Continuous leakage measurement during hyperthermic isolated limb perfusion

Background: Continuous measurement of perfusate leakage into the systemic circulation is of the utmost importance and can be performed with the help of radioactive tracers. The purpose of this study was to assess changes in the perfusion leakage rate between two periods: 1977–1990 and 1991–2000, and to determine the factors responsible for these changes.Methods: During the 1991–2000 period, 119 patients underwent HILP mainly for locally recurrent melanoma or locally advanced soft tissue sarcoma. HILP was performed with melphalan (33%) or in combination with TNF (65%). There were 67 iliacal, 12 femoral, 25 popliteal, and 15 axillary perfusions performed. Leakage into the systemic circulation was monitored continuously with the help of ¹³¹I-albumin and a stationary scintillation detector placed above the heart.Results: The median maximum leakage was 2.7% (range 0%–21%) which is significantly less than the previous period (1977–1990) where leakage of 8% (range 0%–30%) was reported (P < .05). A statistical difference in leakage was detected among perfusion locations where the iliac and femoral vessels showed more leakage than the axillary and popliteal vessels (P < .05). Furthermore, there appeared to be significantly less leakage when TNF was used than when melphalan was the sole drug (P < .05).Conclusions: Nowadays leakage from isolated perfusions into the systemic circulation is further minimized compared with the days when melphalan was the sole drug used. Increased awareness about TNF leakage, continuous external monitoring with ¹³¹I-albumin as the main isotope, flow rate regulation in the perfusion circuit, and regulation of the patients systemic blood pressure have all been major contributors to this improvement.     

Efficacy of hyperthermic isolated limb perfusion for extremity-confined recurrent melanoma

Background: Recurrent melanoma of the extremity has been treated by local excision, systemic chemotherapy, amputation, or a combination of these approaches. Hyperthermic isolated limb perfusion (HILP) provides a method of limb preservation through isolation, allowing the administration of chemotherapy in higher doses than is possible through systemic treatment. Methods: An experimental group of 59 HILP patients with melanoma recurrences of the extremity was studied prospectively. A control group of 248 melanoma patients with similar recurrences was excluded from HILP because their recurrences were in non-extremity locations. The experimental group underwent HILP and excision; the control group had excision only. The experimental procedure consisted of vascular isolation of the affected extremity and a 1-hour perfusion with melphalan. Temperatures were maintained at 40°C in the perfusion circuit. Results: The HILP patients had a lower rate of locoregional recurrence (P=.028) and demonstrated increased survival (P=.026) compared to the control group. In multivariate regression analysis, which included age, ulceration and thickness of the primary, and the treatment variable of perfusion, age (P=.02) and perfusion for the treatment of recurrence (P=.006) were significant predictors of survival. Conclusions: HILP improves prognosis by sterilizing the treated extremity, controlling locoregional disease, and perhaps preventing metastasis, thus having a positive impact on overall survival. Presented at the 50th Annual Cancer Symposium of the Society of Surgical Oncology, Chicago, Illinois, March 20–23, 1997.     

Systemic effects of hyperthermic isolated lower limb perfusion with carboplatin and interferon-beta

The changes in systemic circulation during hyperthermic isolated lower limb perfusion with carboplatin and interferon-beta were investigated in 19 patients with malignant melanoma. The cardiac output (CO) increased significantly (p < 0.01) from 3.81 +/- 0.22 L/min before the procedure to 5.30 +/- 0.49 L/min 1 h after hyperthermic perfusion. The double product (mean arterial pressure x heart rate) also increased significantly (p < 0.01) from 5,145 +/- 372 mm Hg/min to 6,760 +/- 486 mm Hg/min. In some patients, it increased to more than twice the control value. These changes were accompanied by an increase in body temperature, presumably caused by the systemic leakage of both warmed blood and interferon-beta. Blood chemistry data demonstrated no significant changes in the liver or renal function. However, the serum CPK level increased markedly on the first postoperative day, and persisted for 1 week, thus suggesting that some muscle damage occurred during the procedure. There was no operative death or severe complications. From these data, we concluded that hyperthermic isolated limb perfusion with interferon-beta is a relatively safe therapeutic method for malignant melanoma of the extremities. However, care should be taken in patients with ischemic heart disease who may suffer a heart attack due to the rapid increase in cardiac work during the procedure.     

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- 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-, 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 concentrations of plasma PMN clastase were found both in 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-. 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.

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Resumen Catorce pacientes con tumores malignos del hígado y 16 pacientes con melanoma maligno localizado en una extremidad fueron estudiados en relación con la activación de leucocitos con liberación de elastasa de PMN y de neopterina y la formación de citocinas (FNT- e IL-6) en el curso del tratamiento quirúrgico. Pacientes sometidos a resección del hígado (n=10), histerectomía abdominal (n=10) y reemplazo de cadera (n=10) sirvieron como grupos control. Se realizó perfusión hipertérmica aislada del hígado con perfusato citostácico (melfalán y cisplatino). Los pacientes con melanoma maligno recurrente confinado a una extremidad fueron sometidos a perfusión hipertérmica aislada de la extremidad con perfusato citostácico (melfalán). Se tomaron muestras de sangre para determinación preoperatoria de elastasa de PMN, neopterina, FNT- e IL-6, un minuto antes de comenzar la perfusión, 60 y 120 minutos después del comienzo de la perfusión y 24 horas después de la operación. Se tomaron muestras del perfusato a los 60 minutos luego del comienzo de la perfusión. Se encontraron altas concentraciones de elastasa de PMN tanto en los pacientes sometidos a perfusión hepática o de la extremidad, como en los pacientes sometidos a resección hepática. Se encontraron concentraciones elevadas de IL-6 en los pacientes sometidos a perfusión hepática y en los pacientes sometidos a resección del hígado. En ningún paciente se encontraron concentraciones aumentadas de neopterina o de FNT-. El perfusato contenía altas concentraciones de elastasa de PMN, neopterina e IL-6. Se encontró un aumento en la elastasa de PMN y en la IL-6 en respuesta a la perfusión y al trauma quirúrgico.

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Résumé Quatorze patients ayant une tumeur maligne du foie et 16 patients ayant un mélanome malin localisé à une extrémité ont été étudiés en ce qui concerne l'activation des leucocytes associée à un relargage d'élastase PMN et de néoptérine ainsi que la formation de cytokinines (TNF- et IL-6) pendant le traitement chirurgical. Trente patients avant eu soit une résection hépatique (n=10), soit une hystérectomie abdominale (n=10) ou une prothèse de hanche (n=10) ont servi de témoins. On a perfusé le foie avec un perfusât de cytostatiques (mélphalane et cis-platine). Les patients ayant un mélanome malin d'une extrémité ont eu une perfusion isolée hyperthermique avec une perfusion de cytostatique (mélphanane). Des échantillons du sang ont été retirés pour déterminer les taux d'élastase PMN, de la néoptérine, du TNF-, et de l'IL-6 en préopératoire, une minute avant le début de la perfusion, 60 et 120 minutes après le début de la perfusion, et 24 heures postopératoirement. Des échantillons ont été retirés 60 minutes après le début de la perfusion. Des concentration élevées d'élastase PMN ont été retrouvées à la fois chez les patients ayant une perfusion hépatique et de l'extrémité et chez les patients ayant eu une résection du foie. Des concentration élevées en IL-6 ont été retrouvées chez le patient ayant une perfusion du foie et chez le patient ayant une résection hépatique. Les concentrations en néoptérine et en TNF- n'étaient pas élevées. Le liquide de perfusion contenait des concentrations élevées en élastase PMN, néoptérine et en IL-6. Cette étude démontre aussi que la chirurgie majeure est associée avec des concentrations élevées en PMN elastase et IL-6. Une augmentation en PMN-élastase et en IL-6 a été retrouvée en réponse à la perfusion et au traumatisme chirurgical.

     

Predictors of outcome after hyperthermic isolated limb perfusion: role of tumor response

HYPOTHESIS: Analysis of multiple clinical and pathological factors in patients undergoing therapeutic hyperthermic isolated limb perfusion for extremity melanoma can identify variables with prognostic significance. DESIGN: Retrospective review of a prospectively collected limb perfusion database with a median follow-up interval of 32.2 months. SETTING: Single-institution tertiary care surgical oncology unit. PATIENTS: We report a series of 59 consecutive therapeutic hyperthermic isolated limb perfusion treatments (14 upper extremity and 45 lower extremity) in 54 patients with melanoma from January 1, 1995, through December 31, 2002, using a standard melphalan dosing protocol. At the time of perfusion, 31 cases had fewer than 10 lesions, with none greater than 3 cm in diameter. The remaining 28 cases had 10 or more lesions or at least 1 lesion greater than 3 cm in diameter. MAIN OUTCOME MEASURES: Response, recurrence, and survival were assessed in relation to multiple demographic, clinical, and technical variables using chi2, log-rank, and Kaplan-Meier survival analyses. RESULTS: The 3-year survival for the entire cohort was 54%. Thirty-three (56%) of the 59 perfusion treatments resulted in a persistent complete response of at least 6 months' duration. Statistical analysis showed that patients with no evidence of regional nodal involvement had a significantly lower incidence of distant recurrence (P = .02). Those patients achieving a complete response to therapy had a survival advantage (P = .03). CONCLUSION: In patients undergoing therapeutic hyperthermic isolated limb perfusion for in-transit melanoma, the ability to achieve a complete response following treatment, independent of regional nodal status, was the strongest predictor of long-term survival.     

Marked variability of melphalan plasma drug levels during regional hyperthermic isolated limb perfusion

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) with melphalan as treatment for locally recurrent or in-transit malignant melanoma is frequently performed but the principle for calculating drug dosage remains poorly understood. METHODS: This study examined the pharmacokinetic profile of 14 consecutive patients to determine what variables were associated with toxicity and tumor responses. RESULTS: Marked fourfold variability was noted in patient plasma melphalan concentrations. We defined a factor--the ratio of estimated limb volume (Vesti) to melphalan volume of distribution (Vss), Vesti/Vss--that was much more strongly correlated with acute regional toxicity than either area under concentration-time curve or peak plasma concentration. In addition, we found that AUX2 was the best correlate of tumor response. CONCLUSIONS: Pharmacokinetic evaluation of prospective HILP trials is critical to not only understand response and toxicity outcomes but also to potentially improve the therapeutic index of regional perfusion.     

Isolated hyperthermic limb perfusion for soft tissue sarcoma

Background By combining different treatment modalities, function sparing resection of soft tissue sarcoma of the extremities has become possible for the majority of patients. To evaluate the role of isolated hyperthermic limb perfusion in this concept, the patients treated with this method in our institution were reviewed. Methods From January 1982 to December 1991 18 patients with extremity soft tissue sarcoma were treated by isolated hyperthermic limb perfusion. 41% of the patients presented with local recurrence, 67% with high grade malignancy and 61% after incomplete tumor resection. If present, residual tumors were resected several weeks after perfusion. Results The 5-year survival rate is 94% (mean follow-up 30 months). 38.6% of the patients developed local tumor recurrence, but limb sparing treatment had been carried out only after refusal of amputation in 4 of the 7 patients with local failure. Complications of therapy were moderate. Systemic toxicity was not observed. Conclusions We conclude that isolation perfusion is a valuable addition to combined modality treatment of soft tissue sarcomas of the extremities. With the aid of this method limb salvage can be achieved for the majority of patients.     

Long-term results of hyperthermic, isolated limb perfusion for melanoma: a reflection of tumor biology

PURPOSE: To review the long-term duration of limb tumor complete remission (CR) and patient survival following therapeutic hyperthermic isolated limb perfusion (ILP) with cytotoxic drugs for melanoma. METHODS: A retrospective case series of 124 ILPs performed in 111 patients. RESULTS: There were 120 assessable ILPs. Patient staging (M.D. Anderson system) was stage II 11.7%, stage IIIA 44.2%, stage IIIAB 33.3%, and stage IV 10.8%. CR was initially attained after 83 ILPs (69.2%) and partial remission (PR) after 19 ILPs (15.8%). Limb CR was maintained in 28 (33.7%) of the 83 cases. Disease recurred in the perfused limb after an initial CR in the remaining 55 cases (median time to recurrence, 11 months); in 19 of these cases, the limb was disease-free at last follow-up after further locoregional treatment. A long-term CR was achieved, with or without further treatment, in 47 (56.6%) of the 83 cases in which an initial CR had occurred (mean follow-up, 97 months; median, 65 months). There was no significant difference in long-term local remission for stage IIIA and IIIAB patients. Five-year survival for those who had a partial or no response to ILP was 7%. Ten-year survival for those who had a long-term CR was 49%. CONCLUSIONS: ILP, with or without further locoregional treatment, achieved long-term control of recurrent and metastatic limb disease in 56.6% of cases in which an initial CR was achieved. A complete response to ILP was a positive prognostic indicator for survival, probably reflecting more favorable tumor biology in this subset of patients.     

Angiographic response of locally advanced soft-tissue sarcoma following hyperthermic isolated limb perfusion with tumor necrosis factor

Background: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and melphalan is associated with a dramatic anti-tumor effect in which the neo-vascularization of the tumor is supposed to be the major target. The aim of the present study was to correlate the angiographic findings with the pathological response in patients undergoing HILP for locally advanced soft-tissue sarcoma. Patients and Methods: Twenty-five patients, 14 male and 11 female, mean age 47 years (range 18–80) were studied. Angiographies were performed before and a median period of 7 weeks (range 4–14 weeks) after HILP. Eight weeks after perfusion, the residual tumor mass was resected and pathologically examined. The changes in tumor vascularization after treatment were scored and compared with the pathological response. Results: All baseline angiograms showed a hypervascular tumor. After HILP, a normal angiography result (NA) was observed in 18 patients (72%) and an abnormal angiography result (AA) was observed in seven patients (28%). All patients with an NA showed a pathologically complete response (pCR) or a pathological partial response with >90% necrosis of the tumor. Of seven patients with an AA, pathological examination showed a pCR in one patient, 10–50% viable tumor volume in four patients, and no pathological response after perfusion in two patients. A good correlation was seen between angiographic and pathological classification (p<0.001). Conclusion: An angiography performed after hyperthermic isolated limb perfusion with TNF-α and melphalan provides a good indication, regardless of whether a good pathological response is expected. Presented at the 48th Annual Cancer Symposium of The Society of Surgical Oncology, Boston, Massachusetts, March 23–26, 1995.     

Pharmacokinetics and results of dose escalation inCis-platin hyperthermic isolation limb perfusion

Background: We analyzed prospectively collected data on 145cis-platin hyperthermic isolation limb perfusion (HILPs) for melanoma and soft-tissue sarcoma to determine the pharmacokinetics and maximum tolerable dose ofcis-platin. There were 70 melanoma and 75 sarcoma patients. Dosages ranged from 26 to 265 mg/m². Perfusate and systemiccis-platin levels were measured in patients perfused at doses of 190–200 mg/m². Tissue levels were measured in patients perfused at 123–209 mg/m². Methods: Cis-platin HILP was well tolerated up to doses of 250 mg/m² for lower extremities. Higher doses produced toxicities of rhabdomyolysis, myoglobinuria, hyponatremia, and neuropathy. Systemic levels ofcis-platin were equivalent to those of routine intravenous administration, while perfusate levels were 33 times higher. Tissue levels ofcis-platin were five to six times higher than effective intravenous levels. Results: Six melanoma patients have developed local recurrences. All were perfused at doses <120 mg/m². However, regional nodal recurrences have occurred in six other patients perfused at doses 2000 mg/m². Four sarcomas have recurred locally, but three of them were present at the time of perfusion. Conclusions: We conclude that 250 mg/m² is the maximum tolerable dose ofcis-platin for lower-extremity HILPs. Neoadjuvantcis-platin HILP may improve local control rates for sarcomas. However, no tolerable dose ofcis-platin provides control of nodal metastases from melanoma.Presented at the 46th Annual Cancer Symposium of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.     

Functional morbidity of hyperthermic isolated regional perfusion of the extremities

Background: Isolated regional perfusion (IRP) of an extremity is a major operation. The therapeutic value for stage I melanoma is still controversial and is presently being investigated in a prospective, randomized study by the European Organization for Research and Treatment of Cancer. So far there are no reliable data available concerning the morbidity of IRP. Therefore, we performed a prospective, randomized study on this topic. Methods: In a prospective study, a group of 97 patients with a stage I melanoma localized on an arm or leg were randomized for IRP with melphalan followed by wide excision (WE) and fasciotomyor for WE only. Morbidity was evaluated on the basis of the following parameters: duration of hospitalization, postoperative pain, postoperative performance, and grade of perfusion toxicity. At 12-month follow-up, a physical diagnostic examination was performed to measure the mobility of the joints, and the circumference and volume of the treated and untreated extremities. Results: All the parameters, including the physical diagnostic examination, could be evaluated in 83 of the 97 patients (8 patients died of metastatic disease and 1 patient died of another disease before they could be investigated; 2 patients were in too poor physical condition due to metastases to be examined, and 3 patients were unable to participate for nonmedical reasons). Age and sex distribution were comparable in the various patient groups. Treatment mortality was 0%. There were no complications except for urine retention (one patient) and wound dehiscence (one patient). After IRP + WE of the lower limb, the period of hospitalization was an average of 1.9 days longer (p=0.01) than for WE on the limb only. This difference was absent for the arm. Naturally after perfusion, there was a significant difference in toxic reactions (edema and pain) between the IRP + WE patients and the WE-only patients. However, at 12-month follow-up, the difference in morbidity between IRP + WE and WE-only patients was no longer present: Morbidity of joints and circumference of the limb were the same. A number of subjective complaints were encountered fairly often after IRP + WE (e.g., pricking sensations or pain during changes in the weather), which can possibly be explained by fibrosis caused by perfusion. These complaints were not quantified further because they did not hinder the patients' functioning. Conclusions: In the long term, IRP with fasciotomy does not cause any additional morbidity. Immediately after the operation, there was more morbidity as a result of the perfusion, which caused a 2-day- longer period of hospitalization in the patients with lower-limb perfusion compared with those who underwent WE only. These findings are in contrast to those in the literature, in which 25% limitation of motion in the ankle joint after perfusion is mentioned. One explanation may be that we always performed fasciotomy after perfusion to prevent (sub)clinical compression syndrome and avoid late fibrosis.     

Percutaneous isolated limb perfusion with thrombolytics for severe limb ischemia

Patients with severe tibioperoneal disease are poor candidates for a distal bypass. Absence of a distal target, lack of conduit, or multiple medical problems can make these patients a prohibitive risk for revascularization. Acute on chronic ischemia in this group poses a greater challenge. Thrombolytic therapy for acute ischemia can be prolonged and carries a significant risk of bleeding if continued beyond 24 hours. However, if the ischemic limbs can be isolated from the systemic circulation, a higher dose of the lytic agent can be given with lower risk. These are the initial results of a series of 10 patients who underwent percutaneous isolated limb perfusion with a high dose of thrombolytics for severe ischemia. Ten patients (lower extremity 8 and upper extremity 2) presented with severe limb-threatening ischemia. Mean ankle/brachial index (ABI) was 0.15 for the lower extremity, and there were no recordable digital pressures in patients with upper extremity ischemia. No distal target was visible on the initial arteriogram. These patients were then taken to the operating room, and under anesthesia, catheters were placed in an antegrade fashion via femoral approach in the popliteal artery and vein percutaneously. For upper extremity, the catheters were placed in the brachial artery and vein. A proximal tourniquet was then applied. This isolated the limb from the systemic circulation. Heparinized saline was infused through the arterial catheter while the venous catheter was left open. A closed loop or an isolated limb perfusion was confirmed when effluent became clear coming out of the venous port. A high dose of thrombolytic agent (urokinase 500,000 to 1,000,000 U) was infused into the isolated limb via the arterial catheter and drained out of the venous catheter. After 45 minutes, arterial flow was reestablished. In 4 patients, Reopro((R)) was used in addition to thrombolytics. Postprocedure angiograms showed minimal changes, but patients exhibited marked clinical improvement. The ABI changed from 0.15 to 0.5 in the lower extremity and near-normal digital pressures in upper extremity ischemia. Limb salvage and symptomatic relief at 6 months was 90%. All patients except one were kept on anticoagulation postoperatively. No bleeding complications were observed from the procedure. Percutaneous isolated limb perfusion brought symptomatic relief to patients presenting with acute on chronic limb ischemia. This can be an alternate option for patients facing amputation with no revascularization options.     

Pharmacokinetics of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques

OBJECTIVE: Although paclitaxel is widely used as a systemic agent for the treatment of solid tumors, limited information is available concerning administration of this taxane by regional techniques. The present study was undertaken to evaluate the pharmacokinetics and acute toxicity of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques to ascertain its potential for the regional therapy of unresectable pulmonary neoplasms. METHODS: Adult sheep underwent 90 minutes of retrograde isolated lung perfusion with escalating doses of paclitaxel and moderate hyperthermia using a protein-free, oxygenated extracorporeal circuit and a steady perfusion pressure of 14 to 16 mm Hg. An additional animal received paclitaxel by means of 1-hour central venous infusion. Paclitaxel concentrations in lung tissues, perfusates, and systemic circulation were determined by high-performance liquid chromotography techniques. Cytotoxicity of paclitaxel in cancer cells and in normal human bronchial epithelial cells was evaluated in vitro using 4, 5-dimethylthiazo-2-yl-25-dipagnyl tetrazolium bromide assays. Lung tissues were examined by hematoxylin-and-eosin techniques. RESULTS: Paclitaxel concentrations (maximum concentration and area under the plasma concentration time curve) in perfused tissues increased with escalating perfusate doses. Uptake of drug into lung parenchyma appeared saturable at high paclitaxel exposure; a substantial pharmacokinetic advantage was observed. Paclitaxel concentrations in systemic circulation were undetectable or exceedingly low after perfusion. Histopathologic examination of lung tissues harvested 3 hours after completion of isolated lung perfusion revealed no immediate toxicity, even at a paclitaxel exposure 20-fold higher than that achievable after 1 hour of intravenous administration at the maximum tolerable dose in human subjects. Moderate hyperthermia enhanced paclitaxel-mediated cytotoxicity 5- to 100-fold in cultured cancer lines. No paclitaxel toxicity was observed in cultured normal human bronchial epithelial cells after exposure to paclitaxel under normothermic or hyperthermic conditions. CONCLUSIONS: These data support further evaluation of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques for the treatment of unresectable malignant pulmonary tumors.     

Pharmacokinetics, toxicity, and short-term results of cisplatin hyperthermic isolated limb perfusion for soft-tissue sarcoma and melanoma of the extremities

Fifty-nine patients with melanoma or soft tissue sarcoma of the extremities underwent hyperthermic isolated limb perfusion utilizing cisplatin and wide local excision. Doses of cisplatin ranged from 0.75 to 2 mg/kg. The mortality and morbidity rates were 0 and 6.8 percent, respectively. Pharmacokinetic studies indicate that cisplatin is rapidly bound to perfused tissues and remains bound for 1 month. Maximum tumor response in sarcomas occurs 1 to 2 weeks after perfusion, compared with 1 month after perfusions with l-phenylalanine mustard and actinomycin D. Local and regional recurrence rates were 0 and 3.4 percent, respectively, at 1 year. Further studies of hyperthermic limb perfusions with cisplatin are warranted.     

Value of therapeutic hyperthermic limb perfusion in advanced recurrent melanoma of the lower extremity

Twenty-six patients with advanced melanoma metastases confined to the lower extremity underwent 28 therapeutic limb perfusions without a major complication or treatment-related death. A complete response to treatment occurred in 21 patients (81 percent). Of 16 patients, response persisted until death in 13 and was noted at 75, 87, and 96 months follow-up in 3. In five patients, response lasted a median of 5 months (range 3 to 14 months), and repeat perfusion in two of these patients was not beneficial. Unfortunately, despite locoregional disease control, most patients died from distant metastases at a median of 15 months after treatment. In fact, regardless of response to perfusion, the 3 year survival rate of patients with advanced metastatic melanoma of the extremity was only 25 percent or less. Thus, although limb perfusion can be a safe and highly effective means of achieving locoregional disease control, there appears to be little survival benefit. Therefore, perfusion should be reserved for palliative treatment of selected patients with locally advanced melanoma.     

Asanguineous isolated hyperthermic in vivo perfusion of the liver in the rat

An experimental study was conducted in the rat to evaluate the sensitivity of the liver to hyperthermia and ischemia. A 15-min asanguineous isolated hyperthermic in vivo perfusion of the liver was done in rats with a normal liver and in rats with an hepatocarcinoma induced by chronic 3'-diethylaminoazobenzene intoxication. The perfusion was made using various ranges of temperature of the perfusate. In normal rats, the in vivo perfusion was well tolerated as long as the mean intrahepatic temperature remained under 38 degrees C. Postoperative evolution of serum transaminase level was similar whatever the temperature of the perfusate. Histological lesions of the hepatic parenchyma were as severe as the temperature of the perfusate was elevated. In rats with tumors, the mortality rate was elevated in the animals with large tumors. A moderate decrease in the serum alpha-fetoprotein level was observed during the first days after liver perfusion. In all cases, death occurred apparently as a direct consequence of liver injury. This study defines the sensitivity of the normal or neoplastic rat liver to hyperthermia and ischemia using a model of isolated in vivo perfusion of the liver. It provides a basis for further investigations on the effect of hyperthermia on experimental liver tumors.