Eggermont A M, Schraffordt Koops H, Klausner J M, Kroon B B, Schlag P M, Liénard D, van Geel A N, Hoekstra H J, Meller I, Nieweg O E, Kettelhack C, Ben-Ari G, Pector J C, Lejeune F J
Department of Surgical Oncology, University Hospital Rotterdam, Daniel den Hoed Cancer Center, The Netherlands.
Ann Surg. 1996 Dec;224(6):756-64; discussion 764-5. doi: 10.1097/00000658-199612000-00011.
The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible.
To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation.
In 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP.
A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths.
In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.
本研究的目的是通过使用肿瘤坏死因子（TNF）+美法仑（M）进行隔离肢体灌注（ILP）作为诱导性生物化疗，以获得局部控制并使保肢手术成为可能，从而使那些原本只能通过截肢或功能性致残手术治疗的局部晚期软组织肉瘤患者实现保肢。
为了增加局部晚期肢体软组织肉瘤治疗中保肢切除术的数量，术前常应用放射治疗或化疗或两者联合应用。单独使用细胞抑制剂进行ILP是另一种选择，但由于效果较差很少使用。TNF应用于ILP的疗效显著改变了这种情况。
在8个癌症中心，近4.5年期间对186例患者进行了治疗。有107例（57%）原发性肉瘤和79例（43%）复发性肉瘤，大多为高级别（110例III级；51例II级；25例非常大、复发性或多发性I级肉瘤）。该系列患者的构成不寻常：42例患者（23%）有多灶性原发性或多发性复发性肿瘤；肿瘤中位大小非常大（16厘米）；25例患者（13%）在进行ILP时已知有全身转移。患者在39至40摄氏度下接受90分钟的TNF+美法仑ILP。前55例患者还接受了干扰素-tau。ILP后2至4个月对肿瘤残余进行延迟边缘切除。
82%的患者出现主要肿瘤反应，使这些大肉瘤在大多数情况下可切除。临床反应率为：33例完全缓解（CR）（18%），106例部分缓解（PR）（57%），42例无变化（NC）（22%），5例疾病进展（PD）（3%）。最终结果由临床和病理反应定义：54例CR（29%），99例PR（53%），29例NC（16%），4例PD（2%）。中位随访近2年（22个月；范围6-58个月），82%的患者实现了保肢。局部毒性有限，全身毒性轻微至中度，易于处理，无毒性死亡。
在隔离肢体灌注的情况下，TNF是患者的一种活性抗癌药物。TNF+美法仑的ILP可在许多中心安全进行，是一种有效的诱导治疗方法，反应率高，可使局部晚期肢体软组织肉瘤患者实现保肢。
