
.28
.82
.64
.16
.01
.25
.08
.29
.05
.77
Multivariate
Analysisa
P
HR (95% CI)
.003
.2
4.5 (1.7-12)
.06
.4
.1
.006
3.4 (1.4-8.2)
HR indicates hazard ratio; CI, confidence interval; CLM, colorectal liver metastases; CEA, carcinoembryonic antigen.
a
Cox regression multivariate analysis included all variables with P<.2 on univariate analysis.
exceeds 10%, and the median survival rarely exceeds
1 year.
The majority of patients in our series had disease
progression or a suboptimal response following first-line
chemotherapy. Interestingly, patients with progression
during first-line systemic therapy did not appear to have a
worse outcome than patients who were switched to a second regimen because of inadequate response or toxic
effects. We identified synchronous metastases and pathologic response as prognostic factors in our patients and
found that the combination of these 2 factors adversely
affected survival (10% 5-year overall survival rate when
the 2 factors were present). The low rate of major or complete pathologic response (32%) in this study compared
with data reported previously using modern first-line
chemotherapy (45%-58%) probably reflects unfavorable
tumor biology. Although the type of regimen, the duration of chemotherapy, and the use of a monoclonal antibody in first-line or last chemotherapy regimen was not
associated with prognosis, we believe that the administration of a monoclonal antibody (e.g., bevacizumab or
cetuximab) as second-line therapy when it was not
given as first-line therapy may be an option, because it is
associated with improved radiographic response rate or
survival in patients with advanced metastatic colorectal
cancer.11,19,26,27 Other recommendations to optimize
treatment strategy in these patients receiving second-line
4490
chemotherapy for CLM might focus on the timing of surgery that should be proposed as soon as the disease is
resectable.
This study has some limitations. Study inclusion
was not based on the extent of the disease, because the definition of resectability is often controversial,27 but on
treatment with second-line preoperative chemotherapy
regimens and subsequent liver resection with curative
intention. Not all patients received the same chemotherapy regimens before surgery, and we did not analyze
patients with advanced CLM who received second-line
chemotherapy regimen and did not undergo resection. It
was a retrospective review of data acquired prospectively
and thus suffers from the limitations of retrospective
studies, including potential selection bias. However, we
believe that a phase 2 or 3 trial would be impractical to
address this question. The comparison with a nonresected group was not performed, because resectable
CLM remain a surgical indication, and progression during chemotherapy a relative contraindication to resection. It was not possible to select a population of patients
receiving chemotherapy only with comparable disease
extent.
In conclusion, this study showed that resection of
CLM following second-line chemotherapy regimen is feasible and may be associated with a modest survival benefit.
Given the lack of highly effective treatment options for
Cancer
October 1, 2011
CLM Resection After Second-Line Chemotherapy/Brouquet et al
REFERENCES
Figure 5. Overall survival according to timing of detection of
liver metastases (A) and pathologic response (B) is shown (P
¼ .02 and P ¼ .05, respectively).
patients with liver only metastatic disease with suboptimal
response to initial chemotherapy, we consider liver resection for selected patients following second-line therapy an
appropriate alternative. Not all patients receiving second-line chemotherapy for advanced CLM can benefit
from resection, however; in the future, refinements in
the assessment of tumor response should help to select
surgical candidates in this challenging therapeutic
setting.17,28,29
FUNDING SOURCES
Supported in part by the National Institutes of Health through
MD Anderson Cancer Center Support Grant CA016672.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
Cancer
October 1, 2011
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009.
CA Cancer J Clin. 2009;59:225-249.
2. 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;240:644-657.
3. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative
chemotherapy with FOLFOX4 and surgery versus surgery
alone for resectable liver metastases from colorectal cancer
(EORTC Intergroup trial 40983): a randomised controlled
trial. Lancet. 2008;371:1007-1016.
4. Adam R, Pascal G, Castaing D, et al. Tumor progression
while on chemotherapy: a contraindication to liver resection
for multiple colorectal metastases? Ann Surg. 2004;240:
1052-1061.
5. Kopetz S, Vauthey JN. Perioperative chemotherapy for resectable hepatic metastases. Lancet. 2008;371:963-965.
6. Cunningham D, Humblet Y, Siena S, et al. Cetuximab
monotherapy and cetuximab plus irinotecan in irinotecanrefractory metastatic colorectal cancer. N Engl J Med. 2004;
351:337-345.
7. 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;
22:229-237.
8. Kim GP, Sargent DJ, Mahoney MR, et al. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal
carcinoma previously treated with fluorouracil: N9841. J Clin
Oncol. 2009;27:2848-2854.
9. Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO):
a phase III randomised controlled trial. Lancet. 2007;370:
135-142.
10. Seymour MT, Maughan TS, Ledermann JA, et al. Different
strategies of sequential and combination chemotherapy for
patients with poor prognosis advanced colorectal cancer
(MRC FOCUS): a randomised controlled trial. Lancet.
2007;370:143-152.
11. Adam R, Aloia T, Levi F, et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol.
2007;25:4593-4602.
12. Elias D, Bonnet S, Honore C, et al. Comparison between
the minimum margin defined on preoperative imaging and
the final surgical margin after hepatectomy for cancer: how
to manage it? Ann Surg Oncol. 2008;15:777-781.
13. Goere D, Deshaies I, de Baere T, et al. Prolonged survival of
initially unresectable hepatic colorectal cancer patients treated
with hepatic arterial infusion of oxaliplatin followed by radical surgery of metastases. Ann Surg. 2010;251:686-691.
14. Benoist S, Brouquet A, Penna C, et al. Complete response
of colorectal liver metastases after chemotherapy: does it
mean cure? J Clin Oncol. 2006;24:3939-3945.
15. Zalinski S, Abdalla EK, Mahvash A, Vauthey JN. A marking technique for intraoperative localization of small liver
metastases before systemic chemotherapy. Ann Surg Oncol.
2009;16:1208-1211.
16. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines
to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer,
4491
Original Article
17.
18.
19.
20.
21.
22.
National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-216.
Chun YS, Vauthey JN, Boonsirikamchai P, et al. Association of computed tomography morphologic criteria with
pathologic response and survival in patients treated with
bevacizumab for colorectal liver metastases. JAMA. 2009;
302:2338-2344.
Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a
cohort of 6336 patients and results of a survey. Ann Surg.
2004;240:205-213.
Blazer DG, 3rd, Kishi Y, Maru DM, et al. Pathologic
response to preoperative chemotherapy: a new outcome end
point after resection of hepatic colorectal metastases. J Clin
Oncol. 2008;26:5344-5351.
Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based
chemotherapy in patients with metastatic colorectal cancer.
Ann Oncol. 2004;15:460-466.
Kleiner DE, Brunt EM, Van Natta M, et al. Design and
validation of a histological scoring system for nonalcoholic
fatty liver disease. Hepatology. 2005;41:1313-1321.
Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy
regimen predicts steatohepatitis and an increase in 90-day
mortality after surgery for hepatic colorectal metastases.
J Clin Oncol. 2006;24:2065-2072.
4492
23. Boige V, Malka D, Elias D, et al. Hepatic arterial infusion
of oxaliplatin and intravenous LV5FU2 in unresectable liver
metastases from colorectal cancer after systemic chemotherapy failure. Ann Surg Oncol. 2008;15:219-226.
24. de Haas RJ, Wicherts DA, Flores E, et al. R1 resection by
necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg. 2008;248:626-637.
25. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III
trial comparing protracted intravenous fluorouracil infusion
alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to
standard chemotherapy. J Clin Oncol. 2010;28:3687-3694.
26. Ribero D, Wang H, Donadon M, et al. Bevacizumab
improves pathologic response and protects against hepatic
injury in patients treated with oxaliplatin-based chemotherapy
for colorectal liver metastases. Cancer. 2007;110:2761-2767.
27. 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. 2009;11:38-47.
28. de Geus-Oei LF, van Laarhoven HW, Visser EP, et al.
Chemotherapy response evaluation with FDG-PET in
patients with colorectal cancer. Ann Oncol. 2008;19:348-352.
29. Mentha G, Terraz S, Morel P, et al. Dangerous halo after
neoadjuvant chemotherapy and two-step hepatectomy for
colorectal liver metastases. Br J Surg. 2009;96:95-103.
Cancer
October 1, 2011