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

项目摘要/摘要 目前，在PSA失败后接受前列腺癌切除术后放射治疗的患者中，有50%的患者表现出 随后的全身性疾病。与使用分子放射性示踪剂的PET/CT相比，常规成像 这些方法在确定前列腺癌复发部位方面存在不足。我们的目标是向未得到满足的公众发表讲话 提高复发性前列腺癌患者长期生化控制的健康需要。 我们已经验证了一个关键的科学前提，即用合成的氨基推进分子成像 酸性PET放射性示踪剂氟西洛韦(18F)(抗3-[18F]FACBC)导致明显更严重的疾病 检测，管理方面的变化为40.5%，计划量的变化为83.6%(不含剂量 升级)与传统成像相比。在我们的审判过程中，很大程度上是因为 在我们的翻译工作中，Flucicloine(18F)于2016年被FDA批准用于复发前列腺癌， 为新的护理标准做出贡献。从1.2018版开始，Fluciclovine(18F)现已包含在 国家综合癌症网络(NCCN)复发前列腺癌再分期指南。 此外，补救放射治疗的PSA水平越来越低，有证据表明 积累对活动性疾病病灶加大放射治疗剂量可能会产生临床效益。 我们正在进行的临床试验中仍在积累的数据的初步分析(5R01CA129356：NCT01666808) 提示整合Flucicloine可能会导致失败率的小幅改善，但不足以 通过标准放射剂量最终实现持久PSA控制的敏感度。然而，还有很早的 一种新型针对前列腺特异性膜抗原(PSMA)的PET放射性示踪剂的证据 在较低的PSA水平时，受体可能对疾病检测具有更高的敏感性。镓-68(68Ga)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 (氟西洛韦)与基于受体的(PSMA)，显示出优势和劣势。 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 将受益于较低PSA水平的补救放射治疗的患者。此外，我们 假设通过剂量递增的靶点确定的Fluciclovine(18F)或68Ga PSMA，我们 将确定剂量增加本身是否提供了更好的PSA控制。用来检验这些假设的方法 以最高的科学严谨性，我们将进行一项前瞻性的临床试验，在试验中，符合条件的患者将 补救放射治疗被随机分为Flucicloine(18F)或68GaPSMA PET/CT。我们将探索是否 阳性的特定组织生物标志物特征可能有助于预测前列腺切除术后的放射治疗 结果与标准风险标准相结合。我们的建议是及时的，因为最近在 有关前列腺摘除术后挽救放射治疗的文献呼吁整合分子影像。 我们将进行的前瞻性、随机性、对照试验和毒性分析。

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.