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Standards for neoadjuvant Treatment

Pneumology. Istanbul, 7. 5. 2010. Standards for neoadjuvant Treatment. Rudolf M. Huber. University of Munich. Neoadjuvant chemotherapy. Istanbul, 7. 5. 2010. ‘‘ Neoadjuvant ’’ chemotherapy means treatment given prior to surgery Rationale:

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Standards for neoadjuvant Treatment

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  1. Pneumology Istanbul, 7. 5. 2010 Standards for neoadjuvant Treatment Rudolf M. Huber University of Munich

  2. Neoadjuvant chemotherapy Istanbul, 7. 5. 2010 • ‘‘Neoadjuvant’’ chemotherapy means treatment given prior to surgery • Rationale: • shrink the tumour to facilitate and simplify surgery • treat occult micrometastases • inhibit tumour growth factor release during surgery • Does not intend to make an inoperable tumour operable (“downstaging chemo-therapy”) Huber

  3. Expected Outcome After Surgical Resection in Operable NSCLC Pisters and Le Chevalier. J Clin Oncol. 2005;23:3270-3278 Huber

  4. N2 Subgroups and survivalResected NSCLC André F ea. JCO 18 (2000) N = 562 Huber

  5. Accuracy of stagingNSCLC – N2 disease Weder W. Ann Oncol 19 (Supplement 7): vii28–vii30, 2008 Huber Huber

  6. IIIA1 incidental nodal metastases found on final surgical pathology IIIA2single nodal metastasis, recognized intraoperatively IIIA3Mediastinal nodal metastases, detected preoperatively by mediastinoscopy or PET IIIA4„Bulky“, multi-station NSCLC:IIIAN2– subsets Adapted from ACCP Guideline. Chest 2003 Huber

  7. NSCLC Stage III Treatment Modalities Surgery Surgery + Chemo Surgery + RT Tri-modality Chemotherapy RT Chemo + RT Balance between local and systemic control Huber

  8. CT effect & stage CT may be detrimental for stage IA, but stage IA patients were generally not given the potentially best combination cisplatin + vinorelbine (13% of stage IA patients versus ~43% for other stages) META LA CE Huber

  9. NSCLC Stage IIIACT + OP (+ RT) vs. OP (+ RT) DesignPat.pN2Survival (median) Passet al.2 x PE - OP - 4 x PE 27 27 29 1992 OP - RT 16p = 0.1 Rothet al.3 x PEC - OP - (3 x PEC) 60 54 64 1994 OP 11 p = 0.008 Rosellet al. 3 x MIC - OP - RT 60 44 26 1994 OP - RT 8 p = 0.001 Huber

  10. Neoadjuvant Chemotherapy – French Trial Depierre A ea. J Clin Oncol; 20:247-253 2002 • Randomized trial comparing perioperative chemotherapy (PCT) to primary surgery (PRS): • Preoperative CT: two cycles of mitomycin (6 mg/m2, d 1), ifosfamide (1.5 g/m2, d 1 to 3) and cisplatin (30 mg/m2, d 1 to 3) • Postoperative CT (responders): two additional cycles • Thoracic radiotherapy for all pT3 or pN2 pts • Benefit confined to N0 to N1 disease (RR 0.68; 95% CI, .49 to .96; P = .027) Huber

  11. Neoadjuvant Chemotherapy – French Trial Overall survival by treatment arm: arm A, PRS; arm B, PCT + surgery Depierre A ea. J Clin Oncol; 20:247-253 2002 Huber

  12. Neoadjuvant Chemotherapy – French Trial Overall survival by treatment arm and by nodal status Depierre A ea. J Clin Oncol; 20:247-253 2002 Huber

  13. Operable NSCLC: Neoadjuvant CT– MRC LU22/NVALT2/EORTC08012 Gilligan D ea. Lancet 2007; 369: 1929–37 Huber

  14. PFS OS Operable NSCLC: Neoadjuvant CT MRC LU22/NVALT2/ EORTC08012 CT … 3 cycles of platinum based chemotherapy Gilligan D ea. Lancet 2007; 369: 1929–37 Huber

  15. Operable NSCLC Neoadjuvant Chemotherapy Test for heterogeneity: Chi-squared 3.04, 7 degrees of freedom, p=0.88, I2=0%. Test for overall effect: Z=1.78, p=0.07. Gilligan D ea. Lancet 2007; 369: 1929–37 Huber

  16. Stage IB - IIIA NSCLC n = 353 (of planned 600) R Arm A: C + S (+RT) Arm B: S S9900: A phase III trial of surgery alone or surgery plus preoperative paclitaxel/ carboplatin (PC) in early stage NSCLC • P:225 mg/m2 in 3 hours, C:AUC=6 • 3 cycles, q 3 weeks • PS 0-1, postop. FEV1≥1 L Pisters K ea. ASCO 2005, LBA7012 Huber

  17. Neoadjuvant Chemotherapy S9900 Overall survival by treatment arm (median follow-up, 64 months)‏ Pisters KMW ea. J Clin Oncol; 28:1843-1849 2010 Huber

  18. NATCH – Stages at Surgery, Survival Felip E ea. ASCO 2009 Abstract # 7500, mod. from Wakelee H, discussion Huber Huber

  19. Stage IIIA-N2 NSCLC PS 0-1 n = 396 R Arm A: CT/RT (45 Gy) + S + CT Arm B: CT/RT (61 Gy) +CT Neoadjuvant Chemotherapy - Operable: surgery vs. no surgery • CT: Cisplatin 50 mg/m2 d1,8; Etoposid 50 mg/m2 d1-5 • TRD: 6,9% (14) arm A vs. 1,6% (3) Arm B North American Intergroup 0139 (RTOG 9309) K. Albain et al. Proc Am Soc ClinOncol 2003;22:2497(abstr) und 2005 abstr. 7014 Albain KS ea. Lancet 2009; 374: 379–86 Huber

  20. North American Intergroup 0139(RTOG 9309) * albumin was ≥ 85% of the normal value with <10% weight loss within 3 months Mod. from K. Albain ea. Proc Am Soc ClinOncol 2005 abstr. 7014 Huber

  21. North American Intergroup 0139 (RTOG 9309) The primary endpoint was overall survival K. Albain et al. Proc Am Soc ClinOncol 2005 abstr. 7014 Huber

  22. North American Intergroup 0139 (RTOG 9309) The primary endpoint was overall survival Overall survival Albain KS ea. Lancet 2009; 374: 379–86

  23. North American Intergroup 0139 (RTOG 9309) Overall survival pneumonectomy subset of post-pneumonectomy patients from the intention-to-treat population in group 1 vs. matched cohort in group 2 Albain KS ea. Lancet 2009; 374: 379–86 Huber

  24. Stage IIIA-N2 NSCLC Induction chemotherapy n = 572 R Arm A: S (+RT) Arm B: RT Radical surgery vs. thoracic radiotherapy in IIIA-N2 NSCLC after response to induction chemotherapy(EORTC 08941) • 3 cycles of platinum-based chemotherapy • Response  randomisation • In the radiotherapy arm at least 60 Gy + 40 Gy to the mediastinum van Meerbeeck JP ea. ASCO 2005, LBA7015 J. Natl. Cancer Inst. 2007 99:442-450; doi:10.1093/jnci/djk093 Huber

  25. Radical surgery vs. thoracic radiotherapy in IIIA-N2 NSCLC after response to induction chemotherapy (EORTC 08941) • 572 patients induction chemotherapy, 61,5 % response • Radical resection 51 %, mortality 4 % (pneum-ectomy!) • Median, 2- and 5-year OS: surgery vs. TRT 16.4 vs.17.5 months, 35 vs. 41% and 16 vs. 13% • Median and 2-year PFS are 9.0 vs.11.4 months and 27 vs. 24%, (p= 0.6) •  no advantage from surgery van Meerbeeck JP ea. ASCO 2005, LBA7015 Huber

  26. Resection Vs Radiotherapy After Induction Chemotherapy in Stage IIIA-N2 NSCLC Overall survival rates estimated from time of randomization van Meerbeeck JP ea. J. Natl. Cancer Inst. 2007 99:442-450; doi:10.1093/jnci/djk093 Huber

  27. Neoadjuvant Chemo- vs. RCT • Phase III in stage III NSCLC • In both arms, a similar percentage could be sent to surgery (even in stage IIIB) • Bimodality induction: • trend toward better resection rates (R0) • higher complication rate, especially bronchial stump insufficiency Thomas M ea. JCO 22 (2004), 14S, 704. Lancet Oncol, July 1, 2008; 9(7): 636-48

  28. Neoadjuvant therapy: Chemo- vs. Chemoradio-Therapy • In patients with stage III NSCLC amenable to surgery, preoperative chemoradiation in addition to chemotherapy increases pathological response and mediastinal downstaging, but does not improve survival. • After induction with chemoradiation, pneumonectomy should be avoided. Thomas M ea. Lancet Oncol, July 1, 2008; 9(7): 636-48 Huber

  29. NSCLC cN2-Status and Resection Survival with/without neoadjuvant chemotherapy (n = 332) n 5 Y. – Surv.[%] cN2 237 5 cN2 + neoadjuvantCTh 95 18 cN2 + neoadjuvantCTh 69 26 with response + R0 Andre ea., J Clin Oncol 18: 2981 (2000) Huber

  30. Cisplatin vs. Carboplatin Meta-Analysis: Survival HR = 1.12, 95 % CI 1.01-1,23 Ardizzoni A ea. J Natl Cancer Inst 2007;99: 847 – 57 Huber

  31. Cisplatin 50 mg / m2 d 1, 2 Docetaxel 85 mg / m2 d 1 OP * 3 x * If R1/2: RTX (60 Gy; 2 Gy/d) NSCLC Stage IIIA (N2): CT + OP • 90 patients • ECOG 0/1, median age 60 yrs • T 1-3 N2 (mediastinoscopy) • N2-2L (20/62) Betticher et al., J Clin Oncol 21: 1752 (2003) Istanbul, 7. 5. 2010 Huber

  32. NSCLC Stage IIIA (N2): CT + OP RR PD OP R0 TL RTX pCRpN0/1 66 % 10 % 87 % 48 % 3 % 37 % 16 %50 % Survival All Pts pN0/1 pN2 Median 28 Mo. 53 Mo. 16 Mo. 3 Yr. Survival 36 % 61 %11 % Betticher et al., J Clin Oncol 21: 1752 (2003) Istanbul, 7. 5. 2010 Huber

  33. Neoadjuvant Treatment - ACCP ACCP 2007 Stage IIIA3: Induction therapy followed by surgery is not recommended except as part of a clinical trial. Grade 1A Stage IIIB NSCLC as a result of N3 disease:treatment with neoadjuvant (induction) chemotherapy or chemoradiotherapy followed by surgery is not recommended. Grade 1C Huber

  34. Neoadjuvant Treatment - Germany • Stage I: outside of clinical trials not recommended (grade B). • Stage II: outside of clinical trials not recommended (grade B). • Stage III A: interdisciplinary individual decision in centres possible (grade B) German Society of Pneumology. Pneumologie 2010; 64, Supp.2: e1– e164 Huber

  35. Standards for neoadjuvant treatment Thorough preoperative evaluation Interdisciplinary discussion 3 cycles of cisplatin plus „modern“ doublet No preoperative radiotherapy Efficacy is relevant Proper reevaluation, especially of the mediastinum Radiotherapy postoperatively if necessary Huber

  36. Adjuvante Therapie des NSCLC Thank you for your attention München,17.9. 2008 Huber Huber

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