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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. [ABSTRACT FROM AUTHOR]

The article presents a study that compares two approaches of isolated limb infusion (ILI): contralateral venous and ipsilateral venous access approaches, for treatment of cutaneous malignancies. The study compared the performance of the two approaches relative to overall time, number of fluoroscopy procedures, and callbacks for flow-related issues on patients. It concludes that ipsilateral popliteal venous approach is safer with low number of fluoroscopy procedures for catheter placement.

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Abstract: Aims: The administration of a high dose of rTNF-α (3–4mg) 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 (1mg) 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 48h, and in tumors protruding through the skin, hemorrhagic necrosis was evident within 24h. 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. [Copyright &y& Elsevier]

Two forms of regional chemotherapy for the treatment of advanced melanoma or sarcoma of the extremity are isolated limb perfusion (ILP) and the more recently described isolated limb infusion (ILI). Melphalan is the most commonly employed agent in both ILP and ILI, although it is often used in conjunction with other cytotoxic and/or biologic therapies. While ILP and ILI are far more effective for the treatment of extremity disease than is systemic therapy, there is still significant room for improvement in outcomes, from the standpoint of both response rate and toxicity. An understanding of the pharmacokinetics of regional chemotherapy would allow for the prediction of tumor response and toxicity and therefore patient outcomes. In addition, elucidating the mechanisms of drug resistance would lead to opportunities to develop effective chemo-modulators that enhance the effectiveness of ILP and ILI. This paper reviews progress in these two key areas of active investigation. [ABSTRACT FROM AUTHOR]

Patients with recurrent cutaneous or soft tissue malignancies of the extremity provide a unique opportunity to evaluate therapy targeted to the isolated limb. The most common clinical presentation of recurrent extremity malignancy occurs in patients with melanoma. The extremity is the site of primary melanoma in half of patients with the disease 1, and of those with a primary melanoma of Breslow depth ≥1.5 mm, 15% will develop a local or in-transit recurrence 2. Palliation of extremity disease is important in these patients, as median survival after diagnosis of in-transit or locally recurrent disease >2 years 3, 4. Radical approaches to eradication of extremity recurrence are rarely used, although in a highly selected group of patients undergoing amputation, 42% 5-year survival was reported 5. As greater recognition of the palliative nature of extremity therapy has evolved, an emphasis on preservation of limb function has supplanted cure as a more realistic therapeutic goal. While occasional cure can be observed, it would be misleading to propose this as the likely outcome of eradication of recurrent extremity melanoma. Isolated limb perfusion (ILP) was developed as an alternative to amputation in patients with recurrent cancer of the extremity. The concept was that vascular isolation of the limb would allow delivery of higher (and potentially more effective) doses of chemotherapy to the disease in the limb than could be achieved with systemic therapy. [ABSTRACT FROM AUTHOR]

Hyperthermic isolated limb perfusion with tumour necrosis factor alpha (TNF-α) and melphalan was repeatedly reported to achieve extraordinarily high clinical remission rates in advanced and non-resectable soft tissue sarcoma of the limbs, thus avoiding imminent mutilation or amputation for most of those patients. With the limb being isolated throughout the extracorporal perfusion, high doses of recombinant TNF-α as well as melphalan can be applied. Basically, TNF-α directly affects the vasculature of the tumour and induces a severe inflammation with consecutive deterioration of the tumour capillaries. Furthermore, TNF-α increases the tumour-selective uptake of melphalan into the tumour cells thus leading to synergy of antivascular targeted treatment and antineoplastic effects of highest dose chemotherapy supplemented by hyperthermia. Meanwhile, a lot of sarcoma centres in Europe adopted this technique and established referral programmes for patients with non-resectable soft tissue sarcomas of the limbs. Despite these programmes many patients still do not get offered hyperthermic ILP with TNF-α and melphalan as a treatment option and modality. This article summarizes multimodality in treatment of soft tissue sarcoma of the limbs and reviews the current status of melphalan-based ILP with TNF-α (TM-ILP) and its results, to enable comparison and critical consideration of other treatment options. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)-based isolated limb perfusion (ILP) yields high tumor response rates in patients with in-transit melanoma metastases. However, most patients will ultimately experience disease recurrence. The aim of this pilot study was to test the hypothesis that systemic low-dose interferon α-2b (LDI) might consolidate the therapeutic effect of ILP. A total of 12 patients with in-transit melanoma metastases not amenable to surgical excision were given LDI subcutaneously (3 million IU/day, 7 days/week for 12 months) after TNF-based ILP (TNF 1 mg + melphalan (L-PAM) 10 mg/L) (group A). The clinical outcome of these patients was historically compared with that of 19 patients with similar anthropometric and disease characteristics who underwent TNF-based ILP alone (group B). In group A, LDI was well tolerated, only grade 2 systemic toxicity being recorded in 50% of patients. The progression-free survival analysis showed a statistically significant advantage for group A patients as compared with group B (median time to progression: 26 and 17 months, respectively; log-rank test P-value: 0.037). This survival benefit was confirmed at multivariate analysis, where treatment was the only prognostic factor retained by the prediction model. The analysis of the risk of disease progression over time suggested that this survival benefit appears to vanish after LDI discontinuation, which further strengthens the hypothesis that LDI might consolidate the therapeutic effect of TNF-based ILP. These preliminary findings support the conduction of larger trials to formally assess the ability of LDI to improve the clinical outcome of melanoma patients with in-transit metastases undergoing TNF-based ILP. [ABSTRACT FROM AUTHOR]

Extremity soft-tissue sarcomas are a heterogeneous group of rare neoplasms, characterized by a broad spectrum of biological aggressiveness and a uniform tendency for local failure if not adequately treated. Surgery is the mainstay of therapy, and the availability of multidisciplinary surgical skills allows adequate margins with acceptable morbidity to be obtained. Local therapies, such as radiation therapy or isolated limb perfusion, alone or in combination with systemic agents, may help to further improve local control, especially in difficult presentations. The possible impact of systemic treatment on survival is still a matter of debate, and the agents used so far have not provided a major breakthrough, even in selected populations at high risk of disease spread. Nevertheless, soft-tissue sarcomas are no longer considered a unique disease. More than 50 different histotypes can now be well recognized, with distinct biological and molecular characteristics, which lead to different clinical behavior and a potentially different sensitivity to targeted agents. Therefore, it is more essential than ever for treatment of these patients to be delivered in referral centers, where a dedicated multidisciplinary team is able to administer histology and clinically driven approaches. The employment of combined modalities will be able to maximize the chance of local cure even in difficult presentations, and possibly improve survival, especially in high-risk disease. [ABSTRACT FROM AUTHOR]

Isolated limb perfusion (ILP) is a limb salvage surgical modality used to deliver chemotherapy and biologic agents to locally advanced and recurrent extremity soft tissue sarcoma (STS), and may be readily tailored for delivery of gene therapy. We set out to test the feasibility of delivering AdFLAGp53 (replication incompetent adenovirus bearing FLAG-tagged wild-type p53) and Ad.hTC.GFP/E1a.RGD (a fiber-modified, replication selective oncolytic adenovirus) into human leiomyosarcoma xenografts by ILP. Nude rats bearing SKLMS-1 tumors in their hind limbs underwent ILP with escalating doses of AdLacZ or AdFLAGp53 (study 1), or with Ad.CMV.GFP.RGD or Ad.hTC.GFP/E1a.RGD (study 2) following in vitro confirmation of therapeutic potential in STS cell lines and strains. Seventy-two hours after delivery, reverse transcription-polymerase chain reaction confirmed FLAGp53 expression, and immunohistochemistry confirmed diffuse upregulation of p21CIP1/WAF1 in ILP-treated tumors. Ad.hTC.GFP/E1a.RGD perfused tumors demonstrated robust macroscopic transgene expression throughout their substance, but not in perfused normal tissues, 21 days after delivery. Intra-tumoral viral replication was confirmed by immunohistochemical staining for early (E1a) and late (hexon) viral protein expression. Terminal deoxynucleotidyl transferase-mediated-digoxigenin nick end-labeling staining identified foci of cell death within regions of viral replication. In conclusion, therapeutic adenoviral gene therapy against limb borne human STS can be successfully delivered by ILP and warrants further investigation.Gene Therapy (2007) 14, 671–681. doi:10.1038/sj.gt.3302911; published online 8 February 2007 [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the long-term limb salvage rate and overall survival after isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma (STS). From 1991 to 2003, 73 patients (36 men, 37 women, median age 54 [range 14–80] years) with biopsy-proven STS underwent 77 perfusions followed by delayed surgical resection, with or without adjuvant radiation. Limb salvage and overall survival curves were calculated by the Kaplan-Meier method. A total of 21 amputations (28%) were performed. Overall 1, 5, and 10 years’ limb salvage was 80.1% ± 4.8%, 68.2% ± 6.5%, and 60.6% ± 9.2%, respectively. We found that the risk of amputation was linked to three time periods. The first was within a year after perfusion, mainly as a result of massive necrosis of the tumor and overlying skin, resulting in soft tissue deficit or recurrent disease (n = 17). The second was within 5 years, with two amputations performed for late local recurrence. The third occurred 10 years after perfusion, with two amputations performed for critical leg ischemia. Another two patients developed a pathological fracture of the femur due to radiation osteonecrosis. These four patients received adjuvant radiotherapy. Overall, 1, 5, and 10 years’ survival was 82.9% ± 9.2%, 58.7% ± 13.1%, and 42.5% ± 18.2%, respectively. ILP treatment with tumor necrosis factor alpha and melphalan followed by delayed surgical resection and adjuvant radiation treatment is an effective limb salvage treatment regimen for locally advanced STS. However, we observed late morbidity, with two amputations performed for critical leg ischemia and two pathological fractures of the femur in patients receiving adjuvant radiotherapy. [ABSTRACT FROM AUTHOR]

Abstract: In the seventies, limb-sparing surgery and radiation therapy appeared capable of successfully treating the great majority of adult patients with soft tissue sarcomas of the extremities. No survival benefit could be demonstrated in the patients selected for amputation. Microscopically positive surgical margins are related to a greater risk of local recurrence, whereas overall survival is compromised by high grade and large tumor size. Presurgery multidisciplinary discussion, management in reference center and management within cancer network independently predict conformity to the clinical practice guidelines. Reoperation should be a planned part of definitive management whenever the initial surgical procedure was done without a histologic diagnosis or was not planned to be a wide excision. Soft tissue flap reconstruction facilitates therapy for patients with locally advanced tumors so that patients with larger tumors can undergo resection, limiting complications and limb sacrifice. Vascular reconstruction is a feasible option in case of involvement of major vessels. Isolated limb perfusion (ILP) with TNF and chemotherapy is an efficient limb-sparing neoadjuvant therapy for locally advanced limb soft tissue sarcomas. Efficacy and safety of low-dose TNFα could greatly facilitate ILP procedures in the near future. [Copyright &y& Elsevier]

The surgical management of melanoma has changed dramatically over the last few decades. Through the development and conduction of well-designed, prospective, randomized trials, we have been able to refine the way that we surgically manage patients with melanoma. Indeed, many important issues have been addressed through such trials: the proper surgical margins for the primary melanoma, utility of the elective lymph node dissection and the role for selective lymphadenectomy, to name a few. This review will also discuss what we have learned from past clinical trials and address several issues with regards to where we are going in the future. [ABSTRACT FROM AUTHOR]

Abstract: Soft tissue sarcomas belong to the most challenging diseases in oncology amounting to only 1% of all cancers. Soft tissue sarcomas are rare malignant disorders that comprise an extremely heterogenous spectrum of tumors. With the improvement of surgical techniques and radiation therapy the majority of patients with localize disease can be cured. However, for patients with advanced or metastasized disease chemotherapeutic treatments have not greatly changed the poor outcome of the disease. The introduction of combined chemoradiotherapy as well as the isolated limb-perfusion has improved the limb-salvage rate in locally advanced disease but the impact of systemic chemotherapy on overall survival remains still subject of dispute. For patients with metastatic sarcoma long-term survival can only be achieved in a small number of patients with mostly resectable disease. The list of effective drugs for palliative treatment in general still remains short and the duration of remissions usually does not exceed several months. A variety of new drugs or drug combinations seem to exhibit considerable activity in certain histological sarcoma subtypes which may soon broaden the armamentarium of drugs for a subset of patients. The recent success in the treatment of gastrointestinal stromal tumors impressively shows how fast a gain in the understanding of oncogenic mechanisms may translate into a highly efficient, clinically useful treatment. [Copyright &y& Elsevier]

Quality of life (QoL) and posttraumatic stress symptoms (PTSS) were studied in patients with soft tissue sarcoma (STS) of the extremities treated with isolated limb perfusion and delayed resection, with or without adjuvant irradiation. Forty-one patients received a questionnaire that included the RAND-36 and Impact of Event Scale. Thirty-nine STS survivors (16 [41%] male and 23 [59%] female; median age, 59 years; range, 15–78 years) participated in the questionnaire survey (response rate, 95%). The median age at perfusion was 49 years (range, 14–72 years). No significant differences were found in mean scores between STS survivors and the reference group with the exception of a worse physical functioning. Patients with amputations showed significantly worse physical and social functioning and more role limitations than patients whose limbs were saved. Eleven patients (28%) had a PTSS score of 0, and eight patients (20.5%) had a score ≥ 26, which suggested the need for psychological counseling. None of these eight patients had lost a limb. Patients who indicated that the choice of treatment was made by the surgeon rather than collaboratively showed significantly decreased social functioning, more role limitations, and intrusion. Greater treatment satisfaction was significantly related to better social functioning, more vitality, better general health perception, less intrusion, avoidance, and total Impact of Event Scale scores. Even though STS survivors’ QoL was different from that of a reference group only in physical functioning, one fifth of the patients had PTSS. An amputation, the physician’s decision rather than the patient’s decision for the perfusion treatment and a low satisfaction with the performed treatment negatively influenced QoL. [ABSTRACT FROM AUTHOR]

Abstract: Aims: The treatment of melanoma in-transit metastases (IT-mets) can vary widely and is dependant on the size and the number of the lesions. When multiple, large lesions exist, isolated limb perfusion (ILP) has established itself as an attractive treatment option with high response rates. Methods: Review on the various methods of treatment of melanoma in-transit metastases, with a focus on isolated limb perfusion. A Medline based literature search was performed for articles relating to this topic. Additional original papers were obtained from citations in those identified by the initial search. Indications and results are discussed and the extra value of tumour necrosis factor (TNF) is evaluated. Results: ILP with Melphalan results in complete response rates of 40–82% and showed to be 54% in a large retrospective meta-analysis. The addition of TNF can improve these completes response rates (59–85%) and although no data from randomized controlled trials are available, it seems of particular value in large, bulky lesions or in patients with recurrent disease after previous ILP. Conclusions: TNF-based ILP has earned a permanent place in the treatment of patients with melanoma IT-mets. In patients with a high tumour burden, TNF-based ILP is the most efficacious procedure to obtain local control and achieve limb salvage. [Copyright &y& Elsevier]

The aim was to investigate the value of adjuvant radiotherapy for locally advanced soft tissue sarcoma after hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor α and melphalan followed by limb-saving surgery. From 1991 to 2003, 73 patients (median age, 54 years; range, 14–80 years) underwent 77 ILPs, followed by resection in 68 patients (93%). Radiotherapy was administered in case of marginally or microscopically positive resection margins. Local recurrences were scored and calculated according to the Kaplan-Meier method and log-rank test. After residual tumor mass resection, 58% received radiotherapy (external beam radiotherapy [EBRT]+ group), and 42% did not (EBRT− group). The median follow-up was 28 months (range, 2–159 months). A significantly better local control rate was observed in the EBRT+ compared with the EBRT− group ( P < .0001). When only R0 resections in patients without metastasis were considered, the significance remained between groups ( P = .0003). In the EBRT− group, an R1 or R2 resection resulted in earlier relapse of local disease compared with R0 resections ( P = .0475). Adjuvant EBRT reduces the risk for local recurrence after delayed resection in soft tissue sarcoma patients treated with ILP and tumor necrosis factor and is indicated when resection margins are close or microscopically positive. It also seems beneficial after an R0 resection. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Melanocytes are cells of neuroectodermal origin found distributed along the epidermal basal layer of the skin and mucous membranes. Melanoma (Figure 1) is a malignant proliferation of melanocytes which arises, in most cases, from a pre-existing naevus, but which may arise from normal skin. This review focuses on the epidemiology, prognosis, clinical diagnosis, management and follow-up of cutaneous melanoma. [Copyright &y& Elsevier]

Abstract: Aims: Isolated limb perfusion with TNF and melphalan (TM-ILP) is highly effective in the local treatment of advanced sarcoma and melanoma of the limb. The optimal dose of TNF for this procedure is not well established. The aim of this study was to assess the efficacy and toxicity of TM-ILPs with reduced TNF dose. Method: Largest single institution prospective database on TNF-based ILP. Out of 339 TM-ILPs performed between 1991 and 2003, 64 procedures were performed with reduced TNF dose (<3mg in arm perfusions, <4mg in leg perfusions). Response rates and toxicity of the procedure and outcome of the patients are evaluated. Results: Complete response in melanoma patients after reduced-dose ILP was 75 vs 69% after standard-dose ILPs (overall response 94 vs 95%, respectively); overall response in non-melanoma patients was 69 (reduced) vs 74% (standard). Response rates and outcome were comparable with the procedures performed with standard-dose TNF (p=NS for response, local/systemic progression and survival after multivariate analysis, both in melanoma and in non-melanoma patients). Systemic and local toxicity did not differ statistically between reduced- and standard dose TM-ILPs. Conclusion: Provided doses at 1mg or higher are used, TM-ILP with TNF dose reduction for both melanoma and non-melanoma patients seems to be as effective as the standard dose procedure in terms of response rate and patient outcome. Numbers to formally confirm or reject this hypothesis are too large for such a non-inferiority trial to be conducted in patients with these rare conditions. [Copyright &y& Elsevier]

Abstract: Background: Desmoid tumours are soft tissue sarcomas with local aggressive behaviour and a high rate of local recurrence after treatment. Although they do not tend to metastasise systemically, the local aggressiveness can lead to situations in which limb-preserving surgery cannot be performed without severe disability. As isolated limb perfusion (ILP) with TNF and melphalan has proven to be extremely effective in the treatment of soft tissue sarcoma, we studied its potential in locally advanced extremity desmoid tumours. Methods: Prospectively maintained database in a tertiary referral centre. Between 1991 and 2003, 12 ILP procedures were performed in 11 patients for locally advanced desmoid tumours. Local surgical therapy with preservation of limb function was impossible in all patients due to large or multifocal tumours, multiple recurrences or extensive previous treatment. Perfusions were performed with 4–3mg TNF and 10–13mg/l limb volume melphalan form leg and arm perfusions, respectively. Results: Overall response rate was 75%: Two complete responses were recorded (17%) and seven patients had a partial response (58%). Amputation could be avoided in all cases. Local control was obtained after 10/12 ILPs and in the other two patients through repeat ILP and systemic chemotherapy, thus leading to an overall local control rate of 100%. Local toxicity was mild and systemic toxicity was absent in all patients. Conclusion: ILP is a very effective treatment option in the multimodality treatment of limb desmoid tumours. It should be considered in patients with aggressive and disabling disease where resection without important functional sacrifice is impossible. [Copyright &y& Elsevier]

Isolated hepatic perfusion has been used in patients with colorectal cancer (CRC) metastatic to the liver. We sought to determine whether perfusion with antisense oligodeoxynucleotides results in the downregulation of β-catenin and whether this improves tumor response to isolated limb perfusion (ILP) in a heterotopic model of human CRC. Adenomatous polyposis coli–mutant human CRC xenografts were implanted into athymic rats. Animals were randomized to the following groups: (1) no treatment, (2) control ILP, (3) melphalan ILP, (4) ILP with antisense specific for β-catenin, (5) ILP with nonspecific antisense, and (6) melphalan plus β-catenin–specific antisense ILP. Tumor response and Western blot analysis of protein expression were evaluated. The maximal decrease (mean ± SE) in tumor volume was 0% ± 10% for no treatment, 19% ± 14% for control ILP, 58% ± 3% for melphalan ILP, 58% ± 9% for β-catenin–specific ILP, 13% ± 19% for nonspecific antisense ILP, and 73% ± 6% for melphalan plus β-catenin–specific ILP ( P < .05 for melphalan ILP, β-catenin–specific ILP, and melphalan plus antisense ILP). Tumor regrowth was delayed for 6 days after control ILP, 24 days after melphalan ILP, 20 days after β-catenin–specific ILP, 10 days after nonspecific antisense ILP, and 60 days after melphalan plus β-catenin–specific ILP ( P < .05 for melphalan plus β-catenin–specific ILP compared with all others). Western blotting revealed prolonged suppression of β-catenin expression after β-catenin–specific ILP. Short-term β-catenin antisense treatment improves tumor response rates after ILP in a rodent model of human CRC. [ABSTRACT FROM AUTHOR]

Isolated limb perfusion (ILP) is an effective treatment modality for multiple in-transit melanoma metastases confined to the limb. Recurrences after ILP, however, occur in approximately 50% of patients and are a challenge for further treatment. The efficacy of repeat ILPs to prolong local control in this patient category is evaluated in this article. We used a prospective database in a tertiary referral center. Out of 100 tumor necrosis factor (TNF)-based ILPs with TNF and melphalan (TM-ILPs) in melanoma patients between March 1991 and July 2003, 25 repeat ILP procedures were performed in 21 patients in whom prior ILP treatment failed. All patients had bulky and/or numerous lesions and were treated with mild hyperthermic TM-ILP by using 2 to 4 mg of TNF and 10 to 13 mg/L of limb volume for the leg and arm, respectively. The complete response rate was 76%, a partial response occurred in 20%, and no change was recorded in 4%. There was no difference in the complete response rate or local toxicity between first and repeat perfusions. Local recurrence occurred in 72%; the median time to local progression was 14 months. The 5-year survival rate was 47%, which compares favorably with known survival rates of stage IIIA/AB patients. The median follow-up of the patients was 26 months. Patients who experience treatment failure after previous ILP treatment respond very well to repeat perfusion, and prolonged local control can thus be obtained. The subgroup of patients qualifying for repeat ILP represents a relatively favorable biological behavior of the melanoma. [ABSTRACT FROM AUTHOR]

Treatment for extremity soft tissue sarcoma (STS) has shifted in recent years from amputation to local wide excision combined with irradiation. For multiple sarcomas, this limb-sparing approach is often not possible. To avoid amputations, isolated limb perfusion (ILP) with tumor necrosis factor and melphalan is an attractive treatment option for patients with multiple extremity sarcomas. We investigated a prospective database at a tertiary referral institute. From July 1991 to July 2003, out of 217 ILPs, 64 ILPs were performed for either multifocal primary sarcomas or multiple sarcoma recurrences in 53 patients. All ILPs were performed under mild hyperthermic conditions by using 1 to 4 mg of tumor necrosis factor and 10 to 13 mg/L of limb volume for leg and arm perfusions, respectively. The overall response was 88%, with 42% complete response, 45% partial response, 11% no change, and 2% progressive disease. This response rate is significantly better than our experience in 153 locally advanced single-STS cases (88% vs. 69%). The toxicity of the procedure was mild to moderate in almost all cases; no treatment-related amputation had to be performed. The time to local recurrence was 29 months and differed significantly between multiple primary and multiple recurrent STS. The 5-year survival rate was 39%. Limb salvage was achieved in 45 (82%) of 55 treated limbs. In a group of patients who are uniformly candidates for amputation, ILP can achieve limb salvage in approximately four out of five patients. Because this treatment option provides excellent local control, it should be considered before an amputation is planned. [ABSTRACT FROM AUTHOR]

Recurrent extremity soft tissue sarcoma (STS) in a previously operated and irradiated area can usually be managed only by amputation. Tumor necrosis factor (TNF)-α–based isolated limb perfusion (ILP) is an established alternative to achieve limb salvage but is assumed to require sufficient vasculature. Because radiotherapy is known to destroy vasculature, we wanted to evaluate retrospectively whether the outcome of ILP in patients with radiotherapy for their primary tumor nonetheless showed a benefit from TNF treatment. We consulted a prospective database of TNF-based ILPs at the Erasmus MC–Daniel den Hoed Cancer Center in Rotterdam. Out of 342 TNF-based ILPs between 1991 and 2003, 30 ILPs were performed in 26 patients with recurrent STS in the irradiated field after prior surgery and radiotherapy. Eleven patients (42%) had multiple tumors (n = 2–20). All patients were candidates for amputation. We observed 6 complete responses (20%), 15 partial responses (50%), no change in 8 patients (27%), and progressive disease in 1 patient (3%). The median duration of response was 16 months (range, 3–56 months) at a median follow-up of 22 months (range, 3–67 months). The local recurrence rate was 45% in patients with multiple tumors and 27% in patients with single tumors. Ten patients (35%) died of systemic metastases. Limb salvage was achieved in 17 patients (65%). Regional toxicity was limited and systemic toxicity minimal. TNF-based ILP can avoid amputations in most patients with recurrent extremity STS in a prior operated and irradiated field. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)-α–based hyperthermic isolated limb perfusion (HILP) is one of the most active available approaches for locally advanced soft tissue sarcomas (STS) of the limbs. The aim of this study was to investigate the anticancer activity of a novel drug regimen including doxorubicin (DXR) and low-dose TNF-α. HILP with low-dose TNF-α (1 mg) and DXR (8.5 mg/L of limb volume) was given to 21 patients with limb-threatening STS: 14 had primary and 7 had recurrent STS, most of which were high grade (grade 1, n = 3; grade 2, n = 6; grade 3, n = 12). Resection of the tumor remnant was performed 6 to 8 weeks after HILP. TNF-α concentrations in plasma and perfusate were measured throughout perfusion. A major tumor response was observed at histology and clinical evaluation in 90% and 62% of patients, respectively. After a median follow-up of 30 months, limb salvage and local disease control were achieved in 71% and 81% of cases, respectively. Fourteen patients had moderate regional toxicity, which was resolved in all cases. One patient had severe limb toxicity, which did not require amputation. Systemic side effects were minimal, and there were no postoperative deaths. The perfusate/plasma area under the curve ratio for TNF-α was 56. HILP with low-dose TNF-α and DXR seems to be an active neoadjuvant drug regimen against limb-threatening STS. This therapeutic approach can achieve high limb-sparing surgery rates with acceptable local and negligible systemic toxicity. [ABSTRACT FROM AUTHOR]

Background: Regional infusion therapy with melphalan (LPAM) is an accepted treatment for advanced extremity melanoma. However, much room exists for improving the therapeutic index of this type of therapy.Methods: Isolated limb infusion (ILI) with temozolomide (TMZ), a novel methylating agent, was performed using a nude rat bearing human melanoma xenograft. Additional rats were treated systemically with TMZ, or regionally with LPAM or 10% dimethyl sulfoxide (DMSO; control) using ILI.Results: Rats that received systemic TMZ showed a poor tumor response and no tumor regression. In contrast, intra-arterial TMZ demonstrated a prolongation of tumor growth delay in a dose-responsive manner. In comparison with LPAM of equitoxic dose, TMZ provided both longer tumor growth delay and a greater number of tumor regressions.Conclusions: These data suggest that ILI with TMZ is an effective treatment for advanced extremity melanoma and may be better than LPAM in this setting. [ABSTRACT FROM AUTHOR]

The present paper overviews the current knowledge about effects of hyperthermia at temperatures used in clinical oncology on the peripheral nervous system. From the experimental studies it may be concluded that the heat sensitivity of the nerve is determined by the sensitivity of the nerve vasculature. These studies show that in order to avoid induction of severe neuropathy, application of heat to the peripheral nerves should not be in excess of doses of 30 min at 44°C or equivalent. Using modern equipment for application of loco-regional hyperthermia the incidence of even mild neurological complications is very low. In hyperthermic isolated limb perfusion (HILP) tneurotoxicity is an often-mentioned side effect, this is in spite of the fact that in all studies a relatively mild hyperthermic temperature is used that, based on the experimental studies, should be well tolerated by the nerves and other normal tissues in the limbs. It seems that the neurotoxicity observed after HILP results from thermal enhancement of drug toxicity, very probably combined with effects of a high tourniquet pressure that is used to isolate the blood flow in the leg. Whole body hyperthermia (WBH), using anesthesia and appropriate monitoring to avoid cardiovascular stress is at present considered a safe procedure. Still in the recent past cases of neuropathy after treatment have been described. When chemotherapy, and notably cisplatin, is administered before or during hyperthermia there are several clinical and experimental observations that indicate a limited tolerance of the peripheral nervous tissue in such case. Also previous radiotherapy may limit the tolerance of nerves to hyperthermia, notably when radiation is applied with a large field size. Experimental studies show that combined treatment with radiation and heat leads to enhancement of effects of radiation (enhancement ratio ∼1.5 at 60 min at 44°C). A clear contraindication for the application of hyperthermia in patients is the presence of a neurodegenerative disease, such as multiple sclerosis. Vigilance is also required in the treatment of diabetic patients with hyperthermia, this based on experimental animal studies, but so far no clear clinical data are available. [ABSTRACT FROM AUTHOR]

Background: Perfusate acidification with dilute hydrochloric acid augments tumor response rates in a rodent model of isolated limb perfusion (ILP). This study investigates the combination of metaiodobenzylguanidine (MIBG), a mitochondrial inhibitor, and systemic hyperglycemia as a strategy to selectively acidify tumors and thereby sensitize them to ILP. Methods: Human melanoma xenografts were implanted into the hind limbs of athymic rats. When tumors reached 12 to 15 mm in diameter, animals were randomized to ILP with or without melphalan, with or without systemic MIBG, and hyperglycemia of 485 ± 35 mg/dL. Intratumoral pH was measured during MIBG and glucose treatment by using magnetic resonance spectroscopy. Results: MIBG at 30 mg/kg plus hyperglycemia decreased intracellular pH by .6 units and extracellular pH by .8 units. MIBG at 22.5 mg/kg plus hyperglycemia decreased intracellular and extracellular pH by .4 and .5 units, respectively. Tumor growth was unaffected by systemic MIBG and hyperglycemia alone. When MIBG at 30 mg/kg and hyperglycemia were combined with ILP, tumor growth was delayed for 33 days after control ILP and for 44 days after melphalan ILP. However, this dose of MIBG was complicated by a 40% mortality rate after ILP. MIBG at 22.5 mg/kg, in combination with MIBG in the perfusate, did not cause mortality and delayed tumor growth by 51 days after melphalan ILP. Conclusions: MIBG and hyperglycemia improve tumor response rates after ILP in a rodent model of human melanoma. Selective tumor acidification with MIBG and hyperglycemia may offer added benefit to current regional perfusion strategies. [ABSTRACT FROM AUTHOR]

Background: Melphalan (L-PAM) hyperthermic isolated limb perfusion (HILP) is currently considered the standard treatment for patients with in-transit metastases from cutaneous melanoma. We here report on the results of L-PAM and low-dose tumor necrosis factor (TNF)α HILP in patients with bulky disease. Methods: Twenty patients underwent TNFα (1 mg) and L-PAM (10 mg/L) HILP. Perfusion was performed for 90 minutes, and systemic leakage was strictly monitored. Locoregional toxicity was evaluated according to Wieberdink’s criteria, whereas tumor response was evaluated with physical examination and ultrasound scan with or without fine-needle aspiration of any suspected recurrence. Results: In all cases, systemic leakage was <5%. No postoperative deaths occurred, and locoregional toxicity was mild (grade 1 or 2) in 95% of patients. A complete tumor response was obtained in 14 patients (70%), and partial responses were obtained in 5 patients (25%). After a median follow-up of 18 months, six patients are alive and disease free, seven are alive with local or distant recurrence or both, and seven have died of disease. Conclusions: Low-dose TNFα HILP can achieve tumor responses comparable with those reported with higher doses of cytokine. Moreover, this drug regimen is associated with acceptable local toxicity, carries a smaller risk of systemic toxicity, and incurs lower costs. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate whether dynamic contrast-enhanced MR imaging can determine tumor response and localize residual viable tumor after isolated limb perfusion (ILP) chemotherapy in soft tissue tumors. Twelve consecutive patients, with histologically proven high-grade soft tissue sarcoma, prospectively underwent non-enhanced MR and dynamic contrast-enhanced MR imaging before and after ILP. Tumor volume was measured on non-enhanced MR images. The temporal change of signal intensity in a region of interest on dynamic contrast-enhanced MR images was plotted against time. Start, pattern, and progression of enhancement were recorded. Histopathologic response was defined as complete response if no residual viable tumor was present, partial remission if <50% viable tumor was present, and no change if > or =50% viable tumor was present in the resection specimen. Resected specimens for correlation with histopathology were available for 10 patients; 5 patients had partial remission and 5 had no change. Volume measurements correctly predicted tumor response in 6 of 10 patients. Dynamic contrast-enhanced MR correctly predicted tumor response in 8 of 10 patients. Early rapidly progressive enhancement correlated histologically with residual viable tumor. Late and gradual, or absence of enhancement, was associated with necrosis, predominantly centrally located, or granulation tissue. These preliminary results show that dynamic contrast-enhanced MR imaging offers potential for non-invasive monitoring of response to isolated limb perfusion in soft tissue sarcomas due to identification of residual areas of viable tumor and subsequently may provide clinically useful information with regards to timing and planning of additional surgery. Further prospective studies in a larger patient population is warranted. [ABSTRACT FROM AUTHOR]

Background: Isolated limb perfusion (ILP) with recombinant human tumor necrosis factor-α (rhTNF-α) and melphalan harbors the risk of septic shock–like syndrome. Pentoxifyllin (PTX) produced a beneficial effect on cytokine response and survival in animal experiments of septic shock, and we were interested to explore its effect during TNF-ILP in humans. Methods: Eighteen consecutive patients underwent TNF-ILP and received PTX (30 mg/kg/day), whereas another 13 consecutive patients did not. PTX was given systemically after the limb extracorporeal circulation was started. Cardiac index, systemic vascular resistance (SVR), and pulmonary vascular resistance were recorded via a Swan-Ganz catheter. Blood levels of TNF-α, interleukin-6, procalcitonin, and lipopolysaccharide-binding protein were determined before, during, and after ILP. Results: After reperfusion, systemic levels of TNF-α were significantly less increased in the PTX group (peak, 2.8 vs. 1.3 ng/mL; P < .05), as were interleukin-6 values (peak, 68 vs. 22 pg/mL; P < .02) and lipopolysaccharide-binding protein plasma levels (peak, 215 vs. 105 μg/mL; P < .03). Differences in cardiac index, SVR, and mean arterial blood pressure were not significantly different. Norepinephrine or dobutamine to maintain SVR was less required in the PTX group. Conclusions: PTX attenuates systemic cytokine production and influences components of the systemic inflammatory response after TNF-ILP. PTX may play a beneficial role in the management of septic shock–like syndrome, particularly in patients with leakage from the ILP circuit. [ABSTRACT FROM AUTHOR]

Cutaneous Stewart-Treves lymphangiosarcomas represent a rare group of tumors characterized by a high grade of vascularization and by localization in an extremity with lymphedema. The multifocality and the localization makes these tumors eligible for treatment with isolated limb perfusion (ILP). ILP with tumor necrosis factor (TNF) and melphalan is a safe and highly effective procedure that can achieve limb salvage in ≥80% of all patients with nonresectable extremity soft tissue sarcoma or melanoma. In 10 patients with multifocal Stewart-Treves lymphangiosarcoma of the extremities, 16 ILPs with TNF plus melphalan were performed. All patients would have been candidates for exarticulation of the extremity. We observed an 87% overall response rate (complete and partial responses); one patient had a mixed response, and one patient did not respond to the therapy. In nine perfusions (56%), a complete response was achieved, and five perfusions (31%) resulted in a partial response. Limb salvage was achieved in eight patients (80%), with a mean follow-up duration of 34.8 months (range, 3 to ≥115 months). Regional toxicity was limited and systemic toxicity minimal to moderate, with no toxic deaths. Multifocal Stewart-Treves lymphangiosarcomas in extremities with chronic lymphedema can be successfully treated by ILP with TNF and melphalan. [ABSTRACT FROM AUTHOR]

Background: Since the introduction of high-dose tumor necrosis factor-α (TNFα) in the settingof isolated limb perfusion (ILP) in the clinic, prevention of leakage to the body of the patient ismonitored with great precision for fear of TNF-mediated toxicity. That we observed remarkablylittle toxicity in patients with and without leakage prompted us to determine patterns of cytokinesand acute phase proteins in patients with high leakage and in patients without any leakage. Methods: TNFa, interleukin (IL)-6, IL-8, C-reactive protein, and secretory (s)-phospholipase A2 weremeasured at several time points during and after (until 7 days) ILP in 10 patients with a leakage to thesystemic circulation varying in percentage from 12% to 65%. As a control, the same measurements, bothin peripheral blood and in perfusate, were performed in nine patients without systemic leakage. Results: In patients with systemic leakage, levels of TNFaincreased during ILP, reaching valuesto 277 ng/ml. IL-6 and IL-8 peaked 3 hours after ILP with values significantly higher compared withpatients without systemic leakage. C-reactive protein and s-phospholipase A2 peaked at day 1 inboth patient groups, s-phospholipase A2 with significant higher levels and C-reactive protein, incontrast, with lower levels in the leakage patients. Conclusions: High leakage of TNFα to the systemic circulation, caused by a complicated ILP,led to 10-fold to more than 100-fold increased levels of TNFα, IL-6, and IL-8 in comparison withpatients without leakage. The increase of the acute phase proteins was limited. Even when highleakage occurs, this procedure should not lead to fatal complications. The most prominent clinicaltoxicity was hypotension (grade III in four patients), which was easily corrected. No pulmonary orrenal toxicity was observed in any patient. It is our experience that, even in the rare event ofsignificant leakage during a TNFα-based ILP, postoperative toxicity is usually mild and can beeasily managed by the use of fluid and, in some cases, vasopressors. [ABSTRACT FROM AUTHOR]

Background: Hyperthermic isolated limb perfusion with tumor necrosis factor-α and melphalan was used as induction treatment in locally advanced extremity soft-tissue sarcomas for limb sparing surgery. The typical histopathological changes that occur in these tumoral masses are described in a series of 30 patients. Methods: Fresh tumor specimens of 27 high grade extensive soft-tissue sarcomas and 3 recurrent desmoid tumors of the extremities were collected 6 to 8 weeks after hyperthermic isolated limb perfusion with tumor necrosis factor-α plus melphalan. The specimens were studied for surgical margins, extent and type of tumor necrosis, lymph node involvement, perineural and vascular invasion, and the effects on adjacent normal tissues such as nerves, muscles, and blood vessels. Results: The typical histological changes were central cystic hemorrhagic necrosis with pericystic extensive fibrosis. Some nonspecific changes were noted in the soft tissues around the mass. In eight cases, more than 90% necrosis was found. In 17 cases, the extent of necrosis ranged between 60% and 90% (80%–90% in 4 of 17 cases). In five cases, less than 60% necrosis was noted. The best responses (.90% necrosis) were observed in distally located tumors. The responsive types were malignant fibrous histiocytoma, followed by myxoid liposarcoma and synovial sarcoma. Desmoid tumors showed less necrosis than high grade sarcomas. Vascular invasion was observed in two cases and intralesional venous thrombosis in one case. No perineural invasion or lymph nodes involvement were observed. The soft tissues adjacent to the tumor bed did not show major morphological changes. No correlation was found between the histological changes and each of the following: the anatomical (upper vs. lower limb) or compartmental location of the tumor; whether the tumor was primary or recurrent; and the types of previous treatment (systemic chemotherapy or radiotherapy) and tumor size. Conclusions: This is the first serial histological description of the effects of tumor necrosis factor-α and melphalan administered via hyperthermic isolated limb perfusion on the tumoral masses of limb soft-tissue sarcomas. The small number of specimens and, especially, the variability of tumors preclude definite conclusions. Larger numbers and more homogeneity are needed in future studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Melanoma still represents a major challenge for health systems around the world. A classical treatment for patients with a high tumor burden or rapidly recurrent in-transit metastases is isolated limb perfusion (ILP) therapy instead of locoregional surgical resection, or when the latter is no longer feasible. In this era of modern systemic treatments for melanoma, it still remains interesting to analyze the role of management approaches for locoregionally-advanced disease, such as isolated limb perfusion (ILP). With this purpose, we conducted a systematic review updating the available literature on ILP for malignant melanomas. The main objectives of this review were to focus on the effectiveness and safety of ILP. In conclusion, ILP, with its low incidence of regional and systemic toxicity, is a valuable palliative treatment not only for patients with disease confined to a limb, but also for patients with a metastatic melanoma with a bulky or symptomatic disease, in order to improve their quality of life. Background. Isolated limb perfusion (ILP) is a locoregional procedure indicated by the unresectable melanoma of the limbs. Its complexity and highly demanding multidisciplinary approach means that it is a technique only implemented in a few referral centers around the globe. This report aims to examine its potential role in the era of targeted therapies and immunotherapy by conducting a systematic review of the literature on ILP. Methods. PubMed, Embase and Cochrane Library were searched. The eligibility criteria included publications from 2000–2020 providing valid data o effectiveness, survival or toxicity. Studies in which the perfusion methodology was not clearly described, letters to the editor, non-systematic reviews and studies that applied outdated clinical guidelines were excluded. To rule out studies of a low methodological quality and assess the risk of bias, the following aspects were also required: a detailed description of the applied ILP regimen, the clinical context, follow-up periods, analyzed clinical endpoints, and the number of analyzed ILPs. The disagreements were resolved by consensus. The results are presented in tables and figures. Results. Twenty-seven studies including 2637 ILPs were selected. The median overall response rate was 85%, with a median complete response rate of 58.5%. The median overall survival was 38 months, with a 5-year overall survival of 35%. The toxicity was generally mild according to Wieberdink toxicity criteria. Discussion. ILP still offer a high efficacy in selected patients. The main limitation of our review is the heterogeneity and age of most of the articles, as well as the absence of clinical trials comparing ILP with other procedures, making it difficult to transfer its results to the current era. Conclusions. ILP is still an effective and safe procedure for selected patients with unresectable melanoma of the limbs. In the era of targeted therapies and immunotherapy, ILP remains an acceptable and reasonable palliative treatment alternative, especially to avoid limb amputations. The ongoing clinical trials combining systemic therapies and ILP will provide more valuable information in the future to clarify the potential synergism of both strategies. [ABSTRACT FROM AUTHOR]