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Annals of Oncology 23: 26492655, 2012

doi:10.1093/annonc/mds100
Published online 29 April 2012

Colorectal cancer pulmonary oligometastases: pooled

analysis and construction of a clinical lung
metastasectomy prognostic model
S. Salah1*, K. Watanabe2,3, S. Welter4, J. S. Park5, J. W. Park6, J. Zabaleta7, F. Ardissone8,
J. Kim5, M. Riquet9, K. Nojiri10, M. Gisabella8, S. Y. Kim6, K. Tanaka10 & B. Al-Haj Ali1
1
Medical Oncology Department, King Hussein Cancer Center, Amman, Jordan; 2Department of Surgery, Tohoku University, Sendai; 3Department of Surgical Oncology,
National Cancer Center Hospital East, Chiba, Japan; 4Department of Thoracic Surgery and Thoracic Endoscopy, Ruhrlandklinik, Essen, Germany; 5Department of
Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 6Center for Colorectal Cancer, National
Cancer Center. Gyeonggi-do, Korea; 7Thoracic Surgery Service, Hospital Donostia, San Sebastian, Spain; 8Department of Clinical and Biological Sciences, Thoracic
Surgery Unit, University of Turin, San Luigi Hospital, Orbassano (Torino) Italy; 9Department of Thoracic Surgery, Georges Pompidou European Hospital, Paris-Descartes
University, Paris, France; 10Department of Gastroenterological Surgery, Yokohama City University, Yokohama City, Japan

Received 3 December 2011; revised 14 February 2012; accepted 15 February 2012

Background: Although resecting colorectal cancer (CRC) pulmonary metastasis is associated with long-term survival,
identication of prognostic groups is needed for future randomized trials, and construction of a lung metastasectomy
prognostic model (LMPM) is warranted.
Patients and methods: We searched the PubMed database for retrospective studies evaluating prognostic factors
following resecting CRC lung metastasis. Individual patient data were analyzed. Independent prognostic factors were
used to construct an LMPM.
Results: Between 1983 and 2008, 1112 metastasectomies were carried out on 927 patients included in eight studies.
Five-year survival rate was 54.3% following the rst lung resection. Multivariate analysis identied three independently
poor prognostic factors: pre-thoracotomy carcinoembryonic antigen 5 ng/ml, disease-free interval <36 months, and
more than one metastatic lesion. Patients with good-, intermediate-, and high-risk groups according to the LMPM had
a 5-year survival of 68.2%, 46.4%, and 26.1%, respectively (P < 0.001). Perioperative chemotherapy and previously
resected liver metastasis had no inuence on survival.

*Correspondence to: Dr S. Salah, Medical Oncology Department, King Hussein Cancer

Center, Al-Jubeiha, Amman 11941, Jordan. Tel: +962-799-615458; Fax: +962-6-535-
3001; E-mail: ssalah@khcc.jo

The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
original articles
Conclusions: The low- and intermediate-risk groups have a good chance of long-term survival following
metastasectomy. However, more studies are needed to investigate whether surgery offers any advantage over systemic
therapy for the poor-risk group.
Key words: colorectal cancer, metastasectomy, prognostic factors, pulmonary metastasis
introduction
Around 10%15% of patients undergoing surgical resection for
colorectal cancer (CRC) will develop lung metastasis [13].
For the minority of patients with CRC where lungs are the
only site of metastatic disease, although there is absence of
randomized studies, many retrospective studies suggested
improved survival with metastasectomy and curative treatment
of the primary CRC. In several series, encouraging 5-year
survival rates of 40%61% had been reported [47].
Previously, this practice of pulmonary metastasectomy was
applied to few patients with solitary lung metastasis and long
disease-free interval (DFI); however, many retrospective studies
suggested that patients with multiple lung metastases might
benet as well [4, 8].
Most retrospective studies evaluating lung metastasectomy in
the setting of metastatic CRC had evaluated prognostic factors
for survival [913]; however, conicting data regarding some
prognostic factors had been reported.
Some studies had shown better outcome for patients with
longer DFI [1014], solitary rather than multiple metastatic
lesions [11, 15], smaller size of the largest metastatic pulmonary
lesion [15, 16], and normal rather than elevated pre-
thoracotomy carcinoembryonic antigen (CEA) level [10, 12, 16,
17]. On the other hand, some studies failed to show any
inuence on survival based on DFI [8, 18], presence of single
versus multiple lesions [18], or number of metastatic lesions [8].
The international registry of lung metastases had accrued
5206 cases of lung metastasectomy, which is the largest
reported series [19]. A simple prognostic system based on
resectability, DFI, and number of metastases was proposed;
however, it was not specic as it included variety of cancers
including sarcomas, germ cell tumors, melanomas, and
carcinomas.
Constructing a prognostic model specic for CRC
pulmonary oligometastases would be more informative in
assessing the prognosis of this patient population.
Furthermore, such a model may be needed for stratication of
patients enrolled in future randomized trials, as well as for
comparing different cohorts of patients from different
institutions.
methods
search strategy
we searched the PubMed database to identify retrospective studies that
included patients with pulmonary oligometastases from CRC who had
undergone metastasectomy, using the words lung metastasis, colon cancer,
surgery, or metastasectomy.
Articles that were published before the year 2000 and/or included <20
patients were excluded.
The authors of the articles were contacted to provide individual patient
data for each patient included in their studies.
| Salah et al.
Annals Of Oncology
denitions and patients data
We gathered individual patients data about 13 possible prognostic factors
for each of the patients as long as they are available: age, gender, status of
regional lymph node (LN) involvement for the primary CRC, histological
grade of the metastatic cancer, DFI, number of lung metastatic nodules at
rst detection of pulmonary metastasis, maximum diameter of the largest
lung metastatic lesion, type of surgical resection, laterality of metastasis at
rst detection of lung metastasis, pre-thoracotomy CEA level, intrathoracic
LN involvement, whether the patient had received perioperative
chemotherapy or not, and whether the patient had a history of previous
liver metastases.
DFI was dened as the interval from denitive treatment of the primary
CRC until detection of pulmonary metastases. For patients with history of
resection of oligometastases involving another organ, the DFI was dened
as the time from resection of the previous metastasis until the rst
detection of the pulmonary oligometastases. These patients had to be free
of other organ metastases at the time of pulmonary metastasectomy.
Metachronous presentation was dened as detection of pulmonary
oligometastases later than 6 months following the denitive treatment of
the primary CRC or a curative resection of liver metastases.
Synchronous presentation was dened as detection of the pulmonary
oligometastases within 6 months of denitive treatment of the primary
CRC or the curative liver resection, at the same time of initial evaluation of
the primary cancer or before detection of the primary cancer.
patients inclusion and exclusion criteria
Included patients are those who were aged 18 years with oligometastases
conned to one or both lungs and who had undergone surgical resection of
the metastasis.
Patients with any of the following were excluded: extrapulmonary
metastasis at the time of rst detection of lung metastasis, gross residual
disease following resection of the metastases (R2 resection) or positive
resection margins (R1 resection), the primary CRC was not treated
denitively, absence of follow-up data, and if other metastatic sites could
not be ruled out.
statistical analysis
Survival times were calculated from the time of the rst pulmonary
metastasectomy until death or last follow-up.
Survival curves were plotted using the KaplanMeier method.
The 13 possible prognostic factors were evaluated in univariate analysis
using the log-rank test. A P value of <0.05 was considered statistically
signicant.
Factors found to be signicant in the univariate analysis were evaluated
in the multivariate analysis using the backward stepwise regression model.
The impact of each independent prognostic factor on survival was
interpreted for the entire cohort of patients, as well as per study, using
hazard ratios with corresponding 95% condence intervals (CI).
An assessment of heterogeneity among patients included from the
different studies was carried out using a xed effect model, which tests
variation using a 2 test.
All analyses were carried out with SPSS version 13.0 J software (SPSS,
Tokyo, Japan).
Volume 23 | No. 10 | October 2012
Annals Of Oncology original articles
results Table 2. Patients characteristics at the time of rst metastasectomy of
colorectal cancer (CRC) lung metastases
search results and patients
We identied 83 retrospective studies evaluating outcomes Clinical variable No. of patients (%)
following resection of CRC pulmonary oligometastases. Of the Gender
83 studies, 43 were excluded for the following reasons: 18 Male 568 (29)
studies for being published before the year 2000, 14 studies Female 359 (71)
because each included <20 patients, and 10 studies were LN in the primary CRCa
excluded for both reasons. Involved 478 (52)
Of the remaining 41 articles, we were able to collect Not involved 309 (33)
individual patient data from eight retrospective studies Missing data 140 (15)
(Table 1). Pre-thoracotomy CEA (ng/ml)
These eight articles included 988 patients. Of those, 61 were 5 240 (26)
excluded for the following reasons: 24 for synchronous lung <5 474 (51)
and liver metastases, 36 for R1 or R2 resection, and 1 for Missing data 213 (23)
History of liver metastasis
uncertain survival data. After excluding the 61 patients, 927
Yes 236 (25)
patients were eligible for analysis.
No 691 (75)
Status of lymph nodes in thorax
patients characteristics Involved 75 (8)
The characteristic of patients and their metastatic CRC are Not involved 424 (46)
summarized (Table 2). Sampling or dissection not carried out 297 (32)
Missing data 131 (14)
Median age at rst metastasectomy was 62.6 years.
Type of surgical resection
The median DFI was 25.6 months (range, 0181.6 months).
Sublobectomy 555 (60)
Eight hundred and ten patients (87%) had metachronous
Lobectomy 186 (20)
metastasis, 104 patients (11%) had synchronous metastasis,
Pneumonectomy 12 (1)
while data were not available for 13 patients (2%). Previous Missing data 174 (19)
liver resection was carried out on 236 patients (25%). Laterality of metastasisb
Mean follow-up after the rst pulmonary metastasectomy Unilateral 635 (68)
was 43.3 months, standard deviation = 32.5 months. Bilateral 91 (10)
Data on the administration of perioperative chemotherapy Missing data 201 (22)
was available for only 444 patients (48%); 171 patients received Maximum diameter of largest nodule (cm)
chemotherapy and 273 did not. <2 386 (42)
The assessment of heterogeneity among patients included 2 523 (56)
from the different studies using a xed effect model did not Missing data 18 (2)
demonstrate signicant differences regarding age, number of No. of metastatic nodules:
patients with more than one metastatic nodule, number of 1 558 (60)
patients with synchronous versus metachronous metastasis, 2 364 (39)
type of surgical resection, pre-thoracotomy CEA level, DFI, Missing data 5 (1)
and number of patients with maximum size of the largest lung DFI (months)
metastatic lesion of 2 cm, 2 < 0.0001. 36 310 (33)
<36 603 (65)
Missing data 14 (2)
surgical outcomes Histological grade
Between 1983 and 2008, 1112 thoracotomies were carried out Well/moderately differentiated 526 (57)
on the 927 patients. One hundred and forty-eight patients Poorly differentiated 26 (3)
Missing data 585 (40)
Table 1. Retrospective studies that were included in the pooled analysis Perioperative chemotherapy
Given 171 (18)
Not given 273 (29)
First author Year of Number of Study Study
Missing data 483 (52)
publication included patients area period
a
Watanabe [17] 2009 101 Japan 19922004 Status of regional LNs involvement at the time of CRC surgery.
Zabaleta [20] 2011 84 Spain 19982008 b
Laterality of the metastases at the time of rst resection of pulmonary
Nojiri [21] 2011 29 Japan 19922006 metastases: unilateral or bilateral.
Riquet [22] 2010 102 France 19832007 CEA, carcinoembryonic antigen; CRC, colorectal cancer; DFI, disease-free
Borasio [11] 2011 131 Italy 19892008 interval; LN, lymph nodes.
Park [23] 2010 187 Korea 19952007
Hwang [24] 2010 125 Korea 20012007
Welter [25] 2007 168 Germany 19932003

Volume 23 | No. 10 | October 2012 doi:10.1093/annonc/mds100 |

original articles
(16%) had repeated metastasectomy. Of those, 32 (22%) had a
third thoracotomy and 5 (3.4%) had a fourth thoracotomy.
The mode of resection at rst metastasectomy was a
sublobar resection (wedge or segmentectomy or both) in 555
patients (59.9%), a lobectomy with or without wedge or
segmentectomy in 186 patients (20.1%) and a pneumonectomy
in 12 patients (1.3%), while data were not available for the rest
of patients.
Data about LN sampling or dissection during the rst
thoracotomy were available for 796 (86%) patients. Of those,
LN sampling or dissection was not carried out in 279 patients
(35%), showed positive lymph nodes in 75 patients (9%), and
no involvement in 424 patients (53%).
The type of surgical resection during the 185 repeated
thoracotomies were as follows: a sublobar resection in 105
(57%), a lobectomy in 52 (28%), and a pneumonectomy in 2
(1%), while data were not available for 26 cases (14%).
postoperative morbidity and mortality
Data on postoperative morbidity was available for 808
thoracotomies carried out on 672 patients. Of those, 77
patients (11%) had any major postoperative morbidity.
The major postoperative complications were air leak for >7
days in 24 patients (3.6%), atrial brillation in 17 patients
(2.5%), pneumonia in 14 patients (2.1%), empyema in 7
patients (1%), major hemorrhage in 7 patients (1%), intestinal
obstruction in 3 patients (0.4%), and respiratory failure not
attributable to any of the above reasons for additional 5
patients (0.7%).
Of all 927 patients, 5 (0.5%) died within 2 months of rst
thoracotomy, and their death was considered surgery related.
survival outcome
Five-year overall survival rate calculated from the time of rst
thoracotomy for the entire cohort of patients was 54.3%,
(Figure 1).
Univariate analysis demonstrated ve statistically signicant
prognostic factors: DFI, 36 versus <36 months (5-year
survival rate of 61.3% and 50.1%, respectively, P < 0.0398); pre-
thoracotomy, CEA <5 versus 5 (5-year survival rate of 63.0%
and 45.1%, respectively, P < 0.0001); number of metastatic
Figure 1. Overall KaplanMeier survival estimation after the rst
metastasectomy.
| Salah et al.
Annals Of Oncology
lesions, 1 versus 2 (5-year survival rate of 60.5% and 44.6%,
respectively, P < 0.0001); maximum diameter of largest
metastatic lesion, <2 versus 2 cm (5-year survival rate of
57.7% and 51.8%, respectively, P = 0.0015); and status of lymph
nodes in the thorax, not involved versus involved (5-year
survival rate of 55.4% and 27.0%, respectively, P < 0.0001).
The multivariate analysis identied three independent
clinical poor prognostic factors: pre-thoracotomy CEA (<5
versus 5), number of metastatic lesions (1 versus 2), and the
DFI (36 versus <36 months) (Table 3).
The hazard ratios with the corresponding 95% CIs of each
independent prognostic factor for all patients and per study are
illustrated in forest plot (gure 2).
Perioperative chemotherapy had no signicant inuence on
survival, 5-year survival of 54.9% with chemotherapy versus
56.8% without chemotherapy (P = 0.7).
A clinical prognostic model was constructed using the three
independent clinical prognostic factors.
Of the 712 patients assessable for all three factors, the 5-year
survival for the 68 patients (10%) with three poor prognostic
factors (high-risk group), the 250 patients (35%) with two poor
prognostic factors (intermediate-risk group), and the 394
patients (55%) with zero or one risk factor (low-risk group),
were 26.1%, 46.4%, and 68.2%, respectively, P < 0.001 (overall
and for comparison between any two groups). The
corresponding 3-year survival rates were 35.6%, 69.8% and
82.5%, respectively (P < 0.001) (Figure 3).
discussion
Around 50%60% of patients diagnosed with CRC will develop
metastatic disease [26, 27]. Metastases are more likely to
develop metachronously and most likely involve the liver,
which is the most common metastatic site [28].
Lung metastases complicate the course of around 10%15%
of those who had undergone curative CRC surgery [13, 29,
30]. Nevertheless, it is uncommon to have patients where the
lungs are the only metastatic site. Tan et al. [31] reported a
7.4% rate of isolated lung metastasis in a cohort of 754 patients
with CRC.
In this setting, similar to the results after surgical resection
of liver oligometastases, retrospective studies suggested that
resecting pulmonary oligometastases offers a better chance of
survival when compared with the expected 5-year survival rates
of <10% for stage IV CRC managed with palliative
chemotherapy [32, 33].
How to select those patients who are most likely to benet
from surgical resection of pulmonary oligometastases is the
important question that needs to be answered. Selection
criteria had been the main focus of numerous studies
evaluating factors that inuence survival after metastasectomy.
To provide a better understanding about the prognosis of
these patients, we elected to construct a prognostic model
which takes all the probable prognostic factors into
consideration and can be applied in daily practice for every
patient considered for resection.
Our analysis demonstrates signicant and clinically
meaningful differences in survival between the three risk
Volume 23 | No. 10 | October 2012
Annals Of Oncology original articles
Table 3. Independent clinical prognostic factors

Variable No. of patients (%) Hazard ratio 95% condence interval P value
Pre-thoracotomy CEA (ng/ml)
5 240 (26) 1.84 1.4252.381 <0.001
<5 474 (51) 1
DFI (months)
<36 603 (65) 1.39 1.0301.862 0.031
36 310 (33) 1
Number of metastatic nodules
2 364 (39) 2.05 1.5832.648 <0.001
1 558 (60) 1

The three independent poor prognostic factors were used to construct a lung metastasectomy prognostic model. Risk categories according to number of
poor prognostic factors: low risk = 0 or 1 factor, intermediate risk = 2 factors, high risk= 3 factors.
CEA, carcinoembryonic antigen; DFI, disease-free interval.

Figure 2. Forest plot illustration of the hazard ratios with corresponding 95% condence intervals for each of the independent poor prognostic factors per
study: (A) pre-thoracotomy CEA 5 ng/ml, (B) DFI < 36 months, (C) number of metastatic lung nodules 2. The diamond at the bottom of each forest plot
corresponds to the hazard ratio for all pooled patients.

Figure 3. Survival estimation according to risk group (712 assessable patients).

Volume 23 | No. 10 | October 2012 doi:10.1093/annonc/mds100 |

original articles
groups. Five-year survival rate was 26.1% for the highest risk
group versus 68.2% for the most favorable group.
Although patients who belong to the low- and intermediate-
risk groups could have up to two poor prognostic factors, we
found the prognosis of these two groups very favorable when
compared with the known poor survival of stage IV CRC
treated with systemic chemotherapy. However, the survival
benet from surgery in the high-risk group is unclear and
needs further evaluation.
We found that a history of resected liver metastasis has no
detrimental inuence on survival. As a consequence,
pulmonary metastasectomy should not be denied for patients
with history of previous liver metastasectomy with otherwise
favorable prognostic factors.
An interesting nding was the low postoperative mortality of
0.5%. This could be explained by our exclusion criteria for
articles, which included <20 patients and articles published
before the year 2000. Studies including smaller number of
patients are more likely to be reported from centers with low
volume of such surgeries and less experience. Additionally,
excluding older publications would exclude patients treated in
the era of less advanced supportive and intensive care
medicine.
The fact that we could not nd a benet of chemotherapy
prior or after metastasectomy has to be interpreted with
caution. We understand that we have several limitations that
affect our conclusions. First, data about delivery of
chemotherapy was missing for half of patients. Second, we
could not get data about the type of chemotherapy
administered for most patients since many of them had
received it in other centers before or after their referral for
surgery. Additionally, differences in chemotherapy regimens,
doses, and schedules as well as selection bias could inuence
our conclusions.
The role of perioperative chemotherapy requires further
evaluation. This approach was evaluated by the European
Organization for Research and Treatment of Cancer
Intergroup trial 40983 for patients with isolated liver
metastasis, where the use of perioperative FOLFOX4 improved
progression-free survival in patients undergoing liver resection
[34]; however, this approach of perioperative chemotherapy
was never evaluated for CRC pulmonary oligometastases.
Another limitation is that our proposed model was
assessable for only 712 patients (77%); this limitation was
attributable to missing data about pre-thoracotomy CEA level
for 213 patients (23%). To limit the inuence of these missing
data on our results, we assessed the model only for the 712
patients for whom we have data about all three independent
prognostic factors.
Our analysis was focused on survival and prognostic factors
directly associated with the malignancy. This is an important
limitation as other factors, not related to malignancy might be
prognostic as well. These factors are pulmonary function and
comorbidities. Furthermore, associated factors like quality of
life, post-thoracotomy pain syndrome, as well as long-standing
postoperative morbidity could not be addressed in this paper.
These limitations were attributed to limited data. We believe
that these are important factors to be considered for future
studies.
| Salah et al.
Annals Of Oncology
Although numerous retrospective studies in pulmonary
metastasectomy for metastatic CRC had shown encouraging
survival results, we cannot derive a rm conclusion that the
observed long-term survival in these patients is attributable to
surgery rather than the fact that they are a highly selected
population with good performance status, minimal
comorbidities, better pulmonary function, and younger age and
the fact that the natural biology of cancer may had played a role
in their favorable survival, given the absence of randomized
studies in this setting. In fact, both the CEA level and the
number of metastatic sites were reported to have independent
prognostic signicance for poor survival in patients with
unresectable and disseminated metastatic CRC [35, 36], which
adds to the complexity of interpretation of data derived from
single-arm studies evaluating surgical resection, and suggests
that at least the biology of cancer in these patients may had
contributed to their apparent favorable survival. Although the
literature is rich in these retrospective studies and the survival
results with surgery are encouraging, many authors still argue
that the available level of evidence is not sufcient to draw rm
conclusions about the effectiveness of surgery [37, 38].
We think, although randomized studies are lacking, that the
5-year survival approaching 70% for the low-risk group
following surgery is unlikely to be achieved with other
modalities. We recommend surgical resection of lung
metastasis for the low- and intermediate-risk groups until
strong evidence conrming a non-inferiority of systemic
therapy becomes available. On the other hand, for the high-
risk group, conducting a randomized study that compares
metastasectomy with palliative chemotherapy and targeted
therapies is highly justied, given the poor prognosis of this
subset of patients following metastasectomy and the absence of
a strong evidence proving the benet of surgery.
conclusions
According to our proposed prognostic model, patients with
CRC pulmonary oligometastases in the low- and intermediate-
risk groups have an excellent chance of long-term survival
following resection of the pulmonary oligometastases. We
recommend meticulous resection of these metastases after
adequate staging workup had ruled out other metastatic sites.
For patients who belong to the poor-risk group, more studies
are needed to evaluate whether surgery offers any advantage
over systemic therapy.
acknowledgements
We thank all of the following: Dalia Al-Rimawi, Statistical
Programmer at King Hussein cancer center, for statistical help;
Mervat Al-Risheq for some technical assistance in organizing
the data; Salah Abbasi and Alaa Addasi for reviewing the
manuscript.
disclosure
The authors have declared no conicts of interest.
Volume 23 | No. 10 | October 2012
Annals Of Oncology
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