Advanced PET-CT Directed Post-Prostatectomy Radiotherapy to Enhance Prostate Cancer Outcomes

项目总结/摘要 目前，50%在PSA失败后接受前列腺切除术后放疗的患者表现为 随后的全身性疾病。与使用分子放射性示踪剂的PET/CT相比， 这些方法在鉴定前列腺癌复发部位方面存在不足。我们的目标是解决未满足的公众 通过改善复发性前列腺癌患者长期生化控制来满足健康需求。 我们已经验证了一个关键的科学前提，即用合成的氨基化合物进行先进的分子成像。 酸性PET放射性示踪剂氟草胺（18F）（抗3-[18F]FACBC）导致显著更大的疾病 检测，管理变化40.5%，计划体积变化83.6%（无剂量 与常规成像相比，在审判过程中，很大程度上是因为 在我们的转化工作中，氟昔洛韦（18F）于2016年被FDA批准用于复发性前列腺癌， 为新的护理标准做出贡献。自版本1.2018起，氟氯昔洛韦（18F）现已被纳入 国家综合癌症网络（NCCN）复发性前列腺癌再分期指南。 此外，在PSA水平越来越低的情况下提供挽救性放疗，证据表明， 累积对活动性疾病病灶的加强放射治疗剂量可产生临床益处。 我们正在进行的临床试验（5 R 01 CA 129356：NCT 01666808）中仍在累积的数据的初步分析 表明，整合氟氯硝草碱可能会导致失败率的小幅改善，但没有足够的效果。 敏感性，以明确实现持久的PSA控制与标准放疗剂量。然而，早期 有证据表明，一种新的PET放射性示踪剂靶向前列腺特异性膜抗原（PSMA）， 在较低的PSA水平下，受体可能对疾病检测具有更高的灵敏度。镓-68（68 Ga）PSMA是 一种这样的PSMA PET配体，尽管没有FDA批准。每类PET放射性示踪剂，氨基酸代谢 （氟鹿草碱）与基于受体的（PSMA）相比，表现出优点和缺点。 我们的假设是，通过利用更高亲和力的PET配体，我们可以更好地选择和管理 在较低PSA水平下接受挽救性放疗的患者。另外我们 假设通过剂量递增用氟鹿昔洛韦（18F）或68 Ga PSMA鉴定的靶点，我们 将确定剂量递增本身是否能改善PSA控制。为了验证这些假设， 最高的科学严谨性，我们将进行一项前瞻性临床试验， 挽救性放射治疗随机分配至氟昔洛韦（18 F）或68 Ga PSMA PET/CT。我们将探讨，如果 阳性特异性组织生物标志物标记可能有助于预测乳腺癌切除术后放疗 结果与标准风险标准相结合。我们的建议是及时的，因为最近的社论 关于乳腺癌切除术后挽救性放射治疗的文献呼吁将分子成像整合到 前瞻性、随机、对照试验以及我们将要进行的毒性分析。

Project Summary / Abstract Currently, 50% of patients who have undergone post-prostatectomy radiotherapy after PSA failure manifest subsequent systemic disease. Compared to PET/CT with molecular radiotracers, conventional imaging methods fall short in identifying sites of prostate cancer recurrence. Our goal is to address an unmet public health need by improving long term biochemical control of patients with recurrent prostate carcinoma. We have verified a key scientific premise that advanced molecular imaging with the synthetic amino acid PET radiotracer fluciclovine (18F) (anti-3-[18F]FACBC) results in significantly greater disease detection, with a 40.5% change in management and 83.6% change in planning volumes (without dose escalation) compared with conventional imaging. During the course of our trial, and in large part because of our translational work, fluciclovine (18F) was FDA approved in 2016 for recurrent prostate cancer, contributing to a new standard of care. As of Version 1.2018, fluciclovine (18F) has now been included in the National Comprehensive Cancer Network (NCCN) Guidelines for restaging recurrent prostate cancer. Moreover, salvage radiotherapy is being offered at increasingly lower PSA levels, and evidence is accumulating that boosting radiotherapy dose to foci of active disease may result in clinical benefit. Preliminary analysis of still accruing data from our ongoing clinical trial (5R01CA129356: NCT01666808) suggests that integrating fluciclovine may result in a small improvement in failure rate, but not have adequate sensitivity to definitively achieve durable PSA control with standard radiotherapy doses. Yet, there is early evidence that a new class of PET radiotracer targeting the prostate specific membrane antigen (PSMA) receptor may have greater sensitivity at lower PSA levels for disease detection. Gallium-68 (68Ga) PSMA is one such PSMA PET ligand, though not FDA approved. Each class of PET radiotracer, amino acid metabolic (fluciclovine) vs receptor based (PSMA), exhibits advantages and disadvantages. Our hypothesis is that by utilizing a higher affinity PET ligand, we can better select and manage patients who will benefit from salvage radiotherapy undertaken at lower PSA levels. In addition, we hypothesize that by dose escalating targets identified with either fluciclovine (18F) or 68Ga PSMA, we will determine if dose escalation in itself provides improved PSA control. To test these hypotheses with the highest scientific rigor, we will conduct a prospective clinical trial in which patients who are eligible for salvage radiotherapy are randomized to either fluciclovine (18F) or 68Ga PSMA PET/CT. We will explore if positive specific tissue biomarker signatures may be useful to help predicts post-prostatectomy radiotherapy outcomes in combination with the standard risk criteria. Our proposal is timely since recent editorials in the literature regarding salvage radiotherapy post-prostatectomy call for integration of molecular imaging in prospective, randomized, controlled trials with toxicity analyses of the type we will carry out.