Читать книгу Surgical Management of Advanced Pelvic Cancer - Группа авторов - Страница 50

The past few decades have witnessed unprecedented advances in the field of cancer immunology. The focus of systemic therapy is developing novel strategies to enhance the ineffective antitumor response of the immune system. Immunotherapy with checkpoint blockade (mainly programed cell death protein 1 [PD‐1]) has had limited efficacy in the vast majority of patients with metastatic colorectal cancer. Durable responses have predominantly been observed in patients with microsatellite instability‐high (MSI‐H) colorectal cancer [64]. The high mutational burden of microsatellite instability (MSI) tumors is thought to provoke a strong intratumoral T‐cell response, which can be further enhanced with anti‐PD‐1 therapy. Pembrolizumab is now accepted as a first‐line standard of care for MSI‐H stage IV colon cancer based on the KEYNOTE‐177 study [65]. There is concern that over one‐third of MSI‐H patients experience rapid disease progression on immunotherapy even though there is a large sustained survival benefit in the majority. RAS mutations and left‐sided tumor origin had less benefit from immunotherapy, but BRAF mutations did not appear to detract from efficacy. Future characterization of blood and tumoral biomarkers may enable precise selection of patients likely to respond to monotherapy and those who require alternative approaches, potentially facilitating the integration of immunotherapy into the neoadjuvant treatment paradigm. There have been some early reports of dramatic responses to neoadjuvant immunotherapy in MSI‐H rectal cancer [66]. While 10–15% of all colon cancer is MSI‐H, only 3–5% of rectal cancer is. The holy grail of colon cancer research is a means by which to enable immunotherapy to benefit patients with microsatellite stable (MSS) disease. Can radiotherapy render MSS rectal cancer vulnerable to immunotherapy? The upregulation of programed cell death‐ligand 1 (PD‐L1) in rectal cancer post‐radiotherapy may be associated with improved outcomes [67, 68]. Several early phase trials are exploring the PD‐L1 antagonists avelumab (AVANA) and atezolizumab (R‐IMMUNE) in combination with preoperative chemoradiotherapy [69–71]. Other studies such as PEMREC combine pembrolizumab with short‐course radiation therapy [72]. In stage III non‐small cell lung cancer, durvalumab is used following definitive chemoradiation based on the PACIFIC trial [73]. Similar approaches in rectal cancer such as the Dutch TARZAN trial (short‐course radiation therapy followed by atezolizumab and bevacizumab) and the Chinese CHINOREC trial (nCRT followed by ipilimumab and nivolumab) are underway. There is no role for immunotherapy in MSS disease outside of clinical trials.