Journal of Thoracic Oncology:
The Applicability of the Proposed IASLC Staging Revisions to Small Cell Lung Cancer (SCLC) with Comparison to the Current UICC 6th TNM Edition
Ignatius Ou, Sai-Hong MD, PhD*†‡; Zell, Jason A. DO, MPH*†‡
*Chao Family Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, University of Irvine Medical Center, Orange, California; †Genetic Epidemiology Research Institute, and ‡Department of Epidemiology, School of Medicine, University of California Irvine, Irvine California.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Sai-Hong Ignatius Ou, MD, PhD, Chao Family Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, University of California Irvine Medical Center, 101 The City Drive, Bldg 56, RT81, Rm 241, Orange, CA 92868-3298. E-mail: firstname.lastname@example.org
“The collection of cancer incidence data used in this study under subcontract No. 050N-8707-S1527 with the Public Health Institute, State of California, was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Sections 103875 and 103885, the National Cancer Institute's Surveillance, Epidemiology and End Results Program, and the Centers for Disease Control and Prevention National Program of Cancer Registries. The ideas and opinions expressed herein are those of the authors and endorsement by the State of California, Department of Health Services, the National Cancer Institute, the Centers for Disease Control and Prevention, and/or the Genetic Epidemiology Research Institute of the University of California, Irvine is not intended nor should be inferred.”
Background: We examined the impact of the proposed Internal Association for the Study of Lung Cancer (IASLC) tumor, node, metastasis (TNM) and stage grouping revisions on staging and survival outcome of small cell lung cancer (SCLC).
Methods: A total of 10,660 SCLC patients from the California Cancer Registry between 1991 to 2005 with complete TNM staging were identified and reclassified according to the IASLC proposed TNM revisions and new stage groupings. Surveillance Epidemiology and End Results extent of disease codes were used to identify various T4 and M descriptors. Cox proportional hazards regression was used to identify prognostic factors.
Results: Survival was correlated with the current UICC6 and IASLC proposed T descriptors. Patients without mediastinal lymph node involvement (N 0–1) had superior survival compared to patients with mediastinal lymph node involvement (N 2–3). The IASLC proposed stage grouping results in better separation of survival curves among early stage SCLC than the current Union Internationale Centre le Cancer (UICC) 6 stage groupings by both univariate and multivariate analyses. Pleural effusion (IASLC M1a) in SCLC had survival similar to other IASLC M1a categories (pericardial effusion, contralateral intrapulmonary metastasis) by pairwise hazard ratio comparisons.
Conclusions: The IASLC proposed TNM staging changes result in better separation of stage-specific SCLC survival curves than the current UICC6 staging system. The new IASLC M1a descriptors (pleural effusion, pericardial effusion, and contralateral/bilateral intrapulmonary metastasis) adequately prognosticate SCLC patients as having metastatic disease.
Despite the gradual decline of small cell lung cancer (SCLC) incidence in the United States,1 it remains a major cause of lung cancer deaths in the world.2 The prognosis of SCLC remains extremely poor and therapeutic development has lagged behind non-small cell lung cancer (NSCLC). The tumor, node, metastasis (TNM) staging system for lung cancer is also applicable to SCLC but staging of SCLC has generally been functionally defined and separated into limited disease and extensive disease due to the fact that majority of the patients at the time of diagnosis had locally advanced or metastatic disease that are not amenable to surgery.3,4 Changes to the current TNM lung cancer staging system have been proposed by the Internal Association for the Study of Lung Cancer (IASLC) recently.5–8 The majority of the changes were made in the T5 and M7 descriptors and also the subsequent stage groupings.8 IASLC has compared these changes in SCLC to the current 6th edition AJCC TNM staging system.9 The proposed TNM staging changes is better at discriminating SCLC patients into nonoverlapping prognosis groups. However due to the limited number of SCLC patients with in the IASLC database, the individual survival characteristics of the IASLC advanced T and M descriptors were not examined and no data was available on the prognosis of pericardial effusion.9 We have previously performed validation studies of the IASLC proposed TNM changes to both bronchioloalveolar carcinoma (BAC)10 and non-BAC NSCLC11 using the California Cancer Registry (CCR) database. In this article, we reported our findings on the proposed changes in TNM staging system in SCLC and the individual survival characteristic of the advanced IASLC T and M descriptors.
PATIENTS AND METHODS
The primary outcome measure was to compare the stage-specific overall survival (OS) of SCLC between current UICC6 staging system and the proposed IASLC staging modifications.
A case-only analysis was conducted on SCLC patients from CCR diagnosed between 1991 to 2005 who had complete TNM staging data and follow-up data. Tumor site was abstracted as previously described12 and both cytologically- or histologically-confirmed SCLC cases were analyzed. Histology codes (ICD-O-3: 8041-8044) were abstracted for SCLC. Histology 8045 which coded for mixture of small and NSCLC was eliminated from the final patient dataset.13,14 Patient demographic data were abstracted using Surveillance Epidemiology and End Results (SEER) codes. The measurement of socioeconomic status (SES) used in this analysis was a composite measure using CCR and census data as previously described.15,16 Radiation therapy and surgical techniques were abstracted using SEER codes. Chemotherapy given during the first course of therapy was ascertained using CCR codes.
The Extent of Disease (EOD) coding variable was analyzed for each patient and the T and M categories were recoded according into the proposed revised IASLC staging system. This maneuver allowed the comparison between the current and IASLC TNM stage groupings. Specifically, 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 for “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. Finally, patients with unknown EOD, incomplete nodal (NX) or metastasis (MX) data were eliminated from the final patient dataset.
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) or malignant pericardial effusion was changed to M1a in the IASLC staging changes and we restaged these patients as stage IVA. Patients with “ipsilateral intrapulmonary nodules” were changed from M to T4 in the IASLC changes. These IASLC T4 patients were restaged according to their nodal status with both the current UICC6 and proposed IASLC stage grouping. Patients with contralateral intrapulmonary nodules remained as having metastatic disease (M) with a new M1a designation 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 these 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).8
All early stage tumors were also reclassified according to tumor sizes and EOD codes and their stage grouping according to the UICC6 and IASLC proposed changes to allow for the Cox proportional regression analysis.
Comparisons of demographic, clinical, and pathologic variables were made for SCLC patients, using Pearson χ2 statistic or Fisher's 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 (Institutional Review Board #2004-3971 and #2007-6078).
Patients and Tumor Demographics
Incident cases of SCLC (17,164) were identified between 1991 and 2005 in CCR. 6303 cases where EOD, NX, or MX were unknown were excluded. An additional 201 patients with combined small cell/NSCLC histology were excluded. A total of 10,660 patients comprised the final study population for this report used to generate the comparison of the hazards ratio of the Union Internationale Centre le Cancer (UICC) 6 and IASLC stages by Cox proportional hazards regression analysis. The median age of diagnosis of the whole cohort of patients was 67.2 years (95% Confidence interval [CI]: 50–82 years). The median follow-up time was 7 months for all patients (95% CI: 0–50 months).
Increasing clinical T category using the UICC6 TNM staging system (Figure 1A) or the IASLC proposed changes to the TNM system (Figure 1B) resulted in progressively poorer survival in patients who did not have metastatic (M0) involvement. The p value for the ordered log-rank test is less than 0.0001 for both UICC6 and IASLC T categories. The 1-, 2- and 5-year survival rates, and median OS of UICC6 T categories are shown Table 1. The corresponding survival numbers among the IASLC T categories were shown in Table 2. Pairwise comparisons of hazard ratio (HR) for survival between sequential UICC6 T category were all statistically significant similar to what was reported by IASLC.9 However, similar pairwise comparisons between IASLC T categories did not show statistical significance between T3 versus T2 (p = 0.0829) though the survival of T3 was numerically worse than T2. The increase in the number of patients with IASLC T3 category were due to the redistribution of UICC6 T2 patients with tumor >7 cm and UICC6 T4 patients with satellite nodules into the IASLC T3 category.
Similar to T category, increasing N category was associated with progressively worse survival (Figure 2). The p value for the ordered log-rank test is less than 0.0001. The 1-, 2-, and 5-year survival rates, and median overall OS of the N categories were shown in Table 3. Pairwise comparisons of the HR between sequential N categories revealed nonsignificance between N1 versus N0 (p = 0.8187) which was similar to the findings reported by IASLC.9 Survival curves of each IASLC T category according to the N categories were shown in Figures 3A–D with the corresponding survival numbers shown in Table 4. Increasing N category portends poorer survival within each IASLC T category except IASLC T4 category (p = 0.1237).
Survival According to TNM Stage
All 10,660 SCLC patients in this dataset were classified to according to the UICC6 and IASLC stage groupings. The changes in the number of patients from UICC6 to IASLC within each stage were shown in Table 5. Survival curves according to the UICC6 and IASLC stage groupings were shown in Figures 4A, B respectively. The corresponding 1-, 2-, 5-year survival rates, and median OS numbers were shown in Table 6. As shown in Table 6, the median OS of UICC6 stage IB (17 months) and UICC6 stage IIA (22 months) were reversed whereas the median OS of IASLC stage IB (18.5 months) and IASLC stage IIA (19 months) were essentially superimposed. Thus the IASLC staging system allowed a better separation of stage IB and IIA SCLC. Pairwise comparisons of HR for OS between each successive individual UICC6 and IASLC stage were shown in Table 7. The comparison between UICC6 stage IIA versus stage IB were not statistically significant but was better than reported by IASLC where the survival of UICC6 stage IIA was actually statistically significant better than UICC stage IB.9 Comparisons of OS of our CCR database using the UICC6 and IASLC stage groupings with the IASLC database and IASLC SEER validation set were shown in Table 8. Finally the HRs of the various stages of UICC6 and IASLC staging system 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, marital status, surgery, radiation, and chemotherapy and were shown in Table 9. The HR for OS for UICC6 stage IIA was not statistically significant different from UICC6 stage IA (HR = 1.305; 95% CI: 0.970–1.756; p = 0.0782) while IASLC stage IB was marginally not statistically than IASLC stage IA (HR = 1.219; 95% CI: 0.996–1.492; p = 0.05498). HRs for the subsequent IASLC stages (beyond stage IB) were statistically significant worse than IASLC stage IA indicating IASLC staging groupings is an improvement over the UICC6. Our aggregate results demonstrated an improved survival fit for the proposed IASLC changes as compared with the current UICC6 staging system for SCLC. The complete Cox proportional hazards analysis was shown in supplemental Table S1 for UICC6 stage grouping and in supplemental Table S2 for IASLC stage grouping.
Overall Survival of the Seven Subtypes of UICC6 T4 and M Descriptors that Were Reclassified by IASLC Proposed Staging Changes
The 1-, 2-, and 5-year survival estimates, and median OS of UICC6 T4 patients due to additional nodules in the same lobe, UICC6 T4 patients due to malignant pleural dissemination, UICC6 T4 patients due to malignant pericardial effusion, patients with UICC6 T4 invasion, UICC6 M patients due to ipsilateral intrapulmonary nodules, UICC6 M patients due to contralateral intrapulmonary nodules, and UICC6 M patients due to distant metastasis were listed in Table 10. The Kaplan-Mierer survival curves of these seven T4 and M categories were plotted in Figure 5. Patients with contralateral intrapulmonary metastasis, malignant pleural dissemination, or pericardial effusions had similar dismal survival. In contrast with NSCLC where patients with additional/satellite nodules had significantly better survival10,11 partially due to a high rate of surgical resection,17,18 SCLC patients with T4 additional nodules in the same lobe had better but not marked improved survival over patients with other advanced T categories. Of the 89 SCLC patients with “satellite nodules” in our dataset, only two patients underwent surgical intervention (both lobectomy). We also performed pairwise HR comparisons between the seven advanced T and M descriptors (Table 11). Of note, there was no significant difference in OS among patients with contralateral intrapulmonary metastasis (IASLC M1a), malignant pleural effusion (IASLC M1a), or malignant pericardial effusion (IASLC M1a). Furthermore, all IASLC M1a patients had significant OS advantage over IASLC M1b patients indicating all 3 M1a categories in the IASLC proposed staging changes were applicable to SCLC. Due to the limited number of patients (n = 94), it is difficult to determine the prognostic significance of patients with ipsilateral intrapulmonary metastasis (IASLC T4) as the survival of these patients is significant better patients with malignant pleural effusion (M1a) but worse than patients with T4 invasion (IASLC T4).
The current IASLC proposed changes to the TNM descriptors and stage grouping represents a major and significant change to the staging of lung cancer.19 IASLC has applied these changes to SCLC. Due to limited number of SCLC patients with complete TNM staging data in the IASLC database, changes in the prognostic significance for the individual advanced T and M descriptor were not individually examined.9 In this report, we adopted all the proposed changes to the T4 and M descriptors and reclassified SCLC patients according to the new IASLC stage grouping and investigated the applicability of these staging changes to SCLC with comparison to the current UICC6 staging system.
Our results showed that the T category whether it is according to the UICC6 or IASLC staging system can differentiate survival of nonmetastatic (M0) SCLC patients very well regardless of nodal status. There was no change to the N category by IASLC6 and we showed that with exception to pairwise comparison between N1 and N0 the current N category can differentiate survival of T1–3 M0 patients very well except T4 in our study in agreement with the IASLC report.9 Regarding stage groupings, our results showed that IASLC stage grouping is able to better differentiate OS of earlier stage SCLC than the current UICC6 stage grouping. The OS curves were reversed between the UICC6 stage IB and UICC6 IIA similar to the IASLC report.9 However, there was superimposing of survival curves for IASLC stage IB and IASLC stage IIA. Inoue et al. have also reported that stage IIA SCLC had better survival than stage IB SCLC in their surgical series and that T descriptor is a stronger prognostic factor than N descriptor for resectable SCLC.20 Our results and that of IASLC9 also showed that the T descriptor (whether according to UICC6 or IASLC) is better at prognosticating early stage SCLC patients than the N descriptor.
Finally, we reported on the survival characteristics of the seven individual advanced T and M descriptors that would be changed as proposed by IASLC. The absolute OS differences among the seven descriptors are not as widely separated as seen in BAC10 and non-BAC NSCLC11 though the difference remained statistically significant (p = 0.0001). Our report did show that there were no OS differences among patients with contralateral intrapulmonary metastasis, pleural effusion, or pericardial effusion by pairwise HR comparisons and their OS was significantly better than patients with distant metastasis. These results lend support for three categories to be classified as M1a while distant metastasis is classified as M1b in SCLC. IASLC reported that patients with pleural effusion had survival intermediate between limited disease and extensive disease9 and this report is in agreement for SCLC patients with malignant pleural effusion to be classified as having distant metastasis similar to NSCLC patients.
We were less successful in prognosticating the IASLC T4 category for SCLC as patients with “T4 invasion” (IASLC T4) had OS similar to the patients with “satellite lesions in the same lobe” (IASLC T3) by pairwise HR comparison even though there was an absolute 2 months difference in OS favoring patients with “satellite lesions” (IASLC T3). On the contrary patients with “ipsilateral intrapulmonary metastasis” (IASLC T4) had survival significantly worse than patients with T4 invasion by pairwise HR comparison and an absolute 1.5 months shortened OS (Table 5). One of the likely explanations is the small number of SCLC patients with “additional nodules in the same lobe” (n = 89) and “ipsilateral intrapulmonary metastasis” (n = 94) and even smaller numbers of patients who underwent surgical intervention. Out of the 89 SCLC patients with satellite lesions in the same lobe, only two patients underwent surgical intervention (both lobectomy and both with N1 disease) and represented a significant lower proportion of patients than patients with BAC17 or non-BAC NSCLC18 who underwent resection. It can be hypothesized that by adopting the IASLC TNM staging changes for SCLC, more patients will likely undergo anatomic resection in the future and the prognostic significance of between T3 and T4 will be more apparent. In summary, this report revealed that the IASLC TNM staging changes to SCLC is better in prognosticating SCLC patients than the current UICC6.
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. Secondly, there was no centralized review of pathologic specimens as the definition of small cell lung carcinoma has evolved throughout the years;14 however, we have excluded patients with tumor histology that included both small cell/non-small cell carcinoma. The accuracy of NSCLC histologic reporting in SEER has been reported favorably in comparison to independent review.21 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. We believe this report will provide further support to the use of TNM staging system in SCLC especially with the new IASLC staging system.
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