The IASLC Lung Cancer Staging Project Proposals.6

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IASLC STAGING   ARTICLE

The IASLC Lung Cancer Staging Project: Proposals for  the Revision of the TNM Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of  Malignant Tumours  Peter Gol  Peter Goldst dstraw raw,, FRC FRCS,* S,* John Cro Crowle wley, y, PhD PhD,† ,† Kar Karii Cha Chansk nsky, y, MS, MS,† † Dor Doroth othyy J. Gir Giroux oux,, MSc MSc,†  ,†   Patti  Pat ti A. Gro Groome ome,, PhD PhD,‡ ,‡ Ram Ramon on Ram Rami-P i-Port orta, a, MD, MD,§ § Pie Pieter ter E. Pos Postmu tmus, s, PhD PhD,, Valerie Rusch, MD,¶  and Leslie Sobin, MD,# on behalf of the International Association for the Study of Lung Cancer   Intern  Int ernati ationa onall Sta Stagin ging g Com Commit mittee tee and Particip Participati ating ng Ins Instit tituti utions ons

sevent enth h edi editio tion n of the   TNM Clas Introduction:   The sev Classifica sification tion of     Malignant Tumors   is due to be published early in 2009. In preparation for this, the International Association for the Study of Lung Cancer established its Lung Cancer Staging Project in 1998. The recommendations of this committee for changes to the T, N, and M descriptors have been published. This report contains the proposals for the new stage groupings. Methods:  Data were contributed from 46 sources in more than 19 countries. Adequate data were available on 67,725 cases of nonsmall cell lung cancer treated by all modalities of care between 1990 and 2000. The recommendations for changes to the T, N, and M descriptors were incorporated into TNM subsets. Candidate stage groupi gro upings ngs were dev develo eloped ped on a tra traini ining ng sub subset set and tested tested in a validation subset. Results: The suggestions include additional cutoffs for tumor size, with tumors 7 cm moving from T2 to T3; reassigning the category given giv en to add additio itional nal pul pulmon monary ary nod nodule uless in som somee loc locati ations ons;; and  reclassifying pleural effusion as an M descriptor. In addition, it is suggested that T2b N0 M0 cases be moved from stage IB to stage IIA, N1stage M0 cases from stage IIB to stage stage IIA, and T4 N0 –1 M0 casesT2a from IIIB to stage IIIA. *Royal Brom *Royal Brompton pton Hospi Hospital, tal, Imper Imperial ial Colle College, ge, Londo London, n, Unite United d Kingd Kingdom; om; †Cancer Research and Biostatistics, Seattle, Washington; ‡Queen’s Cancer Research Institute, Kingston, Ontario, Canada; §Hospital Mutua de Terrassa, Terrassa, Spain; Vrije Universiteit University Medical Center, Amsterdam, The Netherlands; ¶Memorial Sloan-Kettering Cancer Center,, New Yor ter York, k, New Yor York; k; #Ar #Armed med For Forces ces Ins Instit titute ute of Pat Pathol hology ogy,, Washington, DC. See Appendix for participants. Disclosure: This work was funded by a restricted educational grant from Eli Lilly and Company. No individual from the company had any role in evaluating the data or in preparing the manuscript. The project was also supported suppor ted by the AJCC grant “Improving “Improving AJCC AJCC/UICC /UICC TNM Canc Cancer  er  Staging.” Address Addr ess for corre correspond spondence ence:: Peter Goldstraw, Goldstraw, FRCS FRCS,, Depar Department tment of Thoracic Surgery, Royal Brompton Hospital, Sydney Street, London, SW3 6NP UK. E-mail: [email protected]  Copyright © 2007 by the International Association for the Study of Lung Cancer  ISSN: 1556-0864/07/0208-0706

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Conclusions: Such changes, if accepted, will involve a reassessment of existing treatment algorithms. However, they are based on an intensive and validated analysis of the largest database to date. The  proposed changes would improve i mprove the alignment of TNM stage with w ith  prognosis and, in certain subsets, with treatment.

( J Thorac Oncol.  2007;2: 706–714)

T

he cu curr rren entt (six (sixth) th)   TNM Cla Classifi ssificat cation ion of Mal Malign ignant  ant  1 Tumours, introduced in 2002, made no changes to the  previous  previ ous edit edition ion with rega regards rds to lung canc cancer. er. The propos proposals als with regard to lung cancer in the fifth edition, published in 1997,2 were based on a relatively small database of 5319 cases of non-small cell lung cancer (NSCLC) accumulated  since 1975. During this time, there had been many refinements men ts to the tec techn hniqu iques es ava availa ilable ble fo forr cli clinic nical al sta stagin ging, g,  principal  princ ipally ly the rout routine ine use of compu computed ted tomo tomograph graphy. y. The database was largely from a single institution, containing cases predominantly treated surgically. Repeated iterations of the   TNM Classification of Malignant Tumours  had seen the recommendations for lung cancer staging evolve with little internal validation and no external validation of the descript desc riptors ors or the stag stagee gro groupin upings. gs. Incr Increasin easingly gly repo reports rts from other databases databases were challenging challenging some of the descriptors and suggesting revised stage groupings. The next edition of the  TNM Classification of Malignant Tumours , the seventh, was due to be published early in 2007, now 2009. In preparation for this the International Association for the Study of Lung Cancer (IASLC) established its Lung Cancer Staging Project in 1998 to bring together the large databases available worldwide and to form recommendations tio ns fo forr the sev sevent enth h ed editi ition on tha thatt wo would uld be int intens ensive ively ly valida val idated ted.. Th Thee his histor tory y of the pro projec jectt an and d det detail ailss of the database have been described elsewhere. 3 The project has  been reco recogniz gnized ed by the Inte Internat rnational ional Union Agai Against nst Cancer as the primary source for recommendations for revisions sio ns to the sixth edition edition of the   TNM Classification Classification of     Malignant  Malign ant Tumour Tumourss   and has rec receiv eived ed fu fund nding ing from from the

 Journal of Thoracic Oncology  Oncology    • Volum Volume e 2, Number 8, August August 2007

 

 Journal of Thoracic Oncology  Oncology    • Volum Volume e 2, Number 8, August August 2007 2007

American Joint Committee on Cancer to separately submit  propos als for its revi  proposals revision sion of the stag ing manua manual. l. The recomm rec ommen endat dation ionss of the sta stagin ging g com commit mittee tee hav havee bee been n submitted to the International Union Against Cancer and  are shortly to be submitted to the American Joint Committee on Cancer.

METHODS At a workshop held in London in February 2001, a number of groups presented the data held in their institutions. Our chosen biosciences partner, Cancer Research and Biostatistics, in discussion with the committee members, subsequentl que ntly y dev develo eloped ped the dat dataa fiel fields ds and dic diction tionary ary.. It was decided that the study period should enlist cases diagnosed   between 1990 and 2000. This interval was chosen as it represented repre sented a relativ relatively ely shor shortt perio period d durin during g which staging methods had been constant and allowed 5 years of follow-up  before analysis. Cases treated by all modalities of care, including multimodality treatment, were included. From the coree of con cor contrib tributo utors rs who pre presen sented ted at the wor worksh kshop, op, dat dataa acquisition was widened to eventually involve 46 sources in more than 19 countries. These additional sources were identified from the literature by their response to advertisements in the journals or by contact from individual members of the committee. A total of 100,869 cases were submitted to the data center at Cancer Research and Biostatistics. After an initial sift to exclud excludee cases outsid outsidee the study period, period, those for  whom cell type was not known, cases not newly diagnosed at the point of entry, and those with inadequate information on stage, sta ge, tre treatme atment, nt, or fol follow low-up -up,, 81, 81,015 015 cas cases es rem remain ained ed for  analys ana lysis. is. Of thes these, e, 67, 67,725 725 were NSC NSCLC LC and 13,290 13,290 wer weree small-cell lung cancer (SCLC). Only the NSCLC cases were included in the analyses of the T, N, and M descriptors and  the subsequent analysis of TNM subsets and stage groupings. Surv Su rviv ival al wa wass me measu asure red d fr from om th thee da date te of en entr try y (d (date ate of  diagnosis for registries, date of registration for protocols) for  clinically staged data and the date of surgery for pathologically staged data and was calculated by the Kaplan-Meier  method. Prognostic groups were assessed by Cox regression analysis, using the SAS System for Windows Version 9.0 PHREG procedure. Where the analyses showed descriptors to have a prognosis that differed from the other descriptors in any T or M category, two alternative strategies were considered: (1) Retain tha thatt des descrip criptor tor in the exi existin sting g cate categor gory, y, ide identi ntified fied by alphabetical subscripts. For example, additional pulmonary nodules in the lobe of the primary, considered to be T4 in the sixth edition,1 would become T4a, whereas additional pulmonary nodules in other ipsilateral lobes, designated as M1 in the sixth edition,1 would become M1a. (2) Allow descri descriptors ptors to move between categories, to a category containing other  descriptors with a similar prognosis, e.g., additional pulmonary nodules in the lobe of the primary would move from T4 to T3, and additional pulmonary nodules in other ipsilateral lobes would move from M1 to T4. The first strategy had the advantage of allowing, to a large extent, retrograde compatibility with existing databases. Unfortunately, this generated  a lar large ge num number ber of des descri cripto ptors rs (ap (appro proxim ximatel ately y 20) and an

 

The IASLC Lung Canc Cancer er Stagi Staging ng Projec Project  t 

impractically large number of TNM subsets ( 180). For this reason, backward compatibility was compromised and strategy (2) was preferred for its clinical utility. The resultant TNM subsets and the numbers of cases in each subset by clinical stage and pathologic stage are shown in Table 1. A small sma ll num number ber of can candid didate ate stag stagee gro groupi uping ng sch scheme emess wer weree developed initially using a recursive partitioning and amalgamation algorithm.4 S-PLUS Version 7.0 was the statistical software used to apply this algorithm and draw the initial tree. The analysis grouped cases based on best stage (pathologic, if  available, otherwise clinical) after determination of best-split  points based on overall survival on indicator variables for the newly proposed T/M categories and an ordered variable for N category, excluding NX cases. This analysis was performed  on a randomly selected training set comprising two thirds of  the available data that met the requir requirements ements for conversion conversion to newly proposed T and M categories ( n  17,726), reserving 9133 cases for later validation. The random selection process was stratified by type of database submission and time period  of case entry (1990–1995 versus 1995–2000). The recursive partitioning and amalgamation analysis generated a tree-based model for the survival data using log rank test statistics for recursive partitioning and, for selection of the important groupings, bootstrap resampling to correct

TABLE 1.   Total Number of International Database Cases Classifia Class ifiable ble According to Propo Proposed sed TNM Stage Subset Subsetss for  Clinical Clin ical Stage and Pathologic Pathologic Stage Clinical Stage N Stage Proposed T/M Stage

T1a T1b T2a T2b T3 T4 M1a M1b Total

N0

N1

N2

N3

Total

419 442 1345 411 2452 144 213 626 6052

12 1 2 14 71 33 6 91 69 17 17 41 221 1100 11

66 6 6 78 78 326 107 2355 134 220 1151 4 437 44

13 1 3 5 39 14 6 16 61 44 44 157 790 1678 16

510 539 1781 565 6114 339 631 2788 1 3,267 13

Pathologic Stage N Stage Proposed T/M Stage

T1a T1b T2a T2b T3 T4 M1a M1b Total

Copyright © 2007 by the International Association for the Study of Lung Cancer 

N0

N1

N2

N3

Total

1965 1796 3186 937 2188 224 99 15 10,410

226 343 1123 382 1015 118 42 7 3256 32

191 327 905 90 285 1114 217 94 11 3144 31

4 6 18 18 4 74 74 12 4 5 127 12

2 386 23 24 2 472 5232 1608 16 4391 571 239 23 38 16,937 16

 

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Journal of Thoracic Oncology  Oncology    • Volum Volume e 2, Number 8, August August 2007

FIGURE 1.   Recursive partitioning partitioning and amalgamation–generated gamat ion–generated survival tree based on best stage for 17,726 cases. T and M stages (from proposed new T and M) are combined as 0/1 indicators. N stage is ordered. The number below each terminal node is the log hazard ratio, with the T1aN0M0 category as baseline.

TABLE 2.   Termin Terminal al Nodes from T/M and N Survival Survival Tree, Ordered by Hazard Ratio Term Te rmin inal al No Node de

Samp Sa mple le Si Size ze (T (Tra rain inin ing g Se Set) t)

Haza Ha zard rd Ra Rati tio o

T1a N0 T1b N0 T2a N0 T2b N0 T1ab–T2ab N1 T3 N0 T1–2a N2 T3 N1 T4 N01 T2b N2 T3 N2 M1a (N0–1) T4 N2 M1a (N2) T1-M1a N3 M1b (N0–1) M1b (N2–3)

1373 1257 2346 673 1460 2466 1253 1066 354 250 2006 301 239 212 630 553 1287

1.00 1.28 1.80 2.44 2.72 3.67 3.67 4.48 5.47 5.47 6.69 7.39 7.39 9.97 9.97 13.46 16.44

size cutoffs in addition to the 3-cm limit that separates T1 from T2 tumors be established. Tumors that fulfill the definition for T1 and are 2 cm in greatest dimension should be designated T1a, whereas those that are 2 cm but 3 cm in greates gre atestt dim dimens ension ion be des design ignated ated T1b T1b.. Tho Those se tum tumors ors tha thatt fulfill the present definition of T2 and are 5 cm in greatest dimension become T2a, whereas those that are 5 cm but

The changes proposed to the current T and M descriptors are highlighted in the full list of descriptors shown in

7 cm in greatest dimension become T2b. Tumor dimension   7 cm becomes a T3 descriptor. Additional tumor  nodules in the lobe of the primary become T3, nodules in other ipsilateral lobes become T4, whereas nodules in the contralateral lung remain M1 disease. The presence of a malignant pleural effusion, pleural dissemination, or pericardial disease becomes an M descriptor. The M category is subdivided into M1a, which includes the new descriptors added to this category, i.e., cases with pleural nodules or  malignant malig nant pleu pleural ral or peri pericard cardial ial effu effusion sion and add addition itional al  pulmonary  pulm onary nodul nodules es in the cont contrala ralatera terall lung and M1b for  those cases with other distant metastases. These The se pro propos posed ed cha change ngess wer weree inc incorp orpora orated ted int into o the data and, after analysis of each TNM subset, the resultant stagee gro stag groupi upings ngs wer weree ide identi ntified fied.. The These se are sum summar marized ized in Table 4, in which are highlighted those TNM subsets that it is proposed should move from their present stage grouping. The moving of some cases from within a descriptor in the  present staging system to another in the proposals for the seventh edition of the TNM classification and the creation of  new descripto descriptors rs has led to the migration migration of cer certain tain TNM subsets between stage groups. For example, of 1789 cases in the database designated as T2 N1 M0 according to the sixth edition, 400 were allocated to the new subset of T2b N1 M0 and another 205 migrate into the T3 N0 M0 subset. Consequently, those cases remaining T2a N1 M0 had a survival equivalent to that of stage IIA and not stage IIB as in the sixth edition edi tion.. The num number berss dri drivin ving g thi this, s, and oth other er cha change nges, s, are evident in Table 5. Those T2 tumors   5 cm but   7 cm in great gr eatest est dim dimens ension ion are rec reclas lassifi sified ed as T2b T2b,, and if no node de negative migrate to stage IIA from stage IB. Those T2

Table 3. These changes have been reported in detail in this  journal.5,6 The existing N descriptors were validated, and no changes are proposed.7 The changes proposed suggest that

tumors   7 cm in greatest dimension would become T3 tumors and move to stage IIB from IB if node negative and  to stage IIIA from IIB if associated with N1 disease. If 

Sample size is the number of cases in the training set classifiable by best stage.

for the adaptive nature of the splitting algorithm (Figure 1). An ordered list of groupings from the terminal nodes of the survival tree, with group sizes and hazard ratios, is shown in Table 2. With this as a guide, several proposed stage groupings were created by combining adjacent groups. Selection of  a final stage grouping proposal from among the candidate schemes was based on its statistical properties in the training set and its relevance to clinical practice and was arrived at by consensus.

RESULTS

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Copyright © 2007 by the International Association for the Study of Lung Cancer 

 

 Journal of Thoracic Oncology  Oncology    • Volum Volume e 2, Number 8, August August 2007 2007

TABLE 3.   Propos Proposed ed Definitions Definitions for T, N, and M Descri Descriptors ptors T (Primary Tumor)

TX

T0 Tis

Prim Pr imar ary y tu tumo morr ca cann nnot ot be as asse sess ssed ed,, or tu tumo morr pr prov oven en by th thee  presence of malignant cells in sputum or bronchial washings washi ngs but not visua visualized lized by imagin imaging g or bronc bronchosco hoscopy py No evi vide den nce of pri rima marry tu tumo mor  r  Carcinoma in situ

T1

Tumovisceral r   3 cmpleura, in greatest dimension, surrounded by lung without bronchoscopic evidence of  or 



invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)a T1a Tumor  2 cm in greatest dimension T1b Tumor  2 cm but 3 cm in greatest dimension T2 Tumor  3 cm but 7 cm or tumor with any of the following features (T2 tumors with these features are classified T2a if  5 cm) Involves main bronchus, 2 cm distal to the carina Invades visceral pleura Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung T2a Tumor  3 cm but 5 cm in greatest dimension T2b Tumor  5 cm but 7 cm in greatest dimension T3 Tumor  7 cm or one that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal  pericardium; or tumor in the main bronchus 2 cm distal to the carinaa  but without involvement of the carina; or associated atelectasis or obstructive  pneumonitis of the entire lung or separate tumor  nodule(s) in the same lobe T4 Tumo Tu morr of an any y si size ze th that at in inva vade dess an any y of th thee fo foll llow owin ing: g: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s) in a different ipsilateral lobe N (Regional Lymph Nodes)  NX  N0  N1

 N2

Regional lymph nodes cannot be assessed  No regional lymph node metastasis Metastasis in ipsilateral peribronchial and/or ipsilateral hilar  lymph nodes and intrapulmonary nodes, including involvement by direct extension Metastasis in ipsilateral mediastinal and/or subcarinal lymph

node(s) Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular  lymph node(s) M (Distant Metastasis)

 N3

MX M0 M1 M1a

M1b M1 b

Distan Dist antt me meta tast stas asis is ca cann nnot ot be as asse sess ssed  ed  No distant meta tasstasis Distant metastasis Separa Sep arate te tum tumor or nod nodule ule(s) (s) in a con contra tralat later eral al lob lobe; e; tum tumor or wit with h  pleural nodules or malignant pleural (or pericardial) effusionb Dist Di staant me meta tast staasi siss

a The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1. b Most pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be classified  as T1, T2, T3, or T4.

 

The IASLC Lung Canc Cancer er Stagi Staging ng Projec Project  t 

TABLE 4.   Descri Descriptors ptors,, Proposed T and M Categ Categories, ories, and Proposed Stage Groupings Sixth Edition T/M Descriptor

T1 (2 cm) T1 (2–3 cm) T2 (5 cm) T2 (5–7 cm) T2 (7 cm) T3 invasion T4 (same lobe nodules) T4 (extension) M1 (ipsilateral lung) T4 (ple leu ural effusion) M1 (contralateral lung) M1 (distant)

Proposed T/M

T1a T1b T2a T2b T3

N0

IA IA IB   IIA   IIB IIB IIB IIIA IIIA IV IV IV

   

 

T4   M1a

   

M1b

N1

N2

N3

IIA IIIA IIIB II IIA IIIA IIIB IIA   I II IIA IIIB IIB II IIIA IIIB IIIA   II IIIA IIIB I IIA II IIIA IIIB I IIA II IIIA   IIIB IIIA   II IIIB IIIB IIIA IIIB IIIB IV IV IV IV IV IV IV IV IV

Cells in bold indicate a change from the sixth edition for a particular TNM category.

those cases with additional tumor nodules in the same lobe as the primary are moved to T3 from T4 as proposed, then such cases move from stage IIIB to IIB if node negative and to stage IIIA if associated with N1 or N2 disease. The changes to the T4 descriptor, the removal of cases with additional tumor nodules in the lobe of the primary and  cases with pleural or pericardial disease, and the addition of cases with additional tumor nodules in other ipsilateral lobes result in a lower stage being assigned to most TNM subsets subs ets cont containi aining ng the T4 desc descripto riptor. r. Thos Thosee cases with  pleural  pleu ral or peri pericard cardial ial dise disease, ase, if assi assigned gned to an M desc descripriptor, would consequently fall within stage IV disease. Figures 2 and 3 show survival by stage according to the sixth edition of TNM and by the newly proposed TNM stage  based on the entire set of cases available for reclassification. (Cases without without data on age, sex, and histology histology are excluded.) excluded.) Tables Tab les 6 and 7 sho show w the sta statist tistics ics fro from m Cox proportio proportional nal hazards regression modeling of the sixth edition of TNM and  the proposed new system for clinical and pathologic stage, respectively. wasby parameterized both(Tables as a set6of indicator variablesStage and also ordered variables and 7), adjusted for cell type, sex, region, and age (younger than 60 versus 60 and older). The proposed system better delineates the early stage cases, where problems with overlap between IB and IIA have been noted with the sixth edition of TNM 8 and are clearly seen here on clinical staging. Improvement is also seen in the distinction between clinical IIA and IIB, as well as the proportion of cases assigned to stage IIA (a weakness of the sixth edition of TNM). For both the clinical and pathologic stage models, there is an increase in the value for  R 2, an estimate of the percentage of variance explained by the model. 9 The new system makes use of well-justified changes to T and M and may serve to identify subsets of patients with tumors of different sizes with differing prognoses. Both the proposed new system and the sixth edition of TNM yielded a reversal on pathologic staging from the expected hazards for advanced stage disease

Copyright © 2007 by the International Association for the Study of Lung Cancer 

 

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Journal of Thoracic Oncology  Oncology    • Volum Volume e 2, Number 8, August August 2007

TABLE 5.   Sampl Sample e Sizes for TNM Subsets Providing Providing the Basis for Proposed Proposed Changes T1–T3 T1–T3 by Best Stage, T4 by Best Stage, and M1 by Best Stage T1–T3 by Best Stage Sixth Edition Descriptor

T1 (2 cm) T1 (2–3 cm) T2 (5 cm) T2 (5–7 cm) T2 (7 cm) T3 (invasion) T4 (same lobe nodules)

N0

N1

Overall Stage

Sample Size

Overall Stage

Sample Size

Overall Stage

Sample Size

Overall Stage

Sample Size

T1a T1b T2a T2b T3

IA IA IB IB– >IIA IB– >IIB IIB IIIB– >IIB

2134 1902 3547 1016 457 3113 174

IIA IIA IIB– >IIA IIB IIB–>   IIIA IIIA IIIB–>   IIIA

242 360 1184 400 205 1329 70

IIIA IIIA IIIA IIIA IIIA IIIA IIIB–>   IIIA

257 412 1198 374 211 2735 127

IIIB IIIB IIIB IIIB IIIB IIIB IIIB

19 13 60 20 5 642 5

   

 

 

T4 by Best Stage

   

T4  

 

N2–N3

Overall Stage

Sample Size

IIIB– >IIIA

432

IV– >IIIA

 

97

M1 by Best Stage Sixth Edition Descriptor

T4 (pleural dissemination) M1 (contralateral lung) M1 (distant)

 

N0–N1 Proposed T/M

T4 (extension) M1 (ipsilateral lung)

N3

Proposed T/M

 

Sixth Edition Descriptor

N2

Overall Stage

Sample Size

IIIB IV–>I IIB

320 86

Any N Proposed T/M

M1a M1b

 

Overall Stage

Sample Size

IIIB– >IV

683

IV IV

230 2800

Cells in bold indicate a change from the sixth edition for a particular TNM category. Samples sizes for T/M descriptors are summarized across N-stage categories where possible to highlight the decision points for the proposed stage groupings.

(II (IIIB IB and IV) IV).. Thi Thiss res result ult,, alth althoug ough h ano anomalo malous, us, can mos mostt likely be explained by the nature of advanced-stage surgical cases. By virtue of their expected resectability, they consisted   primarily of small effusions or additional nodules discovered  at surgery or of cases with single isolated central nervous system or adrenal metastases. In summary, the proposed system results in improved  2  R values for both clinical and pathologic stages, improved 

controlling for cell type, sex, age, and region were all statistically significant significant using the pathologic staging data. There weree som wer somee non nonsig signifi nifican cantt dif differ ferenc ences es in the ear earlyly-sta staged  ged  clinical cases, but this problem was present using both the  proposed system and the existing sixth edition of TNM and  may be the result of an unstable comparison as the validation set contained only 3863 cases. External validation was assessed against the Surveil-

separa sep aratio tion n bet betwee ween n sta stages ges II IIB B an and d IIA for cli clinic nical al and   path ologicc stag  pathologi stages, es, a more even dist distribu ribution tion amon among g the stagee gro stag groupin upings gs for both clini clinical cal and path patholog ologic ic stag stages, es, and an increase in the hazard ratio for stage when modeled  as an ordered variable. These advantages, combined with enhanced clinical utility and incorporation of the refined T and M criteria, make this system a strong candidate for a revised staging system. The proposed stage groupings are summarized in Table 8.

lance, Epi lance, Epidem demiol iology ogy,, and End Res Results ults Pro Progra gram m dat databa abase, se, which records best stage and details of this comparison along with survival curves are provided in our validation paper. 10 The Surveillance, Epidemiology, and End Results Program survival curves using the sixth edition of the   TNM Classification of Malignant Tumours  and the IASLC proposed system were compared. Generally, both the new system and the existing performed well, but the separation between the IB and IIA curves was better in the proposed system, whereas the new IIA and IIB curves converged at 5 years.

Validation The proposals derived from the training set of 17,726 cases were internally validated against the validation set of  9133 913 3 case cases. s. Det Details ails of the these se ana analys lyses es are provided provided in the companion paper on the validation process and results. 10 In  brief, the validation set generated survival curves that were

Previous revisions to the TNM classification for lung cancer contained very little internal and no external validation information. In 1974, the second edition of the  TNM Classi-

generally similar to those in the training set and Cox proportional hazards regression analyses that calculated the hazard  ratios rat ios betw between een eac each h pai pairr of adj adjacen acentt stag stagee gro groups ups while

  fication of Malignant Tumours   11 inco incorpo rporat rated ed all of the descriptors suggested by the American Joint Committee on Cancer Task Force on Lung Cancer.12 Although T, N, and M

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DISCUSSION

Copyright © 2007 by the International Association for the Study of Lung Cancer 

 

 Journal of Thoracic Oncology  Oncology    • Volum Volume e 2, Number 8, August August 2007

FIGURE 2.   Overall survival, expressed as median survival time (MST) and 5-year survival, by clinical stage using the sixth edition of TNM (A (A) and proposed International Association of the Study of Lung Cancer recommendations (B  ( B ). ).

 

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FIGURE 3.   Overall survival, expressed as median survival time (MST) and 5-year survival, by pathologic stage using sixth edition of TNM (A (A) and proposed International Association of the Study of Lung Cancer recommendations (B  ( B ). ).

categories were shown to have differing prognoses, there was no validation presented to justify the individual descriptors. In addition, of the 18 possible TNM subsets in that edition, seven contained fewer than 100 cases, some as few as 24 cases, and four other subsets contained too few cases for any analysis. In successive revisions, new descriptors were added  as deemed necessary. In some situations, as with additional  pulmonary nodules,2 these were added to existing T, N, and 

however, led us to arrive at decisions that we recognize will create problems for our colleagues in this field. The necessity to sacrifice backward compatibility with existing databases in the search for a staging system that is manageable in clinical  practice has already been mentioned. We further recognize

M categories retaining existing TNM stage and  stage groupings. groupings. In otherthe revisio revisions, ns, for example, exampl e, subsets the division 13 of T3 and T4 in the fourth edition, existing descriptors were expanded and divided into new TNM subsets and  new stage groupings. Although changes in TNM subsets and stage groupings were internally validated in a limited  way, there was no external validation presented and individual descriptors were not validated. To a large extent, the creation of new descriptors in earlier revisions and their  accommodation within the TNM classification for lung cancer  was driven largely by existing treatment algorithms. The validation process has been an integral part of this  project. The internal and external validation of the T, N, and  M des descri cripto ptors rs pro propos posed ed by thi thiss pro project ject5–7 and that of the TNM stage groupings suggested in this article will be presented sen ted in ano anothe therr art article icle in thi thiss jou journa rnal. l.10 Such intens intensive ive

that moving some descri descriptors ptors within stage catego categories the  proposed changes to the stage groupings will ries cut and across established treatment algorithms. The moving of the larger, node-n nod e-nega egative tive T2 tum tumors ors (T2 (T2b b cas cases es   5 cm in gr grea eate test st dimension) and tumors 7 cm in greatest dimension (which would become T3) from stage IB into stage IIA and stage IIB, respectively, will clearly raise the question as to whether such cases cas es sho should uld hav havee adj adjuva uvant nt che chemot mother herapy apy aft after er com comple plete te resecti res ection. on. Although Although there is stil stilll dou doubt bt as to the value of  adjuva adj uvant nt che chemot mother herapy apy afte afterr com complet pletee res resecti ection on for nod nodee 14,15 negative cases in stage IB, at least two large trials have show sh own n a be bene nefit fit fo forr no node de-p -pos ositi itive ve cas cases es in st stag ages es II an and  d  16,17 IIIA. Thee qu Th quest estio ion n as to wh wheth ether er th thes esee lar large gerr no node de-negative tumors benefit from adjuvant therapy will only be resolved by large, prospective, randomized trials. The reassignment of cases with additional nodules in an ipsilateral,

validation has only been possible by the enormous size of the database and the international spread of the contributions to this th is pr proj oject ect fr from om th thee lu lung ng ca canc ncer er co comm mmun unity ity.. Th This is ha has, s,

nonprimary tumor–bearing lobe into a T4 descriptor rather  than an M1 descriptor and the relocation of T4 N0 M0 and T4  N1 M0 cases into stage IIIA will also lead to questions as to

Copyright © 2007 by the International Association for the Study of Lung Cancer 

 

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Journal of Thoracic Oncology  Oncology    • Volum Volume e 2, Number 8, August August 2007

TABLE 6.   Cox Proportional Hazards Regression Models for  the Sixth Edition of TNM and Proposed Clinical Stage Groupings (IASLC)

TABLE 8.   Propo Proposed sed TNM Stage Groupin Groupings gs

Clinical Stage (Sixth Edition and IASLC Proposed) Modeled as Indicator Variables

Stage Stage Stage Stage

Hazard Ratio Comp Co mpar aris ison onss

IB vs. IA IIA vs. IB IIB vs. IIA IIIA vs. IIB IIIB vs. IIIA IV vs. IIIB  R2

 

Sixt Si xth h Ed Edit itio ion n

IASL IA SLC C

1.31 1.35 1.20 1.30 1.47 1.71 25.86

1.19 1.23 1.46 1.27 1.54 1.64 26.77

p

Sixt Si xth h Ed Edit itio ion n

IASL IA SLC C

 

0.0001

 

0.1978 0.4344 0.0001 0.0001 0.0001

0.0035 0.0020 0.0001 0.0001 0.0001 0.0001

   

       

Clinical Stage (Sixth Edition and IASLC Proposed) Modeled as Ordered Variables Hazard ratio Varia iab ble

Stage

 

Sixth Edition

IASLC

1.36

1.38

p

Sixth Edit itiion  

0.0001

IASLC  

0.0001

Adjusted for cell type, sex, age, and region ( n     11,536 (8944 events). IASLC, International Association of the Study of Lung Cancer.

TABLE 7.   Cox Proportional Hazards Regression Models for  the Sixth Edition TNM and Proposed Pathologic Stage Groupings (IASLC) Pathologic Stage (Sixth Edition and IASLC Proposed) as Indicator Variables Hazard Ratio Comp Co mpar aris ison onss

 

p

Sixt Si xth h Ed Edit itio ion n

IASL IA SLC C

Sixt Si xth h Ed Edit itio ion n

IB vs. IA IIA vs. IB IIB vs. IIA

1.72 1.28 1.26

1.55 1.44 1.29

 

0.0001

 

0.0001

 

0.0001

 

0.0001

0.0002

 

0.0001

IIIA vs. IIB IIIB vs. IIIA IV vs. IIIB  R2

1.48 1.27 0.91 29.44

1.47 1.79 0.86 30.40

   

0.0001 0.0001

   

0.0001 0.0001

0.2921

IASL IA SLC C

0.0974

Pathologic Stage (Sixth Edition and IASLC Proposed) Modeled as Ordered Variables Hazard Ratio Varia iab ble

Stage

Sixth Edition

IASLC

1.35

1.40

 

p

Sixth Editio ion n  

0.0001

IASLC  

0.0001

Adjusted for cell type, sex, age, and region ( n     15,952 (8988 events). IASLC, International Association of the Study of Lung Cancer.

the appropriate treatment algorithm. The limitations of our  database do not allow us to be certain whether this reassignment is appropriate for cases with multiple additional tumor 

712

Occult Carcinoma

0 IA IB IIA

Stage IIB Stage IIIA

Stage IIIB Stage IV

TX

N0

M0

Tis T1a, b T2a T1a, b T2a

N0 N0 N0 N1 N1

M0 M0 M0 M0 M0

T2b T2b T3 T1, T2 T3 T4 T4 Any T Any T

N0 N1 N0 N2 N1, N2 N0, N1 N2 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M1a, b

nodules or for all T4 cases. Multimodality treatment models, some including surgery, will no doubt evolve, informed by appropriate trials. In other situations, the changes suggested  for inclusion inclusion in the seventh edition of the  TNM Classification  might better reflect current practice as of Malignant Tumours with the move of cases with malignant pleural effusions into an M category from a T category. Within our database, there was a clea clearr dif differ ferenc encee in pro progno gnosis sis bet betwee ween n pat patien ients ts wit with h metastases to the ipsilateral pleura or contralateral lung and  those with metastases at distant sites outside the thorax. In general, the latter have the worst prognosis and have been historically considered as stage IV and candidates for primarily sy syste stemic mic tre treatm atment ent.. Wit Within hin the cas cases es pr prop opos osed ed in an ex panded  pand ed stag stagee IV, ther theree is still a pro progno gnostic stic diff differen erence ce betw between een those with spread within the thorax and those with metastases to distan dis tantt sit sites, es, and the theref refore ore dif differ ferent entiat iating ing be betwe tween en M1 M1aa and M1 M1b b seems to be of relevance. These recommendations have been based on the findings of a large international database. The number of cases recruited is 15 to 20 times larger than that which informed  any revision. have beengrateful donatedfor bythe 46 support sources in 19previous countries. We areData all immensely offered by colleagues around the world. Although the treatment of these NSCLC cases included surgery in 53% of the  patients, there were 30% in which chemotherapy was used  and 29% in whi which ch rad radiot iother herapy apy was use used. d. The data wer weree collect col lected ed fro from m cas cases es tre treated ated ove overr a rel relativ atively ely sho short rt per period  iod  during which the techniques used in clinical staging were reasonably reason ably standa standardized rdized world worldwide. wide. The recom recommendat mendations ions have been, for the first time, intensively validated. Internal valida val idation tion has ens ensure ured d tha thatt the rec recomm ommend endatio ations ns are sup sup- ported by data from all geographic areas and across all types of databases. External validation has been established against the Surv Surveillance eillance,, Epidem Epidemiolog iology, y, and End Resul Results ts Progr Program am database. There The re are are,, how howeve ever, r, lim limitat itation ionss to this project. project. The volume volu me of da data ta an and d th thee in inter terna nati tion onal al na natu ture re of th thee da data ta sources have made data audit extremely difficult, and, as a result, only limited checks for consistency have been possi-

Copyright © 2007 by the International Association for the Study of Lung Cancer 

 

 Journal of Thoracic Oncology  Oncology    • Volum Volume e 2, Number 8, August August 2007 2007

 ble. There are glaring deficiencies in the global distribution of  the data with no data at all being included from Africa, South Americ Ame rica, a, or the Ind Indian ian sub subcon contine tinent. nt. Oth Other er vas vastt cou countr ntries ies such as Russia, China, and Indonesia are not represented or  only poorly repres represented. ented. Although less surgic surgically ally domin dominated  ated  than previous databases, the spread of treatment modalities does not reflect the practice in most institutions. The time  period under study predates the widespread and routine use of   positron emission tomography, which has had an enormous impact on clinical staging algorithms. In any retrospective databa dat abase, se, one has to col collect lect the dat dataa tha thatt was consider considered  ed  important by each source, and this reflects the use for which the data wer weree col collect lected. ed. Although Although we hav havee an eno enormo rmous us amount of data on some descriptors, such as tumor dimension, we have too little on many to prove or disprove the validity of some descriptors. We hope that our colleagues in clinical practice will recogn rec ognize ize tha thatt the cha change ngess sug sugges gested ted by this project project are driven by the data available to us from a database of more than 68,000 cases. Even with the acknowledged limitations of  thee da th datab tabas ase, e, its br brea eadt dth h ha hass all allow owed ed th thee ap appl plic icati ation on of  evidence-based standards in terms of statistical power, reliability, and scientific validity that were not possible in previous revisions. Inevitably, existing treatment algorithms will  be challe nged, challenged, butthe weutility hope of bythe such rigorous analysis for of large volumes of data, TNM classification lung cancer will be strengthened. It is our intention to ensure that the exp expans ansion ion of the dat databa abase, se, inc includ luding ing the pro prospe spectiv ctivee collection of data over the coming years, will ensure further, carefully validated proposals concerning thoracic malignancies ci es fo forr th thee eig eight hth h ed editi ition on of th thee   TNM Clas Classific sificatio ation n of     Malignant Tumours  and beyond.

 

7.

8.

9.

10.

11. 12.

13. 14.

The IASLC Lung Canc Cancer er Stagi Staging ng Projec Project  t 

forthcoming forthcomin g (seve (seventh) nth) edition of the TNM Classification Classification of Malig Malignant nant Tumours.  J Thorac Oncol  2007;2:686–693.   2007;2:686–693. Rusch Rus ch V, Cro Crowle wley y JJ, Goldstra Goldstraw w P, et al. The IAS IASLC LC Lung Can Cancer  cer  Stagin Sta ging g Pro Projec ject: t: Pro Propos posals als for rev revisi ision on of the N des descri cripto ptors rs in the forthcomin forth coming g (seve (seventh) nth) edition of the TNM Classification Classification of Malig Malignant nant Tumours.  J Thorac Oncol  2007;   2007;2:706–714. Naruke Naru ke T, Tsuch Tsuchiya iya R, Kondo H, et al. Prognosis and survival survival after  resection for bronchogenic carcinoma based on the 1997 TNM staging classification: the Japanese experience. Ann Thorac Surg  2001;71:1759–   2001;71:1759–  1764. O’Quigley J, Xu R. Explained variation in proportional hazards regresregression. In Crowley J, Ankerst D, eds. Handbook of Statistics in Clinical Oncology, Oncol ogy, 2nd ed. New York: Chapman Chapman and Hall/CRC Press, Press, 2006: 347–363. Groomee PA, Bolejack V, Crowley JJ, et al. The IASLC Lung Cancer  Groom Staging Project: validation of the proposals for revision of the T, N, and  M des descri cripto ptors rs and con conseq sequen uentt sta stage ge gro groupi upings ngs in the for forthc thcomi oming ng (seventh) (seve nth) edition of the TNM Class Classifica ification tion of Malign Malignant ant Tumours. J Thorac Oncol 2007;2:694–705. Internation Inter national al Union Against Cancer. Cancer. TNM Classification Classification of Malign Malignant ant Tumours, 2nd ed. Geneva: UICC, 1974. Mountain CF, Car Mountain Carrr DT, Anderson Anderson WAD. A sys system tem for the clinical clinical staging of lung cancer.  Am J Roentgenol Radiat Ther Nucl Med  1974; 120:130–138. Mountain CF. A new international international staging system for lung cancer. cancer. Chest  1986;89:225s–233s. Strauss Stra uss GM, Hern Herndon don JE, Madda Maddaus us MA, et al. Adjuv Adjuvant ant chemotherapy chemotherapy in stage IB non-small cell lung cancer (NSCLC): update of Cancer and  Leukemia Group B (CALGB) protocol 9633 (Abstract 7007).   J Clin Oncol  2006;24:18s.   2006;24:18s.

15. Pignon Pignon JP, Tribodet Tribodet H, Scagliotti Scagliotti GV, et al. Lung Adjuvant Adjuvant Cispl Cisplatin atin Evaluation (LACE): a pooled analysis of five randomized clinical trails including 4,584 patients (Abstract 7008).  J Clin Oncol  2006;24:18s.   2006;24:18s. 16. Winto Winton n T, Livin Livingston gston R, Johnson D, et al. Vinor Vinorelbine elbine plus cisplatin cisplatin versus observation in resected non-small-cell lung cancer.  N Engl J Med  2005;352:2589–2597. 17. Douil Douillard lard JY, Rosell R, DeLe DeLena na M, et al. Adjuv Adjuvant ant vinorelbine vinorelbine plus cisplatin cispl atin vers versus us obser observatio vation n in patie patients nts with completely completely rese resected cted stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Trial ist Assoc Associatio iation n [ANI [ANITA]) TA]):: a rando randomised mised contr controlled olled trial.   Lancet  Oncol  2006;7:719–727.   2006;7:719–727.

ACKNOWLEDGMENTS  Eli Lilly and Compan Companyy provid provided ed fundin funding g to suppor support  t  the work of the International Association for the Study of    Lung Cancer Stagin Staging g Commit Committee tee to establ establish ish a datab database ase and to suggest revisions to the sixth edition of the TNM  Classification of Malignant Tumours (lung cancer staging) thro th rough ugh a re restr stric icte ted d gra grant nt.. Lil Lilly ly ha had d no in inpu putt int into o th thee committee’s analysis of the data nor suggestions for revi sions to the stagi staging ng syste system. m.

REFERENCES 1. Sobin L, Wittekind Wittekind Ch, eds. TNM Classification of Malignant Tumours, Sixth Edition. New York: Wiley-Liss, 2002:99–103. 2. Mount Mountain ain CF. Revisions in the international international staging staging syste system m for staging lung cancer.  Chest  1997;111:1710–1717.  1997;111:1710–1717. 3. Goldstraw P, Crowley Crowley JJ. The International Association Association for the Study of  Lung Cancer International Staging Project on Lung Cancer.  J Thorac Oncol  2006;1:281–286.   2006;1:281–286. 4. Crow Crowley ley JJ, LeBlanc M, Jacobson J, et al. Some exploratory exploratory tools for  survival analysis. In Lin DY, Fleming TR, eds. Proceedings of the First Seattle Seat tle Symp Symposium osium in Biost Biostatisti atistics: cs: Surv Survival ival Analy Analysis. sis. New York York:: Springer, 1997:199–229. 5. Ra Ramimi-Por Porta ta R, Ball D, Cro Crowle wley y JJ, et al. The IAS IASLC LC Lung Ca Cance ncer  r  Stagin Sta ging g Pro Projec ject: t: pro propos posals als for re revis vision ion of the T des descri cripto ptors rs in the forthcomin forth coming g (seve (seventh) nth) edition of the TNM Classification Classification of Malig Malignant nant Tumours. J Thorac Oncol 2007;2:593–602. 6. Postm Postmus us PE, Bram Brambilla billa E, Chansky K, et al. The IASLC Lung Cancer  Stagin Sta ging g Pro Projec ject: t: pro propos posals als for rev revisio ision n of the M des descri cripto ptors rs in the

APPENDIX IASLC International Staging Committee P. Goldstraw (Chairperson), Royal Brompton Hospital, London, UK; H. Asamur London, Asamura, a, Nation National al Cancer Centre Hospital, Tok Tokyo, yo, Japan; Jap D. Ball, Bal Peter r ejack, MacCall Mac um Cancer cer Centre Cen tre,, Melbou Mel bourne rne, , an; Austral Aus tralia; ia; l,V.Pete Bolejac Bol k,Callum Cancer Can cerCan Resear Res earch ch and  Biostatistics, Seattle, WA, USA; E. Brambilla, Laboratoire de Pathologie Cellulaire, Grenoble Cedex, France; P. A. Bunn, University of Colorado Health Sciences, Denver, CO, USA; D. Carney, Mater Misericordiae Hospital, Dublin, Ireland; K. Chansky, Chans ky, Cancer Resear Research ch and Biost Biostatistics, atistics, Seattle, WA, USA; T. Le Chevalier, Institute Gustave Roussy, Villejuif, France; J. Crowley, Cancer Research and Biostatistics, Seattle, WA, USA USA;; R. Gin Ginsbe sberg rg (de (deceas ceased) ed),, Mem Memori orial al Slo SloananKettering Cancer Center, New York, NY, USA; D. Giroux, Cancer Can cer Res Resear earch ch and Bio Biostat statisti istics, cs, Sea Seattle ttle,, WA, USA USA;; P. Groome, Queen’s Cancer Research Institute, Kingston, Ontario, Canada; H. H. Hansen (retired), National University University Hospital, Hospi tal, Copen Copenhagen hagen,, Denmar Denmark; k; P. Van Houtte, Instit Institute ute Jules Bordet, Bruxelles, Belgium; J.-G. Im, Seoul National University Hospital, Seoul, South Korea; J. R. Jett, Mayo Clinic, Rochester, Rochester, MN, USA; H. Kato (retired), (retired), Tokyo Medical Uni Univer versity sity,, Tok Tokyo, yo, Jap Japan; an; C. Ken Kenned nedy, y, Uni Univer versity sity of 

Copyright © 2007 by the International Association for the Study of Lung Cancer 

 

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Journal of Thoracic Oncology  Oncology    • Volum Volume e 2, Number 8, August August 2007

Sydney, Sydney, Australia; M. Krasnik, Gentofte Hospital, Copenhagen, Denmark; J. van Meerbeeck, University Hospital, Ghent, Belgiu Belgium; m; T. Naruk Narukee (decea (deceased), sed), Saiseikai Central Hospital, Tokyo, Japan; E. F. Patz, Duke University Medical Center, Durham, NC; P. E. Postmus, Vrije Universiteit Medical Center, Amster Amsterdam, dam, The Nether Netherlands lands;; R. RamiRami-Porta, Porta, Hospit Hos pital al Mut Mutua ua de Ter Terras rassa, sa, Ter Terras rassa, sa, Spa Spain; in; V. Rus Rusch, ch, Memorial Memor ial Sloan Sloan-Ketter -Kettering ing Cancer Center Center,, New York, NY, USA; J. P. Sculier, Institute Jules Bordet, Brussels, Belgium; Z. Sha Shaikh ikh,, Roy Royal al Bro Brompt mpton on Hos Hospit pital, al, Lon London don,, UK; F. A. Shepherd, University of Toronto, Toronto, Ontario, Canada; Y. Shimosato (retired), National Cancer Centre, Tokyo, Ja pan; L. Sobin, Armed Forces Institute of Pathology, Washington ing ton,, DC; W. Tra Travis vis,, Mem Memori orial al Slo Sloanan-Ket Ketter tering ing Can Cancer  cer  Center, New York, NY, USA; M. Tsuboi, Tokyo Medical University, Tokyo, Japan; R. Tsuchiya, National Cancer Centre,, Tok tre Tokyo, yo, Jap Japan; an; E. Val Vallier lieres, es, Swe Swedis dish h Can Cancer cer Ins Institu titute, te, Seattl Sea ttle, e, WA WA,, US USA; A; J. Van Vanste steenk enkist iste, e, Leu Leuven ven Lun Lung g Ca Cance ncer  r  Group, Leuven, Belgium; Yoh Watanabe (deceased), Kanazawa Medical University, Uchinada, Japan; and H. Yokomise, Kagawa University, Kagawa, Japan.

Participating Institutions O. Visser Visser,, Amster Amsterdam dam Cancer Registry, Amsterdam, Amsterdam, The Net Nether herlan lands; ds; R. Tsu Tsuchi chiya ya and T. Nar Naruke uke (de (deceas ceased) ed),, Japanese Joint Committee of Lung Cancer Registry, Japan; J. P Van Meerbeeck, Flemish Lung Cance Cancerr Regist Registry-VR ry-VRGT, GT, Brussels, Belgium; H.   u¨ lzebruck, Thorax-Klinik am Universitatsklinikum, Heidelberg, Germany; R. Allison and L. Tripcony, Queensland Radium Institute, Herston, Australia; X. Wang, D. Watson and J. Herndon, Cancer and Leukemia Group B (CALGB), USA; R. J. Stevens, Medical Research Council Clinical Trials Unit, London, UK; A. Depierre, E. Quoix, and Q. Tran, Intergroupe Francophone de Cancerologie Thoracique (IFCT), France; J. R. Jett and S. Mandrekar,  North Central Cancer Treatment Group (NCCTG), USA; J. H. Schiller and R. J. Gray, Eastern Cooperative Oncology Group (ECOG), USA; J. L. Duque-Medina and A. LopezEncuentra, Bronchogenic Carcinoma Co-operative Group of  the Spanish Society of Pneumology Pneumology and Thoracic Surgery (GCCB-S), Spain; Crowley, Southwest Oncology Group (SWOG), USA; J. J.J.J.Crowley and K. M. W. Pisters, Bimodality Lung Oncology Team (BLOT), USA; T. E. Strand, Cancer Registry of Norway; S. Swann and H. Choy, Radia-

714

tion Therapy Oncology Group (RTOG), USA; R. Damhuis, Rotterdam Cancer Registry, The Netherlands; R. Komaki and  P. K. Allen, M. D. Anderson Cancer Center–Radiation Therapy (MDACC-RT), Houston, TX, USA; J. P. Sculier and M. Paesmans, European Lung Cancer Working Party (ELCWP); Y. L. Wu, Guangdong Provincial People’s Hospital, P. R. China;; M. Pesek and H. Krosn China Krosnarova, arova, Faculty Hospital Hospital Plzen, Czech Republic; T. Le Chevalier and A. Dunant, International Adjuvant Lung Cancer Trial (IALT), France; B. McCaughan and C. Kennedy, University of Sydney, Australia; F. Shephe She pherd rd and M. Whi Whiteh tehead ead,, Nat Nation ional al Can Cancer cer Ins Institu titute te of  Canadaa (NCIC Canad (NCIC); ); J. Jassem and W. Ryzma Ryzman, n, Medical Unive Univerrsity of Gda Gdansk nsk,, Pol Poland and;; G. V. Sca Scaglio gliotti tti and P. Bor Borasio asio,, Universita Unive rsita` Degli Studi di Torin Torino, o, S. Luigi Hospital, Orbas Orbas-sano, san o, Ita Italy; ly; K. M. Fon Fong g and L. Pas Passmo smore, re, Prince Charles Charles Hospital, Brisbane, Australia; V. W. Rusch and B. J. Park, Memorial Sloan-Kettering Cancer Center, New York, NY, USA;; H. J. Bae USA Baek, k, Kor Korea ea Can Cancer cer Cen Centre tre Hos Hospit pital, al, Seo Seoul, ul, South Sou th Kor Korea; ea; R. P. Per Perng, ng, Tai Taiwan wan Lun Lung g Can Cancer cer Soc Society iety,, Taiwan; R. C. Yung, A. Gramatikova, Johns Hopkins University, Baltimore, MD, USA; J. Vansteenkiste, Leuven Lung Cancer Group (LLCG), Leuven, Belgium; C. Brambilla and  M. Col Colonn onna, a, Gre Grenob noble le Uni Univer versity sity Hos Hospita pital–I l–Iser seree Can Cancer  cer  Registry, Grenoble, France; J. Hunt and A. Park, Western Hospital, Melbourne, Australia; J. P. Sculier and T. Berghmans, man s, Ins Institu titute te of Jul Jules es Bor Bordet, det, Brussels Brussels,, Bel Belgiu gium; m; A. K. Cangir, Ankara University School of Medicine, Ankara, Turkey; D. Subotic, Clinical Centre of Serbia, Belgrade, Serbia; R. Ro Rose sell ll an and d V. Ab Aber erol ola, a, Sp Span anish ish Lu Lung ng Ca Canc ncer er Gr Grou oup p (SLCG), Spain; A. A. Vaporciyan and A. M. Correa, M. D. Anderson Cancer Center–Thoracic and Cardiovascular Surgery (MDACC-TCVS), Houston, TX, USA; J. P. Pignon, T. Le Chevalier and R. Komaki, Institut Gustave Roussy (IGR), Paris, France; T. Orlowski, Institute of Lung Diseases, Warsaw,, Pol saw Poland and;; D. Bal Balll and J. Mat Matthe thews, ws, Peter Mac MacCal Callum lum Cancer Institute, East Melbourne, Australia; M. Tsao, Princess Margaret Hospital, Toronto, Ontario, Canada; S. Darwish, Policlinic of Perugia, Perugia, Italy; H. I. Pass and T. Stevens, Stev ens, Karm Karmanos anos Can Cancer cer Inst Institut itute, e, Wayn Waynee State Univ Universit ersity, y, Detroit, MI, USA; G. Wright, Vincent’s Hospital,European Victoria, Australia; and C. Legrand andSt. J. P. van Meerbeeck, Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium.

Copyright © 2007 by the International Association for the Study of Lung Cancer 

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