Improved tissue perfusion during pressure-regulated hyperthermic regional isolated perfusion in dogs

To achieve adequate tissue perfusion during regional isolated perfusion, hind limbs of dogs were perfused for 60 min, regulating the extracorporeal circuit on pressure. The dogs were divided into three groups. In groups I and II perfusions were performed at a delta pressure (systemic mean arterial pressure minus hind limb mean arterial pressure) of respectively 50 and 15 mm Hg; in group III delta pressure was also 15 mm Hg but the cytostatic drug Melphalan was added. Tissue perfusion was determined by means of a multiwire polarographic oxygen electrode. Adequate tissue perfusion was obtained only at subnormal perfusion pressures (groups II and III), although in all groups perfusion flow was higher than preoperative flow. At low perfusion pressures (group I), tissue perfusion was severely impaired. In all groups leakage remained less than 10%. During regional isolated perfusion the extracorporeal circuit must be regulated at a delta pressure of 15 mm Hg to achieve adequate tissue perfusion.     

TNF-alpha levels in patients with malignant tumors after hyperthermic isolated regional perfusion

Hyperthermic isolated regional perfusion is an alternative method for the treatment of malignancies especially sited in the pelvic region and extremities. The perfusion is performed via the extracorporeal system with a pump flow and chemotherapeutic agents and some cytokines, like tumor necrosis factor, may be added. It's well known that in the ischemia-reperfusion injury, hemorrhagic necrosis and cell death occurs and these cytokines are produced endogenously. In this study the endogenous TNF-alpha levels before, during and after hyperthermic isolated regional perfusion were compared in 16 patients with malignant tumors. The TNF-alpha levels were determined from the blood samples taken systemically before and after perfusion, and from perfusate at the 15th, 30th, 45th minute. The 15th minute samples were the ones where vascular clamps were applied to the vessels before starting the perfusion. TNF-alpha levels between the 15th minute samples and the blood samples that were taken systemically before and after perfusion were found statistically significant. The cause of this was suggested to be the ischemia-reperfusion injury in this period. It was shown in this study that high endogenous TNF-alpha levels and good clinical results could be achieved with hyperthermic isolated regional perfusion in the treatment of malignant tumors.     

Improved tissue perfusion during pressure regulated hyperthermic regional isolated perfusion. A clinical study

In previous studies on isolated hindlimb perfusions in dogs, the authors proved that the extracorporeal circuit should be regulated at a delta pressure (systemic mean arterial pressure minus hindlimb mean arterial pressure) of not more than 15 mmHg, to achieve adequate tissue perfusion. To confirm this in patients the authors performed clinical perfusions, divided into three groups. In group I and II the extracorporeal circuit was regulated at a delta pressure of 15 mmHg and 50 mmHg, respectively. In group III perfusions were performed using the common technique of a predetermined fixed flow. Tissue oxygenation, determined by means of a transcutaneous pO2 electrode, was adequate in group I and was severely impaired in group II and III. Although in group I high perfusion flows were needed, leakage was less than 10%. To achieve adequate tissue perfusion during clinical regional perfusions, the extracorporeal circuit must be regulated at a delta pressure of 15 mmHg.     

A technique for isolated hyperthermic liver perfusion

Hyperthermia, either alone or combined with chemotherapy, has been shown to be effective in treating cancer. Because some investigators believe that regional hyperthermia may be more effective than whole body hyperthermia, we developed a technique to heat only the liver to 42-43 degrees for 4 hr. The procedure was adapted from a previously described animal model and was performed in four humans. Vascular isolation of the liver was accomplished by cannulating the hepatic artery, the portal vein, and the inferior vena cava followed by occluding the suprahepatic vena cava and the liver was then perfused with blood and nutrients from an oxygenated reservoir. Preliminary results show radiologic and histologic evidence of tumor necrosis or cessation of tumor growth in three of the patients. We believe this technique is safe enough for clinical experimental use and deserves further investigation.     

Temperature distribution and pH changes during hyperthermic regional isolation perfusion

Hyperthermic perfusion was given as a palliative treatment in three patients with a bulky tumour in the leg. During the treatment, temperature and pH data were collected in both tumour and normal tissues. The hyperthermia dose administered was 2 h at 41.9–42.7°C. It was found that the temperature distribution was far from homogeneous. In one case tumour pH could be monitored throughout the whole treatment procedure. The tumour pH showed a steep decrease during the initial phase of the perfusion, from a mean value of 7.11 to 5.94 at the start of the hyperthermic phase. Subcutis pH decreased only 0.29 units during the whole procedure. In all three patients considerable tumour regression was observed, without severe toxicity.Hyperthermic perfusion appeared to be an effective debulking treatment. The pH decrease in tumour tissue, immediately before hyperthermia, may be responsible for the remarkable effectiveness of the hyperthermic treatment.     

The safe use of cisplatin in hyperthermic isolated limb perfusion systems

A patient presenting with aggressive squamous cell carcinoma successfully received cisplatin chemotherapy via hyperthermic, isolated limb perfusion (renal impairment ruled out systemic use). Human tumor stem cell assay identified cisplatin as the drug of choice and supports the potential benefit of this procedure in single therapeutic situations. The case illustrates the safety of cisplatin and the ability to give large doses of the nephrotoxic drug with no damage to renal function. The potential efficacy over systemic cisplatin has yet to be established except when systemic use is limited from renal dysfunction.     

Clinical pharmacokinetics of mitoxantrone in hyperthermic,isolated perfusion of the leg

Summary The clinical pharmacokinetics of mitoxantrone in hyperthermic, isolated perfusion of the leg were studied in five patients exhibiting solitary, localized malignant melanoma. Mitoxantrone was given as four 1-min infusions at 15-min intervals into the arterial line of the perfusion system at a total dose of up to 14 mg/m². The mean half-lives for mitoxantrone in the blood circulation of the leg were:t _1/2 (distribution phase), 25.5 s, andt _1/2 (elimination phase), 14.9 min. The mean volume of distribution at steady state in the leg was 25.6 l. In the arterial part of the perfusion, the mean AUC was 155.9 mg min l^–1, and that in the corresponding venous part was 91.6 mg min l^–1. Leakage of the drug from the leg into the systemic circulation amounted to 1.2% of the total delivered dose; 91% of the delivered dose remained in the leg after the perfusion had been completed. The mean elimination half-life of mitoxantrone in the systemic circulation was 123 min and the corresponding AUC for systemic concentrations was 8.59 mg min l^–1. The present data revealed a high uptake of mitoxantrone into the leg and low systemic drug concentrations due to minor leakage, suggesting that mitoxantrone might be a good candidate for use in isolated, hyperthermic limb perfusion.     

The role of regional hyperthermic cytostatic perfusion in the treatment of extremity melanoma

To evaluate the effectiveness of regional hyperthermic cytostatic perfusion in patients with malignant melanomas of the extremities, 107 patients were included in a prospective randomized study. In a control group (A, n = 54) the tumors were widely excised, and the regional lymph nodes were dissected. The patients in the perfusion group (B, n = 53) received additional hyperthermic (42 degrees C) perfusion with melphalan. The disease-free survival time was chosen as the criterion for success. An intermediate evaluation (average follow-up observation period of 550 days) revealed a highly significant difference between the groups (P = 0.0001): 21 recurrences in the control group versus four recurrences in the perfusion group. In a second analysis 3 1/2 years after premature discontinuation, 26 recurrences were diagnosed in Group A, whereas only six recurrences were noted in Group B (P = 0.0001). A retrospective analysis of the entire test group revealed the following figures. In Group A seven recurrences in Stage I were diagnosed, seven in Stage II, and 12 in Stage III. In Group B one was observed in Stage I, one in Stage II, and four in Stage III. The level of significance was calculated to be P = 0.05 in Stage I, P = 0.05 in Stage II, and P = 0.01 in Stage III. The results of the study show that additional perfusion in the treatment of extremity melanomas is superior to conventional methods.     

Results of regional isolation perfusion with cytostatics in patients with soft tissue tumors of the extremities

From 1975 to 1986, 26 patients with soft tissue tumors of the extremities underwent a total of 29 perfusions. The cytostatics used were doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) (19 perfusions), melphalan (two perfusions), and a combination of these agents (eight perfusions). Before perfusion most patients had been treated by surgical excision(s), radiotherapy, or systemic chemotherapy. Of 17 patients perfused because of local inoperable tumor, four showed prolonged complete remission of the tumor mass, stable disease was seen in three, and ten showed progression. The complete remissions observed in three patients with aggressive fibromatosis and in one with lymphangiosarcoma occurred after perfusion with doxorubicin combined with melphalan. Doxorubicin added to the perfusate as the sole cytostatic was not effective. Local recurrence was observed in five of nine patients treated by adjuvant perfusion, always after dubiously radical tumor excision. Toxicity was high, especially in the first few years. Tissue necrosis necessitated amputation in three cases (in two after perfusion with doxorubicin and melphalan and in one after repeated perfusion with doxorubicin only). This complication was no longer seen after adjustment of the dosage and dose distribution of doxorubicin, but the morbidity after perfusion with doxorubicin remained considerable.     

Prevention of systemic toxicity in hyperthermic isolated lung perfusion using radioisotopic leakage monitoring

Rationale: Hyperthermic isolated lung Perfusion (ILuP) is used to deliver high-dose chemotherapy to pulmonary metastases while sparing systemic toxicity. Accurate leakage monitoring is however necessary. This study aimed to verify the accuracy of radionuclide leakage monitoring in patients undergoing ILuP, by comparing this method with serial blood sampling.

Methods: A total of 15 consecutive ILuP procedures were performed on eleven patients affected by lung metastases from soft tissue sarcoma. After establishing isolated perfusion, erythrocytes of systemic blood (SB) were labelled with 0.2 MBq/kg of ^99mTc. The baseline SB counting rate (CR) was assessed using a γ-probe. Subsequently, erythrocytes of the circuit blood (CB) were labelled with 2 Mbq/kg of ^99mTc. Radioactivity leakage factor (RLF) was continuously measured using a formula, accounting for CR, systemic/circuit activity ratio and total/systemic volume ratio. The TNF-α concentration in SB and CB was measured by enzymelinked immunosorbent assay (ELISA) throughout the procedure.

Results: RLF averaged 2.3?±?1.5%, while the systemic/circuit TNF-α ratio was 0.05?±?0.12%. These two indices were strictly correlated in all of the procedures (average Rvalue 0.88?±?0.07). RLF exceeded 5% during three of 15 procedures, prompting the application of compensatory manoeuvres. ELISA confirmed a marked increase in systemic TNF-α levels in these patients (2.6?±?3.5?ng/ml). Conversely, patients whose RLF did not exceed the 5% threshold presented a mean TNF-α of 0.02?±?0.005?ng/ml (p?Conclusions: In patients submitted to ILuP, RLF monitoring is feasible and accurate. Moreover, it grants immediate results, permitting for the adoption of corrective manoeuvres for leakage, thus minimising toxicity.     

Long-term functional morbidity after mild hyperthermic isolated limb perfusion with melphalan.

AIMS: To assess long-term functional morbidity in patients entered in the prospective randomized EORTC trial investigating the role of adjuvant isolated limb perfusion (ILP) with melphalan for high-risk primary melanoma. METHODS: In 65 patients (ILP 36, wide excision only 29), limb circumference and joint mobility measurements were performed on the treated and the contralateral limb after a mean interval of 48 months after primary treatment. The two treatment groups were comparable regarding age, sex distribution, percentage of skin grafts or regional lymph-node dissections, and interval between primary treatment and physical measurements. RESULTS: None of the patients had severe complaints of the treated limb at the time of analysis. The ankle suffered most from ILP, with a statistical significant restricted extension in approximately 40% of the perfused patients. Abduction of the shoulder was minimally affected in treated upper limbs, probably as a result from the formation of scar tissue after axillary lymph-node dissection. Although no significant differences could be demonstrated in the circumference of upper or lower limbs, atrophy was seen in 24% of perfused lower limbs. Of the five perfused patients who developed oedema, four had also undergone a regional lymph-node dissection. CONCLUSION: This risk of long-term functional morbidity should be weighed against the possible advantages of ILP in patients with limb melanoma or sarcoma.     

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.     

Intractible cutaneous non-Hodgkin's lymphoma of the lower limb. Complete remission after sequential regional isolated hyperthermic perfusion and perfusion with 1-phenylalanine-mustard (melphalan, L-Pam)

A 61-year-old man with an intractible and progressively disabling cutaneous non-Hodgkin's lymphoma (NHL) in the lower limb was treated with sequential regional isolated perfusion at 10-day intervals. The first perfusion was hyperthermic (40.2-43.1 degrees C tumor-temperature); the second was at controlled normothermia with high-dose 1-phenylalanine mustard (melphalan, L-Pam; 11 mg/l perfused tissue). This treatment resulted in a complete remission in the perfused area of significant duration and has prevented amputation.     

Hyperthermic isolated regional perfusion of the limb with carboplatin

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

Toxicities associated with hyperthermic isolated limb perfusion and isolated limb infusion in the treatment of melanoma and sarcoma.

Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) may play a significant role in the treatment of patients with recurrent or in transit extremity melanoma or sarcoma that is unresectable. These procedures may be indicated when patients are otherwise faced with the possibility of a debilitating amputation. Not entirely benign treatment modalities, HILP and ILI can be associated with regional and systemic toxicities. We conducted a literature search of published studies using HILP and ILI for the treatment of extremity sarcomas and melanomas, and associated toxicities was performed. The regional toxicities of HILP and ILI are similar. The most common toxicities reported are mild to moderate. However, when severe regional toxicity occurs, albeit infrequently (<5%), fasciotomies or even amputation may be necessary. Some studies have showed a relationship between acute regional toxicities and long term regional morbidity. Systemic toxicity appears to be more frequent when TNF-alpha is used in combination with other drugs during HILP, however the use of TNF-alpha in the United States is limited to trials. Although regional toxicities are similar, systemic toxicity of ILI is minimal compared to HILP. ILI is easier to repeat, technically less complex, and may be more acceptable in infirmed patients. Long term morbidity and outcomes for ILI are still being evaluated. Both of these techniques may be suitable options in patients with unresectable advanced or recurrent, or in transit extremity melanoma or sarcoma.     

Intraperitoneal hyperthermic perfusion (IPHP)

Intraperitoneal hyperthermic perfusion (IPHP) with a solution that contains CDDP (25 mg/m(2)/l) and MMC (3.3 mg/m(2)/l) was clinically introduced in the treatment of peritoneal carcinomatosis. Twenty-six patients underwent surgical treatment and IPHP. Peritoneal carcinomatosis was classified at laparotomy using the Japanese classification: P1 (n=3), P2 (n=5), P3 (n=15), unclassifiable (n=3). In this series of patients only the creatinine and amylase values were significant in biological toxicity evaluation. The surgical complication rate (2 duodenal fistulas) does not differ from the general extensive abdominal surgery.     

Functional morbidity after regional isolated perfusion of the limb for melanoma

A series of 57 patients still in follow-up after regional isolated perfusion (RIP) of Stage I-II high-risk melanoma is described. Functional morbidity of the perfused limb was investigated. Median interval after RIP was 5 years. With no regard to recurrent disease subjectively only one patient had severe complaints of the perfused limb. Objective investigation showed no edema or atrophy in 80% of the upper limbs and in 64% of the lower limbs. Concerning the mobility of the joints in the upper limb we found in four cases a disturbed function in several movements. More restriction were observed in the lower leg. Especially the ankle showed severe functional restrictions in more than 25%.     

Prophylactic hyperthermic limb perfusion in stage I melanoma

Ninety-three patients with stage I primary cutaneous malignant melanoma of the lower limb were treated by wide local excision and hyperthermic isolated regional perfusion with melphalan (L-phenylalanine dihydrochloride) in a prospective non-randomized study between 1976 and 1982. Eighteen patients (19.4%) developed recurrent melanoma. Nine had recurrent regional disease, one with in transit metastases and eight with positive regional nodes. Nine patients developed distant metastases. No patient had locally recurrent disease. This series confirmed the close correlation between tumour microstaging, melanoma recurrence and survival. Seventy-nine per cent of patients were disease-free at 5 years. Males had deeper lesions (mean 4.56 mm) and increased recurrence (33%) than females (mean 3.36 mm and 13%). Superficial spreading melanoma had the most favourable prognosis of the three histological types. Overall survival was 83% (female 86%; males 64%) at 5 years. Significant morbidity occurred in two patients with deep vein thrombosis. Adjuvant therapy using hyperthermic regional perfusion provides improved local and intransit control of limb melanoma.