Adjuvant and Neoadjuvant Therapy in Non- Small Cell Lung Cancer Seminars in Oncology 2oo5;32 (suppl 2):S9-S15 Kyung Hee Medical Center Department of Thoracic & Cardiovascular Surgery R4 Yi. In-ho

 NSCLC is detected an early stage and curative surgery is performed, is performed, the 5-year survival rates for stage IA, IB, IIA, IIB, IIIA the 5-year survival rates for stage IA, IB, IIA, IIB, IIIA are 67%, 57%, 55%, 39%, 25% respectively. are 67%, 57%, 55%, 39%, 25% respectively.  Most stage I, II pts will experience recurrent disease. - 2/3 : systemic recurrence - 2/3 : systemic recurrence - 1/3 : local recurrence - 1/3 : local recurrence  Surgical resection remains the standard of care for early stage NSCLC. early stage NSCLC. Introduction (I) Introduction (I)

 A dedicated approach to mediastinum is critical because pathologic involvement of N2 LN influences because pathologic involvement of N2 LN influences staging, prognosis, decisions to adjuvant therapy. staging, prognosis, decisions to adjuvant therapy.  Mediastinal lymphadenopathy demonstrated on the initial chest CT or PET always requires further exams. initial chest CT or PET always requires further exams.  False positive and negative rates are remain troublesome.  Mediastinoscopy remains the gold standard for pathologic evaluation of the mediastinum. pathologic evaluation of the mediastinum. Introduction (II) Introduction (II)

Rationale for Adjuvant Therapy in NSCLC (I)  Despite complete surgical removal of all macroscopic disease, macroscopic disease, the presence of micrometastasis at resectection the presence of micrometastasis at resectection is the most reason for recurrence. is the most reason for recurrence. -> adjuvant chemotherapy is a rational treatment. -> adjuvant chemotherapy is a rational treatment.

Rationale for Adjuvant Therapy in NSCLC (II) Rationale for Adjuvant Therapy in NSCLC (II)

Phase III IALT (I) (International Adjuvant Lung Trial) Phase III IALT (I) (International Adjuvant Lung Trial)  IALT showed survival benefit by comparing cisplatin - based adjuvant CTx with observation alone cisplatin - based adjuvant CTx with observation alone following surgical resection following surgical resection in 1867 pts with stage I, II, III NSCLC. in 1867 pts with stage I, II, III NSCLC.  The primary outpoint was overall survival.  The secondary outpoint was disease free survival (DFS), incidence of second primary tumor, toxicity. incidence of second primary tumor, toxicity.

Phase III IALT (II) (International Adjuvant Lung Trial) Phase III IALT (II) (International Adjuvant Lung Trial)  Cisplatin 8o - 12o mg/m 2 for 3 or 4 cycles combined with Vindesine, vincristine, vinorelbine or etoposide. with Vindesine, vincristine, vinorelbine or etoposide.  Median follow - up : 56 months.  2 - and 5 - years overall survival rates and DFS is superior for adjuvant CTx group compared with superior for adjuvant CTx group compared with surgical resection alone. surgical resection alone. - 5 yrs survival rate: 44.5 % vs 4o.4 %, p <.o3 - 5 yrs survival rate: 44.5 % vs 4o.4 %, p <.o3 - DFS : 39.4 % vs 34.3 %, p <.oo3 - DFS : 39.4 % vs 34.3 %, p <.oo3

JBR-1o trial (National Cancer Institute of Canada Intergroup) JBR-1o trial (National Cancer Institute of Canada Intergroup)  482 patients  Stage IB, II  oo1. 4  4 cycles cisplatin/vinorelbine or observation

CALGB 9633 trial  344 (173 vs 171) patients  Stage IB  oo2  4 cycles carboplatin/paclitaxel or observation  Mean follow- up : 34 months  4 yrs survival rate : 71 % vs 59 %, p =.o28  4 yrs relapse free survival rate: 61 % vs 5o %, p =.o35  Death from lung cancer : 11 % vs 19.9 %, p =.o18  38 % reduction in all-cause mortality  49 % reduction in lung cancer related death

Molecular Prognostic Factors  K-ras gene - adenocarcinoma : 3o % - adenocarcinoma : 3o % - large cell carcinoma : 1o % - large cell carcinoma : 1o % - prognostic determinant of survival - prognostic determinant of survival  p53 gene - most common change during malignant change - most common change during malignant change  Epidermal growth factor receptor  HER2/neu  Bcl-2

Neoadjuvant Studies in Early Stage NSCLC (I)  The benefits of neoadjuvant CTx are widely accepted in local advanced resectable (stage III N2) and local advanced resectable (stage III N2) and unresectable disease (stage IIIB) unresectable disease (stage IIIB)  French Thoracic Cooperative Group (2oo2) - 2 cycles mitomycin-C, ifosfamide, cisplatin - 2 cycles mitomycin-C, ifosfamide, cisplatin - response rate : 64% (pathologic complete response 11%) - response rate : 64% (pathologic complete response 11%) - median survival : 37 vs 26 months, p =.15 - median survival : 37 vs 26 months, p =.15 - LN status : No, N1 is more benefit, p =.oo8 - LN status : No, N1 is more benefit, p =.oo8 - DFS time : increased p =.o33 - DFS time : increased p =.o33 - distant metastasis : decreased p =.o1 - distant metastasis : decreased p =.o1

Neoadjuvant Studies in Early Stage NSCLC (II)  Bimodality Lung Oncology Team Trial (2ooo, 2oo3) - paclitaxel + carboplatin - paclitaxel + carboplatin - A: 2 cycles of pre-OP, 3 cycles of post-OP - A: 2 cycles of pre-OP, 3 cycles of post-OP - B: 3 cycles of pre-OP, 2 cycles of post-OP - B: 3 cycles of pre-OP, 2 cycles of post-OP - feasible for T2No, T1-2N, T3No-1 - feasible for T2No, T1-2N, T3No-1 - response rate of neoadjuvant CTx : 56 % - response rate of neoadjuvant CTx : 56 % - complete surgical resection rate : 86 % - complete surgical resection rate : 86 % - Neoadjuvant CTx did not compromise surgery and - Neoadjuvant CTx did not compromise surgery and led to favorable survival in early stage NSCLC led to favorable survival in early stage NSCLC

Current Adjuvant Therapy Trial  Chemotherapy for Early Stage Trial - the role of preoperative CTx in resectable - the role of preoperative CTx in resectable stage IB, II, selective IIIA(T3N1) NSCLC stage IB, II, selective IIIA(T3N1) NSCLC - gemcitabine + cisplatin - gemcitabine + cisplatin  Neoadjuvant Taxol/Carboplatin Hope Trial - compare the benefit of preoperative vs postoperative CTx - compare the benefit of preoperative vs postoperative CTx vs surgery alone in stage I, II, selective IIIA(T3N1) NSCLC vs surgery alone in stage I, II, selective IIIA(T3N1) NSCLC - significant decrease the tumor with preoperative CTx - significant decrease the tumor with preoperative CTx  Frcnch trial - cisplatin/gemcitabine vs carboplatin/paclitaxel - cisplatin/gemcitabine vs carboplatin/paclitaxel - 2 vs 4 cycles

Adjuvant Therapy and Targeted Agents  National Cancer Institite of Canada BR-19 trial - adjuvant gefitinib (Iressa) in resected NSCLC - adjuvant gefitinib (Iressa) in resected NSCLC - tyrosine kinase inhibitor of internal domain of - tyrosine kinase inhibitor of internal domain of epidermal growth factor receptor epidermal growth factor receptor - has shown activity in refractory NSCLC - has shown activity in refractory NSCLC - EGFR is overexpressed in NSCLC and often - EGFR is overexpressed in NSCLC and often correlates with advanced stage & poor prognosis correlates with advanced stage & poor prognosis - excellent tolerability - excellent tolerability - extremely low rate of severe toxicity - extremely low rate of severe toxicity

Conclusion (I)  Cause of the failure of previous adjuvant CTX tral. - trial design - trial design - accuracy of preoperative staging - accuracy of preoperative staging - selection & dosage of CTx agent - selection & dosage of CTx agent - lack of statistical power - lack of statistical power  Adjuvant CTx should be considered the unequivocal standard of care for the treatment of standard of care for the treatment of completely resected early stage NSCLC, completely resected early stage NSCLC, exception of stage IA exception of stage IA

Conclusion (II)  No study has compared the utility of adjuvant CTx with neoadjuvant CTx. adjuvant CTx with neoadjuvant CTx.  A randomized clinical trial is required to compare adjuvant CTx versus neoadjuvant CTx adjuvant CTx versus neoadjuvant CTx for early stage NSCLC pts who are candidates for early stage NSCLC pts who are candidates for complete surgical resection. for complete surgical resection.  Neoadjuvant CTx has the benefit of downstaging disease before surgery & downstaging disease before surgery & decreasing tumor seeding during surgery. decreasing tumor seeding during surgery.

Conclusion (III)  The administration of planned doses of systemic CTx remains a challenge. remains a challenge. - 5o~7o% of pts receiving the planned dosage - 5o~7o% of pts receiving the planned dosage in adjuvant CTx. in adjuvant CTx. - > 9o% of pts receiving the planned dosage - > 9o% of pts receiving the planned dosage in neoadjuvant CTx. in neoadjuvant CTx.  Neoadjuvant Tx with molecular targeted agents may alterates molecular prognostic factor & may alterates molecular prognostic factor & downstream signal event in tumor tissue at resection. downstream signal event in tumor tissue at resection. -> development of individualized treatment approach. -> development of individualized treatment approach.