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* From the Departments of Pulmonary Diseases (Drs. van Rens and van den Bosch), Thoracic Surgery (Dr. Brutel de la Rivière), and Pathology (Dr. Elbers), Sint Antonius Hospital, Nieuwegein, The Netherlands.
Correspondence to: Jules M.M. van den Bosch, MD, PhD, FCCP, Sint Antonius Hospital, Department of Pulmonary Diseases, PO Box 2500, 3430 EM Nieuwegein, The Netherlands; e-mail: antolong{at}knmg.nl
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Abstract |
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Design:
Retrospective study; period from 1970 to 1992; follow-up 
5
years.
Patients: A total of 2,361 previously untreated patients who underwent resection for stage I, II, or IIIA primary NSCLC.
Measurements: Survival was estimated from the date of operation using the Kaplan-Meier survival analysis method. Deaths within 30 days of operation were excluded. Survival comparisons of different surgical-pathologic TNM classification (based on pathologic examination of resected specimens) as well as further discriminative factors were analyzed by log-rank test.
Results: Postoperative death occurred in 3.9% of patients. For survival analyses, 2,263 patients were included. The overall 5-year survival was 937/2,263 (41.4%). Five-year survival in stage IA was 255/404 (63%); in stage IB, 367/797 (46%); in stage IIA, 43/83 (52%); in stage IIB, 210/642 (33%); and in stage IIIA, 63/337 (19%). No significant difference in survival was demonstrated between stages IB and IIA. Until 4 years after surgery, age at operation did not influence survival; after 5 years, patients > 65 years old had a significantly lower survival.
Conclusion: The TNM staging system accurately reflects the prognosis in primary NSCLC, but some stage definitions can be discussed. Despite the fact that the staging system is built on clinical data, the present analysis, which includes postsurgical data, confirms the similar survival of patients with T2N0M0 and T1N1M0. These results also stress the use of two separate substages, especially because these patients are offered surgery when possible.
Key Words: lung neoplasm • neoplasm staging • non-small cell lung carcinoma • prognosis • pulmonary surgical procedures
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our own data from patients who underwent surgery are comparable in numbers as well as in follow-up to those recently presented,2 so we analyzed them for validation. Adherence to the new system is important because many new treatment modalities have been proposed recently. These new strategies may improve survival, but this can only be determined properly if the new staging system is generally accepted and based on large numbers of patients.
We present in this study our results of survival after lung resection in patients with primary non-small cell lung cancer in stages I, II, and IIIA, in order to discuss the recent refinements of the staging system.2
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Patient age ranged from 26 to 85 years, with a median of 64.2 years. Patients were > 65 years old at the time of surgery in 1,115 cases (47.2%). There were 2,196 men (93%) and 165 women. The number of women who underwent resection for stage I, II, and IIIA NSCLC increased from 3.9% in 1970 to 1974 to 9.4% in 1990 to 1992. Surgical-pathologic TNM classification (pTNM) of the studied patients is given in Table 1 .
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Survival was estimated from the date of operation using the Kaplan-Meier survival analysis method.6 Deaths within 30 days of operation were excluded. Survival comparisons of different pTNM classifications as well as further discriminative factors were analyzed by log-rank test.7 The difference was considered significant when the p value was < 0.05.
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Results |
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The best 5-year survival rate (63%) was seen in pT1N0M0, and the worst survival (7%) in pT3N2M0. Survival rates listed by the pTNM status are presented in Table 2 . There were significant differences (p < 0.0001) in survival between pT1N0M0 (n = 404) and pT2N0M0 (n = 797). Survival after resection was better in pT1N1M0 (n = 83) than in pT2N0M0 (n = 797); however, the difference was not significant (p = 0.73). Patients with pT3N0M0 disease (n = 132) showed significantly better survival (p < 0.002) than patients with pT3N2M0 (n = 57) and pT2N2M0 (n = 180) disease, but the difference in survival between pT3N0M0 and pT3N1M0 (n = 87) was not significant (p = 0.31). Using the 1997 staging criteria,2 significant differences in survival were demonstrated between stages IA and IB, between stages IIA and IIB, and between stages IIB and IIIA. No significant difference was demonstrated between stages IB and IIA. Five-year survival rates are shown in Table 3 and Figure 1 . Long-term survival for different stages is given separately in Table 4 .
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Survival was significantly better in patients who had squamous cell lung carcinoma compared with patients who had nonsquamous cell carcinoma in the pT2N1M0 subset (p < 0.0005); this difference was not found in other pTNM subsets.
As shown in Figure 2 , patients aged < 65 years (median age, 58.5 years; n = 1,246) at operation had significantly better survival compared with patients aged > 65 years (median age, 70.0 years; n = 1,017). The overall 5-year survival of patients < 65 years was 44%, compared with 38% for older patients (p < 0.0001). Taking the TNM subsets into account, this was demonstrated in the pT1–3N0M0 subsets (p < 0.005) and the pT2N1M0 subset (p < 0.05).
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Compared with the surgical data published by Mountain,2
the overall survival in the patients in our study was lower, albeit not
significantly different (
2 test, results not
shown). This minor difference may be caused by the pTNM subset
distribution: In our study, the number of patients with advanced lung
cancer is slightly larger. Inclusion of a relatively large number of
patients with limited disease may result in increased overall survival
rates. In analysis of specific pTNM subsets, survival in our patients
is still slightly inferior to the results described by
Mountain,2 although again the differences were not
significant. Inoue et al8
reported better survival rates
in patients who underwent curative operation than the survival results
published by Mountain2
and in the present study. Detailed
comparative analysis of the data of Inoue et al8
was not
possible because 5-year survival rates were reported in only a few pTNM
subsets.8
However, Mountain did not state the definition
of "complete resection"; the stage I and IIA patients he reported
on had all undergone complete resection. If we exclude the patients
with incompletely resected tumors (n = 44) in these stages from our
survival analysis, the 5-year survival rates do not change much (5-year
survival in stage IA, 63%; stage IB, 47%; stage IIA, 52%) and are
still poorer than those reported by Mountain.2
Studies investigating survival in NSCLC have reported that survival is likely to be determined by many factors, including the diversity of patients within one TNM subset, patient characteristics (eg, age), policy-changing preoperative investigations (eg, mediastinoscopy), indication for surgery, treatment after surgery, inclusion of multiple lung carcinoma, and probably histology.5 11 12 13 14 15 16 17 In order to search for groups of patients who may benefit from surgery, different factors were analyzed.
The merits of the TNM classification to predict prognosis have been proved.2 3 9 Although definitions of the T and N parameters are strict, each TNM subset will still contain a variety of patients because of differences in the exact anatomic spread of the tumor and in surgical radicality.5 13 15 18 19 Therefore, a wide range of survival rates can be found within a TNM subset.
Surgery in older patients has been a subject of concern and may be
related to postoperative mortality or poor survival outcome, especially
in advanced cancer.11
20
In the present study, elderly
patients ( 65 years old) had a shorter survival. Decreased life
expectancy contributes to the poorer survival, because the terminal
event is defined as death by any cause. In this study, survival rates
are very similar in older and younger patients until 4 years after
surgery (44% vs 48%; Fig 2
). After this period, there is an increased
mortality in the elderly, probably because of increased age and
comorbidity. This is supported by the finding that the difference in
survival is only found in those pTNM subsets that have a better
prognosis (ie, elderly patients can develop other diseases,
resulting in death, although their surgery for lung cancer had been
curative). This observation corroborates a more aggressive approach in
the older patient, despite increased postoperative mortality.
Survival in relation to histology of NSCLC has been shown previously. Al-Kattan et al11 reported no significant difference in 5-year survival for squamous cell carcinoma and adenocarcinoma in stages I to IIIA. We have found better survival in squamous cell carcinoma only for pT2N1M0. In the past, part of this material was investigated.19 In this cohort of patients, reanalysis showed no relationship between nodal involvement and histology or tumor size (results not shown).
Mediastinoscopy was included in the preoperative assessment of our patients with NSCLC. Patients with positive mediastinoscopy were generally excluded from surgery; therefore, we included in our series a relatively small number of patients with N2 disease (261/2,361; 11%). In the study by Mountain,2 mediastinoscopy was not performed on a routine basis, and more patients with N2 disease were included (346/1,912; 18%). Although survival generally is found to be better in patients with intraoperatively diagnosed N2 disease, in our study population, survival in N2 disease was lower, but not significantly different.2 14 21 22
Also, the impact of postoperative therapy—which was rather diverse and changed over time in our patients—may have resulted in a different overall survival. Generally, patients with incomplete resection were treated with postoperative radiotherapy. Patients with N2 disease, as well as a considerable number of patients with NSCLC and chest wall involvement, were also treated with radiotherapy postoperatively. The benefit of radiotherapy in the individual patient is difficult to assess.23 Pitz et al5 analyzed 125 patients with NSCLC and chest wall involvement who underwent resection. Postoperative radiotherapy had no effect on survival in these patients. Changes in use of (new) chemotherapeutics and alterations of radiotherapeutic regimes may change survival of patients with NSCLC and are of interest in patients with either limited or advanced disease.
The indication for surgery, and whether the procedure is radical or not, also have an impact on the survival rates. In the last decade, more aggressive surgery and more liberal inclusion of patients with advanced disease have been noted. An individual patient may benefit, but in general this policy will result in a lower overall survival rate in these subsets. This is supported by the survival rates published by Mountain in 1997,2 which are slightly lower than those published in 1986.1 Most prominent is the decline in survival of patients with N2 disease: in 1986, Mountain reported a 5-year survival of 28.8% in this group,1 but in 1997, he reported a 23% 5-year survival.2 Patients with N2 disease are frequently offered surgery today. More aggressive neoadjuvant therapeutic regimens are likely to improve survival rates after surgery by downstaging the disease after chemotherapy.
Patients with synchronous multiple lung carcinoma have a worse prognosis, and the definition of multiple lung carcinoma is still under discussion. These patients were not included in this study. In the new staging system, such tumors may be classified as stage IIIB or stage IV disease.2
Concerning the methods used, it should be emphasized that Kaplan-Meier
analysis has its limitations. Some limitations can be overcome, such as
censoring, which is limited in our study by having a follow-up of 5
years. In this study, the terminal event was defined as death by any
cause, which may result in a lower survival rate than
Mountain2
reported because he defined the terminal event
as "death from cancer or unknown cause." Moreover, our definition
was chosen because of the retrospective character of the analysis,
which included data from a 23-year period, during which the cause of
death was not always well documented, and because of possible
insufficient diagnosis in any end-stage disease.
As stated previously, the best survival is found in patients with T1N0M0 and the worst survival in T3N2M0. Other TNM subsets have intermediate survival rates, and staging is still debated.2 8 10 24 Because the staging system is designed to guide the choice of a therapeutic regimen, the staging system was built on clinical data. However, staging with the use of exclusive clinical data is not always exact, as chest physicians do experience in daily practice. Clinical staging turns out to be understaging in a considerable number of patients when surgical data become available for these patients. This can also be derived from the clinical and surgical data of Mountain, in which understaging is most notable in stages IB and IIA. Although we agree that the staging system is meant to guide therapy and to give prognosis and is initially based on clinical data, we want to discuss the staging system after analysis of postsurgical data. In stage II, the subset pT1N1M0 has a better survival than the other subsets, supporting the division of stage II into stages IIA and IIB. However, no significant difference in survival is found between stage IB and stage IIA. This latter observation was also made by Inoue et al8 as well as by Rami-Porta.10 The similar survival rates for stages IB and IIA can be found in both the clinical and the postsurgical data of Mountain2 ; because surgery is advocated for both stage IB and stage IIA, use of two separate substages can be disputed.
Despite inclusion of T3N0M0 in stage IIB, which is supported by survival rates similar to T2N1M0, stage IIIA still represents an inhomogeneous group with regard to both anatomical extent of tumor and survival. T3 has a rather broad definition, including patients with tumor extension in very different tissues, allowing different possibilities for (curative) surgery.5 9 13 24 For this reason, inclusion of T3N1M0 is also under discussion—even more so, because in our study, survival was found not to be significantly different from T3N0M0 survival. By latter observation, downstaging of T3N1M0 to stage IIB is suggested. However, patients with T3 tumors invading the thoracic wall have better survival than T3 patients with central localization.24 The present T definition does not allow separation of these groups of patients with thoracic wall involvement vs central localization.24 Apart from T3 tumors, stage IIIA also includes N2 disease, for which treatment with adjuvant chemotherapy is now advocated. For clinical and therapeutic reasons, inclusion of N2 disease in one stage (IIIA) is supported.
In conclusion, the TNM staging system accurately reflects the prognosis in primary NSCLC, but some stage definitions can be discussed. Despite the fact that the staging system is built on clinical data to assess treatment in individual patients, the present analysis, which includes postsurgical data, confirms the similar survival of patients with T2N0M0 and T1N1M0. This finding stresses the importance of using two separate substages, especially because these patients are offered surgery when possible.
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Footnotes |
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Received for publication February 23, 1999. Accepted for publication August 10, 1999.
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