Effectiveness of IG-IMRT for Locally Advanced Cervix Cancer on NRG Trial CVM-1421

 描述（由申请人提供）：宫颈癌是全球癌症死亡的主要原因之一。患者通常难以获得筛查和疫苗接种，并且处于晚期阶段，放化疗（chemoRT）是标准治疗。然而，这种治疗受到高失败率和毒性的限制。虽然强化化疗可以改善肿瘤控制和生存，但毒性通常高得令人无法接受。因此，需要降低毒性同时提高化疗疗效的策略。 标准盆腔RT技术包括大量正常组织。相比之下，图像引导调强RT（IG-IMRT）是一种现代技术，它可以最大限度地提高靶区剂量，并最大限度地减少正常组织剂量。多项研究发现，IG-IMRT可以显着降低器官剂量和降低毒性相比，标准RT这些研究支持的假设，IG-IMRT可以允许提供更密集的化疗。例如，吉西他滨，一种有效的放射增敏剂，在随机试验中发现可改善宫颈癌患者的生存率（Dueñas-Gonzalez et al.）。然而，当用标准RT递送时，毒性是极端的（>80%的3-4级毒性）。因此，该方案尚未取代单独顺铂作为标准治疗。相比之下，我们的研究小组发现，当给予IG-IMRT时，吉西他滨的最大耐受剂量增加。一项大型国际多机构试验也发现，与标准化疗相比，IG-IMRT的毒性率较低。这些发现支持IG-IMRT通过减少肠道和骨髓剂量可以提供更有效的同步化疗的假设。如果得到证实，这将对许多盆腔恶性肿瘤产生重大影响。然而，这一假设尚未在随机试验中得到验证。 CVM-1421是NRG肿瘤协作组内一项由NCI资助的随机II期试验，该试验将检验以下假设：在顺铂和RT同时治疗的基础上，同时添加一种核糖核苷酸还原酶抑制剂Trifecta，可以改善接受明确放化疗的局部晚期宫颈癌患者的结局。这项试验提供了一个独特的机会，研究IG对正常组织毒性的影响，因为它将是第一个合作组试验，允许IG-IMRT在这一人群中。这项试验也提供了一个研究如何提高IG-IMRT质量的机会，因为由于IG-IMRT计划的复杂性增加，在如何优化设计IG-IMRT计划方面存在相当大的争议。本研究的目的是研究IG-IMRT在不同化疗强度下对毒性、生活质量和治疗结果的影响。我们还将实施一种新的技术，称为基于知识的规划（KBP），以提高计划质量，实现最佳IG-IMRT剂量分布。这项研究可以帮助建立IG-IMRT作为盆腔恶性肿瘤的新护理标准，并将为未来在临床试验环境中测试新技术的研究奠定基础。

 DESCRIPTION (provided by applicant): Cervical cancer is among the leading causes of cancer death worldwide. Patients often have poor access to screening and vaccination, and present in advanced stages, for which chemoradiotherapy (chemoRT) is the standard of care. This treatment is limited, however, by high rates of failure and toxicity. Although intensifying chemotherapy can improve tumor control and survival, toxicity is often unacceptably high. Strategies to reduce toxicity while increasing efficacy of chemoRT are therefore needed. Standard pelvic RT techniques encompass large volumes of normal tissue. In contrast, image-guided intensity-modulated RT (IG-IMRT) is a modern technique that maximizes target dose and minimizes normal tissue dose. Multiple studies have found that IG-IMRT can significantly reduce organ dose and reduce toxicity compared to standard RT. These studies support the hypothesis that IG-IMRT can permit delivery of more intensive chemotherapy. For example, gemcitabine, a potent radiosensitizer, has been found to improve survival for cervical cancer patients in randomized trials (Dueñas-Gonzalez et al.). However, the toxicity when delivered with standard RT is extreme (>80% grade 3-4 toxicity). Therefore, this regimen has not replaced cisplatin alone as the standard of care. In contrast, our research group has found that the maximum tolerated dose of gemcitabine was increased when given with IG-IMRT. A large international multi-institutional trial has also found lower rates of toxicity with IG-IMRT compare to standard chemoRT. These findings support the hypothesis that IG-IMRT, by reducing bowel and bone marrow dose, could permit delivery of more effective concurrent chemotherapy. If confirmed, this would have significant implications for many pelvic malignancies. However, this hypothesis has not been tested in a randomized trial. CVM-1421 is an emerging NCI-funded randomized phase II trial within the NRG Oncology Cooperative Group that will test the hypothesis that adding concurrent triapine, a ribonucleotide reductase inhibitor, to concurrent cisplatin and RT can improve outcomes in patients with locoregionally advanced cervix cancer undergoing definitive chemoradiation. This trial presents a unique opportunity to study the effects of IG- IMRT on normal tissue toxicity, as it will be the first cooperative group trial to permit IG-IMRT in this population. This trial also presents an opportunity to study ways to improve IG-IMRT quality, as there has been considerable controversy in how to optimally design IG-IMRT plans, due to their increased complexity. The goal of our research is to study the effect of IG-IMRT on toxicity, quality of life, and treatment outcomes, under varying intensities of chemotherapy. We will also implement a novel technique called knowledge-based planning (KBP) in order to improve plan quality and achieve optimal IG-IMRT dose distributions. This research could help establish IG-IMRT as a new standard of care for pelvic malignancies, and will lay groundwork for future studies testing novel technologies in clinical trial settings.