Neoadjuvant chemotherapy in the treatment of NSCLC Department of Thoracic Oncology, University Hospital Ghent, Belgium Current Opinion in Oncology 2007, 19:92–97

Background NSCLC - 80% of all lung cancer - operation ; curable with early stage (I~IIIA) - relapse after operation with curative intent : distant metastasis – m/c cause of death after surgery  occult micrometastatic disease Chemotherapy combined with surgery - decreased incidence of recurrence in distant site  Current standard therapy : Surgery + Adjuvant chemotherapy How about Neoadjuvant chemotheray??

Neoadjuvant chemotherapy Rationale - systemic treatment of occult microscopic metastatic disease at earliest possible time  improvement of progression-free / overall survival - cytotoxic for primary tumor  possible clinical or pathological remission - reduction in the primary tumor mass  more radical and smaller resection - better tolerated than adjuvant setting - in vivo assessment of tumor chemosensitivity  selection of responsive patients

Disadvantage - delay in curative surgery - less accurate staging (possible for just clinical staging) - increased surgical morbidity and mortality after chemotherapy Neoadjuvant chemotherapy

Neoadjuvant chemotherapy in early-stage NSCLC [ I,II,IIIA-N1 ]

First small randomized studies - Lung Cancer 1998; 21:1–6 - Lung Cancer 1999; 26:7–14 Large phase III trial by Depierre et al. preop. chemotherapy + surgery Vs surgery alone - lower rate of distant metastasis - improvement of 4-yr survival rate Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA nonsmall-cell lung cancer Preresectional chemotherapy in stage IIIA nonsmall-cell lung cancer : a 7-year assessment of a randomized controlled trial

SWOG S9900 Trial Neoadjuvant chemotherapy : CbTx #3 Major side effect : neutropenia and neuropathy with nausea, vomiting Result - trend toward better progression-free and overall survival for the neoadjuvant treatment arm - NO statistical significance

MRC-EORTC-NVALT Trial - Platinum-based chemotherapy #3 with surgery Vs Surgery alone Results : NO difference between the two groups - complete resection rate - postoperative complication - hospital stays - additional down staging without higher rates of postop. complication in the 10% of the patients

Meta-analysis of six randomized trials by Berghmans et al. - favor of the addtion of neoadjuvant chemotherapy to surgery Meta-analysis of seven randomized trials by Burdett et al. - improvement of survival rate in the neoadjuvant chemotherapy - absolute benefit of 6% at 5 year

Neoadjuvant chemotherapy in NSCLC stage IIIA-N2

Mediastinal LN involvement - inverse correlation with survival rate - prognosis : bulky N2 disease  5~8% of survival rate : single station involvement  35% of survival rate - clinical trial of neoadjuvant therapy : chemoradiation or chemotherapy

Intergroup 0139 Trial Neoadjuvant therapy : VPP #2 + RT  RT Vs surgery  VPP consolidation Results - significant improvement of progression-free survival in surgical arm - NOT in overall survival mainly due to postop. mortality

EORTC Trial For unresectable IIIA-N2 patient : induction chemotherapy  surgery Vs Radiation therapy Results - no difference in progression-free or overall survival - standard therapy : chemoradiation to stage IIIA-N2 patients

GLCCG Induction chemotherapy [VPP] #3  RT with concurrent carboplatin + vindesin  surgery  surgery  radiotherapy Results - no significant difference in the two groups - increased rate of esophagitis due to twice daily radiation

Conclusion Advantage - clinical downstaging - better compliance with treatment - no delay of surgery or increasing hospital stay : Platinum-based two-drug combination more than at least 3 cycles Inconsistent result - no definite survival gain - increased morbidity and mortality with concurrent radiotherapy  NO recommendation neoadjuvant chemotherapy outside of clinical trial in resectable patients with NSCLC