Mount Vernon Cancer Centre, Northwood, Middlesex, UK.
J Gastrointest Oncol. 2013 Sep;4(3):264-84. doi: 10.3978/j.issn.2078-6891.2013.037.
Radiotherapy has a longstanding and well-defined role in the treatment of resectable rectal cancer to reduce the historically high risk of local recurrence. In more advanced borderline or unresectable cases, where the circumferential resection margin (CRM) is breached or threatened according to magnetic resonance imaging (MRI), despite optimized local multimodality treatment and the gains achieved by modern high quality total mesorectal excision (TME), at least half the patients fail to achieve sufficient downstaging with current schedules. Many do not achieve an R0 resection. In less locally advanced cases, even if local control is achieved, this confers only a small impact on distant metastases and a significant proportion of patients (30-40%) still subsequently develop metastatic disease. In fact, distant metastases have now become the predominant cause of failure in rectal cancer. Therefore, increasing the intensity and efficacy of chemotherapy and chemoradiotherapy by integrating additional cytotoxics and biologically targetted agents seems an appealing strategy to explore-with the aim of enhancing curative resection rates and improving distant control and survival. However, to date, we lack validated biomarkers for these biological agents apart from wild-type KRAS. For cetuximab, the appearance of an acneiform rash is associated with response, but low levels of magnesium appear more controversial. There are no molecular biomarkers for bevacizumab. Although some less invasive clinical markers have been proposed for bevacizumab, such as circulating endothelial cells (CECS), circulating levels of VEGF and the development of overt hypertension, these biomarkers have not been validated and are observed to emerge only after a trial of the agent. We also lack a simple method of ongoing monitoring of 'on target' effects of these biological agents, which could determine and pre-empt the development of resistance, prior to radiological and clinical assessessments or even molecular imaging. These shortcomings probably explain our current relative lack of success in the arena of combining these agents with chemoradiation.
放疗在可切除直肠癌的治疗中具有悠久而明确的作用，可降低局部复发的历史高风险。在更晚期的边界或不可切除的情况下，根据磁共振成像（MRI），环周切缘（CRM）被突破或受到威胁，尽管优化了局部多模态治疗以及现代高质量全直肠系膜切除（TME）所取得的进展，但至少有一半的患者无法通过当前方案实现足够的降期。许多患者无法达到 R0 切除。在不太局部晚期的情况下，即使实现了局部控制，这也仅对远处转移产生很小的影响，很大一部分患者（30-40%）仍随后发生转移性疾病。事实上，远处转移现在已成为直肠癌失败的主要原因。因此，通过整合额外的细胞毒性药物和生物靶向药物来增加化疗和放化疗的强度和疗效，似乎是一种有吸引力的探索策略，旨在提高根治性切除率，改善远处控制和生存。然而，迄今为止，除了野生型 KRAS 之外，我们还缺乏这些生物制剂的验证生物标志物。对于西妥昔单抗，痤疮样皮疹的出现与反应相关，但低水平的镁似乎更具争议性。贝伐珠单抗没有分子生物标志物。尽管已经提出了一些用于贝伐珠单抗的较少侵入性临床标志物，如循环内皮细胞（CECS）、循环 VEGF 水平和明显高血压的发生，但这些标志物尚未得到验证，并且仅在该药物的试验后才观察到。我们还缺乏一种简单的方法来持续监测这些生物制剂的“靶向”效果，这可以在影像学和临床评估之前，甚至在分子成像之前，确定并预测耐药性的发展。这些缺点可能解释了我们在将这些药物与放化疗结合方面目前相对缺乏成功的原因。
