Hypofractionated IMRT for Localized Prostate Cancer

描述（由申请人提供）：越来越多的令人信服的证据表明，通过向前列腺输送更高的累积辐射剂量，可以改善许多局限性前列腺癌患者的放射治疗结局。这些剂量递增方案采用1.8-2.0戈伊的相对较小的部分大小，这是基于具有较低α/β比的晚期响应正常组织相对于具有较高α/β比的大多数肿瘤得以保留的证据。对于前列腺肿瘤，需要多达38至45次或更多的治疗，以使用这些小部分尺寸递送74戈伊或更高的递增剂量。 然而，与这些预期相反，最近对临床前列腺癌放射反应数据的分析表明，前列腺癌的α/β比值较低，约为1.5戈伊，而不是大多数肿瘤预期的8戈伊或更高的典型比值。该值低于通常归因于相邻器官（膀胱和直肠）的3值，可能是因为前列腺肿瘤具有异常低的增殖率。这意味着在前列腺癌中有一个不寻常的机会，可以通过更少但更大的放射治疗来提高放射生物学治疗的治疗率-换句话说，就是低分割。低剂量分割有更好的治疗比，可以在不增加晚期毒性的情况下提高肿瘤控制率。 本申请：1）回顾了我们自己和其他人的工作，这些工作为前列腺肿瘤对大剂量辐射的相对高敏感性提供了证据; 2）开发并描述了一项多机构I/II期临床试验，该试验将在250名患者中测试前列腺低分割既可行又有效的假设，以及描述了一项相关研究，该研究检查了放射低分割后某些生物标志物的状态与临床结果之间的关系。该提案结合了四个机构和四组研究人员的努力，这些研究人员在放射生物学建模、放射低分割的临床应用和最先进的前列腺癌放射治疗前列腺癌方面拥有全面的经验。 希望本研究的结果能够证明大分割放射治疗是安全的，并且至少与积极的、常规剂量递增的剂量一样有效。如果证明可行，涉及的较少治疗部分也将产生显著的经济和资源利用优势，并将减少与许多当前剂量递增方案中通常需要的38次或更多治疗相关的患者负担。

DESCRIPTION (provided by applicant): There is increasingly convincing evidence that radiotherapy outcomes for many patients with localized prostate cancer can be improved by delivering higher cumulative radiation doses to the prostate. These dose escalation regimens employ relatively small fraction sizes of 1.8-2.0 Gy, based upon evidence that late responding normal tissues, with their lower alpha/beta ratios, are spared relative to most tumors with their higher alpha/beta ratios. For prostate tumors, as many as 38 to 45 or more treatments have been required to deliver escalated doses of 74 Gy or higher using these small fraction sizes. Contrary to these expectations, however, recent analyses of clinical prostate cancer radioresponse data have indicated a low alpha/beta ratio for prostate cancer on the order of 1.5 Gy, not the typical ratio of 8 Gy or higher expected for most tumors. This value is lower than the value of 3 typically ascribed to the adjacent organs at risk, bladder and rectum, probably because prostate tumors have unusually low proliferation rates. What is implied is an unusual opportunity in prostate cancer to improve the therapeutic ratio radiobiologically by treating with fewer but larger fractions of radiation - in other words, with hypofractionation. With a better therapeutic ratio, hypofractionation should lead to higher rates of tumor control without increase in late toxicity. This application: 1) reviews the work of ourselves and others providing evidence for the high relative sensitivity of prostate tumors to large radiation fraction sizes; 2) develops and describes a multi-institutional phase l/ll clinical trial that will test in 250 patients the hypotheses that prostate hypofractionation is both feasible and efficacious and 3) describes an accompanying correlative study that examines the relationship between the status of certain biomarkers and clinical outcome after radiation hypofractionation. This proposal combines the efforts of four institutions and four sets of investigators who collectively have comprehensive experience with the radiobiological modeling, the clinical application of radiation hypofractionation and state-of-the-art prostate cancer radiotherapy for prostate cancer. It is hoped that outcomes from this study will demonstrate that hypofractionated radiotherapy is safe and is at least as efficacious as aggressive, conventional-fraction-size dose escalation. If proven feasible, the fewer treatment fractions involved would also result in significant economic and resource utilization advantages and would reduce the patient burden associated with the 38 or more treatments typically required in many current, dose escalation regimens.