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.     

Efficacy of isolated limb perfusion (ILP) in patients with Merkel cell carcinoma (MCC): A multicenter experience

Background

Merkel cell carcinoma (MCC) is a rare and potentially aggressive neuroendocrine tumor of the skin, with a propensity for locoregional metastases. In two expert referral centers, isolated limb perfusion (ILP) is used to obtain locoregional control in selected locoregionally advanced MCC patients. This study describes our experience.

Laparoscopic hyperthermic isolated limb perfusion a new minimally invasive approach for HILP

Background: Hyperthermic isolated limb perfusion (HILP) represents a limb-sparing treatment for unresectable soft tissue sarcoma (STS) of the extremities with substantial complete response rates. HILP often provides good functional limb preservation, hence a significant improvement also in terms of quality of life of the patient. Notwithstanding these clear advantages, the traditional technique is still hindered by relatively high post-operative morbidity.

Method: We treated a 78-year-old female with unresectable angiosarcoma of the left leg using a new surgical approach: an entirely laparoscopic HILP.

Results: No conversion from laparoscopic to “open” surgery was necessary. Since no abdominal muscle section was performed, post-operative pain was low and easily manageable; early mobilisation and early discharge were achieved. Patient developed moderate toxicity, which resolved spontaneously within 3–4 weeks, with complete return to normal daily activities after 30?d. Complete clinical response with preservation of leg function was obtained.

Conclusions: We describe for the first time an entirely laparoscopic HILP. Demonstration of this technique’s efficacy and safety on a large series of patients is clearly necessary but its therapeutic efficacy appears to be comparable to the standard technique. Furthermore, laparoscopic HILP has shown low post-operative morbidity: no wound complications, mild and easily manageable post-operative pain and early discharge from the hospital and early resuming of daily activities.     

Oncological outcome after hyperthermic isolated limb perfusion for primarily unresectable versus locally recurrent soft tissue sarcoma of extremities

IntroductionThe management of locally advanced extremity soft tissue sarcomas, particularly in terms of a limb salvage strategy, represents a challenge, especially in recurrent tumors. In the context of a patient-tailored multimodal therapy, hyperthermic isolated limb perfusion (ILP) is a promising limb-saving treatment option. We report the outcome of patients with primarily irresectable and locally recurrent soft tissue sarcoma (STS) treated by ILP.Patients and methodsData about patient demographics, clinical und histopathological characteristics, tumor response, morbidity and oncological outcome of all patients with STS, who underwent an ILP at our institution in a 10-year period, were retrospectively detected and analyzed.ResultsThe cohort comprised 30 patients. Two patients were treated with ILP for palliative tumor control, 13 patients because of a local recurrent soft tissue sarcoma (rSTS) and 15 patients because of primarily unresectable soft tissue sarcoma (puSTS). 25 of the 28 patients with curative intention received surgery after ILP (11 pts with rSTS and 14 pts with puSTS). Histopathologically we observed complete response in 6 patients (24%) and partial responses in 19 patients (76%) with a significant better remission in patients with puSTS (p = 0,043). Limb salvage rate was 75%. Mean follow-up was 69 months [range 13–142 months]. Seven (7/11; 64%) patients with rSTS and one (1/14; 7%) patient with puSTS developed local recurrence after ILP and surgery, whereas eight (8/13; 62%) rSTS patients and seven (7/15; 47%) puSTS patients developed distant metastasis. During follow-up, eight patients (28.5%) died of disease (5/13; 38%) rSTS and 3/15 (20%) puSTS. ILP in the group of previously irradiated sarcoma patients (n = 13) resulted in a limb salvage rate of 69% and was not associated in an increased risk for adverse events.DiscussionILP for advanced extremity STS is a treatment option for both puSTS and rSTS resulting in good local control and should be considered in multimodal management. ILP is also a good option for patients after radiation history.     

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.     

Pharmacokinetics of melphalan in isolated limb perfusion

The pharmacokinetics of melphalan was studied by sampling of tissue and plasma in 72 rats that␣underwent isolated hyperthermic limb perfusion under different conditions. A miniaturized extracorporeal circulation system for small animals was used for␣perfusion of the rat hindlimb. Melphalan levels (l-phenylalanine mustard, L-PAM) were determined by high-performance liquid chromatography (HPLC). The temperature of the perfusate plasma and tissue, pH, administration method, and flow rate were modified and compared with regard to their influence on pharmacokinetic parameters. The highest tissue penetration of melphalan was observed under the following conditions: (a) pH range of the perfusate plasma between 7.3 and 7.7 (physiological environment), (b) temperature range of the perfusate from 40° to 41.5 °C (destruction of cellular carrier systems at higher temperatures and increased inactivation by hydrolysis of melphalan above 41.5 °C), (c) application of melphalan as a single dose into the reservoir of the extracorporeal circuit (optimal tissue penetration), and (d) reduced perfusate flow (prolonged contact time between perfusate and tissue). Received: 23 February 1998 / Accepted: 2 June 1998     

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 is an effective treatment modality for locally advanced Kaposi sarcoma of the extremities

IntroductionKaposi sarcoma (KS) is a rare soft tissue sarcoma. In case of locally advanced disease, mutilating surgery such as amputations or major reconstructive procedures are sometimes inevitable. The aim of this study was to evaluate the effectiveness of isolated limb perfusion (ILP) in patients with locally advanced KS of the extremities.Material and methodsAll patients who underwent ILP for KS between 1996 and 2018 at Erasmus MC, Rotterdam were identified. Clinical data was obtained from either a prospectively maintained database or retrospective assessment of patient files.ResultsA total of 14 primary ILP's were performed in 11 patients. Median follow-up from primary ILP was 30 months (range, 5–98). The overall response rate of primary ILP was 100%, with a complete response (CR) rate of 50%. Only minimal local toxicity (Wieberdink I-III) was observed. Local progressive disease occurred after eight primary ILP's (57%) with a median local progression free survival (PFS) of 18 months (95% confidence interval [CI]: 7.0–28.9). Subsequently, four (46%) patients received a total of 5 recurrent ILP's. After the recurrent ILP on the same leg, the overall response rate was 75% and a CR-rate of 50%. One patient needed amputation post-operatively resulting in a limb salvage rate of 91%. One (9%) patient developed metastases four months after ILP.ConclusionsILP is a highly effective treatment modality with very limited morbidity rates for patients with locally advanced KS of the extremity. ILP should be considered as a treatment modality for locally advanced KS of the extremities.     

Isolated limb perfusion for locally advanced angiosarcoma in extremities: A multi-centre study

BackgroundAngiosarcomas are rare and aggressive soft-tissue sarcomas. The only potential curative treatment is complete surgical excision. This study reports the outcome of isolated limb perfusion (ILP) with high-dose melphalan and tumour necrosis factor α for locally advanced angiosarcoma.Material and methodsAll patients who underwent an ILP for angiosarcomas between 1991 and 2016 in three tertiary referral centres were identified from prospectively maintained databases.ResultsA total of 39 patients were included, with a median follow-up of 18 months (interquartile range 6.1–60.8). Of these patients, 23 (58.9%) patients had a complete response (CR) after ILP, 10 (25.6%) had a partial response, 4 (10.3%) had stable disease and 2 (5.1%) patients had progressive disease immediately after ILP. A total of 22 patients developed local progression (56.4%), whereas nine (23.1%) developed distant metastases. The patients with CR had a significantly prolonged median local progression-free survival (PFS) (15.4 versus 7.3 months, p = 0.015) when compared with non-CR patients, and a trend towards better median overall survival (81.2 versus 14.5 months, p = 0.054). Six patients underwent multiple ILPs, whereby the CR rate of the first, second and third ILPs were 60%, 80% and 67%, respectively. Thirteen (33.3%) patients needed further surgical intervention, consisting of resection in eight patients (20.5%) and amputation in five patients (12.8%).ConclusionILP is an effective treatment option for patients with locally advanced angiosarcoma in the extremities, resulting in a high number of CRs, a high limb salvage rate and prolonged local PFS.     

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.     

Nifedipine improves blood flow and oxygen supply,but not steady-state oxygenation of tumours in perfusion pressure-controlled isolated limb perfusion

Isolated limb perfusion allows the direct application of therapeutic agents to a tumour-bearing extremity. The present study investigated whether the dihydropyridine-type Ca(2+)-channel blocker nifedipine could improve blood flow and oxygenation status of experimental tumours during isolated limb perfusion. Perfusion was performed by cannulation of the femoral artery and vein in rats bearing DS-sarcoma on the hind foot dorsum. Perfusion rate was adjusted to maintain a perfusion pressure of 100-140 mmHg throughout the experiment. Following equilibration, nifedipine was continuously infused for 30 min (8.3 microg min(-1) kg(-1) BW). During constant-pressure isolated limb perfusion, nifedipine can significantly increase perfusion rate (+100%) and RBC flux (+60%) through experimental leg tumours. "Steal phenomena" in favour of the surrounding normal tissue and oedema formation were not observed. Despite the increased oxygen availability (+63%) seen upon application of this calcium channel blocker, nifedipine does not result in a substantial reduction of tumour hypoxia, most probably due to an increase in O(2) uptake with rising O(2) supply to the tumour-bearing hind limb. Nifedipine application during isolated limb perfusion can enhance tumour microcirculation and may therefore promote the delivery (pharmacokinetics) of anti-cancer drugs to the tumour and by this improve the efficacy of pressure-controlled isolated limb perfusion.     

Histological response assessment following neoadjuvant isolated limb perfusion in patients with primary,localised, high-grade soft tissue sarcoma

Purpose: Histological response assessment following neoadjuvant treatment can help identify patients at a higher risk for systemic disease progression. Our goal was to evaluate whether mitotic count and the amount of viable tumour following neoadjuvant isolated limb perfusion (ILP) for primary, locally advanced, non-metastatic, high-grade extremity soft tissue sarcoma correlate with prognosis. Patients and methods: This study is a retrospective analysis of 61 patients who underwent neoadjuvant ILP followed by surgical resection with curative intent between 2001 and 2011. Non-parametric analyses were carried out with the Mann-Whitney U and the Wilcoxon signed-rank test. Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank test. Results: The median follow-up was 44 months for all patients and 55 months for survivors. The amount of viable tumour after ILP had no correlation with overall (OS) (P?=?0.227) or event-free (EFS) (P?=?0.238) survival probability. Patients with a low mitotic count after ILP had a significantly higher OS (P?<?0.001), EFS (P?=?0.002) and post-relapse survival probability (P?=?0.030) compared to patients with an intermediate or high mitotic count. Conclusions: The mitotic count following ILP for primary, high-grade, locally advanced, non-metastatic soft tissue sarcoma appears to significantly correlate with prognosis. If these results are validated in a prospective setting, they could provide a rationale for the design of adjuvant systemic chemotherapy trials with the goal of improving the prognosis of patients with an intermediate or high mitotic count after ILP.     

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.     

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.     

Isolated limb perfusion for soft tissue sarcoma: Current practices and future directions. A survey of experts and a review of literature

Soft tissue sarcomas constitute 1% of adult malignant tumors. They are a heterogeneous group of more than 50 different histologic types. Isolated limb perfusion is an established treatment strategy for locally advanced sarcomas. Since its adoption for sarcomas in 1992, after the addition of TNFα, few modifications have been done and although indications for the procedure are essentially the same across centers, technical details vary widely. The procedures mainly involves a 60 min perfusion with melphalan and TNFα under mild hyperthermia, achieving a limb preservation rate of 72–96%; with an overall response rates from 72 to 82.5% and an acceptable toxicity according to the Wieberdink scale. The local failure rate is 27% after a median follow up of 14–31 months compared to 40% of distant recurrences after a follow up of 12–22 months. Currently there is no consensus regarding the benefit of ILP per histotype, and the value of addition of radiotherapy or systemic treatment. Further developments towards individualized treatments will provide a better understanding of the population that can derive maximum benefit of ILP with the least morbidity.     

Isolated limb perfusion as a treatment option for rare types of tumours

Background: Isolated limb perfusion (ILP) is an established and effective treatment for advanced melanoma and soft tissue sarcomas of the extremities with a high overall response rate. The aim of this study was to describe our experience of ILP for more rare types of tumours.

Methods: Patients with Merkel cell carcinoma (MCC) (n?=?4), squamous cell carcinoma (SCC) (n?=?2), B-cell lymphoma (n?=?1), desmoid tumours (n?=?3), pigmented villonodular synovitis (PVNS) (n?=?1) and giant cell tumour (n?=?1) were treated with ILP and analysed retrospectively.

Results: The four patients with in-transit MCC had three complete responses (CR) and one partial response (PR); the two patients with SCC had one CR and one stable disease (SD); the patients with desmoid tumours had two PR and one SD. A CR was also observed for the patient with a giant cell tumour, but the patient with PVNS had a SD. The patient with cutaneous metastases of B-cell lymphoma showed a CR, however with rapid systemic progression. Local toxicity according to Wieberdink was grade II in 10 patients (83%) and grade III in two patients (17%).

Conclusions: These results show that ILP can be used as a treatment option also for more rare disease entities when other treatments have failed.     

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.     

Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

Previously we demonstrated that addition of Tumour Necrosis Factor-alpha to melphalan or doxorubicin in a so-called isolated limb perfusion results in synergistic antitumour responses of sarcomas in both animal models and patients. Yet, 20 to 30% of the treated tumours do not respond. Therefore agents that synergise with tumour necrosis factor alpha must be investigated. Actinomycin D is used in combination with melphalan in isolated limb perfusion in the treatment of patients with melanoma in-transit metastases and is well known to augment tumour cell sensitivity towards tumour necrosis factor alpha in vitro. Both agents are very toxic, which limits their systemic use. Their applicability may therefore be tested in the isolated limb perfusion setting, by which the tumours can be exposed to high concentrations in the absence of systemic exposure. To study the beneficial effect of the combination in vivo, BN-175 soft tissue sarcoma-bearing rats were perfused with various concentrations of actinomycin D and tumour necrosis factor alpha. When used alone the drugs had only little effect on the tumour. Only when actinomycin D and tumour necrosis factor alpha were combined a tumour response was achieved. However, these responses were accompanied by severe, dose limiting, local toxicity such as destruction of the muscle tissue and massive oedema. Our results show that isolated limb perfusion with actinomycin D in combination with tumour necrosis factor alpha leads to a synergistic anti-tumour response but also to idiosyncratic locoregional toxicity to the normal tissues. Actinomycin D, in combination with tumour necrosis factor alpha, should not be explored in the clinical setting because of this. The standard approach in the clinic remains isolated limb perfusion with tumour necrosis factor alpha in combination with melphalan.     

Melan-A specific CD8+ T lymphocytes after hyperthermic isolated limb perfusion: A pilot study in patients with in-transit metastases of malignant melanoma

Abstract

Purpose: Isolated limb perfusion (ILP) with hyperthermia is an effective treatment for in-transit metastases of malignant melanoma in the extremities. Preclinical studies have shown that hyperthermia may induce an immunogenic death of tumour cells. We therefore decided to study whether ILP may induce tumour-specific immune responses in the clinical setting.

Method: The number of Melan-A/Mart-1 specific CD8+ T cells, as well as other phenotypically different immune cells, was recorded in peripheral blood in 12 HLA-A2+ patients with in-transit metastases undergoing hyperthermic ILP with melphalan.

Results: All patients underwent ILP without any complication and with an overall response rate of 83%. No substantial changes in the number of circulating T-cells, B-cells, NK-cells or monocytes were observed during follow-up. Four out of 12 patients showed an elevation of Melan-A+ CD8+ T-cells 4 weeks after ILP.

Conclusion: We here report our preliminary observations that a small increase in tumour-specific T-cells could be seen in a subpopulation of patients after ILP. However, much more work is necessary to fully delineate the systemic immune response to hyperthermic ILP.