Читать книгу Surgical Management of Advanced Pelvic Cancer - Группа авторов - Страница 49

Integration of targeted agents in the treatment of LARC has been the focus of several modern early phase trials [54]. Preclinical studies have demonstrated that vascular endothelial growth factor (VEGF) blockade in combination with standard chemoradiotherapy enhances tumor regression. VEGF blockade induces alterations to the vasculature of the tumor microenvironment, increasing tumor perfusion and oxygenation and improving intratumoral drug delivery [55]. A meta‐analysis reported a pooled pCR rate of 27% with neoadjuvant therapy including bevacizumab [56]. A small single‐institution prospective phase II trial evaluating induction FOLFOX with bevacizumab followed by radiotherapy reported favorable pathological, toxicity, and survival outcomes [57]. Forty‐three patients with clinical stage II–III low rectal adenocarcinoma and MRI‐defined high‐risk features (cT4, cN2, predicted positive lateral nodal involvement, threatened circumferential resection margin [CRM]) were included. The pCR rate was 37.2% and three‐year DFS was 86%. Irinotecan has no adjuvant role in colon cancer and can have significant toxicities including colitis and sepsis. It has been successfully incorporated into neoadjuvant, adjuvant, and palliative chemotherapy for pancreatic cancer in the FOLFIRINOX regimen [58]. Several French trials use it as the backbone of a TNT approach in rectal cancer, but there is hesitancy to adopt it elsewhere.

The Italian TRUST trial also observed favorable results with induction FOLFOXIRI (5‐FU, leucovorin, irinotecan, and oxaliplatin) and bevacizumab plus nCRT [59]. This phase II single‐arm study of 49 patients with predicted node‐positive or clinical T3/4 disease reported a pCR rate of 36% and two‐year DFS of 80%. The GEMCAD 1402 trial randomized patients to induction mFOLFOX with or without aflibercept (VEGF inhibitor) [60]. In per protocol analysis, a pCR was achieved in 25.2% of the experimental arm and 14.5% of the control group (p = 0.10). In the EXPERT‐C trial, patients with MRI‐defined high‐risk disease were randomized to induction CAPOX with cetuximab (epidermal growth factor receptor [EGFR] inhibitor) or CAPOX alone, followed by standard nCRT [61]. In this study, however, no significant difference in the primary endpoint of pCR was observed among groups. Capecitabine and cetuximab are no longer combined in routine practice as there is unacceptable synergistic skin toxicity. Although the addition of targeted agents has yielded some positive oncological outcomes, concerns exist surrounding their safety profile and associated toxicity. The AVACROSS phase II single‐arm study evaluating induction XELOX with bevacizumab reported a high postoperative complication rate (58%), with 24% of patients requiring surgical reintervention [62]. No agent has emerged as superior to oral or intravenous 5‐FU as a radiosensitizer. In colon cancer there has been no therapy added to systemic adjuvant therapy since oxaliplatin nearly two decades ago. Bevacizumab does not improve survival, and the monoclonal antibodies cetuximab and panitumumab which target EGFR have no adjuvant role even in RAS/RAF wild‐type colon cancer. There was considerable enthusiasm for the poly‐ADP ribose polymerase (PARP) inhibitor veliparib as a radiosensitizer, but unfortunately this was not confirmed by the NRG‐GI002 phase II trial [63].