Download for Multiple Primary Lung Cancers

The Results of Modern Surgical Therapy
for Multiple Primary Lung Cancers*
Samuel A.
Adebonojo, MD, FCCP; Dennis M. Moritz, MD, FCCP; and
Christopher A. Danhy, MD
Study objectives: The purpose of this report is to review our experience with multiple primary
lung cancers (MPLC) at the Walter Reed Army Medical Center, Washington, DC, and to
determine the outcome of our surgical management of this complex problem.
Patients and methods: The data from the
Cancer
Lung
Registry on patients with MPLC from
reviewed.
We
the criteria of Martini and Melamed
used
January
modified by Antakli for the diagnosis of synchronous and metachronous MPLC. Survival
probabilities were calculated by the Kaplan-Meier actuarial method with the dates of resection as
the starting point and included deaths from all causes. The log rank test was used to compare
survival rates between groups and Wilcoxon rank sum test was used to compare the intervals
between the first and the second metachronous cancers. A p value of 0.05 was considered
1984 to December 1995
were
statistically significant.
Results: Fifty-two patients, consisting of 51 patients who had "curative" pulmonary resections and
1 patient who had radiation therapy for previous primary lung cancer, developed second or third
primary lung cancers. Thirty-seven patients developed metachronous cancers within 1 to 15 years
of the first operation (median, 24 months) while 15 patients had synchronous cancers (10
unilateral, 5 bilateral). The probability of cancer-free interval among patients with metachronous
cancers was 41% at 3 years, 16% at 5 years, and 3% at 10 years. Two of the 36 patients who had
pulmonary resection for the second metachronous cancer died in the perioperative period
(operative mortality, 5.6%), and one patient had radiation therapy for the second metachronous
cancer. There were no deaths among patients with synchronous cancers. The actuarial 5-year
survival for second metachronous cancers was 37% and for synchronous cancers was 0%.
Conclusions: We conclude that an aggressive surgical approach is safe and justified in most
patients with MPLC, especially patients with metachronous cancers, while patients with synchro¬
nous lung cancers have poorer prognosis. The operative morbidity and mortality are acceptable
and long-term survival is possible in many patients with metachronous lung cancer.
(CHEST 1997; 112:693-701)
Key words: lung neoplasm; metachronous lung cancer; multiple lung cancers; second primary lung cancer; synchronous
lung cancer
Abbreviations: MPLC
Army Medical Center
=
multiple primary lung cancers; SPLC=second primary lung cancer; WRAMC= Walter Reed
TPhe simultaneous discovery of two pulmonary
-*- nodules in different lobes or
lungs raises the
clinical dilemma of whether these lesions represent
metastases
or
primary synchronous lung
However, when
a new
cancers.
solitary pulmonary nodule
*From the
Department of Cardiothoracic Surgery, Walter Reed
Medical Center, Washington, DC.
Army
The opinions and assertions contained herein are the private
views of the authors and are not to be construed as official or as
of the Department of the Army or the
reflecting theofviews
Defense.
Departmentreceived
October 22, 1996; revision accepted Feb¬
Manuscript
ruary 27, 1997.
Reprint
requests: Samuel A. Adebonojo, MD, FCCP, Surgical
Services Department, Veterans Affairs Medical Center, Dayton,
OH
email:
45428-1008;
[email protected]
develops
2 to 3 years after curative pulmonary
resection, the new lesion may represent a recurrent
cancer, a metastatic process, or a second primary
lung cancer (SPLC). Differentiation of these clinical
entities is important in terms of prognosis but, most
importantly, it will have a great impact on the extent
of surgical resection if the lesion is resectable.
In two series of patients with stage I lung cancer
who were followed up after curative resection, Mar¬
tini and associates1 found that 27% of the patients
developed recurrent disease (70% disseminated,
30% locoregional) while 11.5% developed an SPLC.
Pairolero and his colleagues,2 in an earlier publica¬
tion in 1984, also found that 39% of patients with
CHEST/112 73/SEPTEMBER, 1997
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21750/ on 04/30/2017
693
resected stage I lung cancer subsequently developed
recurrent disease and 10% had multiple primary
provide com¬
lung cancers (MPLC). These findings and
evidence
for
early, sustained
pelling surveillancefrequent,
all
of
patients undergoing
long-term
resection for lung cancer.
MPLC represents an interesting subgroup of can¬
cer cases that may be encountered after curative
resection of bronchogenic carcinoma. The actual
frequency of MPLC is unknown, but varies from 0.8
to 14.5%1"14 depending on whether it was calculated
from cancer registry, autopsy series,4 or from surgical
series.1"3'5-14 This may be due to the difficulty in
or re¬
differentiating a true SPLCin from metastatic
current disease, especially patients with synchro¬
nous lung cancers. Patient selection also plays a
major role as most surgical series tend to focus on
stage I lung cancer patients, reporting a frequency of
10 to 11.5% of MPLC.12 In many series, metachro¬
nous lung cancers constitute 55 to 65% of all MPLC;
these are patients who are most likely to have been
cured of their index cancer and more likely to survive
to develop second and third primary
long enough
The purpose of this report is to
cancers.14
lung
review our experience with MPLC at a tertiary
military health facility with a broad referral base and
to determine the outcome of our aggressive surgical
approach to this complex problem.
Materials
Between
January
and
Methods
1984 and December
1995, 1,325 patients
registered in the Lung Cancer Registry at Walter Reed
Army Medical Center (WRAMC). The data of all patients with
MLPC during this period were reviewed. We used the criteria of
Martini and Melamed5 with the recent modifications by Antakli
and associates6 for the diagnosis of synchronous and metachro¬
nous primary lung cancers (Table 1). Sixty-eight of the 1,325
patients with lung cancer were found to have MPLC for a
frequency of 5.1% among patients with lung cancer at WRAMC.
Sixteen patients were excluded from further analysis because of
incomplete data or because they did not receive optimal "cura¬
tive" therapy for the index cancer. Because of the propensity
toward multicentric disease, patients with bronchoalveolar carci¬
noma were also excluded. During this period, 576 of the 1,325
patients with primary lung cancer had "curative" pulmonary
resections (43.4% resection rate). Fifty-one of these 576 patients
(8.9%) and 1 patient who was initially treated by radiation therapy
for a primary lung cancer were documented to have MPLC. A
review of the medical records of these 52
forms the basis
were
patients
of this report.
All patients who underwent resection for lung cancer at
WRAMC were seen in the outpatient clinic quarterly for the first
2 years, semiannually for the next 3 years, and annually thereafter
for life. History and physical examination along with chest
radiographs in the posteroanterior and lateral projections were
obtained at each clinic visit. Patients with abnormal chest radio¬
graphs, symptoms, or positive physical findings were further
investigated by CT of the chest and upper abdomen. Our
diagnostic protocol for patients with suspected metachronous or
Table 1.Criteria for Diagnosis of MPLC
Martini and
Melamed,5 1975
Metachronous
tumors
Histologic type different
Histologic type the same, if:
I.
II.
A. Free interval between cancers is at least 2 yr, or
B. Origin from carcinoma in situ, or
C. Second cancer in different lobe or lung, but:
1. No carcinoma in lymphatics common to both
2. No extrapulmonary metastases at time of
diagnosis
Tumors physically distinct and separate
Histologic type:
Synchronous tumors
I.
II.
A. Different
B. Same, but in different segment, lobe, or lung, if:
1. Origin from carcinoma in situ
2. No carcinoma in lymphatics common to both
3. No extrapulmonary metastases at time of
Antakli
et
diagnosis
Different histologic condition
Same histologic condition with two or more of the
following:
1. Anatomically distinct
2. Associated premalignant lesion
3. No systemic metastases
4. No mediastinal spread
5. Different DNA ploidy
al,6 1995
A.
B.
synchronous cancers includes sputum cytologic testing, flexible
bronchoscopy with or without transbronchial biopsy, bone scin¬
tigraphy, CT-guided thransthoracic biopsy, MRI of the chest and
brain, and mediastinoscopy. In addition, anterior mediastinal
surgical exploration or video-assisted thoracoscopy was per¬
formed when indicated. Other appropriate studies were per¬
formed to exclude extrapulmonary primary cancer which may
affect diagnosis and treatment options.
When resection was contemplated, full biochemical analysis,
ECG, and pulmonary function tests were obtained. Exercise
testing in the form of stair climbing was used during the latter
half of the review period. In addition, all patients evaluated for
operation of a second metachronous cancer had quantitative
ventilation/perfusion scintigraphs with estimation of the postop¬
erative FEVj_. Maximal oxygen consumption with exercise was
obtained in two patients with marginal pulmonary function test
results. Right heart catheterization with temporary occlusion of
the involved pulmonary artery was not performed in any of the
patients undergoing resection of a second metachronous cancer.
Similarly, we did not use DNA flow cytometry for histologic
differentiation as suggested by Ichinose and associates1516 in any
of these patients.
All lesions were staged according to the new International
Staging System of Lung Cancer as proposed by Mountain17 and
the American Joint Committee on Cancer.18 Operative mortality
included deaths from all causes occurring within 30 days of
surgery or beyond 30 days during the same hospitalization. The
interval between metachronous cancers was calculated from the
date of resection or radiation therapy of the index cancer to the
date of pathologic diagnosis of the second cancer. Survival
interval was calculated from the date of the first or second
operation to the date of last follow-up or death. Survival proba¬
bility was calculated by the Kaplan-Meier actuarial method,19
with the date of resection
as
694
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21750/ on 04/30/2017
the
starting point, and included
Clinical
Investigations
right
lower lobectomy for a stage I (T2N0M0)
squamous cell carcinoma in July 1993 presented with
a new stage I (T1N0M0) left lower lobe adenocarci¬
noma in October 1995. She died of ARDS and sepsis
on the 45th postoperative day. The second death
occurred in a 61-year-old man who had a left lower
for stage I (T2N0M0) adenocarcinoma in
lobectomy
July 1993. He presented with a new stage I
(T2N0M0) right upper lobe squamous cell carci¬
noma a year later and died of ARDS on the 14th
range, 1
36
Discussion
Very little was
written about MPLC until 1924
when
Beyreuther20 identified two separate primary
in a patient with pulmonary tuberculo¬
lung
sis. In 1932, Warren and Gates21 established the
criteria for the diagnosis of multiple primary malig¬
nant tumors while Auerbach and associates4 re¬
ported a frequency of 3.5 to 14.5% of MPLC in
1967. However, it was not until 1975 that Martini
and Melamed5 provided the criteria that have now
become the gold standard for the diagnosis of
MPLC. Although the actual incidence of MPLC is
unknown, its frequency is probably underestimated
in the literature with reported frequency ranging
from 0.8 to 14.5%.1"3'5-14
The diagnosis of synchronous or metachronous
MPLC rests on certain criteria as outlined by Martini
and Melamed5 with recent modification by Antakli
and associates.6 A second lung cancer with different
features or arising from carcinoma in situ
histologic
or located in the contralateral lung should be con¬
sidered as synchronous MPLC and should be staged
separately; however, the higher stage should be
recorded for the patient. However, when two syn¬
chronous lesions of similar histologic condition are
located in different lobes of the same lung, the
diagnosis of synchronous MPLC is difficult. Also, it is
very difficult to distinguish between poorly differen¬
tiated adenocarcinoma, squamous cell carcinoma,
and large cell carcinoma by conventional pathologic
cancers
The overall actuarial 5-year survival for all patients
32% with a median survival of 43 months (range,
1 to 136 months). The actuarial 5-year survival for
second metachronous cancers was 37%, median
survival of 48 months (range, 1 to 136 months), while
the actuarial 5-year survival for synchronous cancers
was 0% with a median survival of 43 months (range,
6 to 58 months). The survival curves of both second
metachronous and synchronous cancers were iden¬
tical up to the fourth year; thereafter no patient with
synchronous cancer survived beyond the fifth year.
When the actuarial 5-year survival rates for second
metachronous cancers were calculated on the basis
of stage of the disease, the 5-year survival for stage I
was 39% (median, 36 months; range, 1 to 136
months) while that of stages II and IIIA was 38%
(median, 53 months; range, 2 to 93 months)
(p 0.21). Also, there was no survival advantage
based on histologic condition of the second meta¬
chronous cancers. The 5-year survival for squamous
cell carcinoma was 46% (median, 53 months; range,
1 to 136 months) and that for adenocarcinoma was
28% (median, 36 months; range, 1 to 78 months)
(p=0.26). The actuarial 5-year survival for second
metachronous cancer in patients with different his¬
tologic features was 36.9% (median, 53 months;
was
=
Table 4.Analysis
of Actuarial Survival of Patients With MPLC*
3-yr
Surv,
Synchronous Ca
months) as compared with 36.5%
months; range, 1 to 136 months) for
75
(median,
patients with similar histologic conditions (p=0.79)
(Table 4; Figs 1-6).
postoperative day.
All patients
to
9i
5-yr
Median
Surv, %
Surv,
mo
Range
Surv, mo
52
15
55
58
32
0
43
43
1-136
6-58
37
37
83
54
64
45
45
63
63
50
58
61
46
75
37
46
28
39
38
63
33
29
37
37
83
48
12-191
1-136
1-136
1-78
1-136
2-93
13-136
1-93
2-74
1-75
1-136
Metachronous Ca
First
cancer
Second
cancer
Squamous cell
Adenocarcinoma
Stage I
Stages II and IIIA
Pneumonectomy
Lobectomy
Wedge resection
Different histologic condition
Same histologic condition
15
22
29
8
6
22
8
17
20
53
36
36
53
75
35
38
53
36
*Surv=survival; Ca=cancer.
CHEST/112/3/SEPTEMBER,
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21750/ on 04/30/2017
1997
697
Classification of Metachronous Lung
(n=37) (Top) and Stage of Second
Metachronous Cancer With Reference to First Cancer
(Bottom)
Table 2.Stage
Cancer
Second Cancer
Index Cancer
Stage I
Stage II
Stage IIIA
27
5
5
Stage I
27
Stage II
5
Stage IIIA
5
29 (78%)
6 (16%)
2 (5%)
Stage I
Stage II
Stage I
Stage II
Stage I
Stage IIIA
22
5
4
1
3
2
Table 3 shows the treatment options for the
second cancer operation based on the procedure
for the index cancer. In patients with
performed
metachronous cancers, the index cancers were
treated by lobectomy in 35, pneumonectomy in one,
and radiation therapy in one patient. The second
metachronous cancers were treated by lobectomy in
22, completion pneumonectomy in six, wedge resec¬
tion in eight, and radiation therapy in the patient
with previous pneumonectomy. Four of the 10 pa¬
tients with unilateral synchronous cancers were
treated by bilobectomy, two patients by pneumonec¬
tomy, one patient by a combination of lobectomy
plus wedge resection,Theandfivethree patientswithby multiple
bilateral
patients
wedge resections.
Table 3.Treatment
First
Results of Treatment
Fourteen of the 37 patients (38%) with metachro¬
nous cancer were alive at the end of the review
Twelve were free of cancer while the remain¬
period.
two
ing patients with stage IIIA disease were receiv¬
ing adjuvant radiation therapy for recurrent disease.
Twenty-three patients died within 1 to 136 months
(median, 34 months; mean±SD, 36.6± 11.4 months)
Management
Metachronous
were offered staged thoracotosynchronous cancers
at 4- to 6-week intervals. Four of the
performed
five index cancers were treated initially by lobectomy
followed later by contralateral lobectomy in two
patients and wedge resection in two other patients.
One patient who had wedge resection for the index
cancer later had a contralateral lobectomy for the
second cancer.
mies
of the second operation, 10 of recurrent cancer (8
after wedge resection and 2 after lobectomy) within
13 to 53 months of the second operation, 6 died of
cancers (4 colon; 2 esophagus), and
extrapulmonary
5 died of myocardial infarction but free of recurrent
cancer at the time of death. The remaining two
patients died in the perioperative period. Twelve of
the 15 patients (80%) with synchronous cancers died
of recurrent disease, while the other 3 patients died
of progressive emphysematous lung disease but were
free of cancer at the time of death.
There were no perioperative deaths among the 15
patients with synchronous cancers, but 2 of the 36
patients (5.6%) who were treated by pulmonary
resection for metachronous cancer died in the peri¬
operative period. A 68-year-old woman who had a
Options for Second Cancer With Reference to First Procedure
cancers
Second Operation
Operation
Lobectomy
Pneumonectomy
therapy
Synchronous cancers
Radiation
Unilateral (10)
First and Second Cancers
Bilobectomy (include RML*)
Wedge + wedge
Pneumonectomy
Lobectomy + wedge
*RML=right middle lobe.
35
Lobectomy
(Contralateral 20)
(Ipsilateral 1)
Wedge resection
(Contralateral 6)
(Ipsilateral 2)
Completion pneumonectomy
Radiation therapy
Lobectomy
21
Bilateral (5)
Index Cancer
Lobectomy
Wedge
696
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21750/ on 04/30/2017
Second Cancer
Lobectomy
Wedge
Lobectomy
Clinical
Investigations
right
lower lobectomy for a stage I (T2N0M0)
squamous cell carcinoma in July 1993 presented with
a new stage I (T1N0M0) left lower lobe adenocarci¬
noma in October 1995. She died of ARDS and sepsis
on the 45th postoperative day. The second death
occurred in a 61-year-old man who had a left lower
for stage I (T2N0M0) adenocarcinoma in
lobectomy
July 1993. He presented with a new stage I
(T2N0M0) right upper lobe squamous cell carci¬
noma a year later and died of ARDS on the 14th
range, 1
36
Discussion
Very little was
written about MPLC until 1924
when
Beyreuther20 identified two separate primary
in a patient with pulmonary tuberculo¬
lung
sis. In 1932, Warren and Gates21 established the
criteria for the diagnosis of multiple primary malig¬
nant tumors while Auerbach and associates4 re¬
ported a frequency of 3.5 to 14.5% of MPLC in
1967. However, it was not until 1975 that Martini
and Melamed5 provided the criteria that have now
become the gold standard for the diagnosis of
MPLC. Although the actual incidence of MPLC is
unknown, its frequency is probably underestimated
in the literature with reported frequency ranging
from 0.8 to 14.5%.1"3'5-14
The diagnosis of synchronous or metachronous
MPLC rests on certain criteria as outlined by Martini
and Melamed5 with recent modification by Antakli
and associates.6 A second lung cancer with different
features or arising from carcinoma in situ
histologic
or located in the contralateral lung should be con¬
sidered as synchronous MPLC and should be staged
separately; however, the higher stage should be
recorded for the patient. However, when two syn¬
chronous lesions of similar histologic condition are
located in different lobes of the same lung, the
diagnosis of synchronous MPLC is difficult. Also, it is
very difficult to distinguish between poorly differen¬
tiated adenocarcinoma, squamous cell carcinoma,
and large cell carcinoma by conventional pathologic
cancers
The overall actuarial 5-year survival for all patients
32% with a median survival of 43 months (range,
1 to 136 months). The actuarial 5-year survival for
second metachronous cancers was 37%, median
survival of 48 months (range, 1 to 136 months), while
the actuarial 5-year survival for synchronous cancers
was 0% with a median survival of 43 months (range,
6 to 58 months). The survival curves of both second
metachronous and synchronous cancers were iden¬
tical up to the fourth year; thereafter no patient with
synchronous cancer survived beyond the fifth year.
When the actuarial 5-year survival rates for second
metachronous cancers were calculated on the basis
of stage of the disease, the 5-year survival for stage I
was 39% (median, 36 months; range, 1 to 136
months) while that of stages II and IIIA was 38%
(median, 53 months; range, 2 to 93 months)
(p 0.21). Also, there was no survival advantage
based on histologic condition of the second meta¬
chronous cancers. The 5-year survival for squamous
cell carcinoma was 46% (median, 53 months; range,
1 to 136 months) and that for adenocarcinoma was
28% (median, 36 months; range, 1 to 78 months)
(p=0.26). The actuarial 5-year survival for second
metachronous cancer in patients with different his¬
tologic features was 36.9% (median, 53 months;
was
=
Table 4.Analysis
of Actuarial Survival of Patients With MPLC*
3-yr
Surv,
Synchronous Ca
months) as compared with 36.5%
months; range, 1 to 136 months) for
75
(median,
patients with similar histologic conditions (p=0.79)
(Table 4; Figs 1-6).
postoperative day.
All patients
to
9i
5-yr
Median
Surv, %
Surv,
mo
Range
Surv, mo
52
15
55
58
32
0
43
43
1-136
6-58
37
37
83
54
64
45
45
63
63
50
58
61
46
75
37
46
28
39
38
63
33
29
37
37
83
48
12-191
1-136
1-136
1-78
1-136
2-93
13-136
1-93
2-74
1-75
1-136
Metachronous Ca
First
cancer
Second
cancer
Squamous cell
Adenocarcinoma
Stage I
Stages II and IIIA
Pneumonectomy
Lobectomy
Wedge resection
Different histologic condition
Same histologic condition
15
22
29
8
6
22
8
17
20
53
36
36
53
75
35
38
53
36
*Surv=survival; Ca=cancer.
CHEST/112/3/SEPTEMBER,
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21750/ on 04/30/2017
1997
697
1.0r,
36
48
60
48 36
72
Figure 1. The overall actuarial survival of 52
patients with
metachronous and synchronous multiple primary lung cancers.
The actuarial 5-year survival was 32%, median survival was 43
months (mean±SD, 52±7 months; range, 1 to 136 months).
studies. In fact, it has been reported that most poorly
differentiated adenocarcinomas contained squamous
cell components when analyzed by electron micros¬
copy.22 Ichinose and his colleagues1516 have shown
that DNA flow cytometry can be used to differenti¬
ate between two synchronous cancers of the same
between the index and the
histologic condition or cancer
of similar histologic
second metachronous
condition by analysis of the DNA ploidy of the first
and second tumors using DNA flow cytometry. The
tumors are considered to be independent of each
other if one tumor showed diploidy and the other
showed aneuploidy or when the two tumors showed
but with different DNA index of abnor¬
aneuploidy
mal clones. The tumors are considered to be related
to each other if they showed diploidy or when at least
36
48
72
84
96
108
120
Figure 3. Actuarial 5-year survival of stage I vs stages II and IIIA
following
operation for the second metachronous cancer. The
actuarial 5-year survival for stage I was 39% (median, 36 months;
mean±SD, 52±10 months) as compared with 38% (median, 53
months; mean±SD, 50±11 months) for stages II and IIIA
(p=0.21).
one
DNA index of abnormal clones between two
tumors was the same or almost identical.
aneuploidy
a promising tool in the diagnostic armamen¬
tarium of lung cancer which, in combination with
molecular markers, will help with better stage clas¬
sification, determination of prognosis, and our un¬
derstanding of the biological behavior of lung cancer
in various individuals.
The mainstay of diagnosis of metachronous MPLC
is careful follow-up of patients after cancer sur¬
gery.23-25 As a result of our aggressive follow-up
29 of the 37 (78%) second metachronous
policy,
cancers were discovered at stage I. Without such
it is possible that most of these patients would
policy,
have been discovered with more advanced disease.
Despite the widespread education on smoking and
lung cancer, it was disturbing to note that all the 37
This is
V
...1st Metachronous <n=37)
_2nd Metachronous (n-37)
Synchronous (n=15)
24
60
Survival (Months)
Survival (Months)
60
72
_Squamous Cell (n=15)
_Adenocarcinoma (n=22)
Survival (Months)
Figure 2. The actuarial survival of the first and second meta¬
chronous lung cancers compared with that of synchronous can¬
cer. The 5-year actuarial survival after the first metachronous
cancer operation was 75%. The survival curve of the second
metachronous cancer is almost identical to that of synchronous
cancer up to the fourth year but reaching statistical significance at
5 years (p<0.001). The actuarial 5-year survival for second
metachronous cancer was 37% (median, 48 months; mean±SD,
54±8 months) as compared with 0% (median, 43 months; mean
±SD, 40±5 months) for synchronous cancer.
24
12
36
48
60
72
84
96
108
120
Survival (Months)
Figure 4. Actuarial 5-year survival of squamous cell carcinoma
and adenocarcinoma following operation for the second meta¬
chronous cancer. The actuarial 5-year survival for squamous cell
was 46% (median, 53 months; mean±SD, 60±15
months) as compared with 28% (median, 36 months; mean±SD,
42±6 months) for adenocarcinoma (p=0.26).
carcinoma
698
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21750/ on 04/30/2017
Clinical
Investigations
the prognosis of metachronous cancers is poorer
than that of primary lung cancer when compared
stage for stage. The actuarial 5-year survival of 37%
for stage I second metachronous cancer is very
when compared with the actuarial
disconcerting
survival
of 75% for primary stage I disease in
5-year
our
12
24
36
48
60
Survival
72
84
96
108
120
(Months)
Figure 5. Actuarial 5-year survival following second operation
for metachronous cancer based on change of histologic condition.
There was no survival advantage between both groups (37%).
However, there was a significant difference in the median
survival. Patients with different histologic conditions had a
median survival of 53 months (mean±SD, 46±7 months) as
of 36 months (mean±SD, 58±4
comparedforto a medianwithsurvival
similar histologic conditions.
months) patients
patients with metachronous cancers were still smok¬
ing at the time of discovery of the second cancer
while 15 continued to smoke after their second
operation. Richardson and associates26 noted fewer
smoking-related second primary cancers in patients
who stopped smoking after their curative lung cancer
surgery and emphasized the need for continuous and
concerted education of patients in smoking cessa¬
tion. From our findings, it appears that continuation
of smoking after lung cancer resection increases the
risk of a new primary lung cancer irrespective of the
stage of the index cancer. Our results also show that
institution.
The diagnosis of synchronous MPLC is commonly
made from chest radiographs and CT. Some are
incidental findings at bronchoscopy or at surgery and
others are less commonly found by pathologists
during examination of resected specimens. In a large
number of cases, the diagnosis is never made but
discovered at autopsy as shown by Auerbach et al4
and other authors.5911 It is our policy to perform
bronchoscopy on all patients undergoing pulmonary
resection
preoperatively or intraoperatively to assess
bronchial anatomy, determine the extent of disease,
and rule out unsuspected endobronchial lesions not
detected by chest radiographs or CT.
The surgical options for second metachronous
cancers depend on the extent of the disease, the
initial surgical procedure, and the patient's pulmo¬
nary reserve. In general, limited resection is favored
for a second peripheral cancer.27-28 However, if the
patient can tolerate another lobectomy, this should
be the procedure of choice. In a recent randomized
trial of lobectomy vs limited resection for T1N0
non-small cell lung cancer, Ginsberg and Rubin¬
stein29 found that limited resection does not confer
improved perioperative morbidity, mortality, or late
postoperative pulmonary function when compared
with a lobectomy. Limited resection was associated
with a 75% increase in recurrence rates attributable
to tripling of the local recurrence rate, and a 30%
increase in overall death rate when compared with
patients undergoing lobectomy.
_Pneumonectomy (n=6)
Lobectomy (n=22)
.Wedge Resection (n=8)
12
24
36
48
60
72
84
96
108
120
Survival (Months)
Figure 6. Actuarial 5-year survival based on the type of pulmo¬
nary resection for second metachronous cancer. The actuarial
for pneumonectomy was 63% (median, 75
5-year survival74±26
months; mean,
months). This apparent survival advantage
of pneumonectomy over lobectomy and wedge resection may be
due to the small number of patients who had pneumonectomy.
However, the survival curve for lobectomy is similar to that of
wedge resection. The actuarial 5-year survival for lobectomy was
33%
(median,
35
months; mean±SD, 45±7 months)
as com¬
with 29% (median, 38 months; mean±SD, 42±10 months)
pared
for wedge resection (p=0.31).
However, if a lobectomy or segmentectomy had
been performed initially, a completion pneumonec¬
tomy is feasible for an ipsilateral cancer; a lobectomy
or limited resection for a contralateral cancer; a
middle lobectomy on the same side or a wedge
resection for an ipsilateral or contralateral can¬
cer.30-32 In few selected patients with adequate
reserve, a left pneumonectomy may be
pulmonary
feasible after an initial right upper or middle lobec¬
tomy. In patients with deep-seated lesions in which
the anatomic locations of the lesions make wedge
resection difficult or impossible, the "precision cau¬
tery excision" technique first described by Perelman33 in 1983 and later popularized by Cooper and
associates34 in 1986 will provide adequate resection
of a second metachronous cancer with little morbid¬
ity and mortality while preserving adequate lung
tissue.
Although a previous pneumonectomy is generally
CHEST 7112/3/ SEPTEMBER, 1997
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21750/ on 04/30/2017
considered a contraindication to further pulmonary
resection, with careful selection, some of these pa¬
tients may be good candidates for limited resection
of a second primary lung cancer in the remaining
lung. Such patients, however, should undergo full
quantitative ventilation/perfusion
with estimation of the postoperative
scintigraphs
con¬
and measurement of maximal
metastatic workup,
FEV1?
sumption with
oxygen
exercise. Patients with borderline
cardiopulmonary reserve may need to undergo right
heart catheterization with balloon occlusion of the
lobe to be resected in order to quantitate the
postoperative pulmonary artery pres¬
expected
sure.3539 Patients with previous left pneumonectomy
may tolerate wedge resection or a right upper or
middle lobectomy if pulmonary function tests justify
such resection. However, patients with a previous
right pneumonectomy will tolerate only very limited
resection of the left lung.3839
When a patient presents with ipsilateral synchro¬
nous cancers, the two cancers can be resected by
pneumonectomy, multiple wedge re¬
bilobectomy,
or
a
combination of lobectomy and wedge
sections,
resection. Patients with bilateral synchronous can¬
cers should be offered staged bilateral thoracotomies
at an interval of 4 to 6 weeks starting with the side
with the higher stage of disease.3941 Median sternotomy may be used for wedge resections of small
cancers, but this approach is
peripheral upper lobe
not recommended for lower lobe cancers.4144
Our overall operative mortality for all patients with
MPLC was 3.9%. Our operative mortality of 5.6% for
metachronous cancers and 0% for synchronous cancers
compares favorably with reported operative mortality
of 0 to 20% for metachronous cancers and 4.5 to 20%
for synchronous cancers.3'5713'27'45 Also, our overall
actuarial 5-year survival of 32% for all patients with
MPLC is in consonant with 18 to 36% actuarial 5-year
survival reported in the literature for this group of
cancers
patients.3'5"7'9-13'46 Patients with metachronous
had a 37% actuarial 5-year survival while no patient
with synchronous cancers had survived 5 years so
of 11 to 36%
This is also similar to other
far.
reports
5-year survival for metachronous cancers and 0 toin28%
5-year survival for synchronous cancers quoted the
literature3'5-7'9-13'45-48
Conclusions
Multiple
pulmonary nodules occurring in different
or lungs may represent synchronous lung
cancers and should not be presumed to be metastatic
disease. A careful search for extrapulmonary primary
cancer is mandatory. In the absence of any positive
findings, such lesions should be considered synchro¬
lobes
Sim¬
surgical considerations.
a
nodule
devel¬
when
new
pulmonary
ilarly,2 or more solitary
years after curative resection for lung
ops
cancer, the patient should be offered surgical ther¬
apy if the lesion is resectable since this offers the best
chance for prolonged survival. We believe that all
patients who have undergone curative resection for
cancer should be followed up for life since a
lung
second cancer appears only in long-term survivors
and appears within the third and fifth year and
as late as 15 to 25 years after initial resec¬
possibly
tion. We conclude that an aggressive surgical ap¬
is safe and justified in most patients with
proach
metachronous lung cancers, the operative morbidity
and mortality are acceptable, and long-term survival
is possible in many of these patients.
nous
MPLC and given
ACKNOWLEDGMENTS: The authors wish to express their
sincere thanks and appreciation to Gayle Taylor for her valuable
in extracting the data from the Cancer Registry7, Robin
help
Plauche for her secretarial assistance, Danielle Howard for her
assistance with data entry, and Professor Oluwatope Abimbola
Mabogunje for his editorial assistance.
1
2
3
4
5
6
7
References
Martini N, Bains MS, Burt ME, et al. Incidence of local
recurrence and second primary tumors in resected stage I
lung cancer. } Thorac Cardiovasc Surg 1995; 109:120-29
Pairolero PC, Williams DE, Bergstralh EJ, et al. Postsurgical
stage I bronchogenic carcinoma: morbid implications of
recurrent disease. Ann Thorac Surg 1984; 38:331-38
Deschamps C, Pairolero P, Trastek V, et al. Multiple primary
lung cancers. J Thorac Cardiovasc Surg 1990; 99:769-78
Auerbach O, Stout AP, Hammond EC, et al. Multiple
primary bronchial carcinomas. Cancer 1967; 20:699-705
Martini N, Melamed MR. Multiple primary lung cancers.
J Thorac Cardiovasc Surg 1975; 70:606-12
Antakli T, Schaefer RF, Rutherford JE, et al. Second primary
lung cancer. Ann Thorac Surg 1995; 59:863-67
Jensik RJ, Faber LP, Kittle CF, et al. Survival following
bronchogenic carcinoma. J Tho¬
8 Kono M, Fujii M, Adachi S, et al. Multiple primary lung
cancers: radiographic and bronchoscopic diagnosis. J Thorac
Imaging 1993; 8:63-68
9 Mathisen DJ, Jensik RJ, Faber LP, et al. Survival following
resection for second and third lung cancers. J Thorac Cardio¬
vasc Surg 1984; 88:502-10
10 Mousset X, Deslauriers J, Beaulieu M, et al. Multiple primary
lung cancers: the importance of early detection and survival
after a new surgical excision. Ann Chir 1989; 43:658-63
11 Ribet M, Dambron P. Multiple primary lung cancers. Eur
J Cardiothorac Surg 1995; 9:231-36
12 Verhagen AF, van de Wal HJ, Cox AL, et al. Surgical
treatment of multiple primary lung cancers. Thorac Cardio¬
vasc Surg 1989; 37:107-11
13 Verhagen AF, Tavilla G, van de Wal HJ, et al. Multiple
primary lung cancers. Thorac Cardiovasc Surg 1994; 42:40-44
14 Wu SC, Lin ZQ, Xu CW, et al. Multiple primary lung cancers.
Chest 1987; 92:892-96
15 Ichinose Y, Hara N, Ohta M. Synchronous lung cancers
defined by deoxyribonucleic acid flow cytometry. J Thorac
102:418-24
resection for second primary
rac
Cardiovasc
Cardiovasc
Surg 1981; 82:658-68
Surg 1991;
700
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21750/ on 04/30/2017
Clinical
Investigations
ploidy patterns of
diagnosed as metachronous or recurrent lung cancers.
Ann Thorac Surg 1991; 52:469-73
17 Moutain CF. A new international staging system for lung
16 Ichinose Y, Hara N, Ohta M, et al. DNA
32
cancer.
Chest 1986; 89:225S-33S
18 Beahrs OH, Henson DE, Hunter RV, et al. American Joint
Committee on Cancer: manual for staging of cancer. 4th ed.
Philadelphia: JB Lippincott, 1992; 117-18
19 Kaplan EL, Meier P. Nonparametric estimation from incom¬
plete observation. J Am Stat Assoc 1958; 53:457-81
20 Beyreuther H. Multiplicitat von carcinomen bei ein fall von
sog: 'schneeberger' lungenkrebs mit tuberculose. Virchows
Arch Pathol Anat 1924; 250:230-36
Multiple primary malignant tumors: a
survey of the literature and a statistical study. Am J Cancer
21 Warren
S, Gates O.
1932; 16:1358-1403
22 McDowell EM, Harris
CC, Trump BF. Histogenesis and
of bronchial neoplasms. In: Shimosato Y,
Melamed MR, Nettessheim P, eds. Morphogenesis of lung
cancer. Boca Raton, Fla: CRC Press, 1982: 1-36
23 Boucot KR, Weiss W, Cooper DA. Second pulmonary neo¬
plasm among long-term survivors of lung cancer. Am Rev
morphogenesis
Respir Dis 1965; 92:767-72
SL, Chopin RH, Muss HB. Multiple primary bron¬
chogenic carcinoma. AJR Am J Roentgenol 1983; 140:253-58
Van Bodegom PC, Vagenaar SS, Corrin B, et al. second
primary lung cancer: importance of long-term follow-up.
Thorax 1989; 44:778-93
Richardson GE, Tucker MA, Venzon DJ, et al. Smoking
cessation after successful treatment of small cell lung cancer
is associated with fewer smoking-related second primary
cancers. Ann Intern Med 1993; 119:383-90
CF, et al. Segmental resection for
Jensik RJ, Faber LP, KittleAnn
bronchogenic carcinoma. Thorac Surg 1979; 28:475-83
Shields TW, Higgins GA Jr. Minimal pulmonary resection in
the treatment of carcinoma of the lung. Arch Surg 1974;
108:420-28
Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy
versus limited resection for T1N0 non-small cell lung cancer:
Lung Cancer Study Group. Ann Thorac Surg 1995; 60:615-22
Temeck BK, Flehinger BJ, Martini N. A retrospective anal¬
ysis of 10-year survivors from carcinoma of the lung. Cancer
24 Bower
25
26
27
28
29
30
1984; 53:1405-08
31 McGovern EM, Trastek VF, Pairolero
PC, et al. Completion
pneumonectomy: indications, complications and results. Ann
Thorac Surg 1988; 46:141-46
Neptune WB,
bronchogenic
tumors
Woods FM, Overholt RH. Reoperation for
J Thorac Cardiovasc Surg 1966;
carcinoma.
52:342-50
33 Perelman M. Precision techniques for removal of pathological
structures from the lung. Surgery 1983; 11:12-16
34 Cooper JD, Perelman M, Todd TRJ et al. Precision cautery
excision of pulmonary lesions. Ann Thorac Surg 1986; 41:
51-53
35 Barker JA, Yahr WZ, Krieger BP. Right upper lobectomy 20
years after pneumonectomy: preoperative evaluation and
follow-up. Chest 1990; 97:248-50
36 Boysen PG, Block AJ, Olsen GN, et al. Prospective evaluation
for pneumonectomy using the 99mtechnetium quantitative
perfusion lung scan. Chest 1977; 72:422-25
37 Williams AJ, Gayton RM, Harding LK, et al. Quantitative
lung scintigrams and lung function in the selection of patients
for pneumonectomy. B J Dis Chest 1984; 78:105-12
38 Kittle CF, Faber LP, Jensik RJ, et al. Pulmonary resection in
patients after pneumonectomy.
Ann Thorac Surg 1985; 40:
294-99
39 Westermann CJJ, van Swieten HA, de la Riviere AB, et al.
Pulmonary resection after pneumonectomy in patients with
bronchogenic carcinoma. J Thorac Cardiovasc Surg 1993;
106:868-74
Independent bilateral primary bronchial carci¬
Thorax 1971; 26:476-80
41 Clifton EE, Gupta TD, Pool JL. Bilateral pulmonary resec¬
tion for primary or metastatic lung cancer. Cancer 1964;
40 Chaudri MR.
nomas.
17:86-94
Ferguson MK, DeMeester TR, Deslauriers J, et al. Diagnosis
and management of synchronous lung cancers. J Thorac
Cardiovasc Surg 1985; 89:378-85
43 Ferguson MK. Synchronous primaiy lung cancers. Chest
1993; 103:398S-400S
44 Payne WS, Clagett OT, Harrison EG. Surgical management
of bilateral malignant lesions of the lung. J Thorac Cardiovasc
Surg 1962; 43:279-90
45 Salerno T, Munro D, Blundell P, et al. Second primary
bronchogenic carcinoma: life-table analysis of surgical treat¬
ment. Ann Thorac Surg 1979; 27:3-6
46 Benfield JR. Multiple primary lung cancers. J Thorac Cardio¬
vasc Surg 1991; 101:937-38
47 Rosengart T, Martini N, Ghosen P, et al. Multiple primary
lung carcinoma. Ann Thorac Surg 1991; 52:773-79
48 Weiss W. Prognosis after resection of metachronous multiple
bronchogenic carcinoma. Am J Surg 1979; 138:658-61
42
CHEST / 112 / 3 / SEPTEMBER, 1997
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21750/ on 04/30/2017
701