Ou, Sai-Hong Ignatius MD, PhD*†‡; Zell, Jason A. DO, MPH*†‡
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The current 6th edition of the Union Internationale Contre le Cancer (UICC6) staging system1 for lung cancer has not been changed since the publication of the 5th edition in 1997.2 Nevertheless, formal processes for continuous improvement of the tumor, node, metastasis (TNM) classification has been established since 2002.3 A new proposed revision of the tumor (T),4 nodes (N),5 and metastasis (M)6 descriptors for the forthcoming (7th edition) UICC lung cancer staging system has been recently proposed by the International Association for the Study of Lung Cancer (IASLC) after a rigorous study by an international panel using data from Europe, Asia, Australia, and North America. The proposed revision maintained the current N descriptors in the non-small cell lung cancer (NSCLC) staging system5 but proposed several changes to the T descriptor.4 For early stage T descriptor, one major revision was to subdivide T1 into T1a (≤2 cm) and T1b (>2 cm to 3 cm) and subdivide T2 into T2a (>3 cm to 5 cm), T2b (>5 cm to 7 cm), and T3 (>7 cm). For advanced T descriptors, one major revision is to reclassify T4 due to additional satellite nodules in the same lobe to T3 while upstaging pleural dissemination (malignant pleural effusion/pleural nodules) and malignant pericardial effusion to M1a.4 The major revision to the M descriptor is to subdivide it into M1a and M1b. “Contralateral intrapulmonary nodules” is grouped together with “malignant pleural dissemination” and “malignant pericardial effusion” into the new M1a category. All other distant metastasis will be grouped as M1b.6 One of the proposed stage grouping changes is reclassifying the new T4N0-1M0 from stage IIIB as stage IIIA.7 All these revisions and new grouping were internally validated and the Surveillance, Epidemiology, and End Results (SEER) database from 1998 to 2000 was used for external validation.8
We have previously shown that patients with T4 disease due to additional nodules in the same lobe and patients with M disease due to ipsilateral intrapulmonary nodules had better survival than T4 and M by other criteria respectively for both bronchioloalveolar carcinoma (BAC) and non-BAC NSCLC using SEER database.9,10 We are thus interested in performing an external validation study of the IASLC proposed staging changes using the California Cancer Registry (CCR) database. Using CCR database we have previously published that patients with BAC had statistically improved survival after the publication of the World Health Organization (WHO) changes in the definition of BAC.11 BAC also has unique clinicopathologic (more female, more nonsmokers, higher incidence of additional nodules in the same lobe, higher incidence of intrapulmonary metastasis) and molecular features (higher percentage of epidermal growth factor receptor mutations).11–13 As such we have performed a separate validation study on these staging changes specifically to BAC using CCR.14
In this study, we adopted all the IASLC proposed changes to the T and M descriptors and reclassified all non-BAC NSCLC patients according to the new stage grouping and primarily analyzed survival differences due to the changes to the T4 and M descriptors. The 1999 WHO change in the definition of BAC15 has changed the proportion and clinicopathologic features of BAC and adenocarcinoma11,12 and may have been affected survival of other NSCLC histologies. Thus we analyzed patients diagnosed after 1998 (1999–2003) similar to how IASLC used the SEER database from 1998–2000 as the external validation set.6
PATIENTS AND METHODS
The primary outcome measure was to compare the stage-specific overall survival (OS) of advanced non-BAC NSCLC using current UICC6 staging system and the proposed IASLC staging modifications.
A case-only analysis was conducted on incident NSCLC patients from CCR diagnosed between 1999 and 2003 who had complete TNM staging data and follow-up data. We limited the analysis to patients diagnosed after 1999, i.e., date of the WHO revised classification of lung tumors.15 Data were abstracted from medical and laboratory records by trained tumor registrars according to Cancer Reporting in California: Vol. IV, Abstracting and Coding Procedures for Hospitals.16
Tumor site and histology were abstracted as previously described.9–11 BAC histology was excluded, as we have separately performed a validation study for this histologic subtype.14 Non-small cell histologies were categorized as undifferentiated NSCLC if they were not coded as adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or as a metastatic lung lesion from a separate primary tumor, as previously described.9–11 Cytology specimens have been shown to be inaccurate in NSCLC diagnosis compared with histology specimens.17 Thus, in an attempt to limit potential variability in histologic classification, only histologically confirmed NSCLC cases were analyzed. Patient demographic data were abstracted using SEER codes. The measurement of socioeconomic status used in this analysis was a composite measure using CCR and census data as previously described.18,19 Radiation therapy and surgical techniques were abstracted using SEER codes. Chemotherapy given during the first course of therapy was ascertained using CCR codes.
For each patient in CCR, the Extent of Disease (EOD) coding variable was analyzed, to allow recoding into and comparison of the existing versus proposed revised staging system. EOD 65 which codes for “separate tumor nodule(s) in the same lobe,” EOD 71 which codes for “heart, visceral pericardium,” EOD 72 which codes for “malignant pleural effusions,” EOD 73 which codes for “adjacent rib,” EOD 75 which codes for “sternum, vertebra(e) skeletal muscle, skin of chest,” EOD 77 which codes “separate tumor nodule(s) in separate lobe,” EOD 78 which codes for “separate tumor nodule(s) in contralateral lung” and EOD 79 which codes for “(malignant) pericardial effusion” were used to identify the various T and M descriptors that were reclassified by IASLC. A total of 226 T3 patients with EOD 73 were reclassified as T4 according to the UICC6 staging system.
Restaging Patients According to the IASLC Revision for T4 and M Descriptors
Based on proposed IASLC revisions and stage grouping, the T4 descriptor for additional tumor nodules in the same lobe was changed to T3. We restaged these patients (T3N0M0) as stage IIB, patients with T3N1–2M0 as IIIA, and patients with T3N3M0 remained staged IIIB. The T4 descriptor for pleural dissemination (malignant pleural effusion/pleural nodules) was changed to M1a and so were patients with malignant pericardial effusion and we restaged these patients as stage IVA. The M descriptor for ipsilateral intrapulmonary nodules was changed to T4. These patients were staged according to the nodal status. Patients with contralateral intrapulmonary nodules were staged as M1a and grouped as stage IVA. Even though the proposed IASLC staging does not officially separate stage IV into stage IVA and stage IVB, we grouped stage IV patients into two groups according to M1a and M1b to facilitate Cox proportional regression analysis. We restaged all T4N0-1M0 patients as stage IIIA (which represents a major change in the current proposed IASLC stage grouping).7
All early stage tumors were also reclassified according to their tumor sizes and EOD codes and their stage grouping according to the UICC6 and IASLC proposed changes for the Cox proportional regression analysis.
Comparisons of demographic, clinical, and pathologic variables were made for NSCLC patients, using Pearson χ2 statistic or Fisher exact test for nominal variables and Student t test for continuous variables. Analysis of variance with Tukey's posthoc test was used for multiple comparisons of continuous variables. Univariate survival rate analyses were estimated using the Kaplan and Meier method, with comparisons made between groups by the log-rank test. Cox proportional hazards modeling using time since diagnosis were performed. Each variable in the model was coded using dummy variables. All statistical analyses were conducted using SAS 9.1 statistical software (SAS Institute, Inc., Cary, NC). Statistical significance was assumed for a two-tailed p value less than 0.05.
This research study was approved by the University of California Irvine Institutional Review Board (IRB #2004–3971).
Patients and Tumor Characteristics
About 43,655 incident cases of NSCLC were identified between 1999 and 2003 in CCR, including 2010 BAC patients that were separately analyzed and reported elsewhere.14 Of the remaining 41,645 non-BAC NSCLC patients, 30,711 (74%) had a histologically confirmed diagnosis. An additional 196 cases where no EOD were available, 997 cases where tumor status were unknown (TXM0), and 5935 cases where nodal status were unknown (NXM0) were excluded. A total of 23,583 patients comprised the final study population for this report used to generate the comparison of the hazard ratio (HR) of the UICC6 and IASLC stages by Cox proportional hazards regression analysis. There were a total of 4122 (17.5%) stage IIIB patients and 8779 (37.2%) stage IV patients. These 12,901 patients comprised the basis for the primary T4 and M descriptor analysis in this report. The median follow-up time for the advanced stage IIIB/IV patients was 9 months (0 to 60 months). Among these IIIB/IV patients, adenocarcinoma (43.2%) was the most frequent tumor histology followed by undifferentiated histology (28.9%), squamous cell carcinoma (22.0%) and large cell carcinoma (5.9%).
Among UICC6 advanced stage IIIB patients, 10.2% had additional nodules in the same lobe, 43.0% had malignant pleural effusion, 7.8% had malignant pericardial effusion, 39.0% were other “T4 invasion.” Among UICC6 stage IV patients, 13.1% had ipsilateral intrapulmonary nodules, 8.5% with contralateral pulmonary intrapulmonary nodules, and 78.4% had distant metastasis. The clinicopathologic characteristics of the seven nonoverlapping T4 and M categories were listed in Table 1.
Both “T4-additional nodules” (50.0%) and “ipsilateral intrapulmonary nodules” (48.2%) categories had the highest proportional of adenocarcinoma. Of note, significantly more patients with additional nodules in the same lobe (58.1%) and ipsilateral intrapulmonary nodules (31.0%) underwent surgical than the other five categories. The proportional of patients with unknown histologic grade increased with more advanced disease. Nevertheless, these patients were included in subsequent Cox proportional hazards regression analyses.
External Validation of Univariate Survival Analysis
OS of the Seven Subtypes of UICC6 T4 and M Descriptors that were Reclassified by IASLC Proposed Staging Changes
The 1-year and 5-year survival estimates and median OS of T4 patients due to additional nodules in the same lobe, T4 patients due to malignant pleural dissemination, T4 patients due to malignant pericardial effusion, patients with T4 invasion (IASLC T4), M patients due to ipsilateral intrapulmonary nodules, M patients due to contralateral intrapulmonary nodules, and M patients due to distant metastasis are listed in Table 2. The Kaplan-Mierer survival curves of the seven T4 and M categories are plotted in Figure 1. Identical survival analyses were performed in each of the four histologies: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and undifferentiated carcinoma. The 1-year and 5-year survival estimates and median OS of the seven subtypes of T4 and M descriptor categories stratified by histologies were listed in Table 3. Patients with T4-additional nodules in the same lobe had significantly better survival as a whole and within each histology. On the other hand, patients with malignant pleural dissemination or pericardial effusions had dismal survival.
The survival characteristics (1-year and median OS) of the CCR validation set was compared with the SEER validation set used by IASLC for their external validation exercise and is shown in Table 4. The survival characteristics between the two database sets were very similar and this provides validity to our analysis. Malignant pericardial effusion was not analyzed separately as a category in the IASLC validation set and thus was not shown in Table 4.
OS of Patients with the New IASLC T4 Descriptor, UICC6 T4 (Malignant Pleural Dissemination) Descriptor and UICC6 T4 (Malignant Pericardial Effusion) Descriptor and without Distant Metastasis (M0) According to Nodal Statuses
The 1-year and 5-year survival estimates and median OS of the new IASLC T4 descriptor, UICC6 T4-pleural dissemination descriptor and UICC6-pericardial effusion descriptors were analyzed and listed in Table 5 and plotted in Figures 2A–C, respectively. Although there were statistically significant survival differences among patients with malignant pleural dissemination or pericardial effusion according to the nodal status, the overall dismal survival of these patients justified reclassifying these patients to a M descriptor independent of nodal status (Figures 2B, C). There were also statistically significant survival differences among patients with T4 invasion according to nodal status and the differences in survival (1-year survival estimate difference of approximately 10% and 5 months improvement in median OS) are large enough to justify reclassifying patients with T4N0-1 from the traditional stage IIIB to stage IIIA. Nevertheless, most of these T4N0-1M0 patients may still not be considered as “resectable” as traditionally considered for IIIA disease.
OS Comparison of Patients with Pericardial Effusion versus Patients with Other M1a Descriptors (Contralateral Intrapulmonary Nodules or Malignant Pleural Dissemination) and M1b Patients
We observed from Tables 2 and 3 that patients with pericardial effusion had dismal survival similar to the IASLC M1b category. The HR of survival of patients with pericardial effusion was compared in a pairwise fashion with other M1a and M1b descriptors and shown in Table 6. Patients with pericardial effusion had statistically significant increased risk of death when compared with other M1a descriptors (contralateral intrapulmonary nodules or malignant pleural dissemination). The HR of patients with pericardial effusion was not statistically significant different from patients with distant metastasis (M1b). Thus, patients with pericardial effusion may be considered as M1b especially if an official subdivision of stage IV into stage IVA and stage IVB is proposed and adopted.
OS of Stage IA, IB, IIA, IIB, IIIA, IIIB, and IV Patients According to Current (UICC6) and Proposed IASLC Stage Grouping
The reclassification of all the patients in the study (23,583) from the UICC6 stage grouping to IASLC stage grouping were shown in Table 7. The 1-year and 5-year survival estimates and median OS of UICC6 and IASLC staging grouping for stages IA, IB, IIA, IIB, IIIA, IIIB, and IV are listed in Table 8. The survival curves based on the UICC6 and IASLC stage groupings are presented in Figures 3A, B, respectively. Similarly to the IASLC staging project findings, there was overlap in OS between stage IB and IIA patients in the UICC6 staging system. Survival comparison of advanced staged NSCLC between the CCR validation set and the IASLC SEER validation set is shown in Table 9.
External Multivariate Survival Analysis Validation
Pairwise comparison of the HRs between each stage in the UICC6 and IASLC were performed and the HRs, 95% confidence interval (CI) and p value were listed in Table 10. The HRs of the various stages of UICC6 and IASLC proposed staging with stage IA as a referent were determined with Cox proportional hazards analyses after adjusting for multiple independent prognostic factors including age at diagnosis, gender, ethnicity, socioeconomic status, histology, tumor histologic grade, surgery, radiation, and chemotherapy. The HRs, 95% CI and p-values of various stages of non-BAC NSCLC as compared with stage I from both UICC6 and IASLC stage are presented in Table 11. The complete list of the HRs, 95% CI and p-values of the various prognostic factors from the Cox proportional analyses were listed in supplemental Table 1 (UICC6) and Table 2 (IASLC).
The current IASLC proposed changes to the TNM descriptors and stage grouping represents a major and significant change to the staging of lung cancer.20 The original external validation of these changes was performed using data from SEER between 1998 and 2000.8 In this report, we adopted all the proposed changes to the T4 and M descriptors and reclassified advanced non-BAC NSCLC according to the new stage grouping and performed a similar validation study using data from the CCR during 1999–2003. We further adopted all the proposed changes to the early T descriptors so as to reclassify the stage all non-BAC NSCLC patients for the Cox proportional hazards regression analysis.
The CCR is the largest contiguous-area population-based cancer registry in the world, collecting over 130,000 of new cancer cases per year in the state of California.19 California legally mandated cancer reporting in 1988, and standardized data collection procedures and quality control procedures have been in place ever since.16 Case reporting is estimated at >98% of the entire state of California,21 and due to data completeness, accuracy, and timeliness, CCR has received the highest level of certification from the North American Association of Central Cancer Registries.22 All the regional cancer registries in California (Greater California) became part of SEER in 2001. Before 2001, the San Francisco-Oakland regional registry was one of the nine original SEER registries which started in 1973, whereas the San Jose-Monterey and the Los Angeles regional registries became part of SEER in 1992. Thus, there is some overlap and some unique features of using CCR for this validation study when compared with SEER validation set. CCR contains additional data on socioeconomic status and chemotherapy use during the first course of treatment, which are not recorded in SEER. Furthermore, California has an ethnically diverse population with a total population of 35 million thus allowing the inclusion of all major US ethnic groups to be analyzed in the validation study. We have further excluded 10,934 NSCLC cases of cytologically diagnosed specimens as cytology specimens have been shown to be inaccurate in diagnosing NSCLC histology when compared with histologically diagnosed specimens,17 and 6932 nonmetastatic cases where either the tumor (TX) or the nodal status is unknown (NX). Finally our Cox proportional regression analysis included other known prognostic factors such as histologic grade,23,24 socioeconomic status,24,25 and treatment into the analysis. The survival characteristics of the seven subtypes of T4 and M descriptors from the CCR validation set and the IASLC SEER validation set were very similar (Table 4).
Our current study on the stage-specific survival of advanced non-BAC NSCLC using the CCR database essentially agree with the improved prognostication of patients by the IASLC proposed revisions to the T4 and M descriptors. The changes are applicable to non-BAC NSCLC as a whole and within adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or undifferentiated carcinomas. We have performed a separated validation study of the IASLC staging modifications for BAC using the CCR database,14 since we had previously shown that the survival of BAC has improved significantly11 after the publication of the change WHO definition change in BAC15 and that some of the proposed changes to the T4 and M descriptors had a much more pronounced survival effects in BAC, i.e., T4 due to additional nodules and M due to ipsilateral pulmonary nodules.9,14
The current UICC6 T4 descriptor essentially encompasses three different tumor types: mediastinal invasion, satellite nodules, and malignant pleural/pericardial dissemination. We believed IASLC had proposed revisions to the T4 descriptor that successfully separated these three categories. T4 due to additional nodules will be reclassified as T3 in the proposed IASLC revision. As shown in Table 2, the survival of T4 patients due to additional nodules in the same lobe was much better than the rest of the T4 and M descriptor group. This observation is also valid among the individual NSCLC histologies with adenocarcinoma having the best survival time (Table 3). In separate analyses of the SEER database, we have demonstrated that BAC patients with T4 due to additional nodules (T4N0M0) have a median OS of 46 months and a 5-year survival estimate of 45%.9 Importantly, 72.0% of the patients (T4N0M0) in that study underwent potential curative lobectomy. Among non-BAC NSCLC patients in our SEER analyses, 59% of the T4 (T4N0-2M0) patients with additional nodules in the same lobe had surgical intervention.10 This indicates that physicians treating NSCLC already consider those T4 patients with additional nodules to have better survival, and that most patients were treated with curative intent. Bryant et al. reported the 5-year survival of 25 (T4-satellite nodules N0M0) patients who were staged by positron emission tomography and underwent complete resection and neo-adjuvant or adjuvant chemotherapy was 57%.26 Thus reclassifying the T4 descriptor due to additional nodules in the same lobe as T3 is clinically appropriate.20
Patients with pleural dissemination (malignant pleural effusion/pleural nodules) in this report had extremely poor survival. Similar to reported in the IASLC staging revision,4 we reported a 5-year survival rate of 3.1% and median survival of 4 months in patients with pleural dissemination but without distant metastasis in this study. We have also shown that the poor survival of T4 due to pleural dissemination is essentially independent of mediastinal nodal status and thus behaves more like distant metastasis (Table 5 and Figure 2B). These patients are considered as “wet IIIB” and treated as stage IV in clinical practice and trials already. Thus reclassifying T4 due to pleural dissemination as M1a codifies what is being practiced in general.
Malignant pericardial effusion is currently staged as T4 in the UICC6 staging but will be reclassified as M1a with the current proposed IASLC revision. The IASLC lung cancer staging project did not separately analyze malignant pericardial effusion from malignant pleural effusion within the current T4 descriptor. In this report, we showed that isolated pericardial effusion is much less common than isolated pleural dissemination in advanced lung cancer. We also showed that median survival of patients with even isolated pericardial effusion without distant metastasis was dismal with a median survival time of 3 months and 5-year survival estimate of 3.4%. This dismal 3-month median survival time is consistent with survival reported in other studies of patients with pericardial effusion who underwent surgical pericardial window for drainage.27,28 This poor survival is essentially independent of mediastinal lymph node status (Table 5 and Figure 2C). In fact, the survival of patients with pericardial effusion is closer to M1b patients in our report than M1a patients. In pairwise comparisons, the HR of patients with pericardial effusion was significantly worse than patients with other M1a classifications such as contralateral intrapulmonary nodules or malignant pleural dissemination but not statistically different from patients with M1b disease (Table 6). Thus consideration should be given to classify pericardial effusion as M1b rather than M1a especially if there is going to be an official subdivision of stage IV into stage IVA and stage IVB.
Similar to a previous analysis of the SEER database,10 in this report patients with M descriptor due to ipsilateral intrapulmonary nodules had significantly better survival among stage IV patients and similar survival to other “T4 invasion” patients (12 months median OS). This survival advantage is again observed with each individual histology (Table 3). Thus it is appropriate to reclassify M descriptor due to ipsilateral pulmonary nodules as T4. In our previous analysis using SEER database,9 BAC patients with ipsilateral intrapulmonary nodules had a median survival of 20 months, which is superior to the 15 months median survival observed for adenocarcinoma in this report. Again a majority of the BAC patients with ipsilateral pulmonary nodules (67.5%) in our previous report underwent surgical treatment and those patients had significantly prolonged survival.9 Nagai et al. reported a 5-year survival of 42.1% in patients who under surgical resection with intrapulmonary metastasis in different lobes without mediastinal nodal metastasis.29 In this report, 31% of the M patients with ipsilateral intrapulmonary nodules had surgical treatment (Table 1). Again these data indicate that physicians are already treating a fair amount of such patients with curative intent. Thus reclassifying patients with ipsilateral pulmonary nodules from M to T4 makes eminent clinical sense and is consistent with what is being practiced in the community.
We adopted all the IASLC proposed T and M descriptors changes and reclassified UICC6 stages IA, IB, IIA, IIB, IIIA, IIIB, and IV into the new IASLC proposed stages IA, IB, IIA, IIB, IIIA, IIIB, IVA, and IVB for the Cox proportional hazards regression analysis. Similar to the IASLC stage grouping analysis,7 there was no significant prognostic significance between stage IB and IIA in the UICC6 clinical staging system. The proposed IASLC stage grouping also allows better separation of stage IB and IIA than UICC6 staging in our analysis (Tables 10 and 11). Furthermore, the HRs for death continue to increase from stage IVA (versus stage IA; HR = 4.90) to stage IVB (versus stage IA; HR = 6.84) indicating that subdividing M descriptor into M1a and M1b are justifiable even though the survival time for both M1a and M1b patients are poor.30
One of the significant but potentially controversial proposed IASLC stage grouping change is to down stage T4N0-1M0 from the current UICC6 stage IIIB to stage IIIA. Stage IIIA NSCLC is generally considered to be resectable whereas stage IIIB is generally considered to be unresectable, although there are exceptions to this conceptual categorization. The 5-year survival estimate and median survival of the IASLC proposed T4N0M0 (14.8% and 14 months) and T4N1M0 (11.3% and 16 months) (Table 5) were closer to UICC6 stage IIIA (14.4% and 15 months, Table 8) than UICC stage IIIB (8.7% and 8 months, Table 8). A review of published series on radical resection of T4 (trachea, carina, left atrial, aortic, vena caval, or vertebral body invasion) lung cancer with minimal nodal involvement reported a median survival of 19 months and 5-year survival of 31%.31 Thus the survival time analysis justifies moving T4N0-1M0 to stage IIIA. Nonetheless, the current concept that stage IIIA NSCLC represents resectable disease may be challenged in the future if tumors that invade vertebral bodies, heart, pericardium, major vessels with minimal mediastinal lymph node involvement are staged as IIIA since the multidisciplinary surgical skills required for radical resection of “T4 invasion” tumors are not often available. Furthermore, practice guidelines will have to be updated accordingly.32
This study is retrospective in nature and thus carried with it limitations of population-based studies. There was no uniform standard protocol on how the lung cancer patients were staged (i.e., lymph node staging or systemic staging), thus all the CCR registry patients were analyzed using “best available stage” based on combined clinical and pathologic staging data. A large number of cases were not analyzed due to unknown histology, nodal status, or T-descriptor, thus limiting our ability to generalize these findings to all non-BAC NSCLC patients. There was no centralized review of pathologic specimens. Nevertheless, the accuracy of NSCLC histologic reporting in SEER has been reported favorably in comparison to independent review.33 There is no uniform protocol on how treatment (surgery, radiation, or chemotherapy) was given. Despite these limitations, our pairwise comparison of survival characteristics of advanced NSCLC of our CCR validation set is very similar to the IASLC SEER validation set. Moreover, we have included many independent prognostic factors into the Cox proportional regression analysis.
In summary, the proposed staging changes reflect a better prognostication of advanced stage IIIB and stage IV NSCLC. Nevertheless, the survival of stage IIIB and stage IV NSCLC regardless of current or proposed staging system remains very poor. Future molecular tumor classifications, lung cancer screening trial evaluations, and increased advocacy of lung cancer research are critically needed.
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