The use of proton therapy has been a topic of debate for years. In the article that accompanies this editorial, Liao and colleagues report the first randomized study to assess the value of proton therapy compared with photon intensity-modulated radiotherapy (IMRT) in non–small-cell lung cancer (NSCLC). Completion of this study is not trivial because the evaluation of the benefit of a new technology rarely has been done during the century-long history of radiation oncology practice. A trial on the effectiveness of proton technology is particularly timely with the growing number of proton facilities in the United States and worldwide and its implication for value-based medicine. Is a randomized trial needed for an advanced radiation technology with a clear benefit in terms of radiation dosimetry, such as proton therapy? A consensus has not been reached in the field with regard to this question. Although some ask for clinical outcome data, somemay believe that a randomized trial is not needed because the dose to the tumor target can be increased, which means that higher tumor control probabilities and/or the dose to normal, nontumor-containing volumes can be decreased, thereby reducing the risks of normal tissue complications. Somemay even argue that conducting a trial to test the significance of such a treatment is unethical, like performing a randomized study to test the value of parachutes, because it will put patients at risk for unneeded radiation complications. Such beliefs have been reflected in the history of radiotherapy technology advancement. From the first uses of x-rays and radium for cancer treatment in the early 1900s, to kilovoltage (superficial) x-ray machines and the era of cobalt-60 and megavoltage two-dimensional treatment, to Linacbased three-dimensional conformal technology and the current widespread use of IMRT, technologies have been developed and implemented routinely in the clinic without randomized trials. Similar scientific and ethical arguments were made erroneously for surgical and medical oncology disciplines, such as for breast cancer, until randomized trials subsequently showed that radical mastectomy was not better than breast-conserving therapy and that high-dose chemotherapy with stem-cell rescue was not beneficial in metastatic breast cancer. Protons have been recognized for their physical dosimetric advantage in phantom andmodel studies as a result of the unique dose distribution described by the Bragg peak (sparing normal tissue distal to the target) and branded as “the sharpest scalpel for cancer treatment” shown in one advertisement. The concept of using protons for cancer therapy was first developed by Robert Wilson, PhD, early in 1946; the first patient was treated in 1954 in the Berkeley Radiation Laboratory; and the first fractionated treatment was performed in 1974. However, implementation in clinical practice has been slow mainly because of the high cost of building the machine and the corresponding facility (a multiroom proton center costs approximately 40 times more than a conventional megavoltage photon radiation or IMRT facility) as well as challenges in developing and implementing reliable dose-computation approaches. In addition, proton treatment and machine maintenance are much more expensive than photon therapy. Although 9,116 patients were treated with protons over 41 years at a joint program of Harvard Cyclotron Laboratory and the Massachusetts General Hospital before the cyclotron was shut down in 2002, hospital-based proton machines were not built until 1989 in the United Kingdom and 1990 in Loma Linda, California. Initially, protons were used mainly on fixed tumors, such as those in the base of the skull, and in pediatric patients. Could lung cancer, which presents a moving target with uncertainty of proton attenuation in low-density lung tissues, be treated effectively and cost-effectively? Comparative clinical outcome data are needed for patients and their families to choose a cancer treatment modality that is not readily available, for physicians tomake treatment recommendations, for investors/industry to determine where to spend resources, for insurance companies and government to make reimbursement policies, and for researchers to know how and where to focus their efforts. Thus, a randomized trial is needed to generate unbiased evidence for this extremely costly technology. The randomized trial reported by Liao and colleagues aimed to determine whether patients treated with proton therapy would have a lower risk of grade $ 3 radiation pneumonitis (RP) in locally advanced NSCLC. The study hypothesized a 10% reduction in grade $ 3 RP for the passive scattering proton therapy (PSPT) arm compared with the photon IMRTarmwithout compromise of local tumor control. No attempt was made in this study to improve tumor control; the rationale was only to decrease toxicity. In contrast to the largest retrospective study of patients from the National Cancer Database, this prospective randomized study failed to prove superiority of proton therapy. Instead, the PSPT arm had 10.5% grade $ 3 RP compared with only 6.5% in the IMRT arm, despite a significant reduction in low-dose volume in the dosimetric histograms for the PSPT arm. Significant dosimetric sparing of the heart and esophagus in the proton armwas found. The primary study outcomes of grade $ 3 RP and local failure were comparable with

中文翻译：

---

当质子遇到随机化时会发生什么：质子治疗有未来吗？

多年来，质子疗法的使用一直是一个争论的话题。在这篇社论随附的文章中，Liao 及其同事报告了第一项随机研究，以评估质子治疗与光子调强放疗 (IMRT) 相比在非小细胞肺癌 (NSCLC) 中的价值。完成这项研究并非易事，因为在长达一个世纪的放射肿瘤学实践中，很少对新技术的益处进行评估。随着美国和世界范围内越来越多的质子设施及其对基于价值的医学的影响，质子技术有效性的试验特别及时。是否需要一项在辐射剂量测定方面具有明显益处的先进辐射技术的随机试验，比如质子治疗？关于这个问题，业界尚未达成共识。虽然有些人要求提供临床结果数据，但有些人可能认为不需要随机试验，因为可以增加肿瘤靶点的剂量，这意味着更高的肿瘤控制概率和/或正常、不含肿瘤体积的剂量可以减少，从而降低正常组织并发症的风险。有些人甚至可能会争辩说，进行试验来测试这种治疗的重要性是不道德的，就像进行一项随机研究来测试降落伞的价值一样，因为它会使患者面临不必要的辐射并发症的风险。这种信念已经反映在放射治疗技术进步的历史中。从 1900 年代初期 X 射线和镭首次用于癌症治疗开始，到千伏（浅表）X 光机和钴 60 和兆伏二维治疗时代，到基于直线加速器的三维适形技术和目前广泛使用的 IMRT，这些技术已经在临床中常规开发和实施，没有随机化试验。类似的科学和伦理争论也被错误地用于外科和肿瘤内科学科，例如乳腺癌，直到随后的随机试验表明，根治性乳房切除术并不比保乳治疗好，并且干细胞挽救的高剂量化疗并不对转移性乳腺癌有益。由于布拉格峰描述的独特剂量分布（保留靶标远端的正常组织），质子因其在体模和模型研究中的物理剂量学优势而被认可，并在一个广告中被称为“最锋利的癌症治疗手术刀” . 使用质子治疗癌症的概念最早由 Robert Wilson 博士于 1946 年提出；1954 年，第一位患者在伯克利放射实验室接受治疗；第一次分次治疗是在 1974 年进行的。 然而，在临床实践中的实施一直很慢，主要是因为建造机器和相应设施的成本很高（多房间质子中心的成本大约是传统兆压光子辐射或 IMRT 设施的 40 倍）以及开发和实施可靠的挑战剂量计算方法。此外，质子治疗和机器维护比光子治疗贵得多。尽管在回旋加速器于 2002 年关闭之前，在哈佛回旋加速器实验室和马萨诸塞州总医院的联合项目中，9,116 名患者在 41 年的时间里接受了质子治疗，但直到 1989 年在英国和 1990 年在洛马才建造了基于医院的质子机器加利福尼亚州琳达。最初，质子主要用于固定的肿瘤，例如颅底和儿科患者中的那些。肺癌是一个移动目标，在低密度肺组织中质子衰减不确定，能否得到有效和具有成本效益的治疗？需要比较临床结果数据，以便患者及其家属选择不易获得的癌症治疗方式，医生提出治疗建议，投资者/行业确定资源的使用地点，保险公司和政府制定报销政策，并让研究人员知道如何以及在哪里集中精力。因此，需要一项随机试验来为这种极其昂贵的技术生成公正的证据。Liao 及其同事报告的随机试验旨在确定接受质子治疗的患者在局部晚期 NSCLC 中是否具有较低的 3 级放射性肺炎 (RP) 风险。该研究假设与光子 IMRTarm 相比，被动散射质子治疗 (PSPT) 臂的 3 级 RP 降低 10%，而不会影响局部肿瘤控制。本研究未尝试改善肿瘤控制；理由只是为了减少毒性。与来自国家癌症数据库的最大的患者回顾性研究相比，这项前瞻性随机研究未能证明质子治疗的优越性。相反，尽管 PSPT 组的剂量学直方图中的低剂量体积显着减少，但 PSPT 组的 3 美元 RP 为 10.5%，而 IMRT 组仅为 6.5%。发现质子臂中心脏和食道的显着剂量保留。3 级 RP 和局部失败的主要研究结果与