Role of biologic therapy in surgical management of hepatic metastases

The multidisciplinary treatment of colorectal hepatic metastasis though heavily grounded in surgical resection, has significantly advanced over the last decade due to more effective chemotherapy resulting in increased tumor responsiveness and enhanced resectability. The recent acquisition of biologic agents has added another major step in achieving complete tumor control. This brief discussion will highlight some of the major advances in the effort to control neoadjuvant colorectal hepatic metastases. Colorectal hepatic metastases are found in 25% of patients at time of primary resection (synchronous) with metachronous metastases occurring in 50–70% of pts by 3 years. Surgical resection is considered the only curative therapy 30% 5-year survival. Current multidrug chemotherapy has improved survival for advanced disease from 6 months (single agent) to 18–20 months, and may be further enhanced by targeted biologic agents. Neo adjuvant therapy prior to resection was pioneered by the Henri Bismuth group in France. An update of that series disclosed that chemotherapy of pts with non-resectable hepatic metastases permitted resection in 14% (205 pts/1,512 pts achieving a 5-year survival of 36% in evaluable pts (64% were NED >4 years) [1]. The recent Nordlinger phase III trial of peri-operative chemotherapy compared chemotherapy with FOLFOX and surgery versus surgery alone and demonstrated a 9.2% increased 3-year PFS (P1⁄4 0.0025) in the pts receiving perioperative chemotherapy. Long-term survival data are awaited in this important study [2]. A recent review of neoadjuvant therapy in 23 series (observational review in 19 and phase II in 3–3,278 pts) revealed a overall response of 64% and 93% chance of obtaining RO resection with median disease free and overall survival (OS) of 21 and 46 months, respectively. More phases II and III defined studies are needed. Role of biologics in therapy in CRC. Two major sites of biologic interaction at the tumor cell surface are the vascular epidermal growth factor receptors (EGFRS) and the vascular endothelial growth factor receptors (VEGFR) [3]. The VEGF family consists of five ligand members VEGFA! E and placental growth factor (PIGF). These ligands bind to three VEGF receptors (VEGF1, 2, and 3) forming VEGFR homodimers and hetero dimmers. VEGF signaling is modulated by variable affinity of ligands for specific receptors. The concept of treating tumors whose growth is angiogenesis driven, was an obvious rationale for developing VEGF inhibitors such as Bevacizumab (BEV), a humanized monoclonal antibody (moAb) which targets VEGFA. Bev added to bolus 5FU and Leucovorin (LV) and Irinotecan (IFL) versus IFL alone significantly improved response rates 45% versus 35%, and time to progression 11 months versus 6 months and overall survival (OS) 20 months versus 16 months in the Hurwitz study [3]. Bevacizumab and FOLFOX (ECOG 3200 trial) given as second line therapy of M-CRC (refractory to Irinotecan), showed significant increased PFS (7.3 months vs. 4.7 months and median overall survival 12.9 months vs. 10.8 months vs. FOLFOX alone (4)). Bev added to 5FU/leucovorin in first line Rx therapy of mCRC was also of benefit with the combination increasing PFS from 5.6 to 8.8 months and median survival from 14.6 months (5FU alone) versus 17.9 months (combination with Bev) [4]. This is at odds with the N016966 trial where Bev plus FOLFOX or CAPOX (Capecitabine/ Oxaliplatin), failed to increase response (38% both arms) and survival 19.9 months versus 21.3 months, although PFS was increased from 8.0 to 9.4 months (HR1⁄4 0.83, P1⁄4 0.0073). This study was compromised due to premature discontinuation of Bev secondary to toxicity. Bev associated toxicity included hypertension in 25% of pts, GI-perforations (1.5–2.0%). Other complications may include arterial thrombotic events (about 1.8–5%), strokes/myocardial infarctions1–2%). The true negative effect of Bev is probably relatively low in properly selected pts and can be obviated by delaying surgical intervention until a full 6–8 weeks after completion of treatment. The EGFR system includes (EGFR 1, 2, 3, 4) and is designated as ErbB-1 HER 1, ErbB-2, HER-2/neg, ErbB-3(HERB) ErbB-4 (HER4). These receptors include an extracellular finding domain, a transmembrane domain and an intracellular domain containing tyrosine kinase activity which transduces signals to proteins involved in tumor cell proliferation, invasion, migration, and inhibition of apoptosis. The EGFR-binding site is an attractive target for monoclonal antibody (the chimeric human–mouse antibody Cetuximab and the fully humanized compound Panitumamab. Initial studies with Cetuximab therapy suggested enhanced responsiveness to cetuximab in combination therapy with FOLFOX [4]. An important recent observation is the effect of the KRAS mutational status on responsiveness to Cetuximab/Panitumamab (Cetux/Pan) [5]. A analysis of the CRYSTAL trial substantiated the hypothesis that cetuximab added efficacy to FOLFIRI chemotherapy of Kras wild-type colorectal tumors. This observation was further confirmed in analysis of responsiveness to Cetux/Pan. When responses and survival were analyzed according to kras mutation status in other trials only patients with KRAS wild-type configured tumors obtained benefit from the addition of Cetux/Pan to chemotherapy or given as single agent therapy. The Crystal study (FOLFIRI and Cetuximab vs. placebo), demonstrated improved PFS (8.7 months vs. 9.9 months) and OS (21 months vs. 24.9 months) with the addition of cetuximab in