Department of Orthopaedic Surgery, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
Clin Orthop Relat Res. 2023 Mar 1;481(3):526-538. doi: 10.1097/CORR.0000000000002243. Epub 2022 May 17.
Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas.
QUESTIONS/PURPOSES: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis?
The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys.
More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups.
There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient.
Level III, therapeutic study.
尽管小儿下肢肉瘤曾经常规采用截肢术治疗，但多种药物化疗以及肿瘤切除和重建技术的发展，使保肢手术（LSS）得以广泛应用。尽管感染和肿瘤复发是 LSS 后早期截肢（<5 年）的既定危险因素，但儿童肉瘤患者中晚期截肢（诊断后≥5 年）的频率和相关因素尚不清楚。此外，与原发性截肢或未因随后截肢而复杂化的 LSS 相比，这些患者的由此产生的心理社会和身体结局尚未得到充分研究。研究这些结果对于提高肉瘤患者的生活质量至关重要。
问题/目的：（1）在参加儿童癌症幸存者研究（CCSS）的下肢肉瘤患者中，治疗方法随时间发生了怎样的变化？在至少存活 5 年的患者中，初次采用截肢术或 LSS 治疗是否会影响 25 年的总体生存率？（2）在诊断为小儿下肢肉瘤 25 年后，LSS 后发生截肢的累积发生率是多少？（3）在 CCSS 中，最初接受 LSS 治疗的下肢肉瘤患者中，哪些因素与晚期截肢（诊断后≥5 年）的时间相关？（4）通过 CCSS 随访问卷、SF-36 和 Brief Symptom Inventory-18，在癌症诊断后 20 年，与接受原发性截肢、无截肢的 LSS 或 LSS 后晚期截肢的患者相比，哪些因素与肉瘤患者的社会、身体和情感健康相关的生活质量（HRQOL）结局相关？
CCSS 是一项长期随访研究，于 1994 年启动，由圣裘德儿童研究医院协调。它是一项回顾性研究，对在美国和加拿大的 31 家合作机构中，31 家合作机构于 1970 年至 1999 年期间治疗的年龄小于 21 岁的儿童癌症幸存者进行了超过 38000 名参与者的纵向随访。在诊断后存活 5 年以上的患者有资格参加 CCSS。在 CCSS 队列中，我们纳入了接受原发性截肢（547 例患者，平均诊断年龄为 13 ± 4 岁）或原发性 LSS（510 例患者，平均诊断年龄为 14 ± 4 岁）治疗的下肢肉瘤患者。LSS 队列分为无截肢的 LSS，定义为在最新随访时无截肢的原发性 LSS；LSS 伴早期截肢，定义为 LSS 并发症少于 5 年的截肢；或 LSS 伴晚期截肢，定义为研究患者在癌症诊断后 5 年或更长时间后进行的原发性 LSS 后截肢。估计原发性 LSS 后晚期截肢的累积发生率。Cox 比例风险回归分析，时间变量包括早期截肢和晚期截肢，以确定与晚期截肢相关的因素。使用验证性调查，改良泊松回归模型比较了接受原发性截肢、无截肢的 LSS 或晚期截肢的 LSS 后患者的心理社会、身体和 HRQOL 结局。
与最近几十年相比，更多的研究参与者接受了 LSS 治疗，而不是原发性截肢。在至少存活 5 年的患者中，该人群的 25 年总生存率在接受原发性截肢（87%[95%置信区间[CI]82%至 91%]）与接受 LSS（88%[95%CI 85%至 91%]）的患者之间无差异（p = 0.31）。在癌症诊断和原发性 LSS 后 25 年的截肢累积发生率为 18%（95%CI 14%至 21%）。根据目前的可用数据，在 20 世纪 70 年代接受治疗的患者中，晚期截肢的累积发生率与 20 世纪 80 年代和 90 年代的患者无差异（分别为 27%[95%CI 15%至 38%]和 19%[95%CI 13%至 25%]和 15%[95%CI 10%至 19%]；p = 0.15）。在控制性别、医疗和手术治疗变量、癌症复发和慢性健康状况后，性别（风险比[HR]2.02[95%CI 1.07 至 3.82]；p = 0.03）和人工关节重建史（HR 2.58[95%CI 1.37 至 4.84]；p = 0.003）与晚期截肢的可能性增加相关。接受原发性截肢（相对风险[RR]2.04[95%CI 1.15 至 3.64]）和 LSS 后晚期截肢（RR 3.85[95%CI 1.66 至 8.92]）的患者比至今未截肢的患者更有可能失业或无法上学。接受原发性截肢和 LSS 后晚期截肢的 CCSS 队列报告的身体健康评分比至今未截肢的患者差，尽管两组的心理和情绪健康结果无差异。
LSS 后晚期截肢的风险很大，原发性和晚期截肢的状态都与身体 HRQOL 结局下降有关。接受原发性截肢和 LSS 后晚期截肢的儿童肉瘤幸存者可能受益于关注改善身体功能和实现教育和就业里程碑的干预措施。应该支持改善那些通过假体设计或与残肢整合来提高截肢患者身体功能的努力。了解在更现代的手术方法和植入物的背景下晚期截肢的相关因素，将有助于外科医生更有效地管理患者的期望，并调整实践，以减轻患者一生中的这些风险。
III 级，治疗性研究。
