Keywords
lung metastases - prognosis - metastasectomy
Introduction
Pulmonary metastasectomy (PM) has been widely practiced over the past decades as an
integral part of multimodal management of the wide range of tumors metastasizing to
the lung. Due to associated low perioperative morbidity and good postoperative survival,
despite weak evidence based mostly on retrospective single-center reviews, PM comprises
even 15% of all lung resections performed in Europe.[1] To date, no randomized controlled trial has clarified whether those satisfactory
outcomes result from more favorable course of a tumor disease in highly selected patient
subgroup, applied systemic therapy or local treatment in the form of PM.
The aim of our single-institution study is to evaluate postoperative outcomes and
to identify factors influencing survival of patients undergoing PM for metastases
of various primary origin. This analysis is part of a series in which we have examined
the survival after PM for metastatic colorectal cancer (CRC), sarcoma, and head and
neck cancer before.[2]
[3]
[4]
Materials and Methods
All patients who underwent PM with curative intent at our tertiary care thoracic center
from January 2008 to December 2018 were retrospectively analyzed. All patients met
the following selection criteria for PM: controlled primary tumor site, no synchronous
extrapulmonary metastases except for colorectal liver metastases, intent of complete
resection (R0) of the lung lesions, and functional operability. Before the surgery
was offered, all patients were presented at the multidisciplinary tumor conference,
where the treatment options were discussed. Patients with initially unstable metastatic
disease were classified for the induction chemotherapy and then reassessed based on
the response evaluation criteria in solid tumors. Resectability of the lung metastases
was assessed preoperatively by computed tomography (CT). A muscle-sparing lateral
thoracotomy enabling a thorough palpation of the lung was the preferred approach in
majority of patients. Single peripheral metastases were resected by a video-assisted
thoracic surgery (VATS) approach; however, the decision was based on surgeon's preference.
The video-assisted minithoracotomy was classified as an open technique. Completeness
of the resection was defined by pathological examination. Patients were followed up
with a CT scan 3 and 6 months after the first PM. If no recurrence occurred, follow-up
intervals were prolonged to half-yearly and then yearly controls.
The following variables were analyzed: gender, age at PM, site of the primary, interval
between completion of definitive treatment of the primary and PM (time to lung metastasis
[TTLM]), number, size and distribution of the resected metastatic nodules, type and
extent of PM, and administration of adjuvant therapy to the primary and/or prior to
PM. As the thoracic lymph node dissection or sampling was not routinely performed,
we could not evaluate the lymph node status as a prognostic survival factor. The study
protocol was approved by the Institutional Ethics Committee (registration number 425_19
Bc). Individual patient consent for this retrospective observational study was not
required.
Statistical Analysis
Overall survival (OS) after PM was estimated by the Kaplan–Meier's method from the
date of the first PM until the date of death or the most recent follow-up. Bilateral-staged
resections for synchronous metastases were performed 4 to 6 weeks apart and were counted
as a single metastasectomy with the date of the first resection used for analysis.
TTLM was calculated as the interval between resection or completion of definitive
treatment of the primary and date of PM. The variables were assessed using the univariable
Cox proportional hazard model, giving data as hazard ratio (HR) with a 95% confidence
interval (CI). The continuous variables were split based on the cutoff values obtained
by a receiver operating characteristic analysis. Independent prognostic significance
of various clinicopathological factors was assessed using multivariable Cox proportional
hazard regression model. The probability value (p) of less than 0.05 was considered statistically significant for both univariable
and multivariable analyses. The software used for statistical analysis was STATISTICA
13.3 (StatSoft, Tulsa, Oklahoma, United States).
Results
Overall, 281 patients (178 male) underwent curative-intent resections for pulmonary
metastases. The clinical characteristics of the 281 patients are listed in [Table 1]. The median age for the patients at the time of first PM was 61 years (range, 16–84
years). CRC was the most common primary (40.9%, n = 115), followed by head and neck cancer (15.7%, n = 44) and sarcoma (14.3%, n = 40). Median TTLM was 21 months (range, 0–290 months). Synchronous metastases with
primary tumor were present in 53 (18.9%) patients. One hundred and eighty-eight (66.9%)
patients had perioperative interval longer than 1 year and 40 (14.2%) patients had
shorter perioperative interval (≤1 year).
Table 1
Preoperative patient characteristics
Characteristics
|
n = 281
|
Age at PM (y), median (range)
|
61 (16–84)
|
Male gender, n (%)
|
178 (63.4)
|
Primary site, n (%)
|
CRC
|
115 (40.9)
|
HNC
|
44 (15.7)
|
Sarcoma
|
40 (14.3)
|
GU
|
30 (10.7)
|
Melanoma
|
24 (8.6)
|
Germ cell
|
8 (2.8)
|
BRC
|
6 (2.1)
|
Other
|
14 (4.9)
|
TTLM (mo), median (range)
|
21 (0–290)
|
Onset of lung metastasis
|
Metachronous
|
228 (81.1)
|
Synchronous
|
53 (18.9)
|
Number of lung metastasis, n (%)
|
Solitary
|
160 (56.9)
|
2
|
47 (16.8)
|
≥3
|
74 (26.3)
|
Size of the largest lung lesion (cm), median (range)
|
1.4 (0.2–8.0)
|
Type of PM, n (%)
|
VATS
|
54 (19.2)
|
Open
|
227 (80.8)
|
Extent of resection, n (%)
|
Wedge resection
|
170 (60.5)
|
Segmentectomy
|
64 (22.8)
|
Lobectomy
|
44 (15.7)
|
Bilobectomy
|
2 (0.7)
|
Pneumonectomy
|
1 (0.3)
|
Complete (R0) resection, n (%)
|
274 (97.5)
|
LoHS (d), median (range)
|
6 (2–33)
|
Abbreviations: BRC, breast cancer; CRC, colorectal cancer; GU, genitourinary cancer;
HNC, head and neck cancer; LoHS, length of hospital stay; PM, pulmonary metastasectomy;
TTLM, time to lung metastasis; VATS, video-assisted thoracic surgery.
The surgical approach consisted of muscle-sparing lateral thoracotomy (80.8%, n = 227) and VATS (19.2%, n = 54). At the time of first pulmonary resection, the majority (60.5%, n = 170) of patients had a wedge resection, followed by anatomical segmentectomy (22.8%,
n = 64) and lobectomy (15.7%, n = 44). Complete (R0) resection was achieved in 274 (97.5%) patients. Majority of
the patients underwent surgery for unilateral disease (77.9%, n = 219) and single pulmonary nodules (56.9%, n = 160). Seventy-four (26.3%) patients had three or more lung metastases (median 5;
range, 3–23). The maximum number of resected metastatic lesions in one patient was
23.
Two (0.7%) perioperative deaths due to aspiration pneumonia, on the third and fourth
postoperative days, occurred. Twenty-three (8.2%) patients had major (grade III/IV)
complications, including six patients with hemothorax and four with bronchopleural
fistula requiring rethoracotomy, four with pneumonia, three with impaired wound healing
requiring surgical revision, two with empyema requiring decortication, two with postoperative
atrial fibrillation, one with postoperative phrenic nerve paresis, and one with mesenteric
ischemia requiring laparotomy. Median hospital stay after surgery was 6 days (range,
2–33 days).
A total of 166 patients (60.1%) had received chemotherapy as an adjuvant to the primary
resection, and 53 (18.9%) patients underwent induction chemotherapy prior to PM.
After the median follow-up of 29 months (range, 0–143 months), 134 (47.7%) patients
had died. The 5-year OS rate after the first PM was 47.1% ([Fig. 1]). The OS rate after complete (R0) metastasectomy was 48.1% at 5 years versus 17.2%
after incomplete (R1) resection. The univariable analysis disclosed that patients
with the age of 66 years or more (area under the curve: 0.58, HR: 1.81, 95% CI: 1.28–2.56,
p = 0.0007) had worse OS, whereas genitourinary (GU) origin of lung metastases (HR:
0.45, 95% CI: 0.23–0.88, p = 0.02) was associated with better survival after first PM ([Table 2]). Multivariable analysis identified the GU primary (HR: 0.30, 95% CI: 0.15–0.60,
p = 0.0008) as independent positive survival prognosticator and the age of ≥66 years
(HR: 1.97, 95% CI: 1.36–2.85, p = 0.0003) and incomplete (R0) resection of pulmonary lesions (HR: 3.53, 95% CI: 1.40–8.91,
p = 0.0077) as independent negative survival prognosticators ([Table 3]). Gender, TTLM, chemotherapy, number, size and distribution of metastases, surgical
approach (open vs. VATS) and resection extent did not significantly influence the
long-term survival ([Table 2]).
Fig. 1 Overall survival of 281 patients after first pulmonary metastasectomy (PM).
Table 2
Univariable analysis of factors influencing patient survival after pulmonary metastasectomy
Factor
|
Groups
|
N (%)
|
5-y OS (%)
|
Univariable HR (95% CI)
|
p-Value
|
Age at PM (y)
|
< 66
|
184 (65.5)
|
54.8
|
1.81 (1.28–2.56)
|
0.0007
|
≥ 66
|
97 (34.5)
|
33.6
|
Gender
|
Male
|
178 (63.3)
|
48.1
|
1.07 (0.75–1.52)
|
0.71
|
Female
|
103 (36.7)
|
45.7
|
Primary site
|
GU
|
30 (10.7)
|
69.7
|
0.45 (0.23–0.88)
|
0.02
|
Non-GU
|
251 (89.3)
|
44.4
|
TTLM (mo)
|
< 12
|
90 (32.0)
|
51.6
|
1.19 (0.81–1.75)
|
0.36
|
≥ 12
|
191 (68.0)
|
45.5
|
Adjuvant therapy to primary
|
Yes
|
166 (60.1)
|
47.8
|
1.01 (0.71–1.44)
|
0.96
|
No
|
110 (39.9)
|
48.1
|
Induction therapy to metastases
|
Yes
|
53 (18.9)
|
46.3
|
1.03 (0.68–1.58)
|
0.88
|
No
|
228 (81.1)
|
47.5
|
Onset of lung metastasis
|
Synchronous
|
228 (81.1)
|
45.5
|
0.74 (0.46–1.19)
|
0.21
|
Metachronous
|
53 (18.9)
|
55.9
|
Number of lung metastases
|
Single
|
160 (56.9)
|
51.0
|
1.26 (0.89–1.77)
|
0.19
|
≥ 2
|
121 (43.1)
|
42.9
|
Size of largest lung lesion (cm)
|
< 1.9
|
193 (68.7)
|
51.1
|
1.39 (0.98–1.98)
|
0.06
|
≥ 1.9
|
88 (31.3)
|
39.3
|
Distribution of lung metastases
|
Unilateral
|
219 (77.9)
|
44.7
|
0.73 (0.47–1.12)
|
0.14
|
Bilateral
|
62 (22.1)
|
55.7
|
Type of PM
|
Open
|
227 (80.8)
|
45.1
|
0.69 (0.42–1.13)
|
0.14
|
VATS
|
54 (19.2)
|
57.8
|
Extent of PM
|
Wedge
|
170 (60.5)
|
49.6
|
1.20 (0.85–1.71)
|
0.31
|
Anatomical
|
111 (39.5)
|
43.1
|
Completeness of resection
|
R0
|
274 (97.5)
|
48.1
|
2.41 (0.98–5.89)
|
0.05
|
R1
|
7 (2.5)
|
17.2
|
Abbreviations: CI, confidence interval; GU, genitourinary; HNC, head and neck cancer;
HR, hazard ratio; OS, overall survival; PM, pulmonary metastasectomy; TTLM, time to
lung metastasis; VATS, video-assisted thoracic surgery.
Note: Statistically significant p-values in bold.
Table 3
Multivariable analysis of factors influencing patient survival after pulmonary metastasectomy
Factor
|
Factor levels
|
Multivariable HR (95% CI)
|
p-Value
|
Age
|
≥ 66 vs. < 66 y
|
1.97 (1.36–2.85)
|
0.0003
|
Primary site
|
GU vs. non-GU
|
0.30 (0.15–0.60)
|
0.0008
|
Completeness of resection
|
Incomplete versus complete
|
3.53 (1.40–8.91)
|
0.007
|
Abbreviations: CI, confidence interval; CRC, colorectal cancer; GU, genitourinary;
HR, hazard ratio.
Discussion
Twenty to 54% of all metastatic lesions are being found in the lung, making this organ
the second most frequent metastatic target in the human body.[5] Since in 1995, Hellman and Weichselbaum proposed the concept of the oligometastatic
state (≤5 metastases) between limited local disease and disseminated cancer, it has
been even more widely believed that PM, as a form of local treatment, could improve
patient survival.[6] In 2006, Niibe and Hayakawa defined oligorecurrence as a stable primary tumor site
with one to several distant metastases/recurrences in one to several organs.[7] Based on the oligorecurrence criteria, PM has become a worldwide standard curative-intent
local treatment in the selected cardiorespiratory fit patients with controlled metastatic
disease. For nonsurgical candidates, radiotherapy and ablation therapy have been proposed.[8] Recent guidelines of the National Institute for Health and Care Excellence and the
National Comprehensive Cancer Network recommend to consider PM within the multidisciplinary
management of metastatic colorectal[9] and head and neck cancer.[10]
In 1997, Pastorino et al published the outcomes of 5,206 PMs from 18 major thoracic
surgical departments from Europe, the United States, and Canada, participating in
the International Registry of Lung Metastases established in 1990. This largest to
date, multicenter retrospective study including patients with lung metastases of various
primary origin identified complete (R0) resection, number of metastases, and long
disease-free interval (DFI) as major prognostic factors after PM. Reporting survival
rates after complete PM of 36% at 5 years, 26% at 10 years, and 22% at 15 years versus
13% at 5 years and 7% at 10 and 15 years after incomplete resection, the authors strongly
supported the concept of a curative-intent PM.[11]
Completeness of resection, germ cell histology, and DFI ≥36 months were independent
positive prognostic factors in another retrospective large cohort study by Casiraghi
et al on a group of 575 patients with mixed origin lung metastases treated by PM over
a 10-year period in a single institution. The study confirmed even higher post-PM
survival rates reaching 46% at 5 years and 29% at 10 years after complete (R0) resection
versus 20% at 5 and 10 years after incomplete (R1) resection.[12] Cheung et al also identified germ cell histology and DFI ≥36 months as positive
survival prognosticators after PM in a group of 243 patients with the lung metastases
of mixed origin. Synchronous metastases, multiple metastases, and incomplete resection
were independently associated with a worse OS.[13] In our study group, the 5-year OS after complete (R0) resection was 48.1%, which
was higher compared with the 5-year OS rate of 17.2% in a small subgroup of patients
(2.5%, n = 7) in whom the lung lesions were not completely resected. Incomplete resection
was identified as an independent negative post-PM survival prognosticator in our study
population (p = 0.007).
There was no association between germ cell histology and better post-PM OS in our
study cohort. Eight (2.8%) patients with germ cell lung metastases had indeed better
5-year OS rate compared with the rest of the group (62.7 vs. 46.9%, respectively),
however, without statistical significance (p = 0.49). This may have resulted from the small number of patients with the germ cell
histology. It is noteworthy that 30 (10.7%) of our patients with GU lung metastases
had significantly better survival than 251 (89.3%) patients with non-GU origin (5-year
OS rate 69.7 vs. 44.4%, respectively; p = 0.02) ([Fig. 2]). Based on multivariable analysis, the GU origin of pulmonary metastases was an
independent positive survival prognosticator in our cohort. Among 30 patients with
GU metastases, there were 23 (76.6%) with metastatic renal cell carcinoma, 3 with
bladder cancer, 2 with prostate cancer, and 2 with genital cancer. Similar high post-PM
survival rates (5-year OS of 75%) in metastatic renal cell carcinoma have been reported
by Meacci et al.[14] We hypothesize that outstanding GU histology-associated OS rates observed in our
cohort may be a sequel of a careful patient selection.
Fig. 2 Overall survival after first PM according to primary site. BRC, breast cancer; CRC,
colorectal cancer; GU, genitourinary cancer; HNC, head and neck cancer; PM, pulmonary
metastasectomy.
Interestingly, our univariable Cox proportional hazard model analysis demonstrated
that patients in the age of 66 years and older had significantly worse survival compared
with the younger patients (5-year OS rate 33.6 vs. 54.8%, respectively; p = 0.0007). Patient age at PM was identified as independent prognostic factor in our
multivariable analysis. However, taking into consideration acceptable survival rate,
we would recommend a curative-intent PM in cardiorespiratory fit elderly patients
in whom complete resection of metastatic lesion is possible. Similar conclusion was
made by Barone et al who reported even less favorable 5-year OS rate of 21.2% in elderly
patient group after complete (R0) metastasectomy for CRC.[15]
Unlike many authors, we found no significant relationship between the onset of pulmonary
metastases (synchronous vs. metachronous) or TTLM (≥12 vs. <12 months) and prognosis
in our study group.[11]
[12]
[13]
[16] We preferred using the term “TTLM” instead of “DFI” as we do not believe that patients
developing metastatic disease were “disease free.” Number, size, and distribution
of the lung lesions were of no prognostic significance in our cohort.
Our study has several limitations: (1) the single-center retrospective design; (2)
postoperative outcomes and survival rates were evaluated in patients highly selected
for a curative intent surgery; (3) heterogeneous primary tumor histology might have
influenced OS in the whole group; (4) due to lacking standard, the prognostic impact
of mediastinal/hilar lymphadenectomy could not be assessed; and (5) there was no control
group which would include patients managed nonoperatively to compare the outcomes
with. Considering the patient recruitment difficulties (n = 93) encountered by the authors of the multicenter randomized Pulmonary Metastasectomy
in Colorectal Cancer trial, assessing whether PM really provides survival benefits
compared with nonsurgical treatment for metastatic CRC, which led to early study termination,
we presume that a well-designed large multicenter cohort study including a control
group and a longer follow-up period could also efficiently be the value of the PM
for particular types of metastatic cancer.[17]
Conclusion
Our 10-year single-center experience demonstrates that PM is associated with long-term
survival benefits. Patient age, primary tumor histology, and feasibility of complete
resection should be taken into consideration during multidisciplinary patient selection
for pulmonary metastasectomy.