1. A Pictorial Guide to the Revised Staging System for Non-Small Cell Lung Cancer Through the Use of PET/CT Bruno P. Soares, MD; Katherine Zukotynski, MD; Mizuki Nishino, MD; Annick Van Den Abbeele, MD Department of Imaging Dana-Farber Cancer Institute

2. Disclosure of Commercial Interest The authors do not have a financial relationship with a commercial organization that may have direct or indirect interest in the content of this exhibit.

3. OBJECTIVE To illustrate the changes to the staging system for non-small cell lung cancer through the use of PET/CT and to discuss the rationale behind these changes.

4. Contents Epidemiology of lung cancer PET/CT in lung cancer staging Changes in the TNM classification system

5. Epidemiology of Lung Cancer Second most common malignancy and the leading cause of cancer death for both men and women In 2009, there were an estimated 219,440 new cases of lung cancer and an estimated 159,390 deaths from lung cancer in the US Direct medical cost for treatment of lung cancer is approximately $5 billion annually Smoking is responsible for 87% of lung cancer deaths Reference: American Cancer Society, Surveillance and Health Policy Research, 2009.

6. Contents Epidemiology of lung cancer PET/CT in lung cancer staging Changes in the TNM classification system

7. What is the TNM staging system? T : extent of primary tumor (size and involvement of contiguous structures) N : extent of involvement of regional lymph nodes M : extent of spread to distant sites

8. Why use TNM staging? –Survival is heavily dependent on TNM tumor stage –Stages IA - IIIB are dependant on T and N classification –Stage IV disease is defined by metastatic disease

9. Role of PET/CT in T Staging Defining extent of invasion of adjacent structures Distinguishing tumor from atelectasis Evaluating additional pulmonary nodules Identification of malignant pleural effusions

10. Role of PET/CT in N Staging Evaluates the entire mediastinum (unlike mediastinoscopy) Relies on metabolic activity (unlike CT) Changes N staging in ~ 20% of cases, due to its ability to: –Detect tumor in anatomically normal lymph nodes –Exclude tumor involvement in enlarged lymph nodes

11. Limitations of PET/CT in N Staging Micrometastases in normal-sized lymph nodes may not be detected Negative predictive value decreases depending on: –Size of metastatic deposits –Avidity of the primary tumor

12. Role of PET/CT in M Staging The strength of FDG-PET is M staging! – Improved detection of metastasis – May reduce futile intervention

13. Contents Epidemiology of lung cancer PET/CT in lung cancer staging Changes in the TNM classification system

14. Limitations of the AJCC Cancer Staging Manual 6 th ed: Based essentially on a single institution series Limited number of patients (small subgroups) Weighted toward surgically treated patients Since the 6th edition in 2002, there have been refinements to the techniques available for clinical staging, especially computed tomography (CT) and positron emission tomography (PET) Background

15. Rationale for Changes (1) Expansion of database of patients treated for lung cancer: 81,015 cases from 46 sources in over 19 countries diagnosed between 1990 and 2000 Treated by all modalities of care 41% surgery only 23% chemotherapy only 11% radiotherapy only 25% combined modalities

16. Rationale for Changes (2) The major determinant for development of subgroups of T, N and M descriptors was the outcome measure of overall survival Proposed changes to the TNM staging system were externally validated against the Surveillance, Epidemiology and End Results (SEER) database from the same time period

17. Histologic Classification of Lung Tumors –Non-small cell carcinoma (NSCLC) »Squamous cell carcinoma »Adenocarcinoma »Large cell carcinoma –Small cell carcinoma –Carcinoid tumor –Other rare types Unlike the prior edition, which was validated only for NSCLC... The new TNM staging system includes small cell carcinoma and carcinoid tumors

18. TNM Staging 7 th Edition: Summary of Changes TNM staging system now also includes small cell carcinomas and carcinoid tumors of the lung T classifications have been redefined: T1 has been divided into T1a (≤2 cm in size) and T1b (>2-3 cm in size) T2 has been divided into T2a (>3-5 cm in size) and T2b (>5-7 cm in size) T2 (>7 cm in size) has been reclassified as T3 Multiple tumor nodules in the same lobe have been reclassified from T4 to T3 Multiple tumor nodules in the same lung but in a different lobe have been reclassified from M1 to T4 No changes in the N classification M classifications have been redefined: M1 has been divided into M1a and M1b Malignant pleural and pericardial effusions have been reclassified from T4 to M1a Separate tumor nodules in the contralateral lung are considered M1a Distant metastases are considered M1b

19. Looks confusing? So let’s describe and illustrate the changes step by step...

20. TNM Staging 7 th Edition: Changes in T Staging T1:Smaller than 3cm T2:>3cm or Involves the main bronchus, 2 cm or more distal to the carina or invades the visceral pleura, or with atelectasis extending to the hilum The size threshold of 3 cm was confirmed to be a significant cutpoint and retained in the definition of T1 vs. T2 tumor. T1a: less than or equal to 2cm; T1b: >2cm and less than or equal to 3cm There was a significant difference in prognosis for lesions less than 2 cm compared to lesions larger than 2 cm (cutpoint), generating subgroups T1a and T1b.

21. TNM Staging 7 th Edition: Changes in T Staging T1a: less than or equal to 2 cm T1b: >2cm and less than or equal to 3 cm T2a: >3cm and less than or equal to 5 cm T2b: >5cm and less than or equal to 7 cm T3: >7 cm Significant cutpoints were identified at 5 and 7 cm, generating new subgroups.

22. Example: 9 mm nodule T1a : less than or equal to 2cm (previously T1)

23. Example: 2,2 cm nodule T1b : >2cm and less than or equal to 3cm (previously T1)

24. Example: 6,4 cm mass T2a : >3cm and less than or equal to 5 cm T2b : >5cm and less than or equal to 7cm T3 : >7cm (previously any tumor larger than 3 cm was considered T2 if there was no invasion of adjacent structures)

25. Example: 7,2 cm necrotic mass Large mass with FDG-avid rim and central photopenia consistent with necrosis T3 : >7cm

26. Example: Chest wall invasion T3: > 7 cm or tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main bronchus < 2cm distal to the carina, but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung. Tumors > 7 cm are T3, irrespective of features mentioned above.

27. TNM Staging 7 th Edition: Additional Lung Nodules  Additional nodules in the same lobe as the primary tumor are now T3 (previously T4)  Additional nodules in another ipsilateral lobe are now T4 (previously M1)  Contralateral lung nodules are now M1a (previously M1)

28. Example: Additional nodules in the same lobe Additional nodules in the same lobe as the primary tumor are now T3 (previously T4)

29. TNM Staging System: Regional Lymph Nodes (N) NXRegional lymph nodes cannot be assessed N0No regional lymph node metastasis N1Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of the primary tumor N2Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) N3Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) No Changes in N Staging!

30. Example: Ipsilateral hilar lymph nodes N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of the primary tumor

31. Example: Subcarinal lymphadenopathy N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)

32. Example: Contralateral hilar nodes N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

33. TNM Staging 7 th Edition: Changes in M Staging MXPresence of distant metastasis cannot be assessed M0No distant metastasis M1Distant metastasis present Additional nodules in another ipsilateral lobe are now T4 (previously M1) M1a Contralateral nodules (previously M1) M1a Pleural dissemination (previously T4) M1b Distant metastasis

34. Example: Pleural dissemination Pleural dissemination is now M1a (previously T4)

35. Example: Distant metastasis in the adrenal Distant metastasis is now M1b (previously M1)

36. Example: Distant metastases in liver and adrenal Distant metastasis is now M1b (previously M1)

37. Example: Distant metastasis in bone Distant metastases in the bones are now M1b (previously M1)

38. So now that we have gone step by step through all the changes… Let’s put it all together in one table!

39. 6th vs. 7th ed : Summary of changes 6 th edition T and M descriptors 7 th edition T and M descriptors N0N1N2N3 T1 (<=2 cm)T1aIAIIAIIIAIIIB T1 (>2-3 cm)T1bIAIIAIIIAIIIB T2 (<= 5 cm)T2aIBIIAIIIAIIIB T2 (>5-7 cm)T2bIIAIIBIIIAIIIB T2 (>7 cm)T3IIBIIIA IIIB T3 invasionT3IIBIIIA IIIB T4 same lobe nodulesT3IIBIIIA IIIB T4 invasionT4IIIA IIIB M1 ipsilateral lungT4IIIA IIIB T4 pleural effusionM1aIV M1 contralateral lungM1aIV M1 distantM1bIV * Changes to the staging groups are in red

40. So after all these changes, here’s what the new TNM staging system looks like:

41. The New TNM Staging System Stage GroupsTNM IaT1a,bN0M0 IbT2aN0M0 IIa T1a,b T2a T2b N1 N0 M0 IIb T2b T3 N1 N0 M0 IIIa T1-3 T3 T4 N2 N1 N0,1 M0 IIIb T4 T1-4 N2 N3 M0 IVany M1a,b

42. Conclusions Staging is critical to selecting patient appropriately for surgery and multimodality therapy. PET/CT is important in staging patients with lung cancer and is becoming increasingly popular. Our presentation provides practical insights into the changes to the TNM staging system for lung cancer.

43. Thank you … We hope you enjoy ECR 2010!

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