Outcomes of isolated limb perfusion in the treatment of extremity soft tissue sarcoma: A systematic review

Background

Isolated limb perfusion (ILP) may provide a limb salvage option for locally advanced soft tissue sarcoma (STS) not amenable to local resection.

Methods

A systematic review was performed for studies reporting outcome of ILP for locally advanced STS performed after 1980 in patients aged ≥12 years old. The main endpoints were tumour response and limb salvage rates. Complication and recurrence rates were secondary endpoints.

Results

Eighteen studies were included, providing outcomes for 1030 patients. Tumour necrosis factor-alpha with melphalan was the commonest chemotherapy regime. When reported, 22% of cases achieved a complete tumour response (216/964, 15 studies) with an overall response rate of 72% (660/911, 15 studies). At median follow-up times ranging between 11 and 125 months, the limb salvage rate was 81% in patients who otherwise would have been subjected to amputation. However, 27% of patients suffered local recurrence and 40% suffered distant failure. ILP was associated with severe locoregional reactions in 4% (22/603) of patients. Amputation due to complications within 30 days was necessary in 1.2% of cases (7/586, nine studies). There was insufficient evidence to determine the effect of ILP on survival.

Conclusion

ILP induces a high tumour response rate, leads to a high limb salvage rate but is associated with a high recurrence rate. It provides a limb salvage alternative to amputation when local control is necessary.     

Isolated limb perfusion of soft tissue sarcomas: A comprehensive review of literature

Patients with primary irresectable, locally advanced soft tissue sarcomas of the limbs form a challenging group for the treating physician. Multimodality treatment is necessary to guarantee optimal limb salvage and survival rates. Since the introduction of isolated limb perfusion in the late fifties, several treatment regimens have been proposed. Isolated perfusion with melphalan and TNF-α, as part of a multimodality treatment, is regarded as the current best treatment option today. Ongoing studies are investigating potential benefit of other doses, new chemotherapeutic agents and new techniques in perfusion and radiotherapy. This article provides a historical overview of published literature and insight in upcoming treatment techniques.     

Health-related quality of life after isolated limb perfusion compared to extended resection,or amputation for locally advanced extremity sarcoma: Is a limb salvage strategy worth the effort?

IntroductionThe aim of this study was to compare long-term patient reported outcomes (PROs) in patients with locally advanced extremity soft tissue sarcoma (eSTS) after isolated limb perfusion followed by resection (IR), compared to extended resection (ER), primary amputation (A) or secondary amputation after IR (IR-A).MethodsPatients were selected from the respondents of a multi-institutional cross-sectional cohort survivorship study (SURVSARC) conducted among sarcoma survivors registered in the Netherlands Cancer Registry (NCR), 2–10 years after diagnosis. Used PROs were the EORTC QLQ-C30, the Cancer worry scale (CWS), the Hospital Anxiety and Depression Scale (HADS), and the Toronto Extremity Salvage Score (TESS).ResultsWe identified 97 eSTS survivors: IR = 20, ER = 49, A = 20, IR-A = 8. While there were no differences in PROs between IR and ER, results showed better functioning and functionality in both groups versus the amputation groups. The amputation groups scored significantly lower on physical functioning (A = 62.7, IR-A = 65.7 versus IR = 78.0, ER = 82.7, p = 0.001) and role functioning (A = 67.5, IR-A = 52.8 versus IR = 79.2, ER = 80.6, p = 0.039), both EORTC QLQ-C30 scales. Also for the TESS, the scores were significantly lower for the amputation groups compared to the limb sparing groups (upper extremity p = 0.007 with A = 68.9, IR-A = 71.6 versus IR = 93.3, ER = 91.1; lower extremity p < 0.001 with A = 72.2, IR-A50.9 versus IR = 84.5 and ER = 85.5). There were no significant differences between the groups on cancer worry, anxiety and depression.ConclusionHRQoL in eSTS survivors treated with IR or ER is equal; for maintenance of physical functioning and functionality IR and ER outperform an amputation.     

Neoadjuvant Treatment of Locally Advanced Soft Tissue Sarcoma of the Limbs: Which Treatment to Choose?

Soft tissue sarcomas (STSs) form a heterogeneous group of malignant neoplasms arising in the mesenchymal connective tissues. They can develop at any anatomic site but 60% occur in the extremities. Initially, treatment of STS relied solely on excision. In the 1970s, Enneking et al. developed the concept of compartmental resection to reduce the local failure rate. Later, Rosenberg et al. demonstrated, in a randomized study, that there was no difference in local tumor control and disease-free survival (DFS) in patients treated with amputation versus limb-saving surgery followed by 50-70 Gy external-beam radiotherapy (EBRT). A considerable proportion of patients present with locally advanced tumors as a primary or recurrent disease and cannot be resected with adequate clearance margins. These patients are threatened with amputation for complete tumor removal. Improvements in surgical techniques, such as microvascular muscle flaps, allow for the avoidance of limb loss in the majority of cases. However, the use of frozen sections to determine intraoperatively whether clear margins have been achieved is limited by the multiplanarity of resection specimens. Thus, local failure rates are 15%-25%, and preoperative measures to sterilize the invasive margin of sarcomas have been explored. High-dose preoperative EBRT for high-grade STS was developed, and its combination with intra-arterial or i.v. chemotherapy was reported to be effective. Recently, systemic chemotherapy combined with deep wave hyperthermia was shown to result in a longer DFS time in a large, randomized, phase III study. Treatment concepts differ significantly among centers and are influenced more by availability of technical equipment than by data. It is the aim of this review to elucidate the rationale of different regimens and analyze their potentials as well as weaknesses.     

Efficacy of high vs low dose TNF-isolated limb perfusion for locally advanced soft tissue sarcoma

Aims

The administration of a high dose of rTNF-α (3–4 mg) and Melphalan via isolated limb perfusion (ILP) for patients with locally advanced limb STS was shown to be effective. Reports that a low dose of TNF (1 mg) is as effective, led to the adoption of the low dose regimen as the treatment of choice. The purpose of this study was to compare two groups of patients with locally advanced limb STS, that was treated with high and low dose TNF-ILP, in terms of limb preservation.

Methods

Retrospective study of 41 patients who underwent ILP, with “high dose” (HD) and “low dose” (LD) TNF. ILP/TNF was performed on candidates to either amputation or significantly mutilating surgery without this treatment. In both groups, all patients, with the exception of three in each group, underwent resection of the residual tumor or tumor bed or limb 8–12 weeks after the procedure.

Results

In the HD group, marked tumor softening occurred within 48 h, and in tumors protruding through the skin, hemorrhagic necrosis was evident within 24 h. The overall response rate was 65.2%. Five patients achieved a CR and 10 had a PR; in five of these patients >90% necrosis of the tumor occurred. In eight patients, only minimal regression was observed (stabilization of disease). The rate of limb sparing was 69.5%. In the LD group, the overall response rate was 30.7%. CR was achieved in one patient. PR was observed in two. Two patients were lost to follow up. Of the remaining 15 patients, limb preservation was achieved in 53.3%.

Conclusion

Despite the retrospective comparison and possible selection bias, it is possible to raise the concern that at least some patients may benefit from a higher TNF dose perfusion in ILP for advanced limb STS.     

野中野照射加大剂量顺铂水化防治软组织肉瘤术后复发的临床研究

目的评价野中野照射加大剂量顺铂（HD-PDD）水化技术在软组织肉瘤综合治疗中的地位及其疗效。方法127例软组织肉瘤术后患者随机分为研究组67例（野中野照射加HD-PDD水化）和对照组60例（常规照射、化疗）。研究组放射治疗：大野40～50 Gy,4～5周,小野20～30 Gy,3～4周,每天2野照射,间隔6 h;化疗：PDD 80～100 mg/m^2,每3周1次,共2～3次。对照组放射治疗：40～50 Gy,4～5周,后缩野加量20～30 Gy,2～3周。结果研究组和对照组1,3,5年生存率分别为95.5%和78.3%（P〈0.05）,82.1%和60.0%（P〈0.05）,70.2%和53.3%（P〉0.05）。研究组和对照组1,3,5年局部复发率分别为4.5%和10.0%（P〉0.05）,9.0%和31.7%（P〈0.05）,25.5%和41.7%（P〉0.05）。结论野中野照射加HD-PDD水化技术可在短时间内使肿瘤区接受较高剂量及获得放射治疗增敏,且明显提高了生存率,降低了局部复发率,作为术后综合治疗技术在软组织肉瘤治疗中具有重要价值。     

Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion

Several possible mechanisms for the synergistic anti-tumour effects between tumour necrosis factor alpha (TNF-alpha) and melphalan after isolated limb perfusion (ILP) have been presented. We found a significant sixfold increase in melphalan tumour tissue concentration after ILP when TNF-alpha was added to the perfusate, which provides a straightforward explanation for the observed synergism between melphalan and TNF-alpha in ILP.     

796例软组织肉瘤分析

目的:了解软组织肉瘤各病种发病情况及相对频率,并调查软组织肉瘤发病趋势。方法:对本院1993年1月至2003年12月所有收治的原发软组织肉瘤796例发病情况进行回顾性分析,从而初步得到各病种发病情况和相对频率,并推测其发病趋势。结果:依据病理分型发病率最高者为恶性纤维组织细胞瘤、滑膜肉瘤、脂肪肉瘤、横纹肌肉瘤等,分别占所收治例数的31.5%,16.8%,16.8%和16.2%。软组织肉瘤可见于各个年龄阶段,可发生于全身任何部位,但各亚型均有各自的特点。结论:软组织肉瘤发病率较低。恶性纤维组织细胞瘤在软组织肉瘤中发病率最高。软组织肉瘤的发病率呈逐年上升趋势。     

High-risk soft tissue sarcoma: Clinical trial and hyperthermia combined chemotherapy

For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. This short overview summarizes the results of the combination with regional hyperthermia as a new treatment strategy to open a new therapeutic window.     

抑癌基因PTEN突变在软组织肉瘤中的研究

目的本研究探讨软组织肉瘤中PTEN突变及与软组织肉瘤发生发展的相关性。方法应用聚合酶链反应．单链构象多态性分析（PCR．SSCP）方法以及DNA测序技术,扩增86例软组织肉瘤PTEN基因的第5～8外显子,根据构象改变检测其基因突变情况。结果86例软组织肉瘤中检测到2例突变：第8外显子第351位密码子由T→C的错义突变,突变使蛋白结构由苯丙氨酸突变为赖氨酸;第8外显子第334位密码子由A→T的错义突变,突变使蛋白结构由天门冬酰胺突变为赖氨酸。结论软组织肉瘤中存在PTEN抑癌基因的突变,但突变率很低,可能在STSs的发生发展中不起主要作用。     

Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas

Purpose: Based on the promising results of a Phase I study with a combination of gemcitabine and DTIC performed in advanced soft tissue sarcoma (ASTS) patients, and due to the limited efficacy of second or third line therapies in those patients, we designed a Phase II study to determine the activity of this new regimen. Methods: Patients with ASTS, measurable disease, pretreated with chemotherapy, received gemcitabine 1,800 mg/m² infused over 180 min followed by DTIC 500 mg/m² (one cycle), every 2 weeks. The pharmacokinetics (PK) of gemcitabine and 2′,2′-difluorodeoxyuridine (dFdU), and the accumulation of gemcitabine triphosphate (dFdCTP) by peripheral blood mononuclear cells were studied. The influence of the sequence of administration on those parameters was examined to exclude potential drug interactions. Results: Twenty-six patients received a total of 158 cycles (mean four cycles, range 1–18). Grade 3–4 anemia (23% of patients), granulocytopenia (46%) or thrombocytopenia (12%), and grade 3 increase in AST (18%), ALT (21%), or γ-glutamyl-transferase (9%) were noted. Response rate in 23 patients was 4% (95% CI: 0–24%), and in 8 of 11 patients stable disease lasted > 6 months. Progression-free rate (PFR) at 3 and 6 months was, respectively, 48 and 28%, and median overall survival 37 weeks. Pooled data from the Phase I and Phase II studies showed clinical benefit in patients with leiomyosarcomas (LMS) (57%) and malignant fibrous histiocytomas (MFH) (33%). The sequence of administration did not influence PK of gemcitabine or dFdU. There was a trend (P = 0.11) toward a lower accumulation of dFdCTP when DTIC preceded gemcitabine. Conclusions: Although the remission rate was low, PFR figures indicate that this regimen has activity in patients with ASTS. It should be compared with DTIC, or other gemcitabine-containing combinations, in patients with LMS or MFH, to determine whether this combination offers advantages in PFR or in overall activity.J. Fra and R. Losa contributed equally to this work.     

软组织肉瘤患者可溶性ST2的临床价值：一项单中心横断面研究

背景与目的：可溶性肿瘤抑制因子2（soluble suppression of tumorigenicity2,sST2）是反映心肌肥厚和心肌纤维化的生物标志物。探讨软组织肉瘤患者sST2检测的临床价值。方法：横断面收集2019年7—8月在复旦大学附属中山医院接受治疗的软组织肉瘤患者的临床信息,包括人口统计学特点、软组织肉瘤分类分期、心血管疾病类型。收集患者治疗前血清sST2、乳酸脱氢酶（lactate dehydrogenase,LDH）和D-二聚体（D-dimer）、高敏C反应蛋白（high-sensitivity C-reactive protein,hs-CRP）、心肌肌钙蛋白（cardiac troponin T,cTnT）和氨基末端脑钠肽前体（amino terminal pro-brain natriuretic peptide,NT-proBNP）检测结果,以及超声心动图左心室射血分数（left ventricular ejection fraction,LVEF）。采用SPSS21.0统计软件进行分析。结果：共收集软组织肉瘤患者64例,包括男性29例,女性35例,平均年龄（45.9±14.6）岁。其中具有心血管疾病史患者12例、糖尿病2例。sST2、LDH、D-dimer、NT-proBNP、hs-CRP、cTnT指标经自然对数转换后符合正态分布。以lnsST2为因变量,各指标自然对数转换后数据和LVEF为自变量进行单因素Spearman相关线性分析显示,sST2与LDH、D-dimer、hs-CRP、NT-proBNP存在相关性,差异有统计学意义（P均<0.01）。进一步将以上自变量纳入sST2多因素线性回归分析,回归方程中LDH偏回归系数差异有统计学意义（P=0.01）。结论：在心功能相对正常的软组织肉瘤患者中,sST2有望成为新型肿瘤标志物。     

大剂量异环磷酰胺持续静滴联合阿霉素治疗进展期软组织肉瘤的临床观察

目的：评价大剂量异环磷酰胺持续７２ｈ静滴联合阿霉素治疗进展期软组织肉瘤的临床疗效和毒副反应。方法：２００８年３月～２００８年１０月收治进展期软组织肉瘤患者１５例,应用大剂量异环磷酰胺联合阿霉素治疗,异环磷酰胺总量１２ｇ／ｍ^２,持续静滴７２ｈ;阿霉素６０ｍｇ／ｍ^２第１天静滴。２１天为１周期。完成２～６周期,中位周期数为４。结果：全组患者ＣＲ１例（６.６７％）,ＰＲ１例（６.６７％）,ＳＤ１２例（８０.０％）,ＰＤ１例（６.６７％）,有效率１３.３％（２／１５）,疾病控制率９３.３％（１４／１５）。中位无疾病进展生存期６个月（３～１０个月）,中位总生存期７个月（３～１０个月）。主要毒副反应为粒细胞减少、胃肠道反应和脱发,其他毒副反应少见。结论：大剂量异环磷酰胺持续７２ｈ静脉滴注联合阿霉素方案治疗进展期软组织肉瘤可行,能够有效控制疾病进展,毒副反应可以耐受,值得进一步深入研究。     

Isolated limb perfusion for locally advanced melanoma in the immunotherapy era

BackgroundPrior to the advent of effective systemic therapy for melanoma, isolated limb perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma (ITM). However, many patients who are now treated by ILP will have received prior immunotherapy. We sought to compare response rates to ILP in patients who had previously received immunotherapy compared to immunotherapy naive patients.Materials and methodsAll patients who underwent ILP for ITM between January 2015 and July 2020 for melanoma were identified retrospectively from two tertiary institutions. Surgical morbidity and oncologic outcomes were compared between immunotherapy naive and immunotherapy pre-treated patients.Results97 perfusions were performed for melanoma. Of those, 18 patients had undergone prior immunotherapy. There were no differences in clinicopathological characteristics or perioperative outcomes between cohorts. Surgical morbidity and local toxicity were similar between both cohorts. Patients who underwent immunotherapy prior to ILP had significantly decreased complete response (CR) rates compared with immunotherapy-naïve (6% vs 47%, p = 0.0018) and a significantly decreased overall survival (OS) and distant progression free survival (DPFS) (p = 0.0031 and p = 0.0006 respectively). There was no difference in overall response (OR), partial response (PR), stable disease (SD), progressive disease (PD) and local progression free survival (LPFS) between cohorts.ConclusionOncological outcomes and complete response rates are worse in patients who have received immunotherapy prior to ILP compared with immunotherapy naïve patients. Despite this, ILP is still a valuable second line treatment for local control in patients who have multiple, bulky and/or recurrent ITM post immunotherapy.