(Chest. 1999;116:144-149.)
© 1999
American College of Chest Physicians
Unfavorable Prognosis of Patients With Stage II Non-small Cell Lung Cancer Associated With Macroscopic Nodal Metastases*
Ichiro Yoshino, MD;
Ryoichi Nakanishi, MD;
Toshihiro Osaki, MD;
Mitsuhiro Takenoyama, MD;
Satoshi Taga, MD;
Takeshi Hanagiri, MD and
Kosei Yasumoto, MD
*
From the Department of Surgery II, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Correspondence to: Ichiro Yoshino, MD, Department of Surgery II, School of Medicine, University of Occupational and Environmental Health, Iseigaoka 1–1, Yahatanishi-ku, Kitakyushu 807, Japan; e-mail: ichiroy{at}med.uoeh-u.ac.jp
 |
Abstract
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Background: Patients with stage II-N1 non-small cell
lung cancer (NSCLC) make up an intermediate group of patients with an
unsatisfactory prognosis even though complete resection is usually
possible. We retrospectively analyzed postoperative prognostic factors
to devise guidelines for the proper management of this patient
population.
Study design: Among 546 patients with
NSCLC who underwent surgical resection from 1979 to 1995, 43 patients
were pathologically defined to be at stage II-N1 (T1–2N1M0). The
influence of the following variables on postoperative survival was
analyzed: gender, age, cell type, pathologic T factor, number of
metastatic nodes, station of metastatic nodes (hilar or pulmonary
nodes), status of nodal metastasis (macroscopic, gross involvement
confirmed histologically; or microscopic, metastasis first defined by
histologic examination), surgical methods, and adjuvant therapy
(including 18 of chemotherapy and 2 of radiotherapy).
Results: The 5-year survival rates (5YSRs) of patients with
microscopic (n = 21) and macroscopic nodal metastasis (n = 22) were
76.0% and 27.6%, respectively (p = 0.001). The 5YSRs of 20 patients
who received adjuvant therapy and 23 who did not receive adjuvant
therapy were 57.6% and 46.6%, respectively (p = 0.036). Other
variables did not affect survival. The Cox proportional hazards model
analysis indicated that the presence of a macroscopic nodal metastasis
and postoperative adjuvant therapy were independent prognostic factors.
Among patients with macroscopic N1 NSCLC, 9 patients who had undergone
adjuvant therapy showed a more favorable prognosis than the 13 patients
who had not received adjuvant therapy (3-year survival rate, 55.6% vs
18.5%; p = 0.037; and recurrence rate, 30.0% vs 77.8%), whereas no
significant influence of adjuvant therapy on survival was observed
among patients with microscopic N1 NSCLC.
Conclusions:
Stage II-N1 NSCLC was categorized into microscopic and macroscopic N1
diseases. The latter had a poor prognosis, which might be improved by
adjuvant therapy, although a suitable regimen has not been
established.
Key Words: nodal metastasis • non-small cell lung cancer • TNM classification
|
Introduction
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Non
-small cell lung cancer (NSCLC) with the main tumor not invading
neighboring organs, and with involvement of hilar or pulmonary nodes as
the sole site of metastasis (stage II-N1, referred to as stage II in
the former TNM classification1
), is well suited for
surgical resection; however, the outcome is still considered
unsatisfactory, with a high rate of recurrence at both local and
distant sites and an overall survival rate of 30 to 50% at 5
years.2
3
4
5
These facts indicate that tumor cells have
already spread systematically beyond the intrathoracic lymphatic system
at the time of surgery in a certain population of the stage II-N1
patients. The characteristics of such a small (approximately 10% of
all resected NSCLC cases) and intermediate population remain to be
investigated.
Radiotherapy or systemic chemotherapy has been performed as an adjuvant
therapy for stage II NSCLC in a number of institutes, but the efficacy
of adjuvant therapy remains to be determined.4
6
7
To make
it more effective, it may be essential to select and characterize the
subpopulation that is best suited for surgical adjuvant treatment.
Until recently, pathologic T factor,3
larger size of main
tumor,4
multiplicity of nodal metastases,4
and hilar nodal involvement5
have been suggested as
indicators of a poor prognosis for stage II-N1 NSCLC, although such
factors still remain controversial. In this study, we investigated the
prognostic factors in an attempt to classify subgroups for a proper
management of stage II disease.
|
Materials and Methods
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Patients
From January 1979 to December 1995, 546 patients with NSCLC
underwent surgical resection at the Department of Surgery II,
University Hospital of Occupational and Environmental Health,
Kitakyushu, Japan. Of these patients, 43 were defined as having stage
II-N1 disease by pathologic determination of T1–2, and intrapulmonary
(Nos. 12 and 13) or hilar lymph node (Nos. 10 and 11) metastases
(N1).8
Mean observation time was 1,240 days. The profile
of the stage II-N1 patients is given in Table 1
. The histologic diagnosis of the tumors was based on the criteria of
the World Health Organization.9
The mean age of the
patients (32 men, 11 women) was 67.5 ± 7.5 years (range, 47 to 81
years). Histologically, 27 patients had squamous cell carcinomas, 13
had adenocarcinomas, and 3 had large cell carcinomas. A standard
surgical procedure, such as a lobectomy or pneumonectomy with complete
dissection of the hilar and mediastinal lymph nodes, was performed in
all patients except one who underwent segmentectomy with mediastinal
dissection. Postoperative adjuvant chemotherapy included platinum-based
combination chemotherapy for 14 patients (two to three courses);
mitomycin for one patient (two shots); cyclophosphamide for one
patients (two courses); and oral administration of tegafur and uracil
for two patients (daily for 2 years). Irradiation was performed for the
ipsilateral hilum (60 Gy) in two patients. TNM stage10
was
determined by preoperative examinations comprising chest radiograph; CT
of the brain, chest, and abdomen; bone scan; and pathologic examination
of surgical specimens. When nodal involvement was macroscopically
recognized at thoracotomy and confirmed by subsequent histologic
examination, the nodal metastasis was defined as macroscopic
(macroscopic N1). When the nodal metastasis was first diagnosed by
postoperative histologic examination of resected specimens, the
metastasis was defined as microscopic (microscopic N1). Fifteen out of
22 patients with macroscopic N1 disease could be diagnosed as clinical
N1 based on preoperative imaging.
Follow Up of Patients
Serial follow-up examinations were, in general, done every 1 or
2 months for the first 2 years and every 3 to 4 months thereafter. The
examinations included physical examination, hematology, blood
biochemistry, and chest radiography. All patients routinely received
screening examinations for recurrence by CT or radionuclide bone
scanning once or twice per year after the operation. Recurrent disease
was then confirmed by biopsy specimen if clinically feasible. In
patients for whom a biopsy was not feasible, radiographic confirmation
(radiography, CT, or radionuclide scan) was accepted. The final date
for evaluation was December 31, 1997.
Statistical Analysis
Survival rates were calculated by the Kaplan-Meier
method,11
and comparisons among the survival curves were
made using the log-rank test.12
The Cox proportional
hazards model was used to identify the factors (gender, age, cell type,
pathologic T factor, number of metastatic nodes, station of metastatic
nodes, status of nodal metastases, surgical methods, and adjuvant
therapy) that had a jointly significant influence on
survival.13
The data were considered to be significant
when the p value did not exceed 0.05.
|
Results
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Overall Survival of Stage II-N1 Patients
There was no event with morbidity or mortality at the time of
surgery and/or adjuvant therapies. For all 43 patients with stage II-N1
disease, the cumulative postoperative 5-year survival rate (5YSR) and
median survival time (MST) were 50.2% and 2,205 days, respectively
(Fig 1 ). These values were significantly different (p < 0.001) from those
for the 217 patients with stage I disease (5YSR, 67.4%; MST, 4,581
days), and for the 94 patients with stage IIIa-N2 disease (5YSR,
25.7%; MST, 730 days), who underwent surgical resection at our
department during the same period (Fig 1)
. The survival curves of stage
II-N1 patients and stage II-T3 patients (5YSR, 43.2%; MST, 769 days)
were very similar (p = 0.430; Fig 1
).
Postoperative Prognostic Factors for Stage II-N1 Patients
The influence of various factors on the postoperative prognosis of
patients was examined by a univariate analysis (Table 2
). There was no association between postoperative survival and the
following variables: gender (male vs female); age (
65 years vs
< 65 years); cell type (squamous cell carcinoma vs others);
pathologic T factor (T1 vs T2); number of metastatic nodes (one vs two
or more); station of metastatic nodes (hilar vs pulmonary nodes);
surgical methods (lobectomy or segmentectomy vs bilobectomy or
pneumonectomy). A significant influence was observed only with regard
to the extent of nodal involvement (macroscopic vs microscopic
metastasis) and adjuvant therapy. The 5YSR and MST of 21 patients in
whom microscopic N1 disease was diagnosed and 22 patients in whom
macroscopic N1 disease was diagnosed were 76.0%/3,123 days and
27.6%/632 days, respectively (p = 0.001; Fig 2
). The 5YSR and MST of 20 patients who received adjuvant therapy
(chemotherapy in 18 patients and radiotherapy in 2 patients) were
57.6% and 1,155 days, respectively, compared with 46.6% and 854 days
in the 23 patients who did not receive adjuvant therapy (p = 0.036;
Fig 3 ).
A multivariate analysis revealed that macroscopic N1 disease was an
independent factor for poor prognosis at a hazard ratio of 7.87
(p = 0.001); postoperative adjuvant therapy was an independent factor
for favorable prognosis, and the hazard ratio was 8.70 when no adjuvant
therapy was performed after resection (p = 0.002; Table 2
).
Significance of Postoperative Adjuvant Therapy for Patients With
Macroscopic Stage II-N1 NSCLC
Considering the results described above, the effect of adjuvant
therapy on the survival of the microscopic and macroscopic N1 subgroups
was examined. Postoperative adjuvant therapy did not influence the
survival of the 21 patients with microscopic N1 disease. The 5YSR of 11
patients who underwent adjuvant therapy (chemotherapy for 11 patients)
was 72.9%, and that of the other 10 patients was 80.0% (p = 0.316;
Fig 4
top, a). On the other hand, in the subgroup with macroscopic
N1 disease, significant survival benefits were observed in 9 patients
who received adjuvant therapy (7 chemotherapy and 2 radiotherapy), as
compared with the 13 patients who did not receive any adjuvant therapy
after resection (3-year survival rates, 55.6% with adjuvant therapy vs
18.5% without adjuvant therapy; p = 0.037; Fig 4
bottom,
b).
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|
Figure 4. Top, a: the survival curves
of the subgroups of patients with microscopic N1 disease who received
adjuvant therapy (n = 11) and those with microscopic N1 disease who
did not receive adjuvant therapy (n = 10). Bottom, b:
the survival curves of the subgroups of patients with macroscopic N1
disease who received adjuvant therapy (n = 9) and those with
macroscopic N1 disease who did not receive adjuvant therapy
(n = 13).
|
|
Occurrence and First Site of Recurrence
Postoperative recurrence was frequently observed in the patients
who did not receive any adjuvant therapy. Recurrence was observed in
only 2 of the 11 patients with microscopic N1 disease who underwent
adjuvant therapy (recurrence rate, 9.1%), whereas 5 of the 10 patients
with microscopic N1 disease who did not receive any adjuvant therapy
developed recurrent tumors (recurrence rate, 50.0%; Table 3
). Among patients with macroscopic N1 disease, the recurrence rate was
higher for the 13 patients who did not receive any adjuvant therapy
(53.9%) than for the 9 patients who received adjuvant therapy
(chemotherapy in 7 patients and radiotherapy in 2 patients), in whom
the recurrence rate was 33.3% (Table 3)
. Among 13 patients in whom the
first site of recurrence was identified, distant metastases (10
patients) including the lungs, brain, and liver were more frequent than
local relapses (3 patients; Table 3
).
|
Discussion
|
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Until recently, several prognostic factors have been suggested for
patients with stage II-N1 NSCLC. Several authors stated that stage
II-N1 patients with adenocarcinoma had a significantly less favorable
prognosis than patients with squamous cell
carcinoma.14
15
16
Martini et al4
reported that
tumor size > 3 cm and multiplicity of nodal involvement were
associated with a poor prognosis. Recently, Yano et al5
reported that hilar nodal involvement revealed advanced disease,
whereas intrapulmonary nodal involvement revealed early disease. In our
study, the extent of nodal involvement (macroscopic or microscopic),
but not the station of metastatic nodes (hilar or pulmonary nodes), was
a strong factor for the postoperative prognosis, even in a relatively
small number of patients. In N2 disease, a relatively better prognosis
has been reported when mediastinal nodal involvement is first
identified at the time of thoracotomy, with a survival of approximately
20% at 5 years after resection; conversely, surgical outcome of
clinically diagnosed N2 disease was extremely poor, with a 5YSR
of almost 0%.8
17
18
Similarly, in the case of N1
disease, microscopic N1 disease showed a favorable outcome with a 5YSR
of 76.0% and a recurrence rate of 28.6% (6 of 21 patients), while
macroscopic N1 disease showed a poor outcome with a 5YSR of 27.6% and
a recurrence rate of 43.4% (10 of 23 patients). Therefore, gross nodal
metastases may reveal the existence of systemically widespread occult
cancer cells. The microscopic N1 and the stage I populations showed
similar prognoses (5YSRs of 76.0% and 67.6%, respectively), and the
macroscopic N1 and stage IIIa-N2 subpopulations also showed similar
prognoses (5YSRs of 27.6% and 23.7%, respectively). Therefore, stage
II-N1 disease is a complex of local disease (microscopic N1) and
systemic disease (macroscopic N1).
Recently, we have reported that micrometastatic cancer cells in the
dissected lymph nodes that are overlooked by conventional histologic
examination are frequently detected by immunohistochemical staining
using monoclonal antibody for p53 in patients with p53-positive NSCLC,
and the incidence of micrometastasis in the lymph nodes was associated
with a poor prognosis.19
In an additional recent study by
us, micrometastatic cancer cells (cytokeratin 18-positive cells) were
also detected in the bone marrow in 39% of the patients with
completely resected NSCLC; of the four patients with stage II-N1 (the
former stage II) disease, two patients tested positive for
micrometastases,20
suggesting that in certain populations
of patients with NSCLC, it is already a systemic disease even though no
distant metastasis is observed by conventional preoperative
examinations such as body and brain CT or bone scan. Such
micrometastases probably are more frequent in macroscopic N1 than in
microscopic N1 disease.
Another influencing factor identified in this study was postoperative
adjuvant therapy. Ferguson et al6
also reported an
improvement of postoperative survival for stage II-N1 NSCLC when
adjuvant radiotherapy and/or chemotherapy were administered. In the
prospective randomized studies performed by the Lung Cancer Study
Group, however, the efficacy of both adjuvant radiotherapy and
chemotherapy for the former stage II (stage II-N1) disease was not
studied. In one of those studies in which 42% of the study population
had stage II-N1 disease, a significant benefit of postoperative
chemotherapy was observed regarding disease-free survival but not
overall survival.7
In another series concerning adjuvant
radiotherapy, there was no significant improvement of the rate of local
recurrence in N1 disease.21
Of the adjuvant therapies
performed in this study, platinum-based combination chemotherapy was
performed in 14 patients for more than two courses. Mild chemotherapy
using daily oral administration of tegafur and uracil for 1 year, which
was recently reported by Wada et al,22
was administered in
two patients. The two patients who received adjuvant radiotherapy are
long survivors (2,321 days and 1,974 days for each). These adjuvant
therapies seem to improve the prognosis of the stage II-N1 NSCLC,
especially that of patients with macroscopic N1 disease, although such
an improvement in survival rate should be demonstrated by a randomized
trial.
|
Acknowledgements
|
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ACKNOWLEDGMENT: We thank Ms. Miki Kiyofuji for her expert help
during preparation of the manuscript.
|
Footnotes
|
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Abbreviations: 5YSR = 5-year survival rate;
MST = median survival time; NSCLC = non-small cell lung cancer
Received for publication July 27, 1998.
Accepted for publication February 17, 1999.
|
References
|
|---|
-
American Joint Committee on Cancer. Manual for staging of cancer. 4th ed. Philadelphia, PA: JB Lippincott, 1992; 116
-
Naruke, T, Goya, T, Tuchiya, R, et al (1988) Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 96,440-447[Abstract]
-
Martini, N, Flehinger, BJ, Nagasaki, F, et al (1983) Prognostic significance of N1 disease carcinoma of the lung. J Thorac Cardiovasc Surg 86,646-653[Abstract]
-
Martini, N, Burt, ME, Bains, MS, et al (1992) Survival after resection of stage II non-small cell lung cancer. Ann Thorac Surg 54,460-466[Abstract]
-
Yano, T, Yokoyama, H, Inoue, T, et al (1994) Surgical results and prognostic factors of pathologic N1 disease in non-small-cell carcinoma of the lung. J Thorac Cardiovasc Surg 107,503-507
-
Ferguson, MF, Little, AG, Golomb, HM, et al (1986) The role of adjuvant therapy after resection of T1N1M0 and T2N1M0 non-small cell lung cancer. J Thorac Cardiovasc Surg 91,344-349[Abstract]
-
Holmes, EC, Gail, M, . Lung Cancer Study Group (1986) Surgical adjuvant therapy for Stage II and Stage III adenocarcinoma and large cell undifferentiated carcinoma. J Clin Oncol 4,710-715[Abstract/Free Full Text]
-
Naruke, T, Suemasu, K, Ishikawa, S (1978) Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 76,832-839[Abstract]
-
. World Health Organization. (1982) Histological typing of lung tumors. Am J Clin Pathol 57,471-476
-
Mountain, CF (1997) Revisions in the international system for staging lung cancer. Chest 111,1710-1717[Abstract/Free Full Text]
-
Kaplan, EL, Meier, P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53,457-481[CrossRef][ISI]
-
Peto, R, Peto, J (1972) Asymptotically efficient rank and invariant procedures. J R Stat Soc (A) 135,185-207[CrossRef]
-
Cox, DR (1972) Regression models and life tables. J R Stat Soc (B) 34,187-220
-
Newman, SB, DeMeester, TR, Golomb, HM, et al (1983) Treatment of modified Stage II (T1 N1 M0, T2 N1 M0) non-small cell bronchogenic carcinoma. J Thorac Cardiovasc Surg 86,180-185[Abstract]
-
Vincent, RG, Takita, H, Lane, WW, et al (1976) Surgical therapy of lung cancer. J Thorac Cardiovasc Surg 71,581-591[Abstract]
-
Mountain, CF (1977) Assessment of the role of surgery in control of lung cancer. Ann Thorac Surg 24,365-373[Abstract]
-
Martini, N, Flehinger, BJ, Zaman, MB, et al (1980) Prospective study of 455 lung carcinomas with mediastinal lymph node metastases. J Thorac Cardiovasc Surg 80,390-399[ISI][Medline]
-
Nakanishi, R, Osaki, T, Nakanishi, K, et al (1997) Treatment strategy for patients with surgically discovered N2 stage IIIA non-small cell lung cancer. Ann Thorac Surg 64,342-348[Abstract/Free Full Text]
-
Dobashi, K, Sugio, K, Osaki, T, et al (1997) Micrometastatic p53-positive cells in the lymph nodes of non-small-cell lung cancer: prognostic significance. J Thorac Cardiovasc Surg 114,339-346[Abstract/Free Full Text]
-
Ohgami, A, Mitsudomi, T, Sugio, K, et al (1997) Micrometastatic tumor cells in the bone marrow of patients with non-small cell lung cancer. Ann Thorac Surg 64,363-367[Abstract/Free Full Text]
-
Weisenburger, TH, Gail, M, . Lung Cancer Study Group (1986) Effects of postoperative mediastinal irradiation on completely resected Stage II and Stage III epidermoid cancer of the lung. N Engl J Med 315,1377-1381[Abstract]
-
Wada, H, Hitomi, S, Teramatsu, T, et al (1996) Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. J Clin Oncol 14,1048-1054[Abstract/Free Full Text]
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TOP
Abstract
Introduction
