主要研究發現
• 適應性治療的成效取決於治療中期的 PET 結果和何杰金氏淋巴癌 (HL) 病人的分期。
• 雖然根據治療中期 PET 掃描的陰性結果，進行降階治療對早期 HL 的成效尚不確定，但可能對於中期 HL 的整體存活率和無惡化存活期影響不大。
• 對於晚期 HL，治療中期 PET 掃描結果呈陰性後減少化學治療或放射治療可能對整體存活率有益。
• 治療中期 PET 掃描呈陽性後，用利妥昔單抗 (rituximab) 升階治療可能會增加不良事件，而不是改善存活率。
什麼是何杰金氏淋巴癌？
何杰金氏淋巴癌 (HL) 是一種屬於淋巴系統的罕見癌症（淋巴是免疫系統的一部分，負責保持體液平衡並保護身體免於感染）。其症狀是淋巴組織無痛腫脹，有些人會發燒、夜間盜汗以及非預期的體重減輕。HL 是世界上治癒率非常高的一種癌症，通常採用化學治療，有時結合放射療法，這取決於疾病分期。
什麼是正子斷層掃描？
正子斷層掃描 (PET) 是一種影像技術，利用注射放射性液體（是以糖質為基底）來觀察體內組織細胞的活動。由於癌細胞通常生長迅速，會需要大量能量。它們因此吸收了更多帶有放射性標記的糖注射液，而在掃描時看起來更亮。正子斷層掃描（PET）通常用於判斷癌症的病程分期，或作為治療反應評估的工具。近年來，也被應用於治療期間，以觀察是否能根據癌細胞的活性程度調整治療方式。對於化學治療反應良好的人，治療可能會減少，因此對於所謂的 PET 陰性病人即其癌細胞活性較低的，可減少長期不良反應（不良事件）的風險。對於反應較差的病人，治療可能會增加，進而提升癌細胞活性，則稱為 PET 陽性。
我們想要了解什麼？
我們想知道治療期間進行 PET 掃描後的治療調整是否能提高整體存活率、無疾病惡化時間（無惡化存活期）、治療相關死亡率、不良反應和生活品質。這包括在中期PET掃描結果為陰性時減少治療，或在結果為陽性時增加治療。
我們做了什麼？
我們系統性地搜尋了相關醫學資料庫中的研究，發現了 10 項於 2023 年 11 月 17 日之前發表的隨機對照研究，並根據 PET 狀態（陰性或陽性）和階段（早期至中期或晚期）對其進行了評估和統合分析。
我們發現了什麼？
我們發現 10 項研究包括：1 項研究納入了 667 名早期 HL 病人；1 項研究納入了 651 名中期 HL 病人；3 項研究納入了 1,639 名早期至中期 HL 病人（其中一項研究將這兩組病人分開）。5 項研究納入 3,629 名晚期 HL 病人。所有研究均探討了 PET 掃描呈陰性後，停止放射治療是否有益，但只有 3 項研究調查了 PET 掃描呈陽性的病人接受更密集治療後的結果。
早期、中期 HL 的標準治療通常包括化學治療和放射治療。對於早期 HL，尚不確定 PET 掃描結果為陰性後，停止放射治療是否對存活期和無惡化存活期有益。它可能對嚴重的不良反應或其他癌症的形成幾乎沒有影響。
對於中期 HL，在治療中期 PET 檢查結果為陰性後，停止放射治療可能不會對整體存活率和無惡化存活期產生負面影響。
目前晚期 HL 的標準治療方法是強度更高的化學治療。根據 PET 掃描的陰性結果，降低化學治療強度可能會提升整體存活率，但對無惡化存活期影響不大。它還可以減少另一種癌症的形成。有些國家採用與早期階段類似的化學治療和放射治療。如果化療期間和化療後 PET 掃描結果均為陰性，則無需進行放射治療，這也許能提高整體存活率和無惡化存活期，並可能減少另一種癌症的形成。
一項研究的證據表明，早期至中期 HL 病人在 PET 掃描呈陽性後進行強度更高的化學治療，可能會提高整體生存率和無惡化存活期，但無法確定病人是否會患上更多或更少的其他癌症。
兩項研究試驗了單株抗體利妥昔單抗合併標準化療是否可以改善療效。它可能不會增加整體存活率或無惡化存活期，但可能會增加嚴重的不良反應和治療相關的死亡率。
本篇文獻回顧的限制為何？
儘管許多研究都有評估不良反應，但並未以我們需要使用的格式報告相關數據。沒有任何研究公佈過有關生活品質的資料。
證據確定性在不同比較中而有所不同。對於早期至中期分期且 PET 結果為陰性的病人省略放射治療、PET 陰性的晚期何杰金氏淋巴癌減少化療強度，以及 PET 陽性的晚期病人使用利妥昔單抗，證據的確定性大多為中等。但對於晚期病人在 PET 陰性後省略放射治療，以及早期至中期病人在 PET 陽性後加強化療，證據確定性則為低至非常低。
In early-stage HL, the effect of interim-PET-based treatment adaptation by omission of radiotherapy is uncertain. No effect was seen on long-term adverse events, although the follow-up of around five years may be too short to see an effect. In intermediate-stage HL, omission of radiotherapy may have little effect on both overall and progression-free survival, serious adverse events and secondary malignancies.
In advanced-stage HL, reducing chemotherapy upon negative interim-PET has the potential to increase overall survival while not negatively affecting progression-free survival and long-term adverse events. If combined modality treatment is opted for, omitting radiotherapy may increase both overall and progression-free survival, while reducing the negative effect of radiotherapy on secondary malignancies.
Interim-PET-positive treatment intensification by providing more chemotherapy in early-to-intermediate stage HL may be beneficial, while adding rituximab to standard chemotherapy in advanced-stage HL does not result in the expected improvement, but increases adverse events.
Hodgkin lymphoma (HL) is one of the most curable cancers worldwide. Treatment options comprise more- or less-intensified regimens of chemotherapy plus radiotherapy depending on the disease stage. An interim-[18F]-fluorodeoxy-D-glucose (FDG)-positron emission tomography (PET), a procedure to illustrate a tumour's metabolic activity, stage and progression, could be used during treatment to distinguish between individuals who are good or poor early responders to therapy. Subsequent therapy could be de-escalated in PET-negative individuals (good responders) or escalated in those who are PET-positive (poor responders).
To assess the effects of interim [18F]-FDG-PET-imaging treatment modification in previously untreated individuals with HL.
For this review update, we searched MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, clinicaltrials.gov and the WHO ICTRP up to 17 November 2023.
We included randomised controlled trials (RCTs) comparing interim-FDG-PET-adapted therapy with non-adapted standard treatment in adults with untreated HL of all stages.
Two review authors independently screened results for inclusion, extracted data into a standardised data extraction sheet and assessed the risk of bias according to the Cochrane risk of bias tool. We collected (modified) intention-to-treat effect estimates for the predefined outcomes: overall survival (OS), progression-free survival (PFS), treatment-related mortality (TRM), adverse events (AE) including secondary malignancies and quality of life (QoL), where available, and used random-effects models for meta-analysis. We analysed early, intermediate and advanced stage HL and PET-negative versus PET-positive participants separately. We used the GRADE approach to rate our certainty in the evidence.
We included 10 studies covering early (1 RCT, 667 participants), intermediate (1 RCT, 651 participants), early-to-intermediate (3 RCTs, 1639 participants) and advanced-stage HL (5 RCTs; 3629 participants). We did not identify eligible ongoing studies.
Generally, the risk of bias was low or, sometimes, unclear except for detection bias, which was rated as high for all studies for subjective outcomes such as PFS, TRM and AE due to the lack of blinding.
PET-based adaptation in early-stage PET-negative participants
The effect of treatment adaptation (omission of radiotherapy with or without additional chemotherapy) on OS and PFS is uncertain (HR 0.84, 95% CI 0.13 to 5.32; and HR 4.52, 95% CI 0.72 to 28.41, 1034 participants). Adaptation may have little to no effect on the incidence of secondary malignancies (RR 0.83, 95% CI 0.46 to 1.50; 984 participants; low-certainty). No studies reported on TRM, serious adverse events (SAE) or QoL.
PET-based adaptation in intermediate-stage PET-negative participants
Treatment adaptation by omission of radiotherapy (with or without additional chemotherapy) may have little effect on OS (HR 0.91, 95% CI 0.42 to 1.96; 1073 participants; low-certainty) and PFS (HR 1.59, 95% CI 0.95 to 2.67; 1073 participants; low-certainty) compared to standard therapy. The effect on TRM is very uncertain. De-escalation may have little effect on the incidence of SAE (RR 1.01, 95% CI 0.84 to 1.21; 1096 participants, low-certainty) and secondary malignancies (RR 1.01, 95% CI 0.57 to 1.82; 1515 participants; low-certainty). No studies reported on QoL.
PET-based de-escalation in advanced-stage PET-negative participants
Three RCTs examined interim-PET-based de-intensification of chemotherapy compared with standard in advanced-stage PET-negative participants; this probably increases OS (HR 0.65, 95% CI 0.40 to 1.07; 2633 participants, moderate-certainty), although the confidence interval included the possibility of no effect, while it has probably little effect on PFS (HR 0.98, 95% CI 0.78 to 1.25; 2633 participants, moderate-certainty). Treatment de-escalation may reduce TRM (RR 0.21, 95% CI 0.06 to 0.73; 2761 participants, low-certainty) and the incidence of secondary malignancy (RR 0.87, 95% CI 0.60 to 1.26; 2757 participants; low-certainty), although for this latter finding, the CI included the possibility of no effect. No studies reported SAE and QoL.
Two RCTs considered combined modality treatment as standard for advanced stages and de-escalated by omitting radiotherapy. De-escalation may increase OS (HR 0.63, 95% CI 0.11 to 3.69; 296 participants; low-certainty), PFS (HR 0.78, 95% CI 0.43 to 1.43; 412 participants; low-certainty), and may reduce the incidence of secondary malignancy (RR 0.41, 95% CI 0.08 to 2.09; 349 participants; low-certainty), although for all these findings, the CI included the possibility of no effect. No studies reported TRM, SAE and QoL.
PET-based escalation in mixed early-and-intermediate-stage, PET-positive participants
One study compared intensified chemotherapy (BEACOPP 升階 ) and radiotherapy with standard chemotherapy (ABVD) and radiotherapy based on positive interim-PET after two cycles in early-to-intermediate-stage HL. Treatment escalation may increase OS (HR 0.92, 95% CI 0.43 to 1.97; 260 participants; low-certainty) and PFS (0.67, 95% CI 0.37 to 1.20; 260 participants; low-certainty), although the CI included the possibility of no effect. The effect on secondary malignancies is very uncertain (RR 1.23, 95% CI 0.43 to 3.55; 234 participants, very low-certainty). No studies reported TRM, SAE and QoL.
PET-based escalation in advanced-stage, PET-positive participants
Two studies examined interim-PET-based escalation of PET-positive participants with rituximab in addition to chemotherapy in advanced-stage HL, which likely does not increase OS (HR 1.39, 95% CI 0.74 to 2.63; 795 participants; moderate-certainty) or PFS (HR 1.03, 95% CI 0.68 to 1.54; 582 participants; moderate-certainty). It may increase TRM (RR 4.00, 95% CI 0.45 to 35.5; 434 participants; very low-certainty), although the CI included the possibility of no effect. Escalation probably increases the number of participants with SAE (RR 1.61, 95% CI 1.00 to 2.60; 148 participants, moderate-certainty), and may reduce the number of participants with secondary malignancy (RR 0.67, 95% CI 0.28 to 1.60; 582 participants; low-certainty), although for this latter finding, the CI included the possibility of no effect. No study reported QoL.
翻譯者：林妤柔 (自由譯者)【本翻譯計畫由臺北醫學大學考科藍臺灣研究中(Cochrane Taiwan)、東亞考科藍聯盟(EACA) 統籌執行。聯絡E-mail：morttot@gmail.com】