Staging of lung cancer provides a common language

The 1997 International Staging System for Non-Small Cell Lung Cancer* Have All the Issues Been Addressed? Swan S. Leong, MD; Caio M. Rocha Lima, MD; Carol A. Sherman, MD; and Mark R. Green, MD The International Staging System for Lung Cancer has been revised recently. Important changes have been made to allow better correlation of prognoses and direction of management. The classification of synchronous pulmonary nodules in the same lobe as the primary tumor as T4 stage IIIB may imply a poorer outcome than is warranted, while the designation of a similar stage for malignant pleural effusion may not be reflective of the very poor prognosis associated with this extent of disease. (CHEST 1999; 115:242 248) Key words: lung cancer; non-small cell; staging Abbreviations: AJCC American Joint Committee for Cancer Staging; NSCLC non-small cell lung cancer; TNM primary tumor, lymph nodes, metastasis Staging of lung cancer provides a common language for communication among health-care providers and investigators. Its main purpose is to allow For related material see page 233 classification of disease according to its extent and severity and to group together patients with similar prognoses. It facilitates meaningful clinical and translational research and allows comparison of research results. Study findings and observations of the clinical course of disease, correlated with an accepted staging system, define prognostic subgroups and provide the rationale for treatment recommendations (Table 1). Over the last two decades, the staging system for non-small cell lung cancer (NSCLC) has undergone significant changes in an attempt to minimize variability of prognosis within each group and correlate different treatment strategies for different stage groups. Efforts have also been made to make some anatomical sense when devising local treatment. With the most recent revision of the tumor, lymph node, metastasis (TNM) staging system, published in *From the Hollings Cancer Center and Division of Hematology/ Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC. Manuscript received April 8, 1998; revision accepted September 1, 1998. Correspondence to: Mark R. Green, MD, Hollings Cancer Center, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425-2225; e-mail: greenmrk@musc.edu CHEST in 1997, 1 some of the deficiencies of previous guidelines have been addressed. However, some issues remain and new concerns have arisen. Staging of certain subgroups of patients may still not be entirely satisfactory. History In 1974, the Task Force on Carcinoma of the Lung from the American Joint Committee for Cancer Staging (AJCC), using the general rules of the TNM system, 2 recommended criteria for clinical staging of NSCLC based on an analysis of 2,155 patients with bronchogenic carcinoma. 3 Disease extent was described according to the primary tumor (T), nodal status (N), and presence or absence of metastasis (M). Stage groupings were generated through analysis of 300 survival curves drawn from various combinations of T, N, and M descriptors. In this initial staging system, tumor was described as T0 to T3, with pleural effusion and direct tumor involvement of mediastinal structures included in the T3 category. Nodal status ranged from N0 to N2. All mediastinal lymph nodes were included in the N2 category. Supraclavicular and contralateral hilar lymph nodes were considered distant metastases. Three stage groupings were defined. Patients with stage I (T1-2N0M0, T1N1M0) disease demonstrated a relatively favorable outcome. Those with stage II (T2N1M0) disease did less well. Stage III (T3 or N2 or M1) disease was very unfavorable. This system did provide a simple schema that 242 Opinions/Hypotheses

Table 1 Goals of a Cancer Staging System Goals Standardize description of disease Reflect prognosis Direct treatment Facilitate research and comparison of results reflected general prognostic difference (most patients still did poorly) and grossly divided patients into surgical (stage I and II) and nonsurgical groups. The stage III category, however, was a very heterogeneous subgroup, ranging from minor amounts of chest wall invasion by the primary tumor to multiorgan metastatic disease. It encompassed patients with very different prognoses. 1,3,4 The T3 category itself included subgroups now recognized to have potentially important outcome differences, such as those with peripheral chest wall invasion or an origin close to the carina without associated nodal involvement vs those with malignant pleural effusion or mediastinal structure invasion. 5,6 At the time, however, available treatment options were so limited that the eventual outcome for nearly all patients with stage III cancer was disease progression and death. Only the time frame differed. In 1985, members of AJCC, Union Internationale Contre Cancer, and Japanese and German representatives proposed a revised International Staging System for lung cancer 7 based on an analysis of 3,753 lung cancer patient records from the M.D. Anderson Cancer Center and the North American Lung Cancer Study Group s Reference Center for Anatomic and Pathologic Classification of Lung Cancer. An additional tumor descriptor, T4, was added. This included tumors with invasion of mediastinal structures or one or more vertebral bodies, or an associated malignant effusion. The node category N2 was limited to involvement of ipsilateral mediastinal and subcarinal nodes. A new N3 category included contralateral mediastinal, contralateral hilar and supraclavicular lymph node involvement. Even though the prognosis of patients with supraclavicular lymph node involvement was recognized to be poor, supraclavicular node involvement was included in this N3 group since these nodes were readily included within a single radiation port and hence considered regional spread. The original three stage groupings were expanded to four groups, stages I through IV, with stage I and II disease amenable to primary surgical management. The overly broad stage III category of the 1974 staging system was split into locally advanced disease (III) and disseminated disease (IV). Patients with locally advanced disease were further divided into those who were candidates for complete resection (IIIA) and those who were not (IIIB). But the prognostic interplay of T and N descriptors and the categorization of patients to reflect and direct treatment decisions were only partially addressed. As the 1986 International Staging System was widely implemented, these limitations became more evident, setting the stage for the most recent revision of TNM lung cancer staging. New International Staging for Lung Cancer The most recent revision of the TNM staging system for lung cancer published in June 1997 1 used a database of 5,319 patients with primary lung cancer treated at the M. D. Anderson Cancer Center from 1975 to 1988 or by the North American Lung Cancer Study Group from 1977 to 1982. The following are new features of the revised staging system: (1) the division of stage I into IA and IB; (2) the division of stage II into IIA and IIB and the assignment of T3N0M0 to stage IIB; (3) designation of tumor with satellite nodules in the same lobe as T4; and (4) the assignment of a primary tumor with one or more synchronous lesions within different lobes of the same lung as M1 (Tables 2 5). Patients with T1N0M0 tumors have a favorable outcome after complete resection of disease. Their survival is substantially better than that of other patients with stage I disease whose tumors are 3 cm or invade visceral pleura (T2) 4,8 12 (Table 6). The Mayo Clinic group 8 evaluated survival data from 495 patients with pathologic stage I NSCLC. They documented a 5-year survival of 80% in patients with T1N0M0 disease vs about 62% for those with T2N0M0 disease. At Duke, Harpole et al 9 reported a similar significant difference of 70% and 50% 5-year survival for T1N0M0 disease and T2N0M0 disease, respectively. The Japanese group led by Watanabe et al 12 demonstrated a statistical difference in 5-year survival between T1N0M0 and T2N0M0 disease (77.6% vs 60.1%). They also showed a further significant drop in survival rate for patients with tumor size 5 cm when compared to those with tumors measuring 3 to 5 cm (46% vs 61%), emphasizing a continuous impact of increasing tumor size on survival. 12 The database for the 1997 staging proposal, as well as the individual series already discussed, clearly demonstrated a significant survival advantage of T1N0M0 compared with T2N0M0 disease, according to both clinical and pathologic staging. 1 Putting patients with T1N0M0 disease into a totally separate stage I, analogous to breast cancer, had been considered but not implemented during the develop- CHEST / 115 / 1/ JANUARY, 1999 243

Tx Table 2 Primary Tumor (T) Tumor proven by malignant cells in bronchopulmonary secretions but not visualized by imaging or bronchoscopically. Same as 1974 primary tumors that cannot be assessed T0 No evidence of tumor Same as 1974 Same as 1974 Tis Carcinoma-in-situ T1 Tumor 3 cm, surrounded by lung or Same as 1974 Same as 1974 visceral pleura, without invasion proximal to a lobar bronchus T2 Tumors with any of the following: 3 cm; Same as 1974 Same as 1974 involve main bronchus but 2 cm distal to carina; invades visceral pleura; associated with atelectasis or obstructive pneumonitis that involves 1 lung T3 Tumor that invades all adjacent structures including mediastinum and its contents; or 2 cm from carina; or associated with atelectasis or obstructive pneumonitis that involves the whole lung; or pleural effusion Tumor that invades: chest wall; diaphragm, mediastinal pleura, parietal pericardium; main bronchus 2 cm from carina but not involving it; associated with atelectasis or obstructive pneumonitis that involves the whole lung T4 Tumor that invades: mediastinal structures including heart, great vessels, trachea, esophagus; vertebral body; or presence of malignant effusion satellite tumor nodule(s) within ipsilateral primary-tumor lobe of lung ment of the 1986 staging system. 7 This same option was again rejected in the current revision, but a compromise was reached by making it a separate stage I subgroup. Stage I disease is now divided into IA (T1N0M0) and IB (T2N0M0), highlighting the prognostic differences between the two groups and facilitating different therapeutic approaches to their management. Conflicting but provocative data on adjuvant chemotherapy have been observed in patients with T2N0M0 disease, 13,14 and currently several postoperative adjuvant chemotherapy trials enroll patients with T2N0 (stage IB) disease while excluding those with T1N0 disease (eg, CALGB 9633, NCIC BR-10). The patients with T1N0 disease are considered candidates for chemoprevention trials since they are recognized as being at substantially increased risk of manifesting a second primary lung cancer 15,16 (recently closed intergroup trial INT- 0125) following cure of their initial lung cancer. In the 1986 International Staging System, all patients with either T3 or N2 disease were designated to have stage IIIA disease. However, several investigators have demonstrated significant differences in survival rates following complete surgical resection between patients with T3N0-1 and T1-3N2 disease. 4,17,18 Patients with T3N0M0 disease, usually with peripheral parenchymal lesions invading the chest wall or when involving the superior sulcus, do better than those with N2 involvement. 19 21 Their survival approximates that of T2N1M0 disease. For example, in a retrospective study of patients with T3 disease based on chest wall invasion, McCaughan et al 20 noted a 5-year survival rate of 56% for those with completely resected T3N0M0 tumor. Aggregate Table 3 Regional Lymph Nodes (N) Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis Same as 1974 Same as 1974 N1 Metastasis to ipsilateral hilar lymph nodes Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes N2 Metastasis to mediastinal lymph nodes Metastasis to ipsilateral mediastinal and/or subcarinal lymph nodes N3 Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral/contralateral supraclavicular nodes 244 Opinions/Hypotheses

Table 4 Distant Metastasis (M) Mx Presence of distant metastasis cannot be assessed M0 No distant metastasis Same as 1974 Same as 1974 M1 Distant metastasis including involvement of scalene, cervical and contralateral hilar lymph nodes Distant metastasis excluding scalene, cervical and contralateral hilar nodes T3N0 data suggest that these patients are candidates for primary surgical management. However, several series demonstrate that essentially all patients with radiographic or mediastinoscopic evidence of N2 involvement, regardless of T category, do poorly with primary surgical resection. 22,23 Under the new staging system, T3N0M0 patients have been moved to stage IIB, together with T2N1M0 patients, to reflect their similar survival outcome and their appropriateness as candidates for primary surgical therapy. Interestingly, this redistribution again brings the lung cancer staging system closer to that used for breast cancer staging. The original 1986 version of the International Staging System for Lung Cancer did not provide clear guidelines for categorization of synchronous pulmonary nodules occurring in the same lung as the primary tumor. Some investigators considered the presence of any intrapulmonary lesions other than the primary tumor indicative of M1 disease, 12 while others considered the presence of any contralateral lung nodules as M1 but ipsilateral nodules as locally advanced disease. The staging conventions were clarified by the footnotes in the fourth edition of the AJCC staging manual published in 1993: satellite lesions in the same lobe led to upstaging of the primary by one T category while the presence of a synchronous ipsilateral lung lesion in a separate lobe was considered T4. In the 1997 staging system, these conventions were modified significantly. Any synchronous satellite pulmonary nodule situated in the same lobe as the primary is now considered T4 (stage IIIB) disease while all other ipsilateral synchronous pulmonary nodules are staged as M1 disease. In 1989, Deslauriers et al 24 evaluated the impact of what they called satellite pulmonary nodules (synchronous ipsilateral intrapulmonary lesions of the same histology but smaller in size than the primary lesion) in 1,105 patients seen between 1969 and 1986 who underwent pulmonary resection as primary treatment for bronchogenic carcinoma. Eighty-four patients had synchronous ipsilateral pulmonary nodules, mostly satellite lesions in the same lobe as the primary tumor (68 of 84). Only a small minority were actually identified on the preoperative chest radiograph. The other 1,021 patients had no synchronous intraparenchymal lesions. Disease was staged according to the 1974 guidelines, independent of the presence or absence of satellite nodules. Among the large group of patients without synchronous nodules, the 5-year survival rates were 54.4%, 40.4%, and 20.3%, respectively, for those with stages I, II, and III disease. Among patients with the additional lesions, the 5-year survival rates for stages I, II, and III were 32%, 12.5%, and 5.6%, respectively. Patients with synchronous lesions more often Table 5 Stage Grouping (TNM Combinations) Occult TxN0M0 Occult TxN0M0 Occult TxsN0M0 Stage 0 TisN0M0 Stage 0 TisN0M0 Stage 0 TisN0M0 Stage I T1N0M0 Stage I T1N0M0 Stage IA T1N0M0 T2N0M0 T2N0M0 Stage IB T2N0M0 T1N1M0 Stage II T2N1M0 Stage II T1N1M0 Stage IIA T1N1M0 T2N1M0 Stage IIB T2N1M0 T3N0M0 Stage III T3, any N, any M Stage IIIA T3N0M0 Stage IIIA T3N1M0 Any T, N2, any M T3N1M0 T1N2M0 Any T, any N, M1 T1N2M0 T2N2M0 T2N2M0 T3N2M0 T3N2M0 Stage IIIB T4, any N,M0 Stage IIIB T4, any N, M0 Any T, N3, M0 Any T, N3, M0 Stage IV Any T, any N, M1 Stage IV Any T, any N, M1 CHEST / 115 / 1/ JANUARY, 1999 245

Table 6 Prognostic Implications of Tumor Size for Patients With Pathologic Stage I Disease First Author No. of Patients T1N0M0 5-yr Survival, % T2N0M0 Naruke 4 653 73 54 Williams 8 495 80 62 Harpole 9 271 70 50 Watanabe 12 286 78 60 were treated with pneumonectomy and in all three stages had poorer prognoses than when these lesions were not present. However, the findings demonstrated that some patients with synchronous ipsilateral nodules could experience long-term survival with resection and suggested that at least synchronous nodules in the same lobe should be approached with primary resection. Watanabe et al 12 evaluated the survival of 49 patients with resected lung cancer with synchronous ipsilateral intrapulmonary satellite nodules. In most of these patients, the satellite lesions were first identified in the resected surgical specimen. The T and N status of these patients was not specified. However, when the survival of these 49 patients was compared with that of a total of 306 patients with resected stage IIIA (225) and IIIB (81) tumors without intrapulmonary nodules, the 3- and 5-year survivals of patients with satellite nodules were no different from those with IIIA disease without satellites, and superior to those with stage IIIB disease. This again suggests that the presence of a small satellite nodule in the same lobe as the dominant primary lesion should not be considered a contraindication to primary surgical management. Satellite lesions in the same lobe as the primary lesion may arise from a different mechanism of disease spread than do synchronous ipsilateral lesions in a different lobe. Among the 84 patients of Deslaurier et al 24 with satellite nodules, 68 (81%) had them in the same lobe, and in 56 of this subgroup, the nodules were located immediately around the primary or peripherally in the same pulmonary arterial distribution as the main tumor. This led to the speculation that most of these nodules were the result of pulmonary artery invasion and tumor embolization. Lesions located more centrally in the same lobe were much more infrequent (14%) and were thought to represent in-transit lymphatic spread or pulmonary vein emboli. Shimizu et al 25 analyzed 42 patients with intrapulmonary satellite nodules that were not detected preoperatively who underwent complete pulmonary resection. Patients with lesions in the same lobe as the primary tumor had a significantly better 2-year survival (41.5%) than those with lesions in a separate lobe (20%). While still more favorable than for patients with extrathoracic M1 disease, these survival data were consistent with the theory that nodules in a different lobe are most consistent with true metastatic deposits. In addition, the observations by Shimizu et al 25 reinforced the concept that patients with a synchronous satellite lesion in the same lobe as the primary may behave more favorably than patients with other subgroups of T4 stage IIIB disease. Despite the fact that the current staging system categorizes satellite nodules within the same lobe as the ipsilateral primary tumor as T4, individuals with this distribution of disease should be strongly considered for definitive resection if there are no other contraindications to surgery. Synchronous lung primaries, as defined by Martini and Melamed 26 as (1) tumors with different histologies or (2) if histology was the same, the second tumor should be in a different segment, lobe, or lung, with origin from different carcinoma-in-situ, with no involvement of lymphatics common to both, and with no extrapulmonary metastasis, are uncommon, accounting for 1% of lung cancer presentations. 27 29 While the outcome for such patients is better than for patients with a single primary lung cancer and a synchronous metastasis in a separate lobe or in the contralateral lung (stage IV disease), it is poorer than that expected from a single tumor of a similar stage. For example, patients presenting with two synchronous stage I tumors have reported survivals of 25 to 41% despite complete resection of both lesions. The lowered rate of long-term survival can be described as the chance of long-term survival from tumor 1 multiplied by the chance of long-term survival from tumor 2. Optimum therapy for patients with truly synchronous primaries is definitive resection of each lesion. Problems associated with this approach are the frequency of underlying lung disease limiting tolerance of multiple lung resections as well as the difficulty in determining whether the lesions are truly separate primaries and not metastatic disease. In the future, new molecular studies may help to determine with greater certainty whether two synchronous lesions of the same histology are, in fact, separate primary tumors. Are There Remaining Areas of Controversy? Currently, definitive management of stage III disease usually involves multimodality therapy. The 246 Opinions/Hypotheses

goal of treatment is cure and components of therapy address both the local tumor and systemic micrometastases. 30 34 In theory, the presence of a malignant pleural effusion precludes curative treatment of documented intrathoracic disease with a local or regional modality (surgery and/or radiation) alone. In the database used to develop the 1974 lung cancer staging system, patients with pleural effusion were found to have a particularly poor prognosis. 3 However, in the 1986 staging revision, pleural effusion was designated T4 disease, suggesting a more favorable outcome for these patients than for those with frank M1 disease. Recently, Sugiura et al 6 compared the survival of 197 patients with stage IIIB disease without pleural effusion, stage IIIB with pleural effusion, and stage IV disease. They found that the median survivals of the three groups were 15.3, 7.5, and 5.5 months, respectively. Survival curves for the stage IIIB patients with effusion were significantly worse than those for stage IIIB patients without effusion, but not significantly different from stage IV patients. They also found that among patients with pleural effusion, there was no significant difference in survival when pleural fluid cytology was positive or negative provided the effusion was exudative and/or bloody, and clinically judged to be resultant from the underlying malignancy, confirming a previous observation of Mountain. 35 Based on these observations and our current approaches to patients with stage III disease, it would seem more appropriate to classify patients with pleural effusion as having stage IV rather than T4 stage IIIB disease, since both prognosis and management for these patients are similar to that for stage IV disease. What about discontinuous pleural nodules in the absence of pleural effusion? Is there a difference in outcome between patients with lesions theoretically confined to the visceral pleura covering the primary tumor lobe, and those with more extensive, multifocal studding on the visceral or parietal pleura? In footnotes to the 1986 staging classification, all of these presentations were called T4 disease. Does the more extensive or more distant pleural involvement have more dire implications? Should such patients, like those with a malignant pleural effusion, be considered to have M1 disease? There is little in the literature addressing the outcome of this group of patients. Shimizu et al 36 treated 38 patients with primary lung cancer and varying degrees of pleural involvement. All patients had parietal pleurectomy plus various extents of lung resection followed by sclerosing therapy. 36 The overall 5-year survival rate of 19.4% for this highly selected group was better than would have been expected for patients with malignant pleural effusion. Patients with primary lung tumors 4 cm in diameter and with negative nodes did much better than the rest. While the actual extent of pleural involvement was not discussed, the few long-term survivors were probably most like patients with T3N0 or even T2N0 disease. Additional survival and patterns-of-failure data on patients presenting with visceral pleural involvement not due to direct local extension of the primary tumor; and those presenting with one or more nodules on the parietal pleura, are needed. Conclusions Our evidence-based, TNM staging system for lung cancer has gone through two major revisions since its development in 1974. The most recent revision acknowledges size alone to be of independent prognostic significance and divides stages I and II disease into A and B subcategories based on the size of the primary tumor. T3N0 disease, recognized as prognostically more favorable and more amenable to primary surgical therapy than other subgroups of stage IIIA disease, has been reclassified as stage IIB. These changes seem sound and are already reflective of current treatment practice. The modified classification of synchronous ipsilateral pulmonary nodules in the 1997 revision as T4 stage IIIB may imply a poorer outcome for patients with intralobar satellites than is warranted. Management of these patients with nonoperative therapy appropriate to stage IIIB (T4) disease may ignore a curative surgical option for some of them. Careful individualization of therapy in these cases is required. Patients with malignant pleural effusions do poorly, with survival experiences very similar to groups with stage IV disease. Whether future therapeutic advances will create important distinctions between patients with malignant effusions and those with frank M1 disease remains to be seen. Current data seem to suggest that the 1997 staging revision may have missed an appropriate opportunity to reclassify malignant effusion disease into the stage IV category. These and other issues will be points for consideration when the third revision of the International Staging System for lung cancer is considered in the next millennium. ACKNOWLEDGMENT: Andrew T. Turrisi, MD, and Carolyn E. Reed, MD, provided a critical review of this article. References 1 Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111:1710 1717 2 Denoix PF. Enquete permanent dans les centres anticancereux. Bull Inst Nat Hyg 1946; 1:70 75 3 Mountain CF, Carr DT, Anderson WAD. A system for the clinical staging of lung cancer. AJR Am J Roentgenol 1974; 120:130 138 CHEST / 115 / 1/ JANUARY, 1999 247

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Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. J Clin Oncol 1995; 13:452 458 35 Mountain CF. Prognostic implications of the international staging system for lung cancer. Semin Oncol 1988; 15:236 245 36 Shimizu J, Oda M, Moita K, et al. Comparison of pleuropneumonectomy and limited surgery for lung cancer with pleural dissemination. J Surg Oncol 1996; 61:1 6 248 Opinions/Hypotheses