Estadiamento do Cancer de pulmão

DOI 10.1378/chest.08-0978 2009;136;260-271Chest

Frank C. Detterbeck, Daniel J. Boffa and Lynn T. Tanoue The New Lung Cancer Staging System

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The New Lung Cancer Staging System

Frank C. Detterbeck, MD, FCCP; Daniel J. Boffa, MD;and Lynn T. Tanoue, MD, FCCP

The International Association for the Study of Lung Cancer (IASLC) has conducted an extensiveinitiative to inform the revision of the lung cancer staging system. This involved development ofan international database along with extensive analysis of a large population of patients and theirprognoses. This article reviews the recommendations of the IASLC International StagingCommittee for the definitions for the TNM descriptors and the stage grouping in the newnon-small cell lung cancer staging system. (CHEST 2009; 136:260–271)

Abbreviations: AJCC � American Joint Committee on Cancer; IASLC � International Association for the Study ofLung Cancer; NSCLC � non-small cell lung cancer; SEER � Surveillance, Epidemiology, and End Results;UICC � Union Internationale Contre le Cancer

D efinition of the stage is an essential part of theapproach to patients with cancer, and it has led

to the development of a universally accepted stageclassification systems for most tumors. The UnionInternationale Contre le Cancer (UICC) and theAmerican Joint Committee on Cancer (AJCC) serveas the official bodies that define, periodically review,and refine the stage classification systems. The 6thedition of the staging system was published in 2002,1and the 7th edition will be published in 2009. Inpreparation for this, much work has been done bythe International Association for the Study of LungCancer (IASLC) to recommend changes that arebased on a large international database and arebacked by careful validation and statistical analysis.This article reviews the development and final rec-ommendations of the IASLC International StagingCommittee for non-small cell lung cancer (NSCLC),

which have been accepted by the UICC and AJCC forthe new edition.

For editorial comment see page 6

The TNM staging system for lung cancer datesback to an initial proposal by Dr. Clifton Mountainthat was adopted by the AJCC in 1973 and by theUICC in 1974. The original system was based heavilyon intuition with limited corroboration from adatabase of 2,155 patients from the MD AndersonCancer Center in Houston, TX. Subsequent revi-sions of the TNM staging system continued to bebased on this database, which grew to include 5,319cases at the time the lung cancer staging system waslast revised in 1997. The limitations of this system arethat it was based on what was essentially a singleinstitution series, included a limited number ofpatients (so that many subgroups were quite small),spanned a long time frame, and was weighted some-what toward surgically treated patients by the natureof the database. Nevertheless, this early work laid asignificant foundation and defined a staging systemthat has held up very well even in comparison withthe new IASLC staging system.

Fundamentals of the UICC/AJCCStaging System

The NSCLC stage classification is based on theTNM system, which is used for most cancers. The Tdescriptor defines the extent of the primary tumor,

From Thoracic Surgery (Drs. Detterbeck and Boffa), Section ofPulmonary and Critical Care Medicine (Dr. Tanoue), YaleUniversity School of Medicine, New Haven, CT.The authors have reported to the ACCP that no significantconflicts of interest exist with any companies/organizations whoseproducts or services may be discussed in this article.Manuscript received April 11, 2008; revision accepted February11, 2009.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).Correspondence to: Frank C. Detterbeck, MD, FCCP, Professorand Section Chief, Thoracic Surgery, Yale University School ofMedicine, 330 Cedar St, BB 205, New Haven, CT 06520-8062;e-mail: [email protected]: 10.1378/chest.08-0978

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the N descriptor the extent of involvement of re-gional lymph nodes, and the M descriptor the extentof spread to distant sites. The staging system is basedsolely on the anatomic extent of disease. Otherfactors, such as clinical symptoms or molecular bio-logical characterization of the tumor, have not beenincluded. Increasing T status reflects tumors that arelarger or invasive into more peripheral (ie, visceralpleura, chest wall) or more central structures (ie,lobar or mainstem bronchus, mediastinum). In lungcancer, nodal staging depends on the location ofinvolved nodes (as opposed to the number of nodes).The M descriptor defines the presence or absence ofmore distant metastatic disease.

The method of staging has a major impact on theprognostic implications of the stage classification, afact that is well recognized by the UICC and AJCCas shown in Table 1. The two most commonlyencountered types of stage assessment are clinicalstaging (the stage determined using all informationavailable prior to any treatment) and pathologicstaging (determined after a resection has been car-ried out). The extent of clinical staging can vary froma clinical evaluation alone (history and physical ex-amination) to extensive imaging (CT/PET scans) orinvasive staging techniques. It must be emphasizedthat a surgical staging procedure (such as mediasti-noscopy) is still part of clinical staging becausesurgical resection as a treatment has not taken place.Clinical stage is denoted by the prefix “c” andpathologic stage by the prefix “p.” The UICC alsodefines a classification system for the presence orabsence of residual tumor after treatment, as shownin Table 2. Typically this is applied to describe thecompleteness of a surgical resection.

Development and Methodology of theIASLC Staging System

A proposal to develop an international effort toinform a future revision of the TNM staging classi-fication for lung cancer originated in 1996 at a

workshop sponsored by IASLC. An internationalcommittee was established and work began in 1999.An unrestricted grant from Eli Lilly and Companyenabled the establishment of a database (Eli Lillyand Company played no role in the data collection,analysis, or recommendation development process).The database was developed in cooperation withCancer Research and Biostatistics (Seattle, WA),which is an independent scientific foundation andthe statistical center for the Southwest OncologyGroup. Data elements and definitions were finalizedin October 2002. Data were collected from multiplesources and sites around the globe. Committeeswere formed to analyze the data and develop recom-mendations (including validation and methodology,T, N, M descriptors, nodal chart, prognostic factors,and small cell lung cancer). The initial recommen-dations were revised and approved by the full IASLCInternational Staging Committee. These proposalswere published in a series of detailed articles in theJournal of Thoracic Oncology in 2007.2–6 The pro-posed staging recommendations were presented tothe AJCC and UICC in 2007, were approved bythese bodies, and are slated to be published in the7th edition of the UICC Staging Manual in 2009.

At the time the database was closed to additionalentries, 100,869 cases had been submitted from 45sources in 20 countries.7 The final data set involved81,015 cases after exclusion of ineligible cases (dueto incomplete information in 42%, outside the 1990to 2000 time frame in 28%, unknown histology in13%, incomplete survival data in 6%, recurrent casesin 6%, and ineligible histologic types in 6% [carci-noid, sarcoma, and others]).5,7 Small cell lung canceraccounted for 16% and NSCLC for 84% of cases.Only the NSCLC cases were used to derive the T, N,M descriptors and stage groupings reviewed in thisarticle. SCLC and carcinoid tumor staging are ad-dressed in separate publications.8,9 The databaseincluded cases from four continents (the proportionof NSCLC cases is as follows: Europe, 58%; NorthAmerica, 21%; Asia, 14%; and Australia, 7%). Sub-mitted cases came from series (40%), registries(30%), and clinical trials (30%). Treatment involved

Table 1—Types of Staging Assessments

Prefix Name Definition

c Clinical Prior to initiation of any treatment, using anyand all information available (eg, includingmediastinoscopy)

p Pathologic After resection, based on pathologicassessment

y Restaging After part or all of the treatment has beengiven

r Recurrence Stage at time of a recurrencea Autopsy Stage as determined by autopsy

Table 2—Residual Tumor After Treatment

Symbol Name Definition

R0 No residual No identifiable tumor remaining;negative surgical margins

R1 Microscopic residual Microscopically positive marginsbut no visible tumorremaining

R2 Gross residual Gross (visible or palpable) tumorremaining

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surgery only in 41%, radiotherapy only in 11%,chemotherapy only in 23%, and combined modalitiesin the rest. Clinical staging included patients subse-quently treated with neoadjuvant (preoperative)therapy, whereas preoperatively treated patientswere excluded from analyses of pathologic staging.

Subsets of the NSCLC patients were defined thatmet the analytic requirements for each T, N, Manalysis. These subsets were substantially smallerthan the entire group of NSCLC patients within theIASLC database. For example, clinical and patho-logic T stage involved 5,760 and 15,234 cases, re-spectively, that were M0 and included a complete set ofcTNM or pTNM as well as sufficient T descriptordetails.2 For clinical and pathologic N stage, 38,265 and28,371 cases, respectively, were selected that were cM0

with sufficient N status assessment (any T).3 For Mstage, 6,596 cases were included that were cM1 or hadan additional nodule in a separate ipsilateral lobe.4 Thedefinition of stage grouping involved 13,267 clinicalstage and 16,937 pathologic stage patients.5

The major determinant chosen for development ofsubgroups of T, N, and M descriptors as well as thestage groupings was the overall survival, based on thebest stage (pathologic, if available; otherwise clini-cal). Regrouping of stage descriptors was allowed,sacrificing backward compatibility with the previousTNM system in favor of greater simplicity. Stagegrouping schemes were developed using a recursivepartitioning and amalgamation algorithm, and vali-dated as described later. Care was taken to prevent adeviant subset involving unstable curves or small

Table 3—Definitions for T, N, M Descriptors

Descriptors Definitions Subgroups*

T Primary tumorT0 No primary tumorT1 Tumor � 3 cm,† surrounded by lung or visceral pleura, not more proximal than the lobar bronchus

T1a Tumor � 2 cm† T1aT1b Tumor � 2 but � 3 cm† T1b

T2 Tumor � 3 but � 7 cm† or tumor with any of the following‡:Invades visceral pleura, involves main bronchus � 2 cm distal to the carina, atelectasis/obstructive

pneumonia extending to hilum but not involving the entire lungT2a Tumor � 3 but � 5 cm† T2aT2b Tumor � 5 but � 7 cm† T2b

T3 Tumor � 7 cm; T3�7

or directly invading chest wall, diaphragm, phrenic nerve, mediastinal pleura, or parietalpericardium;

T3Inv

or tumor in the main bronchus � 2 cm distal to the carina§; T3Centr

or atelectasis/obstructive pneumonitis of entire lung; T3Centr

or separate tumor nodules in the same lobe T3Satell

T4 Tumor of any size with invasion of heart, great vessels, trachea, recurrent laryngeal nerve,esophagus, vertebral body, or carina;

T4Inv

or separate tumor nodules in a different ipsilateral lobe T4Ipsi Nod

N Regional lymph nodesN0 No regional node metastasisN1 Metastasis in ipsilateral peribronchial and/or perihilar lymph nodes and intrapulmonary nodes,

including involvement by direct extensionN2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph nodesN3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or

supraclavicular lymph nodesM Distant metastasis

M0 No distant metastasisM1a Separate tumor nodules in a contralateral lobe; M1aContr Nod

or tumor with pleural nodules or malignant pleural dissemination� M1aPl Dissem

M1b Distant metastasis M1bSpecial situations

TX, NX, MX T, N, or M status not able to be assessedTis Focus of in situ cancer TisT1§ Superficial spreading tumor of any size but confined to the wall of the trachea or mainstem

bronchusT1SS

*These subgroup labels are not defined in the IASLC publications2–5 but are added here to facilitate a clear discussion.†In the greatest dimension.‡T2 tumors with these features are classified as T2a if � 5 cm.§The uncommon superficial spreading tumor in central airways is classified as T1.�Pleural effusions are excluded that are cytologically negative, nonbloody, transudative, and clinically judged not to be due to cancer.

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numbers of patients from driving a recommendation,unless the effect was consistent and externally vali-dated in a population-based series.

The proposed staging revisions were both inter-nally and externally validated.6 Internal validationrequired that differences in outcomes among theproposed subgroups were consistently observedwithin each type of database and geographic region,as well as the time period (from 1990 to 1995 vs from1995 to 2000) for stage groupings.2,5 Furthermore,for the T descriptor size categories and the stagegroupings, the cases used were separated into arandomly selected training set involving approxi-mately two thirds of the cases and a validation setinvolving the rest.2,5,6 In each analysis this validationconfirmed the training set results. Finally, the pro-posed descriptors were externally validated againstthe Surveillance, Epidemiology and End Results(SEER) database from the same time period, con-trolling for cell type, gender, age, and region.

Some details of the analyses are worth noting. Thesize criteria for the T descriptor are quite robust andbroadly applicable, having been extensively vali-dated. The optimal size cutpoints were initially de-termined using a pN0 R0 learning set (rounded tothe nearest whole centimeter).2 This was then testedin a pN0 R0 validation set as well as in other nodestage groups and in incompletely resected patients.The analysis was also confirmed within differenthistologic types of NSCLC, among different types ofdatabases and geographic regions. In contrast, theanalysis of the impact of additional nodules in theprimary tumor lobe or in a different ipsilateral lobe isderived from a potentially skewed population,namely primarily resected patients from Asia andAustralia. Nevertheless, the results were supportedby data from other geographic regions and by SEERdata.2 The N status analysis involved a large numberof patients and was consistently a major prognostic

Figure 1. Prognosis according to size category. A: overallsurvival by tumor size for patients with cT1-3N0M0 tumors usingthe IASLC classification. Modified from Rami-Porta et al.2 B:overall survival by tumor size for patients with pT1-3N0M0 R0tumors using the IASLC classification. Modified from Rami-Porta et al.2 Centr � central; Inv � invasion; MST � mediansurvival time (months); 5-year � 5-year overall survival.

Figure 2. Prognosis according to additional nodules, T4 invasion,and pleural dissemination. A: overall survival for patients withcT3,4/cM1a status due to additional tumor nodules using the IASLCclassification (any cN), compared with other categories of T3 and T4.Modified from Rami-Porta et al.2 B: overall survival for patients withpT3,4/pM1a status due to additional tumor nodules using theIASLC classification (any pN, any R), compared with other catego-ries of T3 and T4. Modified from Rami-Porta et al.2 Add’l �additional; Pts � patients. See the legend of Figure 1 for abbrevia-tions not used in the text.




factor in all regions and database types. However,survival was consistently better in each N category inAsian/Australian patients, intermediate in NorthAmerican, and worse in European patients.6 The Mdescriptor analysis was almost exclusively based onclinically staged patients for distant metastases andcontralateral lung nodules, but 34% of patients withpleural dissemination and 53% of patients withadditional nodules in a different ipsilateral lobe werepathologically staged (ie, resected) patients.4

T Descriptor

The IASLC International Staging Committee an-alyzed the effect of tumor size in detail, in partbecause there were many patients in whom reliableinformation was available. The size threshold of 3 cmwas confirmed as a significant cutpoint and retainedas a definition of a T1 vs a T2 tumor. In addition,significant cutpoints were identified at 2, 5, and 7cm. Tumors � 7 cm had survival that tracked withother definitions of T3 (ie, invasion or central loca-tion) and are therefore placed within this group. The2-cm and 5-cm additional cutpoints were addressedby the definition of subgroups of T1 (T1a and T1b)and T2 (T2a and T2b). The survival differencesbetween each of these size subgroups were highlystatistically significant in pathologically staged pa-tients, regardless of pN status or R status. Amongclinically staged patients, survival differences be-tween cT1a, cT1b, and cT2a were not consistentlystatistically significant, probably due to the smallernumbers of patients for whom these data wereavailable. Table 3 summarizes the definitions of theT descriptor subgroups. The survival curves for thesize categories of the T descriptor for clinically andpathologically staged patients are shown in Figure 1.

The prognostic value of additional tumor noduleswas also investigated. (Nodules were counted assynchronous primary cancers only if they were ofdifferent histologic types or were explicitly definedas synchronous primary cancers in the source data-base.) Patients with additional satellite nodules in thesame lobe as the primary tumor had relatively goodsurvival, similar to T3 patients, and therefore arenow classified as T3 (previously classified as T4). Thesurvival of these patients (T3Satell) was statisticallysignificantly better than patients with T4 tumorsbecause of invasion of major mediastinal structures(T4Inv). However, the prognosis of these patients(T4Inv) is not statistically different than that ofpatients with an additional tumor nodule in a differ-ent ipsilateral lobe (T4Ipsi Nod). Therefore, an ipsilat-eral nodule in a different lobe is now classified as T4(previously classified as M1). In contrast, clinically

staged patients with pleural dissemination clearlyhave statistically significant worse survival than T4 byinvasion (T4Inv) or than patients with an additionalnodule in a different ipsilateral lobe (T4Ipsi Nod).Therefore, patients with pleural dissemination areclassified as M1a. The survival curves for clinicallyand pathologically staged patients in these subgroupsare shown in Figure 2, A and B, respectively.

Although the survival is generally similar for thesubsets of patients included by the revised defini-tions of T3 and T4, some findings in the IASLCanalysis suggest that there are instances where dif-ferences between the subsets of T3 and T4 patientsmay be important. For example, the survival curvesof T4Inv and T4Ipsi Nod patients do not necessarilytrack together closely, suggesting there may be dif-ferent factors at work leading to the observed out-comes in each of these subsets. In addition, it shouldbe noted that resected patients with an additionaltumor nodule in a different ipsilateral lobe exhibit good5-year survival rate (48% for pT4Ipsi Nod N0 M0 R0;

Figure 3. Prognosis according to the N category. A: overallsurvival by cN category (any cT, cM0) using the IASLC classifi-cation. Reproduced from Rusch et al.3 B: overall survival by pNcategory (any pT, pM0) using the IASLC classification. Repro-duced from Rusch et al.3 1-yr � 1-year overall survival. See thelegend of Figure 1 for abbreviations not used in the text.

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42% for pT4Ipsi Nod N0 M0, any R), when comparedwith resected patients with T4 tumors by invasion(5-year survival rate: 35% for pT4Inv N0M0 R0; 30%for pT4Inv N0M0, any R) Furthermore, resected pa-tients who were found to have pleural dissemination donot have statistically different survival than patientswith T4 invasion or with an additional tumor nodule ina different ipsilateral lobe, and they exhibit fairly good5-year survival rate (31% if pTAny N0 M1aPl Dissem, R0;

24% if pTAny N0 M1aPl Dissem, any R).2 The resectedpatients, of course, represent a selected subgroup.However, these observations illustrate how the inter-play between clinical and pathologic staging, treatmentapproach, and patient selection can influence our per-ception of similar outcomes. The T descriptor group-ings do not necessarily reflect fundamental biologicalsimilarities, and we must continue to reevaluate resultsgoing forward.

Figure 4. The IASLC lymph node map, including the proposed grouping of lymph node stations into“zones” for the purposes of prognostic analyses. Reproduced from Rusch.11




There were insufficient numbers of patients forwhom reliable data were available to investigate thevalidity of other traditional T2, T3, or T4 descriptors(eg, visceral pleural invasion, central location within alobar or mainstem bronchus, partial or complete atel-ectasis, or direct invasion of particular structures).These traditional definitions were retained even thoughthey could not be confirmed because there were nodata to suggest that they are not valid. The true prognosticvalue of these factors will require further study.

N Descriptor

Analysis of the prognostic influence of the Ndescriptor resoundingly supported the traditional cate-gorization of N0, N1, N2, and N3, as shown forclinically and pathologically staged patients in Figure 3.3Therefore, no changes were made in the N descrip-tor as defined in the 6th edition of the stagingmanual. Further analyses were done to explorewhether particular node stations within an N cate-gory had any particular impact. No such relationshipcould be identified.3 Specifically, there was no dif-ference in survival between patients with involve-ment of only peripheral N1 nodes or hilar N1 nodes,and no difference based on which N2 nodal stationswere involved. This was true globally as well aswithin geographic regions. The effect of skip metas-tases was also investigated (involvement of an N2node station without involvement of any N1 nodes).Survival among pN2 patients with right upper lobetumors with and without N1 involvement was notdifferent, although there was a slight differenceamong such patients with a left upper lobe tumor.3

Analysis of details of nodal involvement is ham-pered by the fact that there are some discrepanciesbetween the nodal map used in Asia and that used inother geographic regions. Furthermore, there arequestions about how reproducibly some of theboundaries between different nodal stations can bedetermined during mediastinoscopy or thoracot-omy.10 To address this issue prospectively, theIASLC International Staging Committee has devel-oped a new node map (Fig 4).11 To address the issueretrospectively in the database, the committee de-fined several nodal zones: an upper zone (stations 1to 4), an aortopulmonary zone (stations 5 and 6), asubcarinal zone (station 7), a lower zone (stations 8and 9), a hilar zone (stations 10 and 11), and aperipheral zone (stations 12 to 14). There were nodifferences in prognoses between the involvement ofdifferent nodal zones within the N1 or N2 category.Specifically, there was no difference between pa-tients with a left upper lobe tumor and involvement

of nodes only in stations 5 and 6 vs patients with atumor in a different lobe and involvement of anothersingle N2 node zone.3

The number of involved nodal zones did appear tohave a prognostic impact. Patients with single-zoneN1 involvement had better survival than those withmultizone N1 involvement (5-year survival rate, 48%vs 35%, respectively; p � 0.09). Similarly, patientswith single-zone N2 involvement had better survivalthan those with multizone N2 involvement (5-yearsurvival rate, 34% vs 20%, respectively; p � 0.001). Infact, the survival curves of patients with multizone N1and single-zone N2 involvement were almost superim-posed.3 However, the prognostic impact of the numberof nodal zones involved could not be confirmed withinT stage categories because the numbers of patients inthe subsets were too small.3 Therefore, the IASLCInternational Staging Committee decided against thesubdivision of N categories. Definitions of the N de-scriptor subgroups are shown in Table 3.

M Descriptor

The committee on the M descriptor consideredpatients traditionally classified as M0 or M1 (distant

Figure 5. Prognosis according to the M category. A: overallsurvival by T4 and M category by clinical stage. B: overall survivalby T4 and M category using the best stage (pathologic stage ifavailable, otherwise clinical stage). Modified from Postmus et al.4Ipsi � ipsilateral; NS � not significant. See the legend of Figure1 for abbreviations not used in the text.

266 Special Feature



metastases), but it also considered patients with amalignant pleural effusion or with additional tumornodules in the lung.4 After analysis and discussion,patients with an additional tumor nodule in theprimary tumor lobe or a different ipsilateral lobewere redefined along with other aspects of the Tdescriptor (see “T Descriptor” section). The remain-ing cohorts categorized by the M descriptor wereeach markedly different than patients with T4 tu-mors. Their survival separated into two distinctprognostic groups, which led to the definition of anM1a subgroup that includes patients with eitherpleural dissemination or contralateral pulmonarynodules and an M1b subgroup with distant metasta-ses.4 The survival curves of these patients defined by

clinical stage and by best stage (pathologic if avail-able, otherwise clinical) are shown in Figure 5, A andB, respectively. The differences in prognosis be-tween these groups were highly statistically signifi-cant and held up to internal validation (comparisonsacross types of databases and geographic regions), aswell as external validation (comparison with theSEER database).4

The prognostic impact of one vs more than onecontralateral pulmonary nodule could not be as-sessed. Slightly worse survival was seen in patientswith multiple vs a solitary distant metastasis (mediansurvival time, 5 vs 6 months, respectively; 1-yearsurvival rate, 20% vs 23%, respectively; p � 0.006).4However, further subdivision of the M1b categorywas not undertaken.

Stage Grouping

The IASLC International Staging Committee hasdefined stage groupings. Despite the recognition ofmany new subdivisions of the T and M descriptor,

Figure 7. Stage grouping. A: overall survival by clinical stage forthe proposed IASLC stage grouping. Reproduced form Gold-straw et al.5 B: overall Survival by pathologic stage for theproposed IASLC stage grouping. Reproduced from Goldstrawet al.5 See the legend of Figure 1 for abbreviations not used inthe text.

Table 4—TNM Elements Included in Stage Groups

Stage Groups

Descriptors, % of all

Patients, %*T N M

Ia T1a,b N0 M0 15

Ib T2a N0 M0 13

IIa T1a,b N1 M0 2T2a N1 M0 4T2b N0 M0 4

IIb T2b N1 M0 2T3 N0 M0 14

IIIa T1–3 N2 M0 20T3 N1 M0 6T4 N0,1 M0 2

IIIb T4 N2 M0 1T1–4 N3 M0 3

IV TAny NAny M1a,b 14

*Percentage of patients in IASLC database according to best stage(rounded to nearest integer).5

N3N2N1N0SubgroupT/M

IVIVIVIVM1bIVIVIVIVM1a Pl Disem

IVIVIVIVM1a Contra NodM1IIIbIIIbIIIaIIIaT4 Ipsi Nod

IIIbIIIbIIIaIIIaT4 InvT4

IIIbIIIaIIIaIIbT3 Satell

IIIbIIIaIIIaIIbT3 Inv

IIIbIIIaIIIaIIbT3 >7T3IIIbIIIaIIbIIaT2bIIIbIIIaIIaIbT2aT2IIIbIIIaIIaIaT1bIIIbIIIaIIaIaT1aT1

Figure 6. Stage groups according to TNM descriptor andsubgroups.




the stage grouping has not added any new subdivi-sions. However the definition of the stage groups hasbecome more complex due to the additional T and Mdescriptor subgroups. Two different representationsof the stage grouping scheme are shown in Table 4and Figure 6. Survival curves for the stage groupingsbased on clinical and pathologic staging are shown inFigure 7, A and B, respectively. Illustrations provid-ing a graphic representation of the TNM categoriesand subcategories included within each stage groupare shown in Figures 8, 9, and 10.

Discussion

The development of the new NSCLC stagingsystem represents an astounding amount of work.This extends from the careful detailed analysis assummarized in this article, back through the estab-lishment of a database (with the necessary defini-tions, quality controls, and data cleansing), to theindividuals and institutions that collected data in thefirst place with sufficient detail and rigor. An effort ofthis magnitude as a basis for a staging system is quite

Figure 8. Graphic illustration of stages 0, I, and II.

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unique among types of cancer. The IASLC Interna-tional Staging Committee made every effort to go as faras the available data allowed, and issues that were notfully addressed are in areas in which insufficient datawere available. Much work of the committee has notyet been published, and much work is still ongoing.

It is inevitable that the new NSCLC stagingsystem is more complex. An increasing amount ofdata allows one to be able to discern an increasingnumber of details and differences, leading to thedefinition of an increasing number of subgroups.This in turn makes the organization of stage groupsinherently more complex. In addition to the com-plexity, however, the new system is also somewhatless intuitive regarding which T, N, and M categoriesbelong together in a stage group. This reflects thefact that the older systems involved less data andrelied at least to some extent on what seemedintuitively logical, whereas the new system is basedquite strictly on an extensive analysis of a largedatabase.

The definitions of the TNM descriptors and thestage groups and subgroups were determined pri-marily by the outcome measure of overall survival.

This was chosen because prognosis for anatomiccategories of disease was the only outcome measureand method of patient characterization for whichdata exists for a large number of patients. TheIASLC International Staging Committee was carefulto limit the analysis to a recent time period (from1990 to 2000), and it conducted extensive internalvalidation across continents, time periods, and data-base types. The committee was also careful to onlyadopt definitions that were consistently shown to bestatistically distinct (in analyses of smaller subgroups,only a consistent trend was required because the sizeof the subgroups was insufficient to show statisticalsignificance).

Although definition of prognosis is clearly one ofthe major purposes of a staging system, there aremany other goals and uses. The most prominent areprovision of a common nomenclature about patientsand the definition of homogeneous groups of pa-tients. In addition, many people expect a stagingsystem to define an algorithm of treatment, meaningthey expect a staging system to group patients intocohorts for which particular treatment approachesare appropriate. No classification system will meet all

Figure 9. Graphic illustration of stages IIIa and IIIb.




needs equally. Furthermore, the desired goals areinterrelated, and the factors that influence themchange over time. New treatment approaches aredefined that affect prognosis. Advances in imagingalter the stage assignment of a patient (stage migra-tion), which affects the prognosis of all stagegroups.12,13 Finally, changing methods of detection(eg, CT screening) can alter the spectrum of disease

that is encountered.14 As we consider how the newstaging system fulfills our needs, we must keep thesefactors in mind.

The IASLC system clearly meets the need for acommon nomenclature. A balance must be struckbetween a system that is simple and one that isdetailed enough to distinguish subgroups that aredistinct. However, increasing data and knowledgerequire us to collect an increasing amount ofdetail. At a minimum we should track not just theTNM descriptors but also the subgroup of the T,N, or M category (ie, T3Satell or T3Inv instead ofjust T3). A set of data elements to collect prospec-tively for the next revision of the staging system isbeing developed by the IASLC International Stag-ing Committee.15

The IASLC staging system clearly addresses thegoal of defining prognosis. A strict focus on prognosisleads to an emphasis on pathologic staging because itis most accurate. However, pathologic staging isinherently somewhat academic because it is notavailable until after major decisions about treatmenthave been made (ie, surgical resection). Clinicalstaging is more practical because it can guide deci-sions at the outset. Finally, we must remember thatprognosis changes as treatment advances and can bevery dependent on our attitudes and beliefs. Forexample, we typically view patients with pleuraldissemination as having such a poor prognosis thatonly palliative care is appropriate, but the relativelygood prognosis of resected patients with pleuraldissemination suggests there may be a subgroup inwhom such a pessimistic attitude is not appropriate.

We should not be tempted to use the stagegrouping as a simple algorithm that defines treat-ment. The optimal treatment is defined by clinicaltrials, and eligibility for a particular treatment de-pends on multiple factors, including modality-relatedfactors, patient-related factors (eg, performance sta-tus or comorbidities), and tumor-related factors (eg,histology, stage, or proximity to other organs). Fur-thermore, ongoing clinical research should refineour treatment at a faster pace than revisions in thestaging system. Therefore, although a staging systemprovides a nomenclature to facilitate discussion ofone aspect of the applicability of clinical trial resultsto newly diagnosed patients, it is an oversimplifica-tion to use stage group as a treatment algorithm.

Definition of homogeneous cohorts of patientsrequires agreement on which measures best demon-strate homogeneity. Identification of homogeneouscohorts will require attention to details beyond stagegrouping or prognosis alone. Certainly there aregroups that have similar prognosis but have markedlydifferent clinical characteristics (eg, stage IIIa in-cludes patients with N2 disease [T1-3 N2 M0], those

Figure 10. Graphic illustration of stage IV.

270 Special Feature



with extensive local invasion only [T4Inv N0 M0], andthose with ipsilateral additional tumor nodules[T4Ipsi Nod N0 M0]).

The ideal system would reflect the biological behav-ior of the tumor because patients grouped by tumorbehavior characteristics will probably continue to havesimilarities with one another (eg, similar prognosis andtreatment approach), even as new treatments are de-veloped and outcomes change. This suggests that clas-sification by molecular biological characteristics may bemore useful. Unfortunately, however, the ability topredict tumor biology is rudimentary, and only a lim-ited number of patients have data available on nonana-tomic characteristics.16

An attempt to introduce an element of biologicalbehavior into an anatomically based staging system isinherently speculative, given our current under-standing. Clinical observation suggests that theremay be four different types of biological behavior:tumors that are characterized primarily by a propen-sity to spread to regional lymph nodes, those char-acterized primarily by direct local invasion, thosecharacterized by a propensity to develop additionalfoci of cancer within the lung, and those with apropensity for systemic dissemination.17 One canargue that in some instances the observed anatomiccharacteristics may be more reflective of the locationof the tumor or the point in time at which it isdiscovered, rather than the biological behavior.However, it may, in fact, be the tumor biology thatdetermines the location and stage at which a tumor islikely to be found. We believe it is important toexplore potential ways to characterize tumor behav-ior as we implement the IASLC staging system andcontinue to study the course of disease in patientswith lung cancer.

In conclusion, the IASLC staging classification isunquestionably a major advance. The size of thedatabase, the broad international spectrum, the care-ful and detailed analysis, as well as the internal andexternal validation, are tremendous achievementsand relatively unique among types of cancer. Thisextensive effort has allowed the worldwide experi-ence with lung cancer to be brought together tocreate a sound and evidence-based staging classifi-cation. To improve on this will require not onlyprospective collection of more data according to thedata elements defined by our experience so far, butalso thoughtful investigation of novel factors andviews that may enhance our understanding in thefuture.

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DOI 10.1378/chest.08-0978 2009;136; 260-271Chest

Frank C. Detterbeck, Daniel J. Boffa and Lynn T. TanoueThe New Lung Cancer Staging System

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