(Chest. 2000;118:952-958.)
© 2000
American College of Chest Physicians
Survival in Synchronous vs Single Lung Cancer
Upstaging Better Reflects Prognosis
Marcel Th. M. van Rens, MD;
Pieter Zanen, MD, PhD;
Aart Brutel de la Rivière, MD, PhD, FCCP;
Hans R. J. Elbers, MD, PhD;
Henry A. van Swieten, MD, PhD and
Jules M. M. van den Bosch, MD, PhD, FCCP
*
From the Departments of Pulmonary Diseases (Drs. van Rens, Zanen, and van den Bosch), Pathology (Dr. Elbers), and Thoracic Surgery (Dr. van Swieten), Sint Antonius Hospital, Nieuwegein; and Department of Thoracic Surgery (Dr. Brutel de la Rivière), University Medical Center, Utrecht, the Netherlands.
Correspondence to: Marcel Th. M. van Rens, MD, Sint Antonius Hospital, Department of Pulmonary Diseases, PO Box 2500, 3430 EM Nieuwegein, The Netherlands; e-mail: antolong{at}knmg.nl
 |
Abstract
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Objective: To define prognostic parameters for patients
with synchronous non-small cell lung cancer (NSCLC).
Design: Retrospective study of period from 1970 through
1997.
Patients: Patients with a single (n = 2,764)
and synchronous NSCLC (n = 85) who underwent pulmonary
resection.
Methods: All tumors were classified
postsurgically, and the tumors of the patients with synchronous lung
cancer were staged separately. The most advanced tumor was used for
comparison. Actuarial survival time was estimated, and risk factors
influencing survival were evaluated. Patients who died within 30 days
of surgery were excluded.
Measurement and results:
Five-year survival for single NSCLC was 41% and for synchronous lung
cancer it was 19%. The relative risk of death for patients with
synchronous lung cancer was 1.75, compared to that for patients with
single lung cancer. The most advanced tumor in synchronous cancer was a
significant predictor of survival (p < 0.005). The survival of
patients with synchronous lung cancer in which the most advanced tumors
were stage I (n = 40) and stage II (n = 27) was not different from
that of patients with stage II (n = 834) and stage IIIA (n = 405)
single lung cancer, respectively.
Conclusion: The
poorer survival of patients with synchronous NSCLC is confirmed and
quantified. The stage of the most advanced tumor was the best predictor
of prognosis. The prognosis of patients with synchronous NSCLC
resembles the prognosis of patients with a single lung cancer of a
higher stage. Upstaging in synchronous lung cancer is recommended on
the basis of these observations.
Key Words: lung neoplasm • multiple primary neoplasm • neoplasm staging • non-small cell lung carcinoma • prognosis • pulmonary surgical procedures • survival
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Introduction
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Pulmonary
resection remains the most effective treatment for patients with
non-small cell lung cancer (NSCLC) with limited disease.1
In some patients, more than one tumor is present or a second one is
detected later (multiple lung cancer). Generally, multiple lung cancer
is subdivided into synchronous and metachronous lung
cancer,2
with synchronous cancer being defined as two or
more tumors present or detected at the same time, and metachronous
cancer being defined as tumors detected with an interval. However,
diagnosis of multiple lung carcinoma with the same histology may be
difficult because of the possibility of metastatic or recurrent
disease.2
There have been several studies of synchronous lung
cancer,3
4
5
6
7
8
and these studies should be distinguished from
those analyzing primary lung cancer with intrapulmonary
metastasis.9
10
11
12
13
In general, the data of patients with
synchronous lung cancer are not related to therapy and survival of
patients with single lung carcinoma. Therefore, it remains difficult to
probe changes in survival of patients with synchronous lung cancer.
In this report, the results of surgical treatment of patients with
synchronous lung cancer are compared with those for patients with
single lung carcinoma. Possible prognostic parameters in synchronous
lung cancer are defined.
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Materials and Methods
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From 1970 through 1997, a total of 3,372 previously untreated
patients underwent surgery for NSCLC at the Sint Antonius Hospital,
Nieuwegein, the Netherlands. Of these, 3,086 patients underwent
pulmonary resection, 2,849 of whom underwent resection for stage I,
stage II, and stage IIIA NSCLC. These patients were allocated to two
groups.
The first group consisted of 85 patients with synchronous lung
carcinoma. In 27 of these 85 patients, the second tumor was found
accidentally at operation or at pathologic examination. In all 85
patients, the tumors were diagnosed at the same time and were
classified as synchronous lung cancer according the criteria of Martini
and Melamed 2
(Table 1
). The second group consisted of 2,764 patients with single NSCLC.
Recently, 2,361 of these patients with a follow-up of at least 5 years
were analyzed in a study validating refinements of the staging
system.14
The characteristics of the patients with a single lung cancer
(n = 2,764) and synchronous lung cancer (n = 85) are presented in
Table 2
. Tumors were classified postsurgically, according to the 1997 staging
system.1
The tumors of patients with synchronous cancer
were staged separately, and the highest staged/most advanced tumor was
classified as the "reference" tumor, as reported by
others.4
5
Resected specimens were routinely examined
pathologically and reviewed using the current criteria of the World
Health Organization classification.15
Differences in
frequency-based patient data were tested by the
2 test and normally distributed data by
Student’s t test. Differences were considered significant
when the p value was < 0.05.
Two survival analyses were performed. One analysis used the data for
both patients with single or synchronous lung cancer, to focus on
differences between single and synchronous lung cancer. The other
analysis used only the data for the patients with synchronous lung
cancer. Survival was calculated by the Kaplan-Meier survival analysis
method.16
Survival was estimated from date of operation.
Deaths within 30 days after operation were excluded. Differences in
survival between the two groups were tested by the log-rank
test.17
Differences were considered significant when the p
value was < 0.05. To facilitate interpretation, the hazard ratio
(plus 95% confidence interval [CI]) was calculated where needed.
Multivariate Cox’s regression analysis18
was used to
analyze the data of the patients with synchronous lung cancer, to test
the relation between survival and age, stage of tumor, histology, or
tumor localization. The following variables were used as categorical
variables with two classes: age (< 65 years vs 
65 years);
histology (identical vs different); and tumor localization (one lobe vs
different lobes). The variable stage was used as a categorical variable
with three classes (stages I, II, and IIIA). A forward-selection
approach was used.
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Results
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One hundred twelve patients (4.1%) with single lung cancer
(n = 2,764) and 12 patients (14.1%) with synchronous lung cancer
(n = 85) died within 30 days after operation. Eleven patients who
underwent resection for synchronous lung cancer died because of
cardiorespiratory complications. Postoperative mortality was especially
high (6 of 28) among patients with bilateral lesions who underwent
resection in one session. However, the characteristics and the causes
of postoperative death did not differ from those of the other patients
with synchronous lung cancer. Eight patients with single lung cancer
were unavailable for follow-up, and therefore the data for 2,717
patients (2,644 single and 73 synchronous lesions cancer) were included
for detailed survival analysis. The characteristics of the 73 patients
with synchronous lung cancer included in the analysis are given in
Table 3 , but were not different from those of the total group of 85
patients who underwent surgery for synchronous lung cancer.
As of January 1, 2000, 9 of the 73 patients with synchronous lung
cancer were alive, with survival times of 2.1 to 6.4 years (median, 4.6
years) and were free of cancer. Thirty-five of the 64 patients who
died, died of recurrence or metastasis of lung cancer, and 20 died of
noncancer-related causes; in 9 patients, the cause of death was
not recorded. Recurrence or metastases was diagnosed at a median time
of 12 months (range, 2 to 143 months) after resection.
Single and Synchronous Lung Cancer
The demographic characteristics of the two groups did not differ.
The patients with synchronous lung cancer were older (median age
difference, 1.1 year), however not significantly (p = 0.35), and the
stage distribution of the single and reference tumor was not different
(p = 0.36). Overall survival was significantly higher (p < 0.0001)
in patients with a single lung cancer. Five-year survival after surgery
was 41% for patients with single lung cancer and 19% for patients
with synchronous lung cancer (Fig 1
). Survival after surgery in single lung cancer was significantly
different between stage I and stage II disease (p < 0.0001), stage
II and stage IIIA disease (p < 0.0001), and between subsets IA and
IB (p < 0.0001), and IIA and IIB (p < 0.04). Using the reference
tumor as stage marker in patients with synchronous lung cancer, there
was no significant difference between subsets IA and IB (p = 0.42;
hazard ratio, 0.73; 95% CI, 0.34 to 1.55) and between subsets IIA and
IIB (p = 0.80; hazard ratio, 1.17; 95% CI, 0.34 to 4.00). Because of
this observation and the small numbers of synchronous lung cancer
patients, comparative analyses of subsets of patients with single and
synchronous lung cancer were not done. The survival of patients with
stage I synchronous lung cancer (n = 40) was not significantly
different (p = 0.48; hazard ratio, 0.88; 95% CI, 0.61 to 1.26) from
that of patients with stage II single lung cancer (n = 834; Fig 2
, top), and neither was the survival of patients with stage
II synchronous lung cancer (n = 27) significantly different
(p = 0.52; hazard ratio, 0.88; 95% CI, 0.58 to 1.31) from patients
with stage IIIA single lung cancer (n = 405; Fig 2
,
bottom; Table 4
). The relative risk of death was 1.75 higher in patients with
synchronous lung cancer than in patients with single lung cancer,
irrespective of the stage of the disease. When the stage of the
disease was taken into account, the relative risk of death ranged from
1.73 to 1.93 (Table 5
).
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Figure 2.. Top: Estimated 5-year survival of
patients with synchronous lung cancer with reference tumor stage I
(n = 40; broken line), compared to survival of patients with stage II
single NSCLC (n = 834; solid line; no survival difference;
p = 0.48). + = censored cases. Bottom: Estimated
5-year survival of patients with synchronous lung cancer with reference
tumor stage II (n = 27; broken line), compared to survival of
patients with stage IIIA single NSCLC (n = 405; solid line; no
survival difference; p = 0.52). + = censored cases.
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Table 5.. Cox’s Proportional Hazards Model of Factors
Associated With Postoperative Survival After Resection in Patients With
Single and Synchronous Lung Cancer
|
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Synchronous Lung Cancer
With the reference tumor as stage marker, survival was found to be
significantly different for the different disease stages (stages I, II,
and IIIA; p < 0.005). Survival differed significantly between stage
I and stage II disease (p < 0.05) or stage IIIA disease
(p < 0.004), but not between stage II and stage IIIA disease
(p = 0.15; hazard ratio, 0.50; 95% CI, 0.20 to 1.28; Fig 3
; Table 6
). After pooling, the patients with stage II and stage IIIA disease had
a significantly lower survival (p < 0.01) than the patients with
stage I disease. Five-year survival was 13% vs 23%, respectively (Fig 4
; Table 6
).
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Figure 3.. Estimated 5-year survival after tumor resection of
patients with synchronous lung cancer with reference tumor stage I
(n = 40; solid line), stage II (n = 27; intermediate broken line),
and stage IIIA (n = 6; broken line). + = censored cases.
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View this table:
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Table 6.. Cox’s Proportional Hazards Model of Factors
Associated With Postoperative Survival After Resection in Patients With
Synchronous Lung Cancer
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Figure 4.. Estimated 5-year survival after tumor resection of
patients with synchronous lung cancer treated by pneumonectomy or
lobectomy(ies) (n = 41; broken line), compared to surgical procedures
including limited resections (n = 32; solid line). + = censored
cases.
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According to the new staging system,1
synchronous lesions
with the same histology are classified as stage IIIB and stage IV. In
the present survival analysis, 50 patients had synchronous lesions with
the same histology. Although the numbers are small, a significant
difference (p < 0.03) in survival was found between patients with
tumors located within one lobe (n = 7; stage IIIB) and tumors located
in different lobes (n = 43; stage IV). The same result was found when
the data of all the patients with synchronous cancer (n = 73) were
analyzed (p < 0.03; hazard ratio, 0.44; 95% CI, 0.22 to 0.90).
Five-year survival was 29% and 16% for single and multiple lobe
disease, respectively. Further analysis (Cox’s regression analysis)
demonstrated that this difference was related to the stage of the
reference tumor.
Kaplan-Meier analysis demonstrated that tumor histology did not affect
survival (p = 0.79). When the cases were grouped by histologic
subtype, there was no significant difference in survival. Furthermore,
the median survival was poorer in patients treated by a surgical
procedure, including limited resection (such as a wedge or segmental
resection; n = 32), than it was in patients treated by pneumonectomy
or lobectomy(ies) (n = 41); however, this difference was not
statistically significant (p = 0.16; hazard ratio, 1.44; 95% CI,
0.86 to 2.40).
Cox’s regression analysis showed that the stage of the reference tumor
was the only significant predictor of survival in patients with
synchronous lung cancer (p < 0.005); age (p = 0.06), histology
(p = 0.90) and localization of tumors (p = 0.11) were not. Survival
was poorer when the reference tumor was higher than stage I (Table 6)
.
|
Discussion
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This study confirms and quantifies the poorer postsurgical
survival of patients with synchronous NSCLC, compared with that of
patients with single NSCLC. The risk of dying of patients with
synchronous lung cancer was almost double that of patients with single
lung cancer. The stage of the most advanced tumor was the best
predictor of survival in patients with synchronous lung cancer. Our
results as well as the results of others show that surgery is a
treatment option for patients with synchronous lung
cancer.3
4
5
6
7
8
Survival after resection in the patients with
synchronous lung cancer was comparable with that reported in the
literature.3
6
8
19
For patients with stage IA single
NSCLC, survival is poorer after limited resection.20
However, in the present study, this observation was not confirmed
clearly, possibly because several resections were performed.
Nevertheless, the use of limited resections for synchronous lesions is
not supported and should be considered as a viable "compromise"
surgical treatment.20
In the literature, two separate definitions are used to define and
stage synchronous malignant lesions in the lung. The time-dependent
diagnosis (ie, synchronous vs metachronous) is rather
definite. Malignant lesions have to grow before they can be detected.
If CT and other scanning techniques had been available at time of
diagnosis of all the patients, it is possible that more patients would
have been diagnosed with synchronous cancer. However, we aimed to
include only patients whose disease met the strict definitions used by
Martini and Melamed.2
These authors excluded synchronous
tumors affecting common lymphatics if these had the same histology,
because of possible metastatic disease. In contrast to former
definitions, the new staging system limits the staging of multiple
synchronous tumors to lesions with the same histology and possible
metastatic disease.1
Synchronous satellite pulmonary
nodules situated in the same lobe are considered to be locally advanced
disease and are staged as T4 (stage IIIB). Tumors located in different
lobes are staged as metastatic disease (stage IV).1
The
definitions used by Martini and Melamed2
and in the 1997
staging system1
are debatable. Grossly, both definitions
fail to implement the multiple field cancerization
theory21
and to deal with the possibility of
metastatic disease. This is really a problem when the diagnosis is made
on the basis of histology according to World Health Organization
criteria10
and the histology of both tumors is identical.
In the future, new molecular techniques will make it possible to
distinguish metastatic lesions from separate primary
tumors.22
23
Cancer staging is designed to determine therapy and
prognosis.1
In the new staging system, primary lung cancer
with secondary pulmonary nodules is staged by upstaging, but there is
no proposal for the staging of synchronous lung cancers. In order to
analyze the meaning of staging and upstaging in synchronous disease, we
first staged all tumors separately. The most advanced tumor was defined
as the reference tumor. Because the stage of the reference tumor proved
to be the main predictor of survival, we then compared patients with
single and synchronous lung cancer according to the stage of the
(reference) tumor. The survival of patients with synchronous lung
cancer with stage I reference tumor appeared to be comparable to that
of patients with stage II single lung cancer, and the survival of
patients with synchronous lung cancer with reference tumor stage II
appeared comparable to that of patients with stage IIIA single NSCLC.
Although our study included relatively a small number of patients, our
findings may help to stage synchronous multiple NSCLC and to determine
prognosis. We propose that the reference tumor should be upstaged by
one stage. Thus, patients with synchronous lung cancer with reference
tumor of stage I and stage II are eligible for surgery and have a
survival comparable to that of patients with primary stage II and stage
IIIA NSCLC, in whom surgery is performed.
In conclusion, the prognosis of patients with synchronous NSCLC is
worse than that of patients with single NSCLC. After resection, the
risk of dying is almost double that of patients with single NSCLC. The
stage of the most advanced tumor is the best predictor of prognosis,
and survival is significantly better in patients with a stage I
reference tumor than it is in patients with a higher-staged reference
tumor. The survival of patients with synchronous NSCLC with stage I and
stage II reference tumors was not different from that of patients with
single lung cancer stage II and stage IIIA, respectively. These results
indicate that synchronous cancer should be upstaged.
|
Acknowledgements
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The authors thank Jane Sykes for her advice in
editing the manuscript.
|
Footnotes
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Abbreviations: CI = confidence interval;
NSCLC = non-small cell lung carcinoma
Received for publication November 16, 1999.
Accepted for publication May 11, 2000.
|
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Abstract
Introduction
