Cite this article as: Nakajima J, Iida T, Okumura S, Horio H, Asamura H, Ozeki Y et al. Recent improvement of survival prognosis after pulmonary metastasectomy and
advanced chemotherapy for patients with colorectal cancer. Eur J Cardiothorac Surg 2017;51:869–73.
Recent improvement of survival prognosis after pulmonary
metastasectomy and advanced chemotherapy for patients with
colorectal cancer
Jun Nakajima
a,
*, Tomohiko Iida
b
,SakaeOkumura
c
, Hirotoshi Horio
d
, Hisao Asamura
e
,YuichiOzeki
f
,
Norihiko Ikeda
g
, Haruhisa Matsuguma
h
, Masayuki Chida
i
,HajimeOtsuka
j
, Masafumi Kawamura
k
andonbehalf
of the Metastatic Lung Tumor Study Group of Japan
a
Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
b
Department of Thoracic Surgery, Kimitsu Central Hospital, Chiba, Japan
c
Department of Thoracic Surgical Oncology, Cancer Institute Hospital, Japanese Foundation, Tokyo, Japan
d
Department of Thoracic Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
e
Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
f
Department of Thoracic Surgery, National Defense Medical College, Saitama, Japan
g
Department of Thoracic Surgery, Tokyo Medical University, Tokyo, Japan
h
Division of Thoracic Surgery, Tochigi Cancer Center, Tochigi, Japan
i
Department of Thoracic Surgery, Dokkyo Medical University, Tochigi, Japan
j
Department of Chest Surgery, Toho University Medical Center Omori Hospital, Tokyo, Japan
k
Division of General Thoracic Surgery, Teikyo University School of Medicine, Tokyo, Japan
* Corresponding author. Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Tel: +81-3-58008856; fax: +81-3-58008856; e-mail: nakajima-tho@h.u-tokyo.ac.jp (J. Nakajima).
Received 24 July 2016; received in revised form 22 October 2016; accepted 1 November 2016
Abstract
OBJECTIVES: New chemotherapeutic regimens (i.e. FOLFOX or FOLFIRI with molecular targeted drugs) have improved the prognosis of
patients with unresectable or recurrent colorectal cancer. To estimate the prognostic impact of these chemotherapies, we examined the
chronological change in survival rates of patients who underwent pulmonary metastasectomy for colorectal cancer metastasis.
METHODS: Using a large database, we conducted a retrospective, multi-institutional study to collect data of 1223 eligible patients from 26 insti-
tutions who had undergone pulmonary metastasectomy with curative intent. We divided those patients who underwent metastasectomy in
different time periods according to the major trend of chemotherapy regimens for recurrent colorectal cancer: those who underwent metasta-
sectomy between 1990 and 1999 (N = 451, Group A), between 2000 and 2004 (N = 433, Group B) or between 2005 and 2007 (N = 339, Group C).
RESULTS: Five-year overall survival rates after metastasectomy were 45% in Group A, 56% in Group B and 66% in Group C (P < 0.0001)
whereas rates after metastasectomy plus chemotherapy were 32% in Group A, 47% in Group B and 70% in Group C (P = 0.0059). The prog-
nosis of patients who underwent both metastasectomy and chemotherapy in Group C was significantly better than that of the other two
groups. Overall survival of patients who did not receive chemotherapy was not significantly different between the groups.
CONCLUSION: Survival rates of patients after pulmonary metastasectomy for colorectal cancer metastasis who underwent chemotherapy
have increased over the years. It implies that newer chemotherapy regimens might have had a positive impact on these patients.
Keywords: Pulmonary metastasis • Metastasectomy • Colorectal cancer • Survival rate • Adjuvant chemotherapy
INTRODUCTION
Approximately 140 000 Americans and 100 000 Japanese are
diagnosed with colon or rectal cancer annually, and one third
of them will die of the disease, most with metastatic tumours [1,
2]. The liver and lungs are the major organs affected by metasta-
sis. Pulmonary resection can cure selected patients with meta-
static colorectal cancer if the pulmonary metastasis can be
resected; if the patient can tolerate the operation; and if the pri-
mary lesion did not show any local recurrence [3]. The postop-
erative prognosis of these patients depends on the biological
features of the colorectal cancer, that is, the number of pulmon-
ary metastases, the diameter of the metastatic tumour, hilar and
mediastinal lymph node metastasis, tumour doubling time,
disease-free interval and serum carcinoembryonic antigen
(CEA) levels [4].
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C
The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
European Journal of Cardio-Thoracic Surgery 51 (2017) 869–873 ORIGINAL ARTICLE
doi:10.1093/ejcts/ezw401 Advance Access publication 23 March 2017
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On the other hand, most patients with metastatic or recurrent
colorectal cancer are not eligible for surgery and undergo systemic
chemotherapy. Recently, new chemotherapeutic regimens, specif-
ically, folinic acid, 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX)
or folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) with bevaci-
zumab, significantly improve the prognosis of patients with unre-
sectable or recurrent colorectal cancer [5, 6]. We examined the
impact of these regimens on the overall survival of patients who
had undergone pulmonary metastasectomy for colorectal cancer
metastasis. We conducted a multi-institutional study of patients
who underwent metastasectomy of pulmonary metastasis over a
period of about 30 years. From these retrospective data, we sought
to elucidate the effect of chemotherapy on the survival of patients
with pulmonary metastasis from colorectal cancer.
MATERIALS AND METHODS
We established the Metastatic Lung Tumor Study Group of Japan
and collected data from patients who had undergone pulmonary
metastasectomy since 1984. This multi-institutional retrospective
study examined the clinicopathological data of patients with colo-
rectal pulmonary metastasis from 26 institutions who underwent re-
section. This study was approved by the institutional review boards
of Keio University and other institutions. We examined 1223 eligible
patients who had undergone pulmonary metastasectomy with cura-
tive intent between January 1990 and March 2008. The data were
previously analysed, and the results were published elsewhere [7].
The number of pulmonary metastases, maximum pulmonary tu-
mour size, prethoracotomy serum CEA level, hilar or mediastinal
lymph node involvement, completeness of pulmonary resection and
history of hepatic metastasis have been analysed. We concluded
that the number of tumours, the size of the tumour, the level of pre-
thoracotomy serum CEA, lymph node involvement and complete-
ness of resection significantly influenced the probability of
postoperative survival. Adjuvant chemotherapy negatively impacted
postoperative survival in that analysis.However,itwasunclear
whether postoperative overall survival might be changed by adju-
vant therapy. We thus performed a second analysis of the data to
elucidate the change in postoperative overall survival rate based on
the period in which the pulmonary metastasectomy was performed.
In this study, patients were divided into three groups accord-
ing to the year when the first pulmonary metastasectomy was
performed: between 1990 and 1999 (N = 451, Group A), between
2000 and 2004 (N = 433, Group B), and between 2005 and 2008
(N = 339, Group C). The regimens of chemotherapy for colorectal
cancer largely corresponded to these groups: 5-FU monotherapy
was given to most of the patients in Group A, 5-FU with folinic
acid was given in Group B, and FOLFOX or FOLFIRI with or with-
out bevacizumab was mainly given to patients in Group C.
We used the Chi-square test for categorical variables and the
unpaired t-test for continuous variables. The survival curves were
estimated using the Kaplan–Meier method, and the differences
between groups were compared using the log-rank test.
Differences were considered significant when the P-value was
less than 0.05. The statistical analysis was performed with EZR
(Saitama Medical Center, Jichi Medical University, Saitama,
Japan), a graphical user interface for R 2.13.0 (R Foundation for
Statistical Computing, Vienna, Austria) [8].
RESULTS
The demographic and clinical characteristics of the patients in
each group are shown in Table 1. Resection was more frequently
performed for older patients and those with a solitary pulmonary
metastasis, a pulmonary metastasis with a small diameter, and an
extrapulmonary metastasis, in the most recent period. Some data
on postoperative chemotherapy were missing; however, a minor-
ity of patients in each group did not undergo chemotherapy after
pulmonary metastasectomy.
Figure 1 shows the postoperative overall survival rates of the
patients after the first pulmonary metastasectomy in each group.
Three- and 5-year cumulative survival rates after metastasectomy
were 59 and 45% in Group A, 72and 57% in Group B and 76 and
66% in Group C, respectively. Postoperative survival significantly
increased as time passed (P < 0.0001).
Postoperative chemotherapy was given to 83 patients (25%) in
Group A, 89 patients (21%) in Group B and 102 patients (27%) in
Group C. Three- and 5-year survival rates of patients after meta-
stasectomy plus chemotherapy were 48 and 32% in Group A, 65
and 47% in Group B and 72 and 70% in Group C (P < 0.0001).
The postoperative prognosis of patients who underwent both
metastasectomy and chemotherapy in Group C was significantly
better than that in the other two groups (Fig. 2). Multivariate ana-
lysis including factors significantly affecting postoperative survival
Table 1: Characteristics of the groups
Group A
1990–1999
(N=451)
Group B
2000–2004
(N=433)
Group C
2005–2008
(N=339)
P-value
Age (mean ± SD) 62 ± 9.9 65 ± 9.9 66 ± 9.5 0.01
Sex (male/female) 258/193 265/164 199/140 0.38
Primary tumour (colon/rectum) 190/188 181/204 140/164 0.50
Multiple metastases (no/yes) 273/173 244/181 222/111 0.034
Diameter of metastasis 2.9 ± 1.6 2.5 ± 1.6 2.1 ± 1.4 <0.001
Nodal metastases (no/yes) 209/56 164/34 119/13 0.020
Liver metastasis (no/yes) 276/44 262/74 225/45 0.012
Serum CEA (low/high) 59/179 46/156 38/103 0.67
Postoperative chemotherapy (no/yes) 24/83 127/89 86/102 <0.001
Postoperative observation time (months) 56 ± 54 43 ± 27 28 ± 17 <0.001
CEA: carcinoembryonic antigen.
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in the previous study [7] (number of tumours, maximum tumour
size, CEA level, nodal involvement and completeness of resec-
tion) showed that the postoperative survival rates of patients in
Group B and Group C were significantly higher than that of pa-
tients in Group A (P = 0.0038, P = 0.017, respectively).
On the other hand, the postoperative overall survival rates of
patients who had not undergone postoperative chemotherapy
after the first pulmonary metastasectomy were not significantly
different among the three groups (Fig. 3).
Univariate analysis of our data showed that chemotherapy after
pulmonary metastasectomy had a negative impact on postoperative
survival (Fig. 4). This result may be due to bias: Patients who had post-
operative tumour recurrence would be more likely to receive chemo-
therapy. However, in a subgroup analysis of Group C, univariate
analysis showed no significant difference in postoperative survival be-
tween patients who received chemotherapy and those who did not.
DISCUSSION
Pulmonary metastasis is generally a manifestation of systemic dis-
ease caused by highly advanced cancers. Certain patients with
pulmonary metastasis who had undergone pulmonary resection
have survived without recurrence. Patients with pulmonary me-
tastasis from colorectal cancer can be good candidates for pul-
monary metastasectomy because the lungs are thought to be the
first place of spread through the bloodstream.
No randomized trials have evaluated the benefit of surgery in
patients with pulmonary metastases from colorectal cancer [9].
However, multiple retrospective studies suggested that pulmon-
ary metastasectomy had the benefit of longer survival and pos-
sibly of complete cure [10].
Approximately 20% of patients with colorectal cancer experi-
ence distant metastases [11]. The lung is the second most fre-
quent organ to which colorectal cancer metastasizes.
Metastasectomy has been performed to cure systemic disease in
the liver and lung more frequently for colorectal cancer metasta-
ses than for any other malignant neoplasm. The 5-year survival
rate after pulmonary metastasectomy for colorectal cancer me-
tastasis was reported to be 30–60% in retrospective studies
[4, 10]. Postoperative prognosis depends mainly on the biological
characteristics of the primary colorectal cancer. Stage of the pri-
mary tumour, liver metastasis, disease-free interval, serum CEA
level, age of the patient, histological characteristics of the primary
Figure 1: Overall survival of each group. Groups A, B and C: patients who had
undergone metastasectomy between 1990 and 1999, 2000 and 2004 and 2005
and 2008, respectively. OS: overall survival rate.
Figure 2: Overall survival of patients who had undergone chemotherapy after
pulmonary metastasectomy, divided into three groups. OS: overall survival rate.
Figure 3: Overall survival of patients who had not undergone chemotherapy
after pulmonary metastasectomy, divided into three groups. OS: overall survival
rate.
Figure 4: Overall survival of patients who had undergone chemotherapy with
metastasectomy (CT+) and those who had not undergone chemotherapy (CT-).
OS: overall survival rate.
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tumour, extension of lung resection, radicalness of the surgery,
number of pulmonary lesions, involvement of thoracic lymph
nodes, maximum tumour size, vascular invasion and some biolo-
gical markers are significant prognostic factors after pulmonary
metastasectomy.
In our study, the prognostic factors derived from the data
analysed in this study were published previously [7]. In this study,
the overall 5-year survival rate was 53.5% and the median survival
time was 69.5 months. Older age, male sex, multiple metastases,
larger diameter of the metastatic tumour, high CEA level, positive
nodal involvement, incomplete resection and history of hepatic
metastasis were poor prognostic factors as determined by univari-
ate analysis. History of chemotherapy also had a negative impact
on postoperative survival as determined by univariate analysis.
In this study, we also found that the survival rates of patients
who underwent chemotherapy after pulmonary metastasectomy
for colorectal cancer metastasis have increased over time. This
result implies that newer chemotherapy regimens have had a
positive impact on patients who had undergone pulmonary
metastasectomy for colorectal cancer metastasis. We also found
that the prognosis of patients who had undergone chemotherapy
was poorer than those who had not undergone chemotherapy.
However, this survival difference has decreased in recent years.
We have seen further advances in the treatment of metastatic
colorectal cancer in the last 10 years. In the 1970s, when 5-fluo-
rouracil was the sole effective agent, overall survival was approxi-
mately 8 months to 1 year and 5 months if the patient was not
treated [12, 13].
In the modern era, the average median survival duration has
doubled, and patients often live longer than 2 years. This increase
has been mainly due to the availability of new active agents,
namely, irinotecan and oxaliplatin, along with the molecularly
targeted drugs bevacizumab [5, 14], cetuximab [15] and panitu-
mumab [16].
Accordingly, a multi-institutional study showed that overall
survival of patients with metastatic colorectal cancer had
increased: The median overall survival time for patients diag-
nosed in 1990–97 was 14.2 months, which increased to 18.0,
18.6 and 29.3 months for patients diagnosed in 1998–2000,
2001–03 and 2004–06, respectively [17].
Several studies published a decade ago reported the influence
of adjuvant chemotherapy on postoperative survival after pul-
monary metastasectomy; all studies showed that chemotherapy
was of no significance for long-term survival [18–22], except for
one study that reported marginal significance [23]. However, we
found from analysis of the data that the postoperative survival
rate has increased in accordance with the period when pulmon-
ary metastasectomy was performed. The majority of the patients
with pulmonary metastasectomy who underwent systemic
chemotherapy eventually had systemic recurrence of colorectal
cancer . Recently, neoadjuvant chemotherapy has been reported
to improve the outcome of colorectal cancer patients with unre-
sectable pulmonary metastases [17, 24].
It is interesting that subsets of patients in our series who had
not undergone chemotherapy showed no significant improve-
ment in postoperative survival throughout the three periods. It
implies that the postoperative survival of patients who under-
went pulmonary metastasectomy of colorectal cancer metastasis
strongly depends on chemotherapy regimens and not on the sur-
gical procedures.
As shown in Fig. 5, the 5-year overall survival rate of the
patients with pulmonary metastasectomy of colorectal cancer
metastasis and the year when the studies were published were
plotted. We found a positive relationship between the 5-year sur-
vival rate and the published year. Moreover, the slope became
steeper in the last 10 years (shown by a dashed line). It is interest-
ing that the improvement of overall survival by year in patients
with colorectal cancer who underwent pulmonary metastasec-
tomy is parallel to that of patients undergoing systemic chemo-
therapy. Recently published phase III trials of combination
regimens for patients with previously untreated metastatic colo-
rectal cancer have demonstrated substantial improvements in
overall survival, with median overall survival times ranging be-
tween 18 and 24 months with combination regimens [17].
The limitation of this study is that it was multi-institutional and
retrospective. No detailed information on the type of chemother-
apy was available from the data. However, based on our data, we
suggest that chemotherapy has a positive effect on survival of pa-
tients who have undergone pulmonary metastasectomy for colo-
rectal cancer metastasis.
In conclusion, we suggest that the recent advances in chemo-
therapy might have contributed to improvement of postopera-
tive overall survival of patients who had undergone pulmonary
metastasectomy because of colorectal cancer. We speculate that
the role of surgery in the treatment of pulmonary metastasis
from colorectal cancer might change in the future.
ACKNOWLEDGEMENTS
We are thankful to Ai Yamakawa for secretarial assistance, and
all members of the Metastatic Lung Tumor Study Group of
Japan for their efforts in input of detailed data into the database.
Conflict of interest: none declared.
REFERENCES
[1] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer
J Clin 2013;63:11–30.
Figure 5: Relationship between postoperative 5-year overall survival rate of the
patients who underwent pulmonary metastasectomy and published year of the
article. Five-year overall survival rates of the patients with pulmonary metasta-
sectomy for colorectal cancer metastasis and published year of the study were
plotted. A positive relationship between the 5-year survival rate and the pub-
lished year is shown. Moreover, the slope became steeper in the last 10 years
(dashed line).
872 J. Nakajima et al. / European Journal of Cardio-Thoracic Surgery
Downloaded from https://academic.oup.com/ejcts/article/51/5/869/3084530 by U.S. Department of Justice user on 16 August 2022
[2] Nishimoto H, Katanoda K, Tsukuma H, Mikami H. Cancer statistics in Japan
– 2012. Tokyo, Japan: Foundation for Promotion of Cancer Research, 2012.
[3] Thomford NR, Woolner LB, Clagett OT. The surgical treatment of meta-
static tumors in the lungs. J Thorac Cardiovasc Surg 1965;49:357–63.
[4] Pfannschmidt J, Dienemann H, Hoffmann H. Surgical resection of pul-
monary metastases from colorectal cancer: a systematic review of pub-
lished series. Ann Thorac Surg 2007;84:324–38.
[5] Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn
AL et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens
with or without bevacizumab as first-line treatment of metastatic colo-
rectal cancer: results of the TREE Study. J Clin Oncol 2008;26:3523–9.
[6] Tournigand C, Andre´ T, Achille E, Lledo G, Flesh M, Mery-Mignard D et al.
FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colo-
rectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229–37.
[7] Iida T, Nomori H, Shiba M, Nakajima J, Okumura S, Horio H et al.
Prognostic factors after pulmonary metastasectomy for colorectal cancer
and rationale for determining surgical indications. A retrospective ana-
lysis. Ann Surg 2013;257:1059–64.
[8] Kanda Y, Free statistical software: EZR (Easy R) on R commander. http://
www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html (9 October
2016, date last accessed).
[9] Treasure T, Hunt I, Utley M. When professional opinion is not enough.
BMJ 2007;21:831–2.
[10] Nakajima J. Pulmonary metastasis: rationale for local treatments and
techniques. Gen Thorac Cardiovasc Surg 2010;58:445–51.
[11] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009.
CA Cancer J Clin 2009;59:225–49.
[12] Meta-analysis Group in Cancer. Efficacy of intravenous continuous infu-
sion of fluorouracil compared with bolus administration in advanced
colorectal cancer. J Clin Oncol 1998;16:301–8.
[13] Scheithauer W, Rosen H, Kornek GV, Sebesta C, Depisch D. Randomised com-
parison of combination chemotherapy plus supportive care with supportive
care alone in patients with metastatic colorectal cancer. BMJ 1993;306:752–5.
[14] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J,
Heim W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin
for metastatic colorectal cancer. N Engl J Med 2004;350:2335–42.
[15] Jonker DJ, O’callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ et al.
Cetuximab for the treatment of colorectal cancer. N Engl J Med
2007;357:2040–8.
[16] Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M et al.
Randomized, phase III trial of panitumumab with infusional fluorouracil,
leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line
treatment in patients with previously untreated metastatic colorectal
cancer: the PRIME study. J Clin Oncol 2010;28:4697–705.
[17] Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW et al.
Improved survival in metastatic colorectal cancer is associated with
adoption of hepatic resection and improved chemotherapy. J Clin Oncol
2009;27:3677–83.
[18] Higashiyama M, Kodama K, Higaki N, Takami K, Murata K, Kameyama M
et al. Surgery for pulmonary metastases from colorectal cancer: the im-
portance of prethoracotomy serum carcinoembryonic antigen as an indi-
cator of prognosis. Jpn J Thorac Cardiovasc Surg 2003;51:289–96.
[19] Lee WS, Yun SH, Chun HK, Lee WY, Yun HR, Kim J et al. Pulmonary resec-
tion for metastases from colorectal cancer: prognostic factors and sur-
vival. Int J Colorectal Dis 2007;22:699–704.
[20] Melloni G, Doglioni C, Bandiera A, Carretta A, Ciriaco P, Arrigoni G et al.
Prognostic factors and analysis of microsatellite instability in resected
pulmonary metastases from colorectal carcinoma. Ann Thorac Surg
2006;81:2008–13.
[21] Saito Y, Omiya H, Kohno K, Kobayashi T, Itoi K, Teramachi M et al.
Pulmonary metastasectomy for 165 patients with colorectal carcinoma: a
prognostic assessment. J Thorac Cardiovasc Surg 2002;124:1007–13.
[22] Kim CH, Huh JW, Kim HJ, Lim SW, Song SY, Kim HR et al. Factors influ-
encing oncological outcomes in patients who develop pulmonary meta-
stases after curative resection of colorectal cancer. Dis Colon Rectum
2012;55:459–64.
[23] Kanemitsu Y, Kato T, Hirai T, Yasui K. Preoperative probability model for
predicting overall survival after resection of pulmonary metastases from
colorectal cancer. Br J Surg 2004;91:112–20.
[24] Shao YC, Chang YY, Lin JK, Lin CC, Wang HS, Yang SH et al. Neoadjuvant
chemotherapy can improve outcome of colorectal cancer patients with
unresectable metastasis. Int J Colorectal Dis 2013;28:1359–65.
THORACIC
873J. Nakajima et al. / European Journal of Cardio-Thoracic Surgery
Downloaded from https://academic.oup.com/ejcts/article/51/5/869/3084530 by U.S. Department of Justice user on 16 August 2022