Isolated limb perfusion for melanoma

Isolated limb perfusion with high-dose chemotherapy is an accepted treatment modality to achieve locoregional control in advanced melanoma of the extremities. The drug of choice is melphalan. Tumor necrosis factor-alpha is frequently added to melphalan in bulky disease, and this combination may be an option for repeat perfusion for recurrent melanoma after a first perfusion. Results of perfusions performed with tissue temperatures between 37 degrees C and 38 degrees C seem to be equivalent to those of the perfusions performed under mild hyperthermic conditions. Perfusion cannot be recommended as an adjunct to wide local excision in patients who have primary melanoma. Adjuvant perfusion in repeatedly recurrent limb melanoma, however, may be of value because it lengthens the limb recurrence-free interval and decreases the number of lesions per recurrence significantly. Regional toxicity of perfusion should be mild when risk factors are taken into account.     

Isolated limb perfusion in regional melanoma

Adjuvant perfusion to excision of a primary melanoma cannot be recommended because of its limited effect. In patients who have frequently recur-ring resectable locoregional melanoma, perfusion may provide valuable loco-regional disease control by decreasing the number of recurrences and lesions per recurrence. Randomized studies are needed to further establish the role of perfusion as an adjuvant treatment for resectable recurrences of melanoma. Unresectable limb melanoma is the primary indication for perfusion. Better response rates tend to be seen when TNF-a is used in patients who have a high tumor load. Repeat perfusion is feasible, resulting in response rates similar to those of a first perfusion for locoregional melanoma.Older age itself is not a contraindication for perfusion. The long-term health-related quality of life of survivors of melanoma who underwent treatment with perfusion is comparable to that of their healthy peers in the general Dutch population.     

Isolated limb perfusion for extremity sarcoma

Isolated limb perfusion has been used in patients with extremity sarcomas for over 40 years. In the majority of patients this approach has been employed as a limb-sparing alternative for patients with amputation as their only treatment option. Despite this long history of use in the treatment of patients with extremity sarcomas, many questions remain with respect to the appropriate drug or combination of drugs to be used in the perfusion circuit, the role of hyperthermia in isolated perfusion, and the use of hyperthermic perfusion in the neoadjuvant or adjuvant setting. Although many non-randomized studies have been performed, they suffer from a variety of problems, including small patient numbers, variety of chemotherapeutic agents employed, multiple levels of hyperthermia, and subjective evaluation of what constitutes amputation as a potential treatment option.     

Isolated limb perfusion in locally advanced cutaneous melanoma

Isolated limb perfusion (ILP) is a well-established locoregional procedure to deliver high doses of cytostatics to an extremity with multiple in-transit lesions from cutaneous melanoma, with minimal systemic and mild local toxicity. This approach is quite sophisticated and requires accurate monitoring of systemic leakage and of the temperature of the affected limb in order to avoid major systemic and local side effects. Mephalan (L-PAM) is considered the reference drug, although complete responses are reported in only about 50% of patients. Since the early 1990s, tumor necrosis factor-alpha (TNF-alpha) was administered with melphalan in ILP aiming to improve the therapeutic index of this procedure. However, despite the impressive results reported, its role still remains controversial, seemingly confined to large tumor bulk. Fotemustine ILP was proposed as a less toxic alternative to L-PAM, after the results of a pilot experience claiming similar response rates with less local toxicity. A formal phase 1-2 study is now underway to confirm these findings. More straightforward procedures, such as isolated limb infusion, are appealing, as they seem capable of achieving good response rates, are easily repeatable, and are less costly. Larger series are required to validate such results. As potential agents to be delivered through ILP, new vasoactive drugs and agents with new mechanisms of action that interplay with chemotherapy, as well as virus-mediated gene therapy, are being developed.     

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.     

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.     

Isolated limb perfusion for the management limb threatening soft tissue sarcomas: The role of histological type on clinical outcomes

Background

Hyperthermic isolated limb perfusion (HILP) is an effective neoadjuvant treatment to avoid amputation in patients with locally advanced extremity soft tissue sarcomas (STS). We aimed to investigate whether STS histological type plays a role in predicting clinical outcomes.

Isolated limb perfusion in the management of locally advanced extremity soft tissue sarcoma

In conclusion, ILP is an interesting and important treatment option in the management of locally advanced extremity soft tissue sarcomas. Large medical centers, dealing with referrals and an important caseload of STS patients, should develop this treatment option and have it readily available to offer patients the best chances for limb salvage. In Europe, the success of TNF-based ILP has lead to the training, accreditation, and activation of TNF-based ILP programs in over 30 cancer centers since the approval of TNF for this indication in 1999. Thus, country by country centers for referral programs are established to deal with those categories of patients that can greatly benefit from the availability and integration of this treatment option in the STS treatment programs.     

Isolated limb perfusion with melphalan for femoral metastases of breast cancer: case report

BACKGROUND AND OBJECTIVES: Complications of bone destruction occur in 10-29% of breast cancer patients with skeletal metastases. Palliative treatment consists of systemic chemotherapy, hormonal treatment, radiotherapy, and/or surgery in the case of (impending) fracture. A case is presented where isolated limb perfusion was applied for this indication. METHODS: A 43-year-old woman with extensive femoral metastases of breast cancer with impending fracture was treated with isolated limb perfusion (ILP) with melphalan. Radiotherapy had resulted only in pain reduction, and intramedullary fixation was opted against because stable fixation was considered not feasible due to the location of the metastases. ILP with high-dose melphalan (10-20 times the amount that can be administered systemically) under normothermic (37-38 degrees C) conditions, resulted in partial remission and reossification. RESULTS: One year after ILP, until her death 2 years later, due to progressive metastases at other sites, the patient was able to bear weight again on her left leg. CONCLUSIONS: In selected patients with symptomatic large bone metastases from breast cancer, and no other treatment options, ILP with melphalan may be used for successful palliation.     

Hyperthermic isolated limb perfusion in locally advanced limb soft tissue sarcoma: A 24-year single-centre experience

Background: Hyperthermic isolated limb perfusion (HILP) is a locoregional treatment aimed at avoiding amputation in patients with advanced extremity soft tissue sarcomas (STS). Over the last 25 years, HILP procedure has been implemented to maximise its therapeutic ratio. Methods: A retrospective analysis including 117 patients who underwent HILP from 1989 to 2013 was performed. Three different drug schedules were applied: 1) doxorubicin (n?=?47), 2) high dose (3–4?mg) tumour necrosis factor-alpha (TNF-α) plus doxorubicin (n?=?30), 3) low dose (1?mg) TNF-α plus melphalan (L-PAM) (n?=?40). Tumour response was evaluated by MRI or CT and surgical specimens. Toxicity and local progression-free survival (LPFS) were also evaluated. Results: In total 92 (78.6%) patients had primary, 25 (21.4%) had recurrent and 17 (14.5%) had metastatic disease. The subjects in the three groups were homogeneous for clinical-pathological features. Pathological response was complete in 55 patients (47%), partial in 35 (29.9%), regardless of drug schedule (p?=?0.501) and tumour presentation (p?=?0.094). Wieberdink III–V toxicity was registered in 19.1%, 20% and 2.5% of patients, respectively (p?<?0.051). Twenty-eight patients (23.9%) received adjuvant radiotherapy with no relevant toxicity. Five-year LPFS was 81.6% and 74.2% in patients with primary or recurrent disease, respectively (p?=?0.652). After a median follow-up of 36.5 months, the limb sparing rate was 77.8%. Conclusions: HILP performed with different drugs was equally active, either in primary, recurrent or metastatic STS, providing effective limb sparing and durable local control. Low dose TNF-α plus L-PAM had the most favourable toxicity profile. Adjuvant radiotherapy was not associated with relevant toxicity.     

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.     

Isolated limb perfusion for unresectable extremity sarcoma: results of 2 single-institution phase 2 trials

BACKGROUND:

Controversy has surrounded the role of isolated limb perfusion (ILP) for unresectable extremity sarcomas. However, there remains a group of sarcoma patients for whom amputation is the only potential treatment. Because systemic therapies are limited, the authors evaluated ILP in an effort to provide a limb‐salvage option.

METHODS:

Since 1995, patients with unresectable extremity sarcomas were entered in 2 prospective trials using ILP. Study 1 used tumor necrosis factor (TNF) and melphalan in the perfusion circuit at hyperthermic temperatures (39‐41°C). Study 2 used doxorubicin at normothermic temperatures. All ILPs were performed using the standard, previously described technique.

RESULTS:

Seventeen patients were entered into study 1; there were 10 (58%) partial responses, 1 (6%) near complete response (CR), 1 (6%) CR, and 5 (30%) no response/minor response. Fourteen patients died of their disease, with a median follow‐up of 17 months. Seven (41%) patients maintained their limb intact until the time of death. Twelve patients were entered into study 2; there were no partial or CRs and 2 (20%) minor responses. With a median follow‐up of 35 months, there are 3 patients alive (2 with their extremity intact and 1 with an amputation). Six patients developed myonecrosis with creatine phosphokinase levels up to 54,000 U/dL.

CONCLUSIONS:

Although doxorubicin is active systemically, TNF and melphalan appear to have greater activity and less toxicity during ILP. Future clinical trials are needed to clearly identify the role for ILP in patients with unresectable extremity sarcomas. Cancer 2011. © 2011 American Cancer Society.     

Isolated limb perfusion based anti-p21ras gene therapy in a rat rhabdomyosarcoma

BACKGROUND: Inhibition of ras oncogene is a promising new strategy. Gene therapy against ras proved successful in human and murine tumour cell lines. Previously we demonstrated effective targeted transfection of tumour in a rat model by using an isolated limb perfusion (ILP) for the delivery of adenoviral vectors. MATERIALS AND METHODS: This study explores the anti-tumour activity of an adenoviral construct encoding an intracellular single-chain antibody (scFv) against p21ras (Y28). In order to determine the influence of the ras status on the efficacy of the scFv, we used a wild-type rat rhabdomyosarcoma and its ras-oncogene transfectant, for in vitro studies. In vivo we used the ILP delivery method to study anti-tumour activity on established limb tumours. RESULTS: In vitro studies demonstrated an inhibition of growth caused by the Y28 construct. No significant difference between transfected and wild-type cell lines could be demonstrated. Upon ILP, homogeneous transduction was observed in 5% of tumour cells. Perfusion with the Y28 construct, however, did not result in any additional anti-tumour activity compared to controls. CONCLUSION: Despite in vitro activity and in vivo transfection, no significant tumour response could be detected using anti-p21ras gene therapy in this ILP-tumour model.     

Isolated limb infusion: A review

Isolated limb perfusion is the preferred treatment option for locally advanced melanoma and sarcoma confined to a limb. This treatment results in high response rates with a satisfying duration of response in both tumours. A drawback of isolated limb perfusion, however, is the invasive and complex character of the procedure. Isolated limb infusion has been designed as a minimally invasive alternative to isolated limb perfusion. Treatment results of this simple technique, reported by various centres worldwide, show comparable response rates for melanoma and sarcoma. Therefore isolated limb infusion may replace isolated limb perfusion in the future as the preferred treatment option for these locally advanced limb tumours. J. Surg. Oncol. 2009;100:169–177. © 2009 Wiley‐Liss, Inc.