Hyperthermic Limb Perfusion Research Articles

Diagnosis and treatment of soft-tissue sarcomas of the extremities and trunk.

The relatively low incidence and often atypical clinical presentation of soft-tissue sarcomas (STS) impedes early and adequate diagnosis. Patients may report on recently enlarged soft-tissue swellings, infrequently complain of painful lesions, or even have no symptoms at all.A thorough diagnostic work-up is essential in order to distinguish between benign soft-tissue tumours and STSs. Patient history, clinical features and radiological findings all help in assessing the underlying pathology. ‘Worrying’ features such as recent increase in size, deep location relative to the fascia, a tumour exceeding 4 cm in size, and invasive growth patterns seen on imaging should prompt verification by biopsy.Even though acquisition of biopsy material may be incomplete, one should bear in mind some essential rules. Regardless of the biopsy technique applied, the most direct route to the lump in question should be identified, contamination of adjacent structures should be avoided and a sufficient amount of tissue acquired.Treatment of STS is best planned by a multidisciplinary team, involving experts from various medical specialities. The benchmark therapy consists of en bloc resection of the tumour, covered by a safety margin of healthy tissue. Depending on tumour histology, grade, local extent and anatomical stage, radiotherapy, chemotherapy and isolated hyperthermic limb perfusion may be employed.Due to the complexity of treatment, any soft-tissue swelling suspected of malignancy is best referred directly to a sarcoma centre, where therapeutic management is carefully planned by an experienced multidisciplinary team.Cite this article: EFORT Open Rev 2017;2:421-431. DOI: 10.1302/2058-5241.2.170005

Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Complete and lasting healing of bone melanoma metastasis after hyperthermic limb perfusion

Complete and lasting healing of bone melanoma metastasis after hyperthermic limb perfusion

Current status of hyperthermic limb perfusion for in-transit melanoma

In-transit disease is a unique form of regional lymphatic spread of melanoma that is considered an infrequent event although certain high-risk subgroups have been identified with higher incidence rates. Although this disease entity is associated with a high risk for distant relapse, regionally focused treatment of disease is important due to the high morbidity associated with in-transit disease. Isolated limb perfusion has been a utilized method of regional treatment since the 1950's. The technical aspects, indications, historical results, and toxicity of limb perfusion are reviewed. Finally, perfusion based treatment of in-transit melanoma is an excellent model for studying novel agents and regimens in both the pre-clinical and patient care setting.

Treatment of In-Transit Metastases from Merkel Cell Carcinoma with Isolated Hyperthermic Limb Perfusion

Treatment of In-Transit Metastases from Merkel Cell Carcinoma with Isolated Hyperthermic Limb Perfusion

TNFα-Based Isolated Hyperthermic Limb Perfusion (HILP) in the Treatment of Limb Recurrent Melanoma: Update 16 Years after Its First Clinical Application

SummaryHyperthermic Limb Perfusion (HILP) with Tumor Necrosis Factor alpha (TNFα) and interferon gamma (IFNγ) was pioneered by Liénard and Lejeune in 1988. TNFα was empirically employed at a dosage of 3–4 mg that is ten times the systemic maximum tolerated dose (MTD). Sixteen years after its first clinical application more than 300 patients have been treated and some clarifications can be made regarding three major questions: the real role of IFNγ, the TNFα dose and eligibility criteria for patient selection. A randomized phase II study has demonstrated that IFNγ does not increase significantly the efficacy but does increase side-effects. Experimental and clinical results seem to indicate that patients with bulky melanoma disease can really benefit from TNFα HILP carried out with only 1 mg.

Complete Remission of Previously Intractable Peripheral Cutaneous T-Cell Lymphoma of the Lower Extremity Using Isolated Hyperthermic Limb Perfusion with Melphalan (1-Phenylalanine Mustard)

The patient is a 74-year-old woman first diagnosed with a peripheral cutaneous T-cell lymphoma (PCTCL) in April of 1994. Initially she presented with subcutaneous indurated areas in the right forearm, scapula, and submadibular region. After chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), she went into remission for 2 years before relapse of her PCTCL localized to the right lower extremity. Persistent isolated disease in the extremity since then led to numerous chemotherapy regimens and localized radiation therapy. Due to dramatic limb threatening progression of the disease in 2001, she underwent isolated hyperthermic limb perfusion with melphalan (1-phenylalanine mustard). Although limb preservation could not be achieved, this treatment resulted in complete clinical and pathological regression of the lesions of the perfused extremity.

Metastatic Melanoma in a Patient with Clouston Syndrome Successfully Treated with Isolated Hyperthermic Limb Perfusion

Background: Clouston syndrome is an autosomal dominant disorder characterized by nail dystrophy, partial or total alopecia, and hyperkeratosis of the palms and soles. Objective: Although a variety of unusual cutaneous manifestations have been described, the incidence of melanoma in this population is unknown. Methods: This article reports a case of in-transit metastatic subungual melanoma in a patient with Clouston syndrome successfully treated with hyperthermic limb perfusion with melphalan. Results: Six months postperfusion, the patient is doing well, with resolution of the extremity erythema and edema. Followup ultrasonography revealed reduction in size of the eight subcutaneous nodules, with the largest measuring 3.3 cm in maximum diameter, representing nearly a 50% reduction in tumor volume postperfusion. Conclusion: Although melanoma has also been associated with some forms of ectodermal dysplasia, such as ectrodactyly—ectodermal dysplasia—clefting (EEC) syndrome, the incidence of melanoma in patients with Clouston syndrome is unknown. Thus far, to our knowledge, this is the first case report of melanoma arising in a patient with Clouston syndrome.

Expression of multidrug resistance genes MVP, MDR1, and MRP1 determined sequentially before, during, and after hyperthermic isolated limb perfusion of soft tissue sarcoma and melanoma patients.

Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor alpha and melphalan is a highly effective treatment for advanced soft tissue sarcoma (STS) and locoregional metastatic malignant melanoma. Multidrug resistance (MDR)-associated genes are known to be inducible by heat and drugs; expression levels of the major vault protein (MVP), MDR1, and MDR-associated protein 1 (MRP1) were determined sequentially before, during, and after ILP of patients. Twenty-one STS or malignant melanoma patients were treated by ILP. Tumor tissue temperatures were recorded continuously and ranged from 33.4 degrees C initially to peak values of 40.4 degrees C during ILP. Serial true-cut biopsy specimens from tumor tissues were routinely microdissected. Expression analyses for MDR genes were performed by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry. In 83% of the patients, MVP expression was induced during hyperthermic ILP. MVP-mRNA inductions often paralleled the increase in temperature during ILP. Increased MVP protein expressions either were observed simultaneously with the MVP-mRNA induction or were delayed until after the induction at the transcriptional level. Inductions of MDR1 and MRP1 were observed in only 13% and 27% of the specimens analyzed. Temperatures and drugs applied preferentially led to an induction of MVP and were not sufficient to induce MDR1 and MRP1 in the majority of tumors. This study is the first to analyze the expression of MDR-associated genes sequentially during ILP of patients and demonstrates that treatment might lead to increased levels of MVP, whereas enhanced levels of MDR1 and MRP1 remain rare events.

Neuromuscular damage after hyperthermic isolated limb perfusion in patients with melanoma or sarcoma treated with chemotherapeutic agents.

To evaluate the incidence and entity of muscle damage after hyperthermic limb perfusion (HLP) with doxorubicin or melphalan, two widely used chemotherapeutic agents. We collected muscle biopsies from eleven patients with lower limb sarcoma or melanoma immediately before and at a variable time after the chemotherapeutic procedure (mean = 49.4 days). Biopsy specimens were stained with standard histochemical and immunohistochemical methods on cryostat sections and the grade of fiber atrophy was calculated. Clear neurogenic alterations were present in pre-HLP biopsies of seven patients related to age and previous therapy. In six patients, the comparison between biopsies before and after HLP demonstrated worsening of preexisting neurogenic condition and appearance of mitochondrial-related damage. Reduction in type I or type II fiber diameter was present in nine patients, but no relation to doxorubicin or melphalan treatment was clear. An unexpected, large accumulation of desmin was detected in the muscle biopsy of one patient receiving doxorubicin, probably related to the mechanism of doxorubicin-induced myotoxicity. The observed neuromuscular toxic effects could be related to the physical or chemical conditions of HLP, in particular perfusion temperature; in addition, the present study demonstrates that preexisting neuromuscular changes, i.e. neuropathy, modulates the degree of further damage following HLP.

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 degrees to 41.5 degrees C (destruction of cellular carrier systems at higher temperatures and increased inactivation by hydrolysis of melphalan above 41.5 degrees 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).

Technique and results of regional hyperthermic cytostatic arm perfusion for malignant melanoma

Isolated hyperthermic cytostatic limb perfusion has been established as an efficient procedure for the treatment of malignant melanoma of the limbs. However, perfusions of the upper extremities are generally carried out much less frequently than would be expected given the distribution pattern of malignant melanoma and sarcoma. Thus, isolated descriptions of treatment results for perfusion of the upper extremities are not available. Between 1991 and 1994, arm perfusions using melphalan 1.0 mg/kg body weight were given to 14 patients with malignant melanoma, using the standardized method of perfusion described herein. Within an average observation period of 34.9 months (range, 12-65 months), 11 (78.7%) of the 14 patients who had M.D. Anderson stage II-IV melanoma remained free of local recurrence. In fact, 10 (71.6%) of the patients were still alive at the end of the observation period. None of the 14 patients showed any systemic adverse effects, although 1 patient developed a lymphedema 32 months after perfusion and 2 patients showed a postoperative temporary neurologic deficit. These results demonstrate that isolated perfusion of the upper limb with heat and melphalan under standardized conditions remains the treatment of choice for melanoma of the arm, as for melanoma of the leg, without a higher rate of complications.

Hyperthermic limb perfusion with melphalan

Santos, IDAO; de, Carvalho LMY; Brunstein, F; Minami, E; Haddad, A; Gomes, W; Gomes, H C; Ferreira, L M Author Information

Pharmacokinetics of melphalan in ???mild??? and ???true??? hyperthermic lower limb perfusion

Pharmacokinetics of melphalan in ???mild??? and ???true??? hyperthermic lower limb perfusion

A randomized controlled trial of prophylactic isolated cytotoxic perfusion for poor-prognosis primary melanoma of the lower limb

A randomized controlled trial of prophylactic isolated hyperthermic limb perfusion (IHLP) using melphalan at 2 mg/kg body weight has been performed on a total of 30 patients with primary melanoma of the lower limb > or = 1.7 mm thick. Excision (control, n = 14) was compared to excision plus IHLP (n = 16). The two groups were well matched for sex, tumour thickness and duration of follow-up (control group median: 63 months (range: 16-108), perfusion group median: 80 months (range: 37-113)). Recurrent disease developed in nine of the control group, seven of whom have died. In the perfusion group only two patients have developed recurrent disease, both of whom have died (recurrence: P < 0.004, mortality: P < 0.03, using Fishers' exact probability test). Inguino-femoral nodal recurrence occurred in five of nine control patients, but in only one patient in the perfusion group. These data support the use of adjuvant IHLP in the management of poor-prognosis primary melanoma of the lower limb.

Results of isolated hyperthermic extremity perfusion in soft tissue sarcomas within the scope of a multimodality treatment concept

Soft-tissue sarcomas (STS) of the extremities are characterized by a high rate of local recurrences. Limb salvage approaches using multimodality therapy protocols have replaced amputation. In order to evaluate isolated hyperthermic limb perfusion (ILP) in a multimodality therapy concept, we reviewed our patients treated using this method. Between January 1982 and December 1995, 25 ILPs, using cisplatin, melphalan and adriamycin, were performed in 22 patients with STS. Forty percent were treated for local recurrences; histology was dominated by malignant fibrous histiocytoma (MFH) and synovial sarcoma. In all, 68% of the STS were classified as UICC stage IIb or IIIa/b. Most of the cases (14) underwent wide or radical resection, 4 patients received intraoperative radiotherapy, and 5 were treated with external beam radiation. Complications were recorded in 32% of the cases. With a median follow-up of 45 months (range 1-143), the 5-year overall survival rate was 81%. The median recurrence-free time was 19 months and the 5-year disease-free survival rate 34%. There were 13 local failures, and distant metastases developed in 36% of the patients. Concerning high-grade sarcomas (UICC stage IIb, IIIa/b), we found local recurrences in 75% of all cases. Five of 11 patients with local failures underwent perfusion after they refused amputation, and 7 incompletely resected STS received ILP without reoperation. All of these demonstrated local recurrence. This rate of local recurrence proved to be different from patients with tumor-free resection margins (p = 0.0001, log-rank test). The amputation rate after isolated limb perfusion was 27% (mean 11 months after treatment). Long-term results of ILP showed a considerable local recurrence rate and a low disease-free survival. Perfusion in patients without tumor-free resection margins does not prevent local recurrence. We conclude that ILP with cisplatin, melphalan and adriamycin should be considered carefully and is not an additional treatment strategy of fist choice.

Melanoma of the foot in white South Africans.

There have been few studies that have compared the outcome of treatment of melanoma on the sole and dorsum of the foot or defined their prognostic factors. We describe 44 white patients (30 women and 14 men, mean age 53 years) with melanoma on the foot (sole, n = 25, dorsum, n = 19) seen over a 15 year period. Forty patients presented with stage I, two with stage II, one with stage III, and one with stage IV disease. The median Breslow depth of penetration was 2.8 mm (sole 3.3, dorsum 2.3). Of the 40 patients with stage I disease, 34 patients (17 dorsum, 17 sole) were treated by wide local excision (2 cm or more) and none developed local recurrence. Six patients (five sole, one dorsum) who had narrow excision margins (less than 1 cm, stage I disease) developed local recurrences. Ten patients underwent prophylactic hyperthermic limb perfusion. Sixteen patients with stage I disease (10 sole, six dorsum) developed metastases in the inguinal nodes. All 16 underwent block dissection of the nodes and five are alive. The overall survival for both dorsum (73%) and sole (66%) (stage I disease) was similar at 60 months. Both patients with stage II disease were alive at the time of writing, but the two patients with stage III and IV disease had died. The foot is an anatomical subsite associated with a poor prognosis for melanoma. There is little difference in prognostic factors and outcome between the sole and dorsum.

Leukocyte activation by isolated hyperthermic liver and limb perfusion due to malignancy.

Fourteen patients with liver tumor malignancy and sixteen patients with malignant melanoma localized to one limb were studied regarding leukocyte activation with the release of polymorphonuclear neutrophilic (PMN) elastase and of neopterin and formation of cytokines (TNF-alpha and IL-6) during the surgical treatment. Patients undergoing liver resection (n = 10), abdominal hysterectomy (n = 10), or hip replacement surgery (n = 10) served as control groups. Isolated hyperthermic liver perfusion was performed with cytostatic-containing perfusate (melphalan and cisplatinum). Patients with recurrent malignant melanoma confined to one limb underwent isolated hyperthermic limb perfusion with cytostatic-containing perfusate (melphalan). Blood samples for determination of PMN elastase, neopterin, TNF-alpha, and IL-6 were drawn from the patients preoperatively, 1 minute before the start of the perfusion, 60 and 120 minutes after the start of the perfusion, and 24 hours postoperatively. Samples from the perfusate were drawn 60 minutes after the start of the perfusion. High concentration of plasma PMN elastase were found in both patients undergoing liver and limb perfusion and in patients undergoing liver resection surgery. Elevated concentrations of IL-6 were found in the patients undergoing liver perfusion and in patients undergoing liver resection. In none of the patients were there increased concentrations of neopterin or TNF-alpha. The perfusate contained high concentrations of PMN elastase, neopterin, and IL-6. This study also demonstrated that major surgery leads to elevated concentrations of PMN elastase and IL-6. An increase of PMN elastase and IL-6 was seen in response to perfusion and to surgical trauma.

Pharmacokinetics of two different delivery regimens of doxorubicin in isolated hyperthermic limb perfusion

Evaluation of doxorubicin (DOX) pharmacokinetics in hyperthermic isolated limb perfusion (HILP) is limited. In this study two administration regimens of DOX were compared in terms of area under the time concentration curve (AUC) in plasma. HILP was performed in 13 dogs. In group 1 (n = 7) four single doses of DOX were injected in intervals of 15 minutes, in group 2 (n = 6) DOX was administered continuously during the first 30 min. The total dose in both groups was 1 mg/kg body weight, and the perfusion lasted 60 min. Concentrations of DOX and its major metabolite doxorubicinol (DOXol) were measured in perfusate and muscle tissue by high performance liquid chromatography (HPLC). Pharmacokinetic estimates were calculated. The two investigated administration modes provided sufficient drug levels of DOX during the whole perfusion time. Maximum concentrations in the perfusate and areas under the time concentration curves were nearly the same. The tissue concentrations also did not show significant differences. Both regimens are practicable avoiding high peak levels of the drug in order to minimize toxic side effects.

Surgery and other local-regional modalities for all stages of melanoma.

The recommendations for the surgical management of clinically localized melanoma are now more clearly defined. Based on the results of two large randomized trials, optimal excision margins for primary tumors of varying thickness up to 4 mm have been determined: 1 cm for lesions smaller than 1 mm and 2 cm for lesions that are between 1 and 4 mm. In 90% of patients, the soft-tissue defect created by 2-cm excisions can be closed primarily, allowing surgery for early-stage melanoma to be performed predominantly on an outpatient basis. The role for an elective lymph node dissection in those patients with higher risk primary tumors is still under debate. "Selective lymphadenectomy" using lymphatic mapping and sentinel node biopsy offers a rational approach to clinically negative regional lymph node basins. The promising early results with lymphatic mapping are exciting, but need to be confirmed in a multi-institutional trial. Renewed interest has developed in hyperthermic limb perfusion for the treatment of transit and locally advanced recurrent disease because of the availability of melphalan and the recent reports of higher response rates with the addition of tumor necrosis factor and interferon gamma to melphalan. In the management of metastatic disease, recent large series have demonstrated that surgery can offer excellent palliation and, in some selected clinical settings, prolong survival. In those patients with surgically inaccessible lesions, radiation therapy can provide valuable palliation. The value of hyperthermia in addition to radiation therapy in the treatment of metastatic melanoma is still under investigation.