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RESTAGING AFTER NEOADJUVANT THERAPY

RESTAGING AFTER NEOADJUVANT THERAPY. Prof. Dr. Nezih Özdemir Ankara University School of Medicine Department of Thoracic Surgery 2006. STAGE The most important factor affecting treatment plan and prognosis. Importance of restaging after induction treatment. N2

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RESTAGING AFTER NEOADJUVANT THERAPY

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  1. RESTAGING AFTER NEOADJUVANT THERAPY Prof. Dr. Nezih Özdemir Ankara University School of Medicine Department of Thoracic Surgery 2006

  2. STAGEThe most important factor affecting treatment plan and prognosis

  3. Importance of restaging after induction treatment N2 • The most important prognostic factor • 5 year survival pN0 %35.8 pN1-2 %9 • 3 year survival pN0 %59 pN2 %0 P. Van Schil “The restaging issue” Lung Cancer 2003;42:39-45

  4. Induction Treatment objectives • to improve survival by controlling subclinical metastases • other: • to increase resectability • to reduce the extent of resection

  5. Good prognostic factors after induction therapy: • downstaging • complete pathological response • pN0 • complete resection

  6. Staging patterns • c – clinical • p – pathologic • y – restaging after first treatment • r – staging at the time of recurrence • a – autopsy

  7. cTNM staging methods induction therapy restaging methods assessment of objective response yTNM ChT - RT surgery pTNM

  8. Objective Response • complete response: disappearance of all known disease • partial response: 50% or > decrease • progressive disease: 25% or > increase, or newly appearing lesions • stable disease: no change • progressive after response EORTC, A practical guide to EORTC studies, 1994.

  9. Objective response • ‘It is also clear from these studies (trials on induction therapy) that radiographic assessment of response is relatively inaccurate’. • complete resection rates similar for stable disease and objective responses • stable disease may have complete response Bunn Jr PA. 1994.

  10. TNM classification and staging cTNM / yTNM • based on the evidence acquired before treatment, arising from: • physical examination • imaging • endoscopy • biopsy • surgical exploration

  11. TNM classification and staging • it can be done by clinical, radiological, and invasive techniques • the C-Factor (Certainty Factor) reflects the validity of the classification according to the methods used

  12. Factor Description of staging methods Applicability C1 standard diag. means cTNM, rTNM, and yTNM C2 special diagnostic means(CT, MRI, PET, scintigraphy) C3 invasive staging (biopsy and cytology) C4 definitive surgery and pathological examination pTNM C5 evidence from autopsy aTNM Certainty factor Sobin LH, Wittekind Ch. TNM classification, 1997.

  13. Methods for mediastinal restaging • non-invasive means • computed tomography • magnetic resonance imaging • positron emission tomography • invasive means • remediastinoscopy • video-assisted thoracic surgery • alternativeapproaches • transbronchial biopsy • ultrasound-guided biopsies low sensitivity higher sensitivity, 100% specificity, highest certainty -C3- little experience to date P. Van Schil The restaging issue Lung Cancer 2003;42:39-45

  14. Computed Tomography • Sensitivity 41 – 69 % • Specifity44 – 84 % *** No superiority of MRI on CT !

  15. CT • Clinical and pathologic TNM adaptation 46.6% (Goldstraw) 35.1% (Van Schill) • For N2-3 disease, FP rate 45% (Detterbeck) FN rate 13%

  16. CT • After induction treatment, reasons are nonneoplasic in 40% of patients in whom lymph node progression is seen on CT • CT sensitivity 41 % specifity 75 % accuracy 58 % Rami-Porta et al. Ann Thorac Surg 2000;70:391–5

  17. CT Mistakes • Atelectasis, radiation pneumonia and fibrosis T? • LAP inflammatory ?, micrometastases ? • Because of cell viability decreases more rapidly than tumor volume, CT may show insufficient response to treatment • Evaluation with CT: decrease = partial or complete remission ?

  18. Positron Emission Tomography • SPN • Restaging ? >CT • Can establish the residual disease better in primary tumor than mediastinal lymph nodes • High sens. limited spec. in SUV based analysis • Lower sens. higher spec. for nodal status • Can not distinguish biological alive and methabolic active but still dying cells • Insufficient in determining residual microscopic focuss

  19. Ryu et all. 26 patients / stage III disease sensitivity and specifity (SUV cut-off 3) 88 ve 67% After pathological examination sensitivity 67, specifity 63% Qualitative analysis of LN sensitivity and specifity 58 & 93, diagnostic accuracy 85% • Memorial Sloan–Kettering 56 LASLC patients retrospective sensitivity and specifity 90 & 67% for residual N disease, sensitivity and specifity 67 & 61% • FDG-PET is more successful for determining recurrences after curative treatment (after high dose RT specifity decreases) • Ryu JS. et al. FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology. Lung Cancer 35(2):179-187, 2002 • Akhurst T, Downey RJ, Ginsberg MS. An initial experience with FDG-PET in the imaging of residual disease after induction therapy for lung cancer. Ann Thorac Surg 73:259-266, 2002

  20. 47 NSCLC patients 1998/2003 • 16 cases mediastinoscopy / all patients ChT + 33 cases RT • yTNM (CT) 3 CR, 35 PR, 9 stable disease • FDG-PET 5 weeks after the ending of induction treatment • 37 patients resection and systematic LND • FDG-PET found 9 cases of unsuspected M1 disease • 1 FN brain metastasis fixed on CT later • Sensitivity 81% specifity 64% diagnostic accuracy 76% PPV 84% NPV 58% Hellwig D. et al. Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma J Thorac Cardiovasc Surg 2004;128:892-9

  21. FP results after RT FN results related to small tumors and BAC • The role of PET is not clear for restaging • Especially for N status, more studies are needed • An important feature of PET is exposing the newly developed or old but, couldn’t be determined by conventional methods before, distant metastases • FDG uptake can be used as a prognostic indicator in initial application, early period after chemotheraphy, during RT or after curative treatment Hellwig D. et al. Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma J Thorac Cardiovasc Surg 2004;128:892-9

  22. Hellwig D. et al. Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma J Thorac Cardiovasc Surg 2004;128:892-9

  23. 25 patients, 2 different phase II study groups • 19 patients staged with mediastinoscopy • PET performed to all patients before and after induction therapy + surgical resection • PPV and NPV 43 & 100% whom major pathologic response observed in primary tumor • Could not show nodal status correctly 52% of cases • For LN (+) cases PPV and NPV 73 & 64% • For N2 disease PPV ‹%20 • For pN2 sens. and spec. 20 & 70%, PPV-NPV-diag. accuracy 14-77-60% • Accuracy of CT for nodal disease after treatment 56% • PET is insufficient in restaging after induction, for both T and N Port JL. et al. Positron Emission Tomography Scanning Poorly Predicts Response to Preoperative Chemotherapy in Non-Small Cell Lung Cancer Ann Thorac Surg 2004;77:254 –9

  24. Comparison of PET and pathologic stages for nodal disease • PET stage Pathologic stages N0 N1 N2 • N0 (14) 9 3 2 • N1 (4) 0 2 2 • N2 (6) 3 2 1 • N3 (1) 0 1 0 • 25 12 8 5 Port JL. et al. Positron Emission Tomography Scanning Poorly Predicts Response to Preoperative Chemotherapy in Non-Small Cell Lung Cancer Ann Thorac Surg 2004;77:254 –9

  25. 3 studies investigating the value of PET after induction therapy • For restaging of T, PET sensitivity 90, 88, ve 97 % • For residual nodal disease sensitivity 71% and specifity 88% • Although overall sensitivity for residual nodal disease 50%, for paratracheal LN 100% but hilar LN 15% • Specifity is better when the induction includes only ChT / FP results are more frequent for the reason of induced inflamation due to RT • Today; invasive techniques like EUS-NAB or remediastinoscopy should continue for mediastinal restaging and, role of PET should be guidance as well as in the initial staging Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Positron-emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review Lancet Oncol2004; 5: 531–40

  26. Candidates for surgical resection INVASIVE STAGING

  27. Invasivestaging • Does not totally eliminate nodal disease but, • Prevent unnecessary thoracotomies • Obtain high complete resection rates • Select neoadjuvantchemotherapy indicated cases (extracapsular spread, N3 disease) • Seperate downstaged or showing progression cases after induction treatment

  28. Invasive methods Method Sensitivity% Specifity% FP% FN% Patient population • Mediastinoscopy 81 100 0 9 clinical N0–2 • Mediastinostomy 87 100 0 15 clinical N0–2 • TTNA 91 100 0 22 clinical N2 • EUS-FNAB 88 91 2 23 clinical N2 • TBNAB 76 96 0 29 clinical N2 Detterbeck et al. CHEST 2003; 123:167S–175

  29. Bronchoscopy/TBNAB • T description -Lobe bronchus -Carina -Trachea • TBNAB -mediastinal LAP on CT (Subcarinal) -Sensitivity %76 -Specifity %96 -FN %30 • If CT/flouroscopy assisted, sensitivity arises to 86-100% and specifity 100% (Toloza EM et al. Chest 2003;123:157S-166S)

  30. Remediastinoscopy indications • incomplete first mediastinoscopy • delayed treatment • second primary tumours • recurrent tumours • assessment of response after induction treatment First report: Palva T et al. Arch Otolaryngol 1975; 101:748-50.

  31. Restaging & treatment protocol mediastinoscopy: N2-N3?disease inductionchemoradiotherapy response/stabledisease remediastinoscopy No mediastinal involvement persistent N2 or N3 disease thoracotomy radiotherapy

  32. Rami Porta 2004 • Jan 1994- April 2002 • 43 NSCLC patients • 41 N2 • 2 N3 • Induction therapy • ChT: 37 • ChT&RT: 6

  33. Remediastinoscopy results • persistent N2 disease: 20 • New N3 disease: 1 • No nodal disease: 22 True (+) RT thoracotomy

  34. Thoracotomy results • resection: 21/22 (%95.4) • systematic nodal dissection • N0: 13 • N1: 3 • N2: 6 True (-) False (-)

  35. Remediastinoscopy Staging value CT sensitivity-specifity-accuracy 41-75-58 %

  36. Remediastinoscopy Staging value

  37. Conclusion Restaging • Usually done by CT and PET • important to assess objective response • should be aimed to identify patients who will benefit from lung resection • to rule out persistent N2-N3 disease • invasive techniques offer the highest classification certainty

  38. Conclusion Remediastinoscopy • technically feasible • has low morbidity • has high accuracy • best method to identify patients who will benefit from lung resection • should be performed routinely when there is no evidence of progressive disease

  39. Stamatis et all. • 279 lung cancer cases --- remediastinoscopy • Incomplete first procedure, recurrence, second primary tumor • 165 cases after induction ChT/RT (116 N2–49 N3) • Interval between two mediastinoscopies 132 days • No mortality, 7 minor complications, 5 patients unsuccessful • 126 N0, 20 N2, 14 N3 • Persistent N2 + surgery ---- 5 year survival 5% • FP rate related to PET 18.8% Ann Thorac Surg 1999;68:1144-9 / Pneumologie 2005 59(12):862-6

  40. After induction therapy, remediast. 32 patients • 26 ChT, 6 ChT/RT ---- complication (-) • 12 (+) and RT, 20 (-) and thoracotomy • RM --- sens, spec ve accuracy 71, 100 and 84% • Median survival + RM 7 months - RM 41 months FN RM 24 months • Only nodal disease significant prognostic factor • Diagnostic accuracy is lower compared with initial mediastinoscopy but, for persistent N2 most valuable method Van Schil P. Nodal status at repeat mediastinoscopy determines survival in non-small cell lung cancer with mediastinal nodal involvement, treated by induction therapy Eur J Card Thorac Surg 2006; 29:240-3

  41. 1988-1996, 103 stage IIIA (N2) NSCLC patients, all invasive staged and received induction therapy • 76 ChT, 18 RT, 9 ChT&RT • All restaged with CT • Anatomic resection + radical lymphadenectomy performed to all • Complete pathologic response (T0N0) 4 cases 29 N0, 25 N1 (downstaging) --- 49 persistent N2 • 74 adjuvant treatment (RT - 58) • 5 year survival for all patients 17.5%, N0 35.8%, N1-2 9% (No statistical difference between N1 and N2) • To identify patients downstaged and will benefit from surgery, re-invasive staging (VATS, remediastinoscopy, TBNAB or endoscopic USG-NAB) is needed Bueno R, Sugarbaker DJ. et al. Ann Thorac Surg 2000;70:1826 –31

  42. 1996-1999, 36 NSCLC patients, N2 (+) with mediastinoscopy* restaging with CT* nonsurgical group medium survival 8 months* surgical group 3 year survival “downstaged” group 59 % persistent N2 0 % Voltolini L. et al. Results of induction chemotherapy followed by surgical resection in patients with stage IIIA (N2) non-small cell lung cancer: the importance of the nodal down-staging after chemotherapy European Journal of Cardio-thoracic Surgery 2001; 20:1106–12

  43. EUS-FNAB 89-95% accuracy • Multiple advantages: tissue samples taken, minimally invasive and multiple repetitions if wanted • 19 invasively staged N2 patients • Not taken into consideration for firstly positive lymph nodes were which stations • Taken biopsies from accessible all lymph nodes with guidance of “real time USG” by 22G fine needles • All materials “on-site” determined Jouke T. Annema et al. Mediastinal restaging: EUS-FNA offers a new perspective Lung Cancer (2003) 42, 311-18

  44. Procedure lasted on average 20 mins and no complications occured • 8 cases persistent N2, sonography suspected but could not be biopsied one case confirmed by mediastinotomy (4R) • PPV, NPV, sensitivity, specifity and diag. accuracy 100, 67, 75, 100 83 • Because of air in the trachea and main bronchi obscuring visualisation, procedure has limitations at paratracheal stations (2L, 2R & 4R) • But 4L, 5, 7, 8 and 9 can be reached (not accessible with mdstcopy) • Only contraindication esophageal stricture • A major advantage is the real-time controlled biopsy where the tip of the needle is visible during the complete biopsy procedure.With the current technique it has not been possible to perform EBUS guided TBNA • Diagnostic accuracy of this study is near remediastinoscopy Jouke T. Annema et al. Mediastinal restaging: EUS-FNA offers a new perspective Lung Cancer (2003) 42, 311-18

  45. Jouke T. Annema et al. Mediastinal restaging: EUS-FNA offers a new perspective Lung Cancer (2003) 42, 311-18 EUS-FNAB results Final stage pN2 pN0 Total pN2 9 3 12 pN0 0 6 6 Total 9 9 18

  46. RESULT Progress RT Partial response/stable disease Invasive staging (-) PET ± Resection

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