STUDY QUESTION What is the impact of the EuroNet-PHL-C2 treatment for boys with classical Hodgkin lymphoma (cHL) on semen parameters? SUMMARY ANSWER More than half of the patients (52%, n = 16/31) had oligozoospermia or azoospermia at 2 years from cHL diagnosis; particularly boys treated for advanced-stage cHL had low sperm counts and motility. WHAT IS KNOWN ALREADY Chemotherapy and radiotherapy to the inguinal region or testes can impair spermatogenesis and result in reduced fertility. The EuroNet-PHL-C2 trial aims to minimize radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. The present study aims to assess the (gonadotoxic) impact of this treatment protocol on semen parameters and reproductive hormones in boys aged ≤18 years. STUDY DESIGN, SIZE, DURATION This international, prospective, multi-centre cohort study was an add-on study to the randomized phase-3 EuroNet-PHL-C2 trial, where the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) was compared to intensified OEPA-DECOPDAC-21 chemotherapy (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide). Patients were recruited between January 2017 and September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligibility criteria included male patients, diagnosed with classical HL before or at the age of 18 years, and treated according to the EuroNet-PHL-C2 protocol in any of the 18 participating sites in the Netherlands, Germany, Belgium, Czech Republic, and Austria. Sperm parameters (sperm concentration, progressive motility, sperm volume, and calculated total motile sperm count) were assessed at diagnosis and 2 years after diagnosis in (post)pubertal boys. Laboratory measurements (serum follicle-stimulating hormone (FSH) and inhibin B) were performed in samples drawn at diagnosis, during treatment (2–3 times), and at 2 years post-diagnosis, and (age-adjusted) analyses were conducted separately for pre-pubertal and (post)pubertal boys. Outcomes were compared between the treatment levels (TL1, TL2, and TL3) and consolidation treatment schemes (COPDAC-28 and DECOPDAC-21). MAIN RESULTS AND THE ROLE OF CHANCE In total, 101 boys were included in the present analysis: 73 were (post)pubertal (median age 15.4 years, (IQR 14.4; 16.6), 10 TL1, 29 TL2, 34 TL3, 62% of TL2/3 patients received COPDAC-28) and 28 boys were pre-pubertal (median age 9.6 years (IQR 6.6; 11.4), 4 TL1, 7 TL2, 17 TL3, 38% of TL2/3 patients received COPDAC-28). The study included six boys who had received pelvic radiotherapy; none were irradiated in the inguinal or testicular area. At diagnosis, 48 (post)pubertal boys delivered semen for cryopreservation; 19 (40%) semen samples were oligospermic and 4 (8%) were azoospermic. Low sperm concentration (<15 mil/ml) appeared to be related to the HL disease itself, with a higher prevalence in boys who presented with B symptoms (76% vs 26%, aOR 2.3 (95% CI 1.0; 3.8), P = 0.001) compared to those without such symptoms. At 2 -years post-diagnosis, 31 boys provided semen samples for analysis, of whom 12 (39%) boys had oligozoospermia and 4 (13%) had azoospermia, while 22 boys (71%) had low total motile sperm counts (TMSC) (<20 mil). Specifically, the eight boys in the TL3 group treated with DECOPDAC-21 consolidation had low sperm counts and low progressive motility after 2 years (i.e. median sperm count 1.4 mil/ml (IQR <0.1; 5.3), n = 7 (88%), low sperm concentration, low median progressive motility 16.5% (IQR 0.0; 51.2), respectively). Age-adjusted serum FSH levels were significantly raised and inhibin B levels (and inhibin B:FSH ratios) were decreased during chemotherapy in (post)pubertal boys, with subsequent normalization in 80% (for FSH) and 60% (for inhibin B) of boys after 2 years. Only 4 out of the 14 (post)pubertal boys (29%) with low sperm concentrations after 2 years had elevated FSH (>7.6 IU/l), while 7 (50%) had low inhibin B levels (<100 ng/l). In pre-pubertal boys, reproductive hormones were low overall and remained relatively stable during chemotherapy. LIMITATIONS, REASONS FOR CAUTION The present analyses included sperm and laboratory measurements up to 2 years post-diagnosis. Long-term reproductive outcomes and potential recovery of spermatogenesis remain unknown, while recovery was reported up to 5- or even 10-year post-chemotherapy in previous studies. Boys who were pre-pubertal at diagnosis were still too young and/or physically not able to deliver semen after 2 years and we could not assess a potential difference in gonadotoxicity according to pubertal state at the time of treatment. Overall, the statistical power of the analyses on sperm concentration and quality after 2 years was limited. WIDER IMPLICATIONS OF THE FINDINGS Results of the semen analyses conducted among the 31 boys who had provided a semen sample at 2 years post-treatment were generally poor. However, additional long-term and adequately powered data are crucial to assess the potential recovery and clinical impact on fertility. The participating boys will be invited to deliver a semen sample after 5 years. Until these data become available, benefits of intensified chemotherapy in cHL treatment to reduce radiotherapy and lower risk for development of secondary tumours should be carefully weighed against potentially increased risk of other late effects, such as diminished fertility due to the increased chemotherapy burden. Boys with newly diagnosed cHL should be encouraged to deliver sperm for cryopreservation whenever possible. However, patients and clinicians should also realize that the overall state of disease and inflammatory milieu of cHL can negatively affect sperm quality and thereby reduce chance of successful fertility preservation. Furthermore, the measurement of FSH and inhibin B appears to be of low value in predicting low sperm quality at two years from cHL treatment. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M.-K., D.K., W.H.W., D.H., MC, A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors declare no potential conflict of interest. TRIAL REGISTRATION NUMBER N/A.

中文翻译：

---

根据 EuroNet-PHL-C2 方案治疗的经典霍奇金淋巴瘤男孩的精液分析和生殖激素


研究问题 EuroNet-PHL-C2 治疗经典霍奇金淋巴瘤 （cHL） 男孩对精液参数有什么影响？总结答案 超过一半的患者 （52%，n = 16/31） 在 cHL 诊断后 2 年患有少精症或无精子症;特别是接受晚期 cHL 治疗的男孩，精子数量和活力较低。已知的 腹股沟区域或睾丸的化疗和放疗会损害精子发生并导致生育能力下降。EuroNet-PHL-C2 试验旨在通过加强化疗来最大限度地减少标准儿童 cHL 治疗中的放疗。本研究旨在评估该治疗方案对 18 ≤男孩精液参数和生殖激素的（性腺毒性）影响。研究设计、规模、持续时间 这项国际、前瞻性、多中心队列研究是随机 3 期 EuroNet-PHL-C2 试验的附加研究，其中 OEPA-COPDAC-28 的标准 cHL 治疗疗效（OEPA：长春新碱、依托泊苷、泼尼松和阿霉素;COPDAC-28：环磷酰胺、长春新碱、泼尼松和达卡巴嗪）与强化 OEPA-DECOPDAC-21 化疗（DECOPDAC-21：COPDAC 加额外的阿霉素和依托泊苷以及 25% 以上的环磷酰胺）进行了比较。患者于 2017 年 1 月至 2021 年 9 月期间招募。参与者/材料、设置、方法 资格标准包括男性患者，在 18 岁之前或时被诊断患有经典 HL，并根据 EuroNet-PHL-C2 方案在荷兰、德国、比利时、捷克共和国和奥地利的 18 个参与地点中的任何一个进行治疗。 在诊断时和诊断后 2 年评估青春期男孩的精子参数 （精子浓度、进行性运动、精子量和计算的总活动精子计数）。在诊断时、治疗期间（2-3 次）和诊断后 2 年抽取的样本中进行实验室测量（血清促卵泡激素 （FSH） 和抑制素 B），并分别对青春期前和（后）青春期男孩进行（年龄调整）分析。比较治疗水平 （TL1 、 TL2 和 TL3） 和巩固治疗方案 （COPDAC-28 和 DECOPDAC-21） 之间的结局。主要结果和机会的作用 本分析共纳入 101 名男孩： 73 名为（后）青春期（中位年龄 15.4 岁，（IQR 14.4;16.6），10 名 TL1,29 TL2,34 名 TL3,62% 的 TL2/3 患者接受了 COPDAC-28），28 名男孩为青春期前（中位年龄 9.6 岁（IQR 6.6;11.4），4 名 TL1,7 名 TL2， 17 TL3,38% 的 TL2/3 患者接受了 COPDAC-28）。该研究包括 6 名接受过盆腔放疗的男孩;没有在腹股沟或睾丸区域进行照射。在诊断时，48 名（青春期后）男孩输送精液进行冷冻保存;19 例 （40%） 精液样本为少精液，4 例 （8%） 为无精子液。低精子浓度 （<15 mil/ml） 似乎与 HL 疾病本身有关，与没有此类症状的男孩相比，出现 B 症状的男孩患病率更高 （76% vs 26%，aOR 2.3 （95% CI 1.0;3.8），P = 0.001）。诊断后 2 年，31 名男孩提供精液样本进行分析，其中 12 名 （39%） 男孩患有少精症，4 名 （13%） 患有无精子症，而 22 名男孩 （71%） 的总活动精子计数 （TMSC） 较低 （<20 mil）。 具体而言，TL3 组中接受 DECOPDAC-21 巩固治疗的 8 名男孩在 2 年后精子数量低，进行性活力低（即中位精子计数 1.4 mil/ml （IQR <0.1;5.3），n = 7 （88%），精子浓度低，中位进行性活力低 16.5% （IQR 0.0;51.2），分别为）。在（青春期后）男孩化疗期间，年龄调整后的血清 FSH 水平显着升高，抑制素 B 水平 （和抑制素 B：FSH 比率） 降低，随后 2 年后 80% （FSH） 和 60% （抑制素 B） 的男孩恢复正常。14 名精子浓度低的（青春期后）男孩中，只有 4 名 （29%） 在 2 年后 FSH 升高 （x3E7.6 IU/l），而 7 名 （50%） 抑制素 B 水平低 （<100 ng/l）。在青春期前的男孩中，生殖激素总体上较低，并且在化疗期间保持相对稳定。局限性，谨慎的原因 目前的分析包括诊断后长达 2 年的精子和实验室测量。长期生殖结果和精子发生的潜在恢复仍然未知，而在以前的研究中，据报道化疗后长达 5 年甚至 10 年即可恢复。诊断时处于青春期前的男孩仍然太年轻和/或身体上无法在 2 年后输送精液，我们无法根据治疗时的青春期状态评估性腺毒性的潜在差异。总体而言，2 年后精子浓度和质量分析的统计功效有限。研究结果的更广泛意义 在治疗后 2 年提供精液样本的 31 名男孩中进行的精液分析结果普遍较差。 然而，额外的长期和有足够把握度的数据对于评估潜在的恢复和对生育能力的临床影响至关重要。参与的男孩将被邀请在 5 岁后提供精液样本。在获得这些数据之前，应仔细权衡 cHL 治疗中强化化疗对减少放疗和降低继发性肿瘤发展风险的益处与可能增加的其他迟发效应风险，例如由于化疗负担增加而导致的生育能力下降。应鼓励新诊断的 cHL 男孩尽可能输送精子进行冷冻保存。然而，患者和临床医生也应该意识到，cHL 的整体疾病状态和炎症环境会对精子质量产生负面影响，从而降低成功保留生育能力的机会。此外，FSH 和抑制素 B 的测量在预测 cHL 治疗后两年的低精子质量方面似乎价值较低。研究资金/利益争夺 本研究由荷兰慈善基金会 KiKa（项目 257）资助，该基金会资助所有形式的儿童癌症研究。C.M.-K.、D.K.、W.H.W.、D.H.、MC、A.U. 和 A.B. 参与了 EuroNet-PHL-C2 方案的开发。其他作者声明没有潜在的利益冲突。试验注册号 N/A。