改进隔离热灌注化疗技术治疗肢体恶性肿瘤

目的：改进肢体隔离热灌注化疗技术,可简化操作,缩短灌注时间,提高恶性肿瘤治疗安全性,本研究观察其对治疗肢体恶性肿瘤的效果。方法：对97例肢体恶性肿瘤实施了隔离热灌注化疗。其中,Ⅲ/Ⅳ期恶性黑色素瘤71例,均行淋巴结清扫术后灌注。骨肉瘤8 例,软组织肉瘤18例。上肢22例,下肢75例。16例按传统方法手术,81例按改进方法手术。改进方法包括：改进动静脉插管方式,灌注液中加入扩血管药物、监控肌肉温度等。结果：灌注后均有病灶变软、变小、变薄。切除标本病检,23例瘤组织完全坏死,52例瘤组织大部分坏死,22例瘤组织小部分坏死。均行保肢手术。无手术死亡。无血栓形成。改进组无筋膜室综合症发生,灌注速度加快,肢体肿胀较轻。结论：经头静脉、大隐静脉断端插入静脉导管可明显缩短手术时间,降低手术难度,未发现影响肢体血液回流。灌注液中加入血管扩张药可明显加快灌注速度,特别是上肢,能使肢体温度较快达到热化疗的要求。灌注中监控肌肉组织的温度不超过43℃,可以防止发生小腿或前臂肌肉坏死引起的严重并发症。     

肢体隔离热灌注化疗术辅助治疗软组织肉瘤的12例报告

目的：探讨术前肢体隔离热灌注化疗术辅助治疗局部晚期肢体软组织肉瘤(softtissue sarcoma,STS)的疗效。方法对2002年1月至2013年6月,我科收治的12例IIB期的肢体STS患者行肢体隔离热灌注化疗术。化疗后14～21天行原发病灶切除术,并行病理学检查。术后11例行6周期表柔比星＋异环磷酰胺( epirubicin＋ifosfamide,AI )方案的辅助化疗,1例行局部放射治疗。观察并记录肢体隔离热灌注化疗后肢体疼痛、肿胀程度、原发肿瘤的变化情况;术后随访观察术后疗效、局部复发、转移、并发症及化疗毒性反应等情况。肿瘤坏死情况评价肢体隔离热灌注化疗破坏肿瘤的情况;生化检查观察治疗后患者肝肾功能的变化;毒性反应评价采用Wieberdink分级标准。结果本组12例肢体隔离热灌注化疗后2天均出现患肢肿胀、皮温升高,化疗后7～10天达到高峰,化疗后10天肿胀逐渐消退、皮温逐渐下降,化疗后2周原发病灶表现为不同程度的肿瘤缩小、皮肤移动性增大、患肢周径缩小。化疗后3天,患者转氨酶有不同程度的升高,但均未超过正常值上限的4倍,未见肾功能异常变化。肿瘤坏死率≤60%者2例(16.66%),～90%者5例(41.67%),～100%者5例(41.67%)。12例均获得随访,平均随访(27.25±37.71)个月。1例达完全缓解( complete response,CR ),5例达部分缓解( partial response ,PR ),总缓解[ overall response,OR ( CR＋PR )]率为50%。5例转移,2例局部复发并截肢,总局部复发率( local recurrence,LR )16.66%,总保肢率( limb salvage,LS )83.34%。1例跟腱挛缩者行跟腱延长术,恢复良好。1例肌间静脉血栓,给予溶栓治疗后治愈。Wieberdink毒性反应分级为I、II、III级,未见IV、V级毒性反应发生。结论术前肢体隔离热灌注化疗术辅助治疗肢体 STS 疗效满意,能明显杀灭肿瘤组织、降低术后局部复发率、改善患者的预后、副反应较小、安全性较高,对局部晚期软组织肿瘤的保肢具有重要作用。     

热或热药区域灌注治疗下肢恶性黑色素瘤（附5例报告）

报告用热或热药区域灌注治疗下肢恶性黑色素瘤５例，男４例，女１例；年龄３９～７３岁。肿瘤位于足４例，小腿１例，４例经髂外动静脉插管并切除腰交感神经节，１例经股动脉插管，灌注温度４１．５℃～４２℃。持续２小时，其中２例在灌注中加入ＤＤＰ（３．２ｍｇ／ｋｇ体重）。治疗后第１天即见肿瘤缩小，６天后所有病人的肿瘤均有明显缩小甚至消失，并可见不同程度脱色和萎缩，除１例术后小腿轻度肿胀，其它无不良反应。随诊２年除１例肺转移外，余未见病灶复发或转移。本组结果显示，热或热药区域灌注对治疗下肢恶性黑色素瘤有明显疗效，且保留了患肢，又提高了患者生存质量。     

肢体恶性黑色素瘤综合治疗进展

皮肤发病率及病死率在全球均有升高趋势,其治疗包括手术、生物、化学、放射以及内分泌治疗。手术是主要治疗手段,切除后部分原发灶的缺损需要修复与重建。高剂量的干拢素（IFN）α-2b是经美国食品与药品监督管理局批准的辅助性生物治疗手段。对于转移性病灶,化疗是主要治疗手段,单药氮烯脒胺治疗仍是标准方案。放射治疗在原发灶、区域淋巴结及转移性病灶的治疗中均有一定意义;而现尚无证据支持内分泌治疗在恶性黑色素瘤治疗中的应用价值。     

肢体恶性黑色素瘤综合治疗进展

皮肤发病率及病死率在全球均有升高趋势,其治疗包括手术、生物、化学、放射以及内分泌治疗。手术是主要治疗手段,切除后部分原发灶的缺损需要修复与重建。高剂量的干拢素(IFN)α-2b是经美国食品与药品监督管理局批准的辅助性生物治疗手段。对于转移性病灶,化疗是主要治疗手段,单药氮烯脒胺治疗仍是标准方案。放射治疗在原发灶、区域淋巴结及转移性病灶的治疗中均有一定意义;而现尚无证据支持内分泌治疗在恶性黑色素瘤治疗中的应用价值。     

体腔热灌注化疗治疗恶性胸腹腔积液临床研究

目的:研究体腔热灌注化疗治疗恶性胸腹腔积液的疗效与不良反应。方法:67例恶性胸腹腔积液患者分为治疗组(35例)和对照组(32例)。胸腹腔穿刺行闭式引流干净胸腹腔积液后,治疗组给予5-氟尿嘧啶1000mg加上43℃-45℃的生理盐水,胸腔积液患者需2000ml-2500ml生理盐水;腹腔积液患者需2500ml-3000 ml生理盐水,以HGGZ-102体腔热灌注治疗系统注入胸腹腔,使进入胸腹腔的液体温度维持在41℃-43℃,循环2h;对照组给予生理盐水100ml+5-氟尿嘧啶1000mg胸腹腔注入。两组均每周灌注1次,连续灌注3周,评定疗效。结果:治疗组有效率88.6%,Karnofsky评分增加率85.7%;对照组有效率62.5%,Karnofsky评分增加率59.4%。治疗组胸腹腔积液控制率、Karnofsky评分增加率均优于对照组(P<0.05)。两组不良反应无明显差异。两组生存期无统计学差异(P>0.05)。结论:体腔热灌注化疗治疗恶性胸腹水近期疗效好且安全。     

体腔热灌注化疗治疗恶性胸腹腔积液临床研究

目的：研究体腔热灌注化疗治疗恶性胸腹腔积液的疗效与不良反应。方法：67例恶性胸腹腔积液患者分为治疗组（35例）和对照组（32例）。胸腹腔穿刺行闭式引流干净胸腹腔积液后,治疗组给予5-氟尿嘧啶1000mg加上43℃-45℃的生理盐水,胸腔积液患者需2000ml-2500ml生理盐水;腹腔积液患者需2500ml-3000 ml生理盐水,以HGGZ-102体腔热灌注治疗系统注入胸腹腔,使进入胸腹腔的液体温度维持在41℃-43℃,循环2h;对照组给予生理盐水100ml＋5-氟尿嘧啶1000mg胸腹腔注入。两组均每周灌注1次,连续灌注3周,评定疗效。结果：治疗组有效率88.6%,Karnofsky评分增加率85.7%;对照组有效率62.5%,Karnofsky评分增加率59.4%。治疗组胸腹腔积液控制率、Karnofsky评分增加率均优于对照组（P〈0.05）。两组不良反应无明显差异。两组生存期无统计学差异（P〉0.05）。结论：体腔热灌注化疗治疗恶性胸腹水近期疗效好且安全。     

142例恶性黑色素瘤的分期治疗

目的探讨恶性黑色素瘤分期治疗的意义。方法收集1961—1999年住院治疗的恶性黑色素瘤142例，按照1997年TNM分期标准，Ⅰ期20例（14．1％）、Ⅱ期36N（25．3％）、Ⅲ期64例（45．1％）、Ⅳ期22例（15．5％）；Ⅰ期手术治疗、Ⅱ期手术＋放疗、Ⅲ期化疗＋手术或放疗、Ⅳ期以化疗为主要综合治疗。结果Ⅰ期5年生存率高达97％，Ⅱ期5年生存率47％～74％，Ⅲ期5年生存率13％～41％，Ⅳ期3年生存率0～10％。结论分期治疗恶性黑色素瘤有助于提高患者的5年生存率及降低医疗费用。     

持续热灌注腹腔化疗结合体外高频热疗治疗恶性腹腔积液36例

目的 观察持续热灌注腹腔化疗结合体外高频热疗治疗恶性腹腔积液的疗效及安全性.方法 利用腹腔热灌注化疗仪持续热灌注顺铂60～80 mg,替加氟1g,0.9％氯化钠溶液2000 ～3000 ml.使灌注入腹腔的液体温度控制在41～43℃,同时结合腹部体外高频热疗.分析患者疗效及生存情况.结果 36例恶性腹腔积液患者中,治疗后完全缓解14例（38.9％）,部分缓解12例（33.3％）,无变化10例（27.8％）,有效率为72.2％（26/36）.患者中位生存期9.6个月,1年生存率76％.生存质量改善,不良反应轻,无治疗相关死亡.结论 持续热灌注腹腔化疗结合腹部高频热疗治疗恶性腹腔积液安全、有效、简便,值得临床推广.     

Prognostic factors for survival after isolated limb perfusion for malignant melanoma

AIMS: Risk factors were determined for mortality within 1 year after isolated limb perfusion (ILP). METHODS: All of 439 patients who underwent ILP for melanoma of the extremities were studied. Ninety percent of the patients had MD Anderson stage IIB or III disease at the time of ILP. ILP was performed with melphalan with or without TNFalpha under mild hyperthermic (38-40 degrees C) or normothermic (37-38 degrees C) conditions in 80% of the cases. RESULTS: Sixty-nine patients died within this period, 64 of metastatic melanoma. The indication for ILP was an unresectable primary (n=3), a local recurrence (n=24) or adjuvant to excision of primary lesions (n=17) in patients with stage IIIB regional lymph node metastases. These patients or patients with stage IIIAB melanoma with satellites and/or in-transit metastases with regional lymph node metastases had a relative risk of 4.6 (95% CI 2.0-6.6) and 3.6 (95% CI 2.1-10) of dying within 1 year from ILP, respectively (p<0.001). In patients with stage IV disease (distant metastases), the relative risk was 22 (95% CI 3.8-127, p=0.001). CONCLUSION: Patients with advanced limb melanoma have an increased risk of death within 1 year after ILP when regional lymph node or distant metastases are present.     

Hyperthermic isolated regional perfusion of the limb with carboplatin

AIMS: To investigate the feasibility of hyperthermic isolated regional perfusion (HIRP) with carboplatin in the management of locally recurrent and/or intransit metastases of melanoma or locally advanced soft tissue sarcoma. METHODS: Three patients, two with locally advanced melanoma and one with a low-grade liposarcoma of the lower extremity, were treated with HIRP under mild hyperthermia (39-40 degrees C) with 125 mg carboplatin/l perfused limb volume. RESULTS: No systemic toxicity was observed. Local toxicity consisted of post-perfusion oedema present in all three patients which resolved within 2 weeks. Clinically, a persistent local neuropathy was observed in all three patients, two of which were confirmed by electromyogram and nerve conduction study. Severe motor-sensory neuropathy was located mainly in the peroneal and sural nerves of the perfused limbs. Pharmacokinetic parameters of the carboplatin showed a higher concentration of carboplatin in the skin compared to the muscle. The two melanoma patients showed a complete response but developed local recurrences within 1.5 years after perfusion. The third patient underwent a delayed excision of the sarcoma 8 weeks after perfusion which revealed 50% viable tumour. One of the melanoma patients and the sarcoma patient died from lung metastases 56 and 31 months post-perfusion treatment, respectively. The other melanoma patient is alive 95+ months post-perfusion treatment. CONCLUSIONS: The local neurotoxicity observed did not warrant further research of carboplatin in HIRP.     

Results of isolated limb perfusion for metastasized malignant melanoma

Background and objectivesLocoregional metastases are typical biological manifestations of advanced malignant melanomas. Treatment with hyperthermic isolated limb perfusion (HILP) should be considered in affected patients. In the present study, we have analyzed the results of HILPs performed in our department.Patients and methodsEighty patients with locoregional metastases of the extremities received HILP at the Department of Surgery between January 2007 and December 2016. The mean follow-up was 38 months.ResultsThe study included 50 men and 30 women (mean age: 63 years). The median time between melanoma diagnosis and HILP was 25 months (range: 1–219 months). HILP was performed in curative (n = 45) and palliative (n = 35) intention. Seventy-five patients received a drug combination of melphalan/dactinomycin and five patients received a drug combination of melphalan/tumor necrosis factor-alpha. Remission rates were determined in 72 of 80 patients (90%) as follows: partial response n = 28, complete response n = 25, no response n = 19. Of the 25 patients with complete response, 13 patients developed a new tumor manifestation during follow-up (locoregional recurrences n = 4; distant metastases n = 3; both n = 6). The median overall survival rate was 33 months. Tumor stage influenced the survival rate significantly (p = 0.001). Patients with complete response showed a significantly better overall survival than patients with partial or no response (p = 0.016).ConclusionHILP is an effective therapeutic option in patients with locoregional metastases. This procedure carries a certain risk of side effects and adverse events but overall results in good response rates. Therefore, HILP should be offered to selected patients based on an individual discussion, considering their health status and oncological prognosis.     

Long-term outcome of hyperthermic isolated limb perfusion (HILP) in the treatment of locoregionally metastasised malignant melanoma of the extremities

Objective: The aim is to analyse a modified standardised HILP procedure regarding the response rates, local recurrences and complication rates.

Patients and methods: 152 patients (101 females, 51 males) with an average age of 62 years and locoregionally metastasised malignant melanoma underwent HILP using melphalan and dactinomycin between 1992 and 2007. Using M.D. Anderson's classification at the time of the perfusion 51 patients presented in stage IIIA, 43 patients in stage IIIAB and 58 patients in stage IV. If indicated, lymph node dissection was performed simultaneously just before perfusion of the extremity.

Results: Complete remission was observed in 91 (62.7%) of 145 patients, partial remission in 26 (17.9%) patients. 28 (19.3%) patients showed no response. The overall response rate was 80.7% (117 of 145 patients). Severe complications (Wieberdink IV/V) were seen in eight cases. The average recurrence-free survival was 17 months. The median survival was 39 months; the five-year overall survival rate was 38%. The overall survival rate was significantly influenced by the stage of the disease.

Conclusion: HILP is an efficient therapy for multiple or recurrent in-transit metastases of malignant melanoma of the lower extremities. The efficiency increased by improving the technique of the perfusion. Long-term survival can be observed in patients without regional lymph node metastases or distant metastases.     

Long-term follow-up of 163 consecutive patients treated with isolated limb perfusion for in-transit metastases of malignant melanoma

Abstract

Purpose: The aim of the present study is to describe our experience with isolated limb perfusion (ILP) in the treatment of in-transit metastases of malignant melanoma and to determine prognostic factors for response, local progression, survival and toxicity. Materials and methods: A retrospective follow-up of all patients (n?=?163) treated between January 1984 and December 2008 using data collected from individual patient records and the Swedish National Patient Register. Results: Clinical response was evaluable in 155 patients, 65% had a complete response (CR) and 20% had a partial response (PR). Local progression occurred in 63% of the patients after a median time of 16 months. Negative prognostic factors in univariate analyses were proximal location of the primary tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, proximal location of the primary tumour and no CR after ILP were significant prognostic factors. Median cancer-specific survival was 30 months, and negative prognostic factors in univariate analyses were male gender, positive lymph node status, systemic metastases, bulky tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, positive lymph node status, bulky tumour and no CR after ILP were significant prognostic factors. A majority (97%) of the patients had a Wieberdink grade II–III local toxicity. Four patients underwent limb amputation after a median of 19 months, none because of toxicity. Conclusion: We found that ILP is a safe method with a high response rate for the treatment of patients with in-transit metastases of malignant melanoma.     

Palliative isolated limb perfusion for advanced limb disease in stage IV melanoma patients

INTRODUCTION: Two to three percent of the patients with extremity melanoma develop in-transit metastases in the course of their disease. When local treatments fail, isolated limb perfusion (ILP) is a reasonable option, but is generally only applied to patients without evidence of distant metastases. We assessed the value of ILP in stage IV melanoma patients with symptomatic unresectable limb melanoma at our institutions. PATIENTS AND METHODS: A computerized database, containing all patient, tumor, ILP, and follow-up data of 505 ILPs performed in 451 patients between 1978 and 2001, allowed the selection of eight (1.8%) stage IV patients who underwent a palliative ILP for unresectable melanoma lesions on the limbs. All patients had high tumor burden limb disease, according to the combined Fraker and Rossi criteria. RESULTS: The overall tumor response rate was 88%, with 13% complete and 75% partial response rates. One patient did not respond to ILP. Three partial responding patients attained a complete remission (CR) after excision of the remaining limb lesions. The median duration of hospital stay was 12 days and acute regional toxicity was mild with slight erythema and edema in six and no signs of reaction in two patients. The median limb recurrence-free interval after CR was 6 months and the median duration from the time of distant metastases to death was 15 months. Overall ILP leads to the desired palliative effect in six patients (75%). CONCLUSION: ILP should be considered as a palliative treatment in selected stage IV melanoma patients with symptomatic advanced limb disease.     

Individual treatment for malignant melanoma

Much has been learned in the recent decade about the predictable biologic behavior of cutaneous malignant melanoma. Indeed, such knowledge permits highly individualized treatment based on simple demographic data on the patient, location of the lesion, and its thickness according to the Breslow scale. The thoughtful surgeon may individualize his treatment according to the likely biologic behavior of the tumor, minimizing treatment morbidity while maintaining optimum results from primary and secondary surgical treatment.     

Hyperthermic limb perfusion for malignant melanoma and soft tissue sarcoma

From 1982-1989, 113 hyperthermic limb perfusions were carried out in 102 patients. Ninety-three patients were treated for malignant melanoma and nine for soft tissue sarcoma. 47/93 patients had high-risk stage I melanoma with a 5-year survival rate of 89%. For the 46 patients treated for recurrent and metastatic melanoma the projected 5-year survival rate was 40%. The nine patients with soft tissue sarcoma were perfused for local recurrences or because of anatomically difficult tumor locations. 3/9 patients subsequently developed recurrent disease of the extremity; two of these patients had to be treated by amputation. The rate of major complications was low: no patient died in the postoperative course, an amputation due to toxic reaction was never required. Erythema and oedema (57%), severe skin reaction (6%) and transient nerve palsy (15%) were common side effects of therapy. Only two cases of leucopenia were observed (2%). The favourable results after hyperthermic limb perfusion show the efficacy of this method in the treatment of malignant melanoma and selected cases of soft tissue sarcoma.     

Hyperthermic isolated limb perfusion (HILP) in malignant melanoma. Experience with 101 patients.

AIMS: To analyse results with a standardized HILP procedure in terms of response rate, recurrence pattern and complication rate. PATIENTS AND METHODS: From 1992 to 2003 HILP with melphalan and dactinomycin was performed in 101 patients with loco-regional metastases of malignant melanoma of the limbs. Among these were 66 women and 35 men with a median age of 62 years. Forty patients were in M. D. Anderson stage IIIA, 51 patients in stage IIIAB and 9 had stage IV disease at the time of perfusion. If not been done before, regional lymph node dissection preceded limb perfusion in the same setting. RESULTS: A complete response (CR) was observed in 58 out of 87 evaluable patients. Twenty-one patients achieved a partial response (PR) and eight patients were non-responders. The overall response rate was 90.8%. The median recurrence-free interval after CR was 21 months. Severe toxicity (Wieberdink IV/V) was observed in five patients necessitating fasciotomy in four of them and above knee amputation in one patient. All further cases presented with grade II-III toxicity. The overall survival was 42 months, with a 5-year survival rate of 38%. Survival significantly differed according to stage of disease. CONCLUSION: HILP is an effective treatment for loco-regional tumour relapse of malignant melanoma of the extremities and has improved by modification of technique. In the absence of regional lymph node and distant metastases long-term survival can be achieved in responders.