1. Rome, May 15-16, 2009 Enrico Cortesi, Martina Puglisi “Sapienza”, Università di Roma

2. Which rate of patients with Malignant Pleural Effusion (MPE) experiences reaccumulation of fluid within 30 days after thoracentesis? 28 / 30 Cross-tab label 1.30-40% 2.80-90% 3.95-100% 4.10-20% 5.0%

3. In which cases should pleurodesis be considered as a valid therapeutic option? 1.Adeguate PS and patient’s life expectancy (eg longer than 3 months) 2.Patient’s dyspnea improved after therapeutic thoracentesis 3.The underlying tumor and resulting Malignant Pleural Effusion are not responsive to chemotherapy or radiotherapy 4.All the answers above 5.None of the answers above 1.Adeguate PS and patient’s life expectancy (eg longer than 3 months) 2.Patient’s dyspnea improved after therapeutic thoracentesis 3.The underlying tumor and resulting Malignant Pleural Effusion are not responsive to chemotherapy or radiotherapy 4.All the answers above 5.None of the answers above 29 / 30 Cross-tab label

4. The presence of Malignant Pleural Effusion is required to stage a NSCLC as : 1.Stage III B 2.Stage III A 3.Stage IV 4.It is not arleady established 5.Malignant Pleural Effusion is not considered for staging 1.Stage III B 2.Stage III A 3.Stage IV 4.It is not arleady established 5.Malignant Pleural Effusion is not considered for staging 29 / 30 Cross-tab label

5. Malignant Pleural Effusion (M.P.E.) “An M.P.E. is defined by the presence of cancer cells in the pleural space ”

6. Malignant Pleural Effusion (M.P.E.) “An M.P.E. is defined by the presence of cancer cells in the pleural space ” Underlying Primary Cancer 1.Lung tumors (including malignant pleural mesothelioma)  NSCLC: 14% at the time of diagnosis, 50% with advanced disease 2. Breast cancer 3. Ovarian cancer, gastric cancer 4. Hodgkin’s and non-Hodgkin’s lymphoma

7. Malignant Pleural Effusion (M.P.E.) “An M.P.E. is defined by the presence of cancer cells in the pleural space ” Cancer cells reach the visceral pleura (through the pulmonary vasculature)or the parietal pleura (through hematogenous spread Cancer cells reach the visceral pleura (through the pulmonary vasculature)or the parietal pleura (through hematogenous spread) Cancer cells in the pleural space (tumor deposit along parietal pleura) A. Obstruct lymphatic stromata (which drain intrapleural fluid) B. Release chemockines ( increasing vascular permeability)

8. Malignant Pleural Effusion (M.P.E.) ≠ ≠≠ ≠ Paramalignant Effusion Paramalignant Effusion 1. Mediastinal lymph node tumor infiltration 2. Bronchial obstruction/Atelectasis 3. Pulmonary embolism 4. “Superior vena cava syndrome” 5. Decreased oncotic pressure (cachexia) 6. Radiotherapy/Chemotherapy

9. Malignant Plural Effusion AndDiagnosis

10. M.P.E. and Diagnosis Cytologic or tissue biopsy confirmation is required to establish a diagnosis of MPE

11. M.P.E. and Diagnosis Cytologic or tissue biopsy confirmation is required to establish a diagnosis of MPE Diagnostic thoracentesis: Diagnostic yield of PF cytology ranging from 62 to 90% Diagnostic yield of PF cytology ranging from 62 to 90% Positive results on cytology might not differentiate Positive results on cytology might not differentiate between adk subtypes or between pleural adk and between adk subtypes or between pleural adk and mesothelioma mesothelioma Additional PF studies could complement standard Additional PF studies could complement standard cytology: Electrochetoluminescence for tumor markers, cytology: Electrochetoluminescence for tumor markers, genetic analysis genetic analysis

12. M.P.E. and Diagnosis Cytologic or tissue biopsy confirmation is required to establish a diagnosis of MPE Diagnostic thoracentesis, if cytology not diagnostic:

13. M.P.E. and Diagnosis Cytologic or tissue biopsy confirmation is required to establish a diagnosis of MPE Diagnostic thoracentesis, if cytology not diagnostic: Pleural Biopsy: Closed-needle pleural biopsy (sensitivity of 40-75%) Closed-needle pleural biopsy (sensitivity of 40-75%) Ultrasonography or chest CT-guided percutaneous Ultrasonography or chest CT-guided percutaneous pleural biopsy (higher sensitivities and specificities) pleural biopsy (higher sensitivities and specificities) Medical thoracoscopy, or Video Assisted Thoracoscopic Surgery (VATS)

14. M.P.E. and Diagnosis Is diagnosis with cytology or histology always requested (and useful) in our clinical practice?

15. M.P.E. and Diagnosis Does the presence of M.P.E. add prognostic and therapeutic informations?

16. M.P.E. and Diagnosis Non Small Cell Lung Cancer Does the presence of M.P.E. add prognostic and therapeutic informations?

17. M.P.E. and Diagnosis Non Small Cell Lung Cancer Poor PS Poor PS Known advanced cancer Known advanced cancer DIAGNOSIS NOT NECESSARY

18. M.P.E. and Diagnosis Non Small Cell Lung Cancer Poor PS Poor PS Known advanced cancer Known advanced cancer DIAGNOSIS NOT NECESSARY Good PS Good PS multimodality treatment multimodality treatment DIAGNOSIS IS CRITICAL FOR TREATMENT PLANNING

19. NSCLC with M.P.E: Prognosis Patients with M.P.E. (without other metastatic disease) had a Patients with M.P.E. (without other metastatic disease) had a median OS of 8 months median OS of 8 months Versus 13 months of other cT4 M0 Versus 13 months of other cT4 M0 Versus 6 months of patients with distant metastases Versus 6 months of patients with distant metastases Postmus, JTO 2007

20. NSCLC with M.P.E: Prognosis Goldstraw, JTO 2007 TNM staging Six Edition: T4 (Stage III B) TNM staging Seventh Edition: M1 a (Stage IV)

21. NSCLC with M.P.E: Prognosis Goldstraw, JTO 2007 TNM staging Six Edition: T4 (Stage III B) TNM staging Seventh Edition: M1 a (Stage IV) If P.E. is cytologically negative. and is evaluated as not related to the tumor by clinical judgment, patient should be classified as T1, T2, T3, T4.

22. Malignant Pleural Effusion AndTreatment

23. M.P.E. and Treatment 1) THERAPEUTIC THORACENTESIS 2) PLEURODESIS

24. M.P.E. and Treatment Management of MPE is palliative... 1) THERAPEUTIC THORACENTESIS 2) PLEURODESIS

25. M.P.E. and Treatment When to proceed with treatment of Pleural Effusion?

26. M.P.E. and Treatment When to proceed with treatment of Pleural Effusion? Patient is symptomatic Patient is symptomatic (for dyspnea or cough or chest pain), and (for dyspnea or cough or chest pain), and symptoms are considered to be caused from symptoms are considered to be caused from pleural effusion. pleural effusion. Patient is not suitable for specific cancer Patient is not suitable for specific cancer treatment (eg. chemotherapy), or Pleural treatment (eg. chemotherapy), or Pleural Effusion is resistant to specific cancer treatment. Effusion is resistant to specific cancer treatment.

27. M.P.E. and Treatment Is patient symptomatic?

28. M.P.E. and Treatment Is patient symptomatic? No intervention No

29. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis

30. M.P.E. and Treatment THERAPEUTIC THORACENTESIS Symptoms can improve after thoracentesis Symptoms can improve after thoracentesis But 98% to 100% of patients experience But 98% to 100% of patients experience reaccumulation of fluid and recurrence of reaccumulation of fluid and recurrence of symptoms within 30 days symptoms within 30 days

31. M.P.E. and Treatment THERAPEUTIC THORACENTESIS Symptoms can improve after thoracentesis Symptoms can improve after thoracentesis But 98% to 100% of patients experience But 98% to 100% of patients experience reaccumulation of fluid and recurrence of reaccumulation of fluid and recurrence of symptoms within 30 days symptoms within 30 days Repeated THORACENTESES THORACENTESES PLEURODESIS

32. M.P.E. and Treatment THERAPEUTIC THORACENTESIS Symptoms can improve after thoracentesis Symptoms can improve after thoracentesis But 98% to 100% of patients experience But 98% to 100% of patients experience reaccumulation of fluid and recurrence of reaccumulation of fluid and recurrence of symptoms within 30 days symptoms within 30 days Repeated THORACENTESES THORACENTESES PLEURODESIS

33. M.P.E. and Treatment PLEURODESIS Selection of patients should be based on:. Selection of patients should be based on:. Patient’s characteristics Tumor’s characteristics 1 2

34. M.P.E. and Treatment PLEURODESIS Selection of patients should be based on:. Selection of patients should be based on:. Patient characteristics Tumor characteristics 1 2 “Does the patient’s life expectancy warrant pleurodesis?” * (PS has the most value) * 32% of p. do not survive 30 days after pleurodesis

35. M.P.E. and Treatment PLEURODESIS Selection of patients should be based on:. Selection of patients should be based on:. Patient characteristics Tumor characteristics 1 2 “Does the patient’s life expectancy warrant pleurodesis?” * (PS has the most value) * 32% of p. do not survive 30 days after pleurodesis

36. M.P.E. and Treatment PLEURODESIS Pleural Effusion is unlikely to respond to pleurodesis if: There is an airway obstruction from an There is an airway obstruction from an endobronchial tumor (the lung does not expand endobronchial tumor (the lung does not expand to the chest wall after therapeutic thoracentesis) to the chest wall after therapeutic thoracentesis) Effusion is multiloculated Effusion is multiloculated There are large tumor masses along pleural surfaces There are large tumor masses along pleural surfaces

37. M.P.E. and Treatment PLEURODESIS Chest-catheter Pleurodesis Thoracoscopic Pleurodesis TALC is considered a superior pleurodesis agent when compared with other commonly used sclerosant (as Bleomycin or tetracycline) Cochrane Review, 2004 Cochrane Review, 2004

38. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis

39. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis Improvement in symptoms?

40. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis Improvement in symptoms? No

41. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis Improvement in symptoms? No Adequate Re-expansion? Yes

42. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis Improvement in symptoms? No Adequate Re-expansion? Good PS? Yes Yes

43. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis Improvement in symptoms? No Adequate Re-expansion? Good PS? Yes Yes Pleurodesis Yes

44. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis Improvement in symptoms? No Adequate Re-expansion? Good PS? Yes Yes Pleurodesis No Yes

45. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis Improvement in symptoms? No Adequate Re-expansion? Good PS? Yes Yes Pleurodesis No No Yes

46. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis Improvement in symptoms? No Adequate Re-expansion? Good PS? Yes Yes Repeated Thoracentesis Pleural Catheter Pleurodesis No No Yes

47. M.P.E. and Treatment Repeated THORACENTESES THORACENTESES Should be reserved for patients who: Should be reserved for patients who: (1) Appear unlikely to survive beyond 1 to 3 months (2) Cannot tolerate other more interventional procedures to control pleural fluid, such as pleurodesis. procedures to control pleural fluid, such as pleurodesis. (3) Have a PE that does not respond to pleurodesis

48. M.P.E. and Treatment Repeated THORACENTESES THORACENTESES Should be reserved for patients who: Should be reserved for patients who: (1) Appear unlikely to survive beyond 1 to 3 months (2) Cannot tolerate other more interventional procedures to control pleural fluid, such as pleurodesis. procedures to control pleural fluid, such as pleurodesis. (3) Have a PE that does not respond to pleurodesis (4) Have cancers that commonly respond to therapy with resolution of the associated effusions with resolution of the associated effusions...OR...

49. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis Improvement in symptoms? No Adequate Re-expansion? Good PS? Yes Yes Repeated Thoracentesis Pleural Catheter Pleurodesis No No Yes

50. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis Is tumor likely to respond to chemotherapy? Improvement in symptoms? No Adequate Re-expansion? Good PS? Yes Yes Repeated Thoracentesis Pleural Catheter Pleurodesis No No Yes

51. SCLC M.P.E. and Treatment Is tumor likely to respond to chemotherapy ? SCLC is an aggressive disease associated with early  SCLC is an aggressive disease associated with early loco-regional and distant metastases  Extensive Stage (ED- loco-regional and distant metastases  Extensive Stage (ED- SCLC) is present at diagnosis in more than 60%–70% of cases SCLC) is present at diagnosis in more than 60%–70% of cases [median OS of 9 months] [median OS of 9 months]  Highly sensitive to both chemotherapy and RT  Platinum/Etoposide regimens are usually associated with a rapid Platinum/Etoposide regimens are usually associated with a rapid objective response in 50% to 80% of patients with ED-SCLC objective response in 50% to 80% of patients with ED-SCLC  Patients who not respond to initial chemotherapy (“Refractory disease”) have a worse prognosis, with an expected median survival of 2-3 months

52. SCLC M.P.E. and Treatment Is tumor likely to respond to chemotherapy ? SCLC is an aggressive disease associated with early  SCLC is an aggressive disease associated with early loco-regional and distant metastases  Extensive Stage (ED- loco-regional and distant metastases  Extensive Stage (ED- SCLC) is present at diagnosis in more than 60%–70% of cases SCLC) is present at diagnosis in more than 60%–70% of cases [median OS of 9 months] [median OS of 9 months]  Highly sensitive to both chemotherapy and RT  Platino/Etoposide regimens are usually associated with a rapid Platino/Etoposide regimens are usually associated with a rapid objective response in 50% to 80% of patients with ED-SCLC objective response in 50% to 80% of patients with ED-SCLC  Patients who not respond to initial chemotherapy (“Refractory disease”) have a worse prognosis, with an expected median survival of 2-3 months SCLC patients can occasionally be palliated with only 1 thoracentesis

53. M.P.E. and Treatment SCLC About 30% of SCLC patients present with Limited Stage disease  About 30% of SCLC patients present with Limited Stage disease  80–90% of these respond to combination chemotherapy, with or  80–90% of these respond to combination chemotherapy, with or without thoracic radiation, and 40%–70% achieve complete without thoracic radiation, and 40%–70% achieve complete remission. remission. [median OS of 12–20 months, 5-year survival of 5–10%] [median OS of 12–20 months, 5-year survival of 5–10%]  LD-SCLC with ipsilateral pleural effusion accounted for 9% of all the patients with SCLC and 17% of all the patients with LD –SCLC the patients with SCLC and 17% of all the patients with LD –SCLC

54. M.P.E. and Treatment SCLC About 30% of SCLC patients present with Limited Stage disease  About 30% of SCLC patients present with Limited Stage disease  80–90% of these respond to combination chemotherapy, with or  80–90% of these respond to combination chemotherapy, with or without thoracic radiation, and 40%–70% achieve complete without thoracic radiation, and 40%–70% achieve complete remission. remission. [median OS of 12–20 months, 5-year survival of 5–10%] [median OS of 12–20 months, 5-year survival of 5–10%]  LD-SCLC with ipsilateral pleural effusion accounted for 9% of all the patients with SCLC and 17% of all the patients with LD –SCLC the patients with SCLC and 17% of all the patients with LD –SCLC WhichTreatment? WhichStaging?

55. M.P.E. and Treatment SCLC LD-SCLC with pleural effusion...Which staging? LD-SCLC with pleural effusion... Which staging?

56. 1989, IALSC classification LIMITED STAGE: “ disease confined to the ipsilateral hemithorax, which can be encompassed within a tolerable radiation field” Loco-regional extension Loco-regional extension Ipsilateral supraclavicular Ipsilateral supraclavicular nodes nodes LIMITED STAGE: Ipsilateral and controlateral Ipsilateral and controlateral hilar nodes hilar nodes Ipsilateral and controlateral Ipsilateral and controlateral mediastinal nodes mediastinal nodes Ipsilateral and controlateral Ipsilateral and controlateral supraclavicular nodes supraclavicular nodes Ipsilateral pleural effusion Ipsilateral pleural effusion regardless of the cytology regardless of the cytology M.P.E. and Treatment SCLC 1957, VALG classification LD-SCLC with pleural effusion...Which staging? LD-SCLC with pleural effusion... Which staging?

57. Retrospective study to compare the prognostic impact of the two staging systems (VALG vs IASLC)  e.g. Pleural effusion Micke,2002 M.P.E. and Treatment SCLC LD-SCLC with pleural effusion...Which staging? LD-SCLC with pleural effusion... Which staging?

58. Patients treated for bronchogenic carcinoma from 1990 to 2000 were registered in the IASLC database: 13,032 SCLC  12,620 elegible  8088 with clinical TNM The revised UICC/AJCC staging system: Implication for SCLC Survival analyses were performed Aim: Looking to the impact of the TNM system on the clinical staging of SCLC Pleural effusion and Staging

59. LD-SCLC with pleural effusion...Which staging? LD-SCLC with pleural effusion... Which staging? SCLC The revised UICC/AJCC staging system: The survival of patients with LD with effusion is intermediate between those of patients with LD without effusion and patients with ED. (p value 0.0001) Result of cytologic examination of PE (available for only 68 patients): The survival of patients with LD with effusion, whether cytologically negative or positive, remained intermediate Shepherd, 2007 M.P.E. and Treatment

60. SCLC LD-SCLC with pleural effusion...Which treatment? LD-SCLC with pleural effusion... Which treatment?

61.  The indication for definitive TRT in patients with LD-SCLC and ipsilateral pleural effusion with LD-SCLC and ipsilateral pleural effusion have not been thoroughly investigated have not been thoroughly investigated  Definitive TRT is contraindicated in patients with malignant pleural effusion with malignant pleural effusion M.P.E. and Treatment SCLC LD-SCLC with pleural effusion...Which treatment? LD-SCLC with pleural effusion... Which treatment?

62. M.P.E. and Treatment SCLC LD-SCLC with pleural effusion...Which treatment? LD-SCLC with pleural effusion... Which treatment?

63. 26 pz: CT + TRT 8 pz: Did not receive TRT in spite of the disappearance of pleural effusion after I-line CT 28 pz: Did not receive TRT, and pleural effusion persisted after I-line CT 3: TRT concurrently 3: TRT concurrently with I course with I course 10: TRT concurrently 10: TRT concurrently with II or III or with II or III or IV course IV course 13: TRT sequentially 13: TRT sequentially Niho, J Thorac Oncol 2008 M.P.E. and Treatment SCLC 62 LD-SCLC with ipsilateral pleural effusion (citologically negative and positive) Retrospectivestudy

64. Pleural effusion and Treatment Niho, J Thorac Oncol 2008 SCLC long-term survival was achieved by LD-SCLC patients who underwent definitive TRT after their ipsilateral pleural effusion disappeared after induction CT TRT after their ipsilateral pleural effusion disappeared after induction CT. 62 LD-SCLC with ipsilateral pleural effusion (citologically negative and positive) Retrospectivestudy

65. M.P.E. and Treatment Is patient symptomatic? No intervention Yes No Therapeutic Thoracentesis Is tumor likely to respond to chemotherapy? Improvement in symptoms? No Adequate Re-expansion? Good PS? Yes Yes Repeated Thoracentesis Pleural Catheter Pleurodesis No No Yes

66. Which rate of patients with Malignant Pleural Effusion (MPE) experiences reaccumulation of fluid within 30 days after thoracentesis? 0 / 0 Cross-tab label 1.30-40% 2.80-90% 3.95-100% 4.10-20% 5.0%

67. In which cases should pleurodesis be considered as a valid therapeutic option? 1.Adeguate PS and patient’s life expectancy (eg longer than 3 months) 2.Patient’s dyspnea improved after therapeutic thoracentesis 3.The underlying tumor and resulting Malignant Pleural Effusion are not responsive to chemotherapy or radiotherapy 4.All the answers above 5.None of the answers above 1.Adeguate PS and patient’s life expectancy (eg longer than 3 months) 2.Patient’s dyspnea improved after therapeutic thoracentesis 3.The underlying tumor and resulting Malignant Pleural Effusion are not responsive to chemotherapy or radiotherapy 4.All the answers above 5.None of the answers above 0 / 0 Cross-tab label

68. The presence of Malignant Pleural Effusion is required to stage a NSCLC as : 1.Stage III B 2.Stage III A 3.Stage IV 4.It is not arleady established 5.Malignant Pleural Effusion is not considered for staging 1.Stage III B 2.Stage III A 3.Stage IV 4.It is not arleady established 5.Malignant Pleural Effusion is not considered for staging 0 / 0 Cross-tab label