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Combo of RT and Chemoimmunotherapy: Best for Early FL? 放疗与免疫化疗联合：早期滤泡性淋巴瘤的最佳治疗策略？
Alexander M. Castellino, PhD July 17, 2018
For the management of early-stage follicular lymphoma (FL), a randomized trial shows that the combination of radiotherapy (RT) with chemoimmunotherapy gives better clinical outcomes that treatment with radiation alone, and the researchers reporting these results say that they should change clinical practice. 一项随机临床试验显示，对于早期滤泡性淋巴瘤，放疗与免疫化疗联合比单独放疗有更好的临床效果，报道这项成果的研究人员认为这将改变临床实践。
After a median follow-up of 9.6 years, the estimated 10-year progression-free survival (PFS) was 59% for patients who received involved-field RT (IFRT) and systemic therapy and 41% for patients who received IFRT alone. 在经过9.6年的中位随访期后，接受了受累野放疗和系统性治疗的患者与仅接受了受累野放疗的患者相比，预计的10年无进展生存率分别为59%和41%。
However, this benefit was apparent only after 5 years; it was at that point that the Kaplan-Meier PFS curves began to separate, not sooner. 然而，获益只在5年后才显示出来，到那个时间点后，PFS曲线开始出现分离，而之前则没有。
The results, from the Trans-Tasman Radiation Oncology Group (TROG), were published online July 5 in the Journal of Clinical Oncology. Radiation oncologist Michael MacManus, MBBCh, MD, from the Peter MacCallum Cancer Center in Melbourne, Australia, was its corresponding author. TROG研究组的结果发表在2018年7月5日的临床肿瘤学期刊上。来自澳大利亚墨尔本Peter MacCallum癌症中心的放射肿瘤学专家Michael Macmanus是通讯作者。
"For patients with stage I to II FL who are treated with curative intent, we recommend treatment with IFRT followed by chemoimmunotherapy as a reasonable evidence-based choice for the standard of care," MacManus and colleagues conclude. “对于I-II期滤泡性淋巴瘤患者，如果以治愈为目的，我们建议采用受累野放疗，然后免疫化疗，以此作为具有一定的循证医学根据的标准治疗手段。”
Will Results Change Management of Early FL? 试验结果能否改变早期滤泡性淋巴瘤治疗的临床实践？
MacManus explained to Medscape Medical News that for early FL, several approaches have been used in its management, but the results of this study should make a difference. MacManus对Medscape医疗新闻解释说，对于早期滤泡性淋巴瘤，各种手段都采用过，但是这项临床试验的结果应该能对未来产生影响。
Because of its long natural history, typically slow rate of progression, and initial responsiveness to chemotherapy, there is a perception that initial therapy in localized FL, or even the withholding of therapy, may not influence the natural history of the disease and that it therefore may not matter very much, MacManus noted. "In the absence of properly conducted randomized trials, all of these approaches have been potentially supportable," he said. "However, our trial indicates that initial therapy does matter in early-stage FL and that a nihilistic or laissez-faire approach may not be appropriate in patients who would otherwise have a long life expectancy," MacManus pointed out. 由于滤泡性淋巴瘤自然病程很长，发展通常较为缓慢，最初对化疗应答良好，所以存在一种观念，那就是最初治疗方案的选择，或者暂不治疗，对疾病的自然病程没有什么影响，所以无关紧要，MacManus说。“在没有开展很好的随机试验的前提下，所有这些做法都有一定道理。”“然而，我们的试验显示，对于早期滤泡性淋巴瘤，最初方案的选择是有影响的，对那些原本可以有很长的预期寿命的患者来说，采取一种虚无或者无所谓的态度恐怕是不合适的。”MacManus指出。
"Our standard approach in the light of our new data is to offer combined-modality therapy to patients with a long life expectancy to give them the best chance of long-term disease-free survival," he said. “有鉴于我们最新的数据，对于那些有很长预期寿命的患者，现在我们的标准做法是联合放化疗以便使其能够有机会获得长期的无疾病生存”，他说。
"To our knowledge, this is the first RCT [randomized clinical trial] providing high-level evidence that the long natural history of localized FL can be affected by adding systemic therapy to standard IFRT," MacManus and colleagues write. “据我们所知，这是到目前为止提供了高级别证据表明在标准的受累野放疗的基础上加上系统性治疗可以影响局限期滤泡性淋巴瘤自然病程的第一项随机临床试验，”MacManus和其同事在文章中写道。
Medscape Medical News reached out to Nadia Khan, MD, a lymphoma expert from the Department of Hematology/Oncology at Fox Chase Cancer Center, Philadelphia, Pennsylvania, to weigh in on the significance of this study and its impact on clinical practice. Medscape医疗新闻联系到了宾州Fox Chase癌症中心的淋巴瘤专家Nadia Khan，请她就此项研究对临床实践的影响给予评论。
"While this is a well-designed study, with statistically meaningful results, the conclusions are not clinically impactful because of practice trends in early-stage FL," Khan said. “尽管这是一项设计很好的试验，试验结果也具有统计学意义，但是因早期滤泡性淋巴瘤临床实践上的趋势的原因，不具有很大的临床意义”。
"The current guidelines are not likely to change based on the results of this study," she predicted. “目前的指南不大可能因为此项研究的结果而改变，”她预测道。
Khan explained that patients with early-stage, low-tumor-burden FL are typically managed with watchful waiting. "Initiating treatment at early time points is reserved for specific scenarios, including nodal disease confined to a radiation treatment field," she said. Khan解释说，早期低肿瘤负荷的滤泡性淋巴瘤通常采用观察等待的策略。“在较早的时间点开始治疗仅限于某些情况，包括结节型疾病局限于同一个放射野。”
Referring to a Stanford University study, Khan explained that in these instances RT provides 5-year and 10-year disease-free survival of 55% and 44%, respectively and is currently the treatment of choice (J Clin Oncol. 1996;14:1282-1290). 参考斯坦福大学的一项研究，Khan解释说在这种情况下放疗可以提供55%和44%的5年和10年无疾病生存率，是目前推荐的治疗选择。
Details of the TROG 99.03 Study TROG 99.03研究的细节
TROG 99.03 was a phase 3 randomized, multicenter, international study that enrolled patients with grade 1, 2, or 3a FL who were staged by using CT, bone marrow aspiration, and trephine biopsies. Staging with 18F-labeled fluorodeoxyglucose was allowed but not mandated. TROG 99.3是一项3期随机多中心国际临床研究，入组的患者包括1级，2级或3a级滤泡性淋巴瘤患者，这些患者通过CT，骨穿和骨髓活检进行分期。也允许用PET分期，但PET分期不是必须。
The trial originally planned to accrue 200 patients, but following slow accrual of 150 patients over 12 years the data monitoring committee approved a sample size revision after reviewing trial events blinded to study group. 这项研究最初计划入组200位患者，但是由于入组较慢，在12年内才入组了150位患者，数据监督委员会经讨论批准了样本数的改变。
MacManus explained to Medscape Medical News that accrual was slow mainly because the study arms were so different in intensity. "It was hard for some patients to accept random allocation to six cycles of chemo with no proven benefit. Alternatively, it was hard for other patients to accept RT alone when an MD Anderson phase 2 study showed that combined-modality therapy could be much better than RT alone," he said. MacManus向Medscape医疗新闻解释说，入组慢的主要原因是各组的治疗强度相差太大。“在没有明确证据可以获益的情况下很难让一些患者随机接受六个疗程的化疗。换过来说，当MD Anderson的2期试验显示放化疗联合明显比单独放疗更好的情况下，也很难让其他患者接受只做放疗的选择。”
"Many patients just declined randomization and decided that they would choose their own therapy," he added. “很多患者干脆拒绝入组而决定采用自己想要采取的治疗手段”，他补充道。
RT volume included all disease and resected (nodal and extranodal) sites with a margin of 1 to 2 cm. Specified anatomic locations received small conformal treatment volumes; nonbulky sites received 30 Gy in 1.5- to 2-Gy fractions. 放疗靶区包括所有的疾病部位以及切除部位（结内或结外）并留有1到2厘米的裕量。特殊解刨部位接受小的适形放疗；非巨块部位接受30Gy的剂量，每次1.5Gy到2Gy。
Systemic therapy was initially CVP (cyclophosphamide, vincristine, and prednisolone) until a protocol amendment required rituximab (R; Rituxan, Genentech/Roche) to be added; R-CVP was given 4 weeks after completion of IFRT at standard doses. 系统性治疗最初采用CVP方案，后来改为R-CVP。标准剂量的R-CVP在受累野放疗结束四周后开始。
TROG 99.03 Study Results TROG 99.03研究结果
The trial accrued 75 patients to each study group. Half the patients had stage I FL, and positron emission tomography was used for staging in approximately half the patients. A higher proportion of patients in the combination IFRT and R-CVP group had infradiaphragmatic involvement (59% vs 41% for IFRT alone), extranodal disease (58% vs 42% for IFRT alone), and grade 1 disease (62% vs 38%). Approximately half the patients had bulky disease (>5 cm). 研究的每个试验组入组75位患者。一半患者是I期滤泡性淋巴瘤，大约有一半的患者用PET做分期。在放化疗联合组有较高比例的患者存在膈下病灶（59%对单独放疗组的41%），结外疾病（58%对单独放疗组的42%），和1级疾病（62%对38%）。大约一半的患者是巨块型疾病（>5cm）。
For the primary endpoint, PFS was superior for patients who received combined IFRT and R-CVP (hazard ratio [HR], 0.57; P = .033). When an analysis was done only on the basis of study population that received R-CVP (after protocol amendment), the HR was 0.26 (P = .045), favoring the combined modality. Indeed, R-CVP was better than CVP because an analysis done for the pre-rituximab period provided a nonsignificant HR of 0.70 (P = .24) for the combined modality vs IFRT alone. However, the data were insufficient to determine whether R-CVP was superior to CVP. 作为试验的主要终点，接受放化疗联合治疗的患者的PFS占优（风险比HR，0.57, P=.033）。当仅分析接受R-CVP治疗的患者时，HR为0.26（P=.045），更加偏向于联合治疗。确实，R-CVP比CVP更好，因为在美罗华出现之前放化疗联合与单独放疗相比的HR为0.7（P=.24），优势并不明显。不过，确定R-CVP优于CVP的数据还不够充分。
The authors noted that none of the patients who had a follow-up beyond 3.5 years experienced a relapse. Moreover, only 2 of 148 patients who received IFRT experienced progression within the IFRT volume. Of 11 local progressions, 1 occurred 5 years beyond randomization and 14 of 49 distant progressions occurred before 5 years. 作者注意到随访时间超过3.5年的患者没有一例复发（原文如此，疑为笔误，应该是13.5年）。此外，148位接受了放疗的患者中仅有2位出现了靶区内的复发。在11位出现局部进展的患者中，1例发生在入组5年之后，49例远端复发的中14例发生于5年之内。
Ten-year overall survival was nonsignificant between the two study groups (95% for combined modality vs 86% IFRT alone), and transformation to aggressive lymphoma (eg, diffuse large B-cell lymphoma, Burkitt's lymphoma) was reported for 14 patients (4 given combined modality and 10 given IFRT alone). 两个试验组的10年的总生存率相差不大（放化疗联合组95%对放疗组86%），14例转化为侵袭性淋巴瘤（例如弥漫大B细胞淋巴瘤，伯基特淋巴瘤），其中4例来自放化疗联合组，10例来自放疗组。
Acute grade 1/2 toxicity was frequent in the 148 patients who received IFRT, but grade 3/4 toxicity was rare (2%). One patient experienced grade 3 mucositis and one patient experienced grade 4 esophageal/pharyngeal mucosal toxicity. 急性1/2级毒性反应在148位接受放疗的患者中发生频繁，但是3/4级毒性反应罕见（2%）。一位患者出现3级粘膜炎，一位患者经历了4级食道/咽喉粘膜毒性反应。
Acute grade 1/2 toxicity was also frequent in the 69 patients who started systemic therapy. Grade 3 toxicity (neutropenia, infection, diarrhea, elevated γ-glutamyltransferase, fatigue, febrile neutropenia) was seen on 35 occasions. Grade 4 neutropenia occurred in 10 patients and acute grade 3 vincristine-related neuropathy occurred in three patients. 急性的1/2级毒性在69位接受系统性治疗的患者中也很普遍。3级毒性（中性粒缺乏，感染，腹泻，转氨酶异常，疲劳，发热性中性粒缺乏）出现了35人次。10位患者出现4级中性粒缺乏，3位患者出现3级急性长春新碱相关的神经炎。
Use of Only Chemo in Early FL Inappropriate 早期滤泡性淋巴瘤患者仅做化疗不合适
MacManus told Medscape Medical News that despite the effectiveness, low toxicity, and curative potential of RT, systemic therapy with combination chemotherapy, which is typically more toxic than RT and not generally considered curative, is already widely used in the community for treating curable early-stage FL. MacManus告诉Medscape医疗新闻尽管放疗有效、低毒并有治愈潜能，毒性更大而且通常不具有治愈潜能的系统性治疗，即联合化疗在早期的可治愈的滤泡性淋巴瘤中应用却更广泛。
"Our trial suggests that a combination of RT and effective systemic therapy upfront might cure a much greater proportion of patients than RT alone, especially if the systemic therapy contains rituximab," he said. “我们的试验提示，在一线治疗中将放疗与有效的系统性治疗相结合，有可能可以治愈比单独放疗高很多的比例的患者，特别是当系统性治疗中包含美罗华的时候”，他说。
With a 10-year PFS of 59% for patients receiving the combined modality, can these patients be considered cured? MacManus told Medscape Medical News that the Stanford experience referred to earlier had a 30-year follow-up and indicated that relapses are rare after 10 years and that patients who are free from relapse after 10 years are "close to a cure," he commented. 鉴于接受了放化疗联合治疗的患者的10年PFS达到59%，可否认为这些患者是被治愈了呢？MacManus告诉Medscape医疗新闻，根据先前提到的斯坦福的经验，在30年的随访期中发现10年后复发的情况非常罕见，所以，10年尚未复发的患者可以认为是“接近被治愈了”。
However, he expressed disappointment in clinical practice because RT was often requested for patients with localized FL who were treated with one or more chemotherapy regimens and relapsed at original sites of disease. "Although radiotherapy remained effective, unnecessary therapy had been given," he said. 但是，他对目前的临床实践表示失望，局限期的滤泡性淋巴瘤通常会接受一个或更多的化疗方案的治疗，然后在原位复发，这时候才会被推荐去做放疗。“尽管放疗仍然会有效，但是患者之前接受了不必要的治疗。”
Khan expressed surprise to hear that chemotherapy may typically be used in treating low-volume FL. "Chemotherapy is not considered the mainstay of treatment for early-stage FL," she said. "When there is no OS [overall survival] advantage, administering chemotherapy is controversial because of short-term and long-term toxicities. Chemotherapy is reserved for patients who are symptomatic from their FL or who have bulky lymphoma," Khan said. Khan对低负荷滤泡性淋巴瘤通常采用化疗治疗表示了惊讶。“化疗不是早期滤泡性淋巴瘤的主要治疗手段，”她说，“当没有总生存期上的获益的时候，采用化疗是存在争议的，因为其短期以及长期的毒性。化疗仅限于有症状的滤泡性淋巴瘤或者巨块型疾病。”
Conflict-of-interest disclosures are available at the end of the publication. MacManus has disclosed no relevant financial relationships.
J Clin Oncol. Published online July 5, 2018. Abstract
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