Patients presenting with unresectable, large, primary or recurrent extremity soft tissue sarcoma or locally advanced extremity tumors may benefit from treatment options in the form of isolated regional perfusion therapy. Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) have proved to be efficacious with acceptable systemic and regional toxicity profiles. Both procedures are attractive as options for patients who might otherwise be facing amputation as limb salvage procedures. HILP and ILI can be offered as either definitive treatment or as neoadjuvant therapy followed by surgery and/or radiation treatment. Response rates are encouraging as are limb preservation rates after regional therapy. Ongoing multicenter collaborations and clinical trials are required to gain knowledge on HILP and ILI for unresectable extremity sarcoma and expand the indications for use in the management of advanced extremity soft tissue sarcoma.
Patients with large, locally advanced soft tissue sarcoma (STS) of the extremities represent a small percentage of adult malignancies and have a high risk of local recurrence and distant metastasis. Obtaining adequate local control may require radical, functionally debilitating surgery, which could have a profound impact on limb function and the patient’s quality of life. Amputation of the affected extremity may provide durable local control, but at the expense of loss of function and without an improvement in overall outcome. For patients with STS who present with unresectable bulky primary tumors or recurrent tumors with distant disease, selecting the most appropriate treatment that allows patients to maintain function without compromising quality of life, limb function, and long-term outcomes is a challenge.
Over the past few decades, there has been a growing trend toward limb-preservation therapies when treating patients with unresectable, recurrent or bulky, locally advanced primary STS tumors. Offering the potential for limb salvage by treating the local or regional disease process without compromising extremity function ultimately may allow patients to maintain a better quality of life while avoiding the need for amputation. Regional delivery of chemotherapy addresses these concerns and can be used as a potential adjunct to surgical resection with radiation therapy for advanced extremity STS tumors previously deemed unresectable. Two techniques, hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI), allow the regional administration of chemotherapy, delivering drug concentrations 15 to 25 times higher than systemic dosages without the systemic side effects. For patients with advanced, unresectable STS with limited treatment options, both procedures are well tolerated, repeatable (especially in the case of ILI), and have acceptable toxicity profiles. This article describes the role of HILP and ILI in the management of patients with advanced, limb-threatening extremity STS.
Indications for regional therapy
Patients who are referred to centers that specialize in regional therapies have often been maximally treated with one or more previous surgical operations or have received adjuvant radiation treatment or chemotherapy. For those patients who relapse, many are deemed “unresectable” based on involvement of critical structures, such as neurovascular bundles, or have developed distant disease. Others may present with primary tumors that are potentially marginally resectable, but after radical surgery and adjuvant radiation treatment would be disfigured or left with a functionally impaired extremity. For these reasons, many patients in these situations are referred for ultimate local control by extremity amputation. Unfortunately, amputation confers no long-term survival benefit over limb-sparing. However, these patients may be the ideal candidates for regional therapy with HILP or ILI.
The indications for regional therapy are numerous, most importantly those patients with unresectable, extremity STS or those in whom resection would result in a disfigured or severely functionally impaired limb. Other indications include multifocal primary tumors, recurrent disease, prior resection with irradiation, bulky primary tumor size, or high-grade tumors. Elderly patients and those treated in the palliative setting also have been shown to gain a benefit in local control and limb salvage rates with regional therapy. Finally, other less frequently encountered noncutaneous and STS types have also been described in the literature to be amenable to regional chemoperfusion therapy including Kaposi sarcoma, Stewart-Treves lymphangiosarcoma, desmoid tumors, Merkel cell carcinoma, and osteosarcoma.
Technique of HILP
First reported in the 1950s for treating melanoma patients with regional disease, HILP was the first established therapy to gain acceptance for regional chemoperfusion to improve limb salvage rates in patients with extremity STS. The technique has been extensively described in the literature. Briefly, HILP requires surgical exposure and cannulation of the iliac or femoral vessels for lower-extremity tumors or subclavian or axillary vessels for upper-extremity tumors. Cannulae are connected to an extracorporeal circuit that contains a membrane oxygenator and heat exchanger. The circuit is primed with blood, Ringer’s lactate solution, and heparin. To ensure complete vascular isolation and target tumor perfusion, a pneumatic cuff or Esmark tourniquet is applied proximally on the affected extremity. Systemic leakage is measured continuously during the procedure by a precordial Geiger counter that monitors 99 Tc radiolabled human serum albumin or red blood cells previously injected into the perfusate. Flow rates are set as high as possible, generally 35 to 40 mL/L of limb volume per minute, and are adjusted based on the percentage of leakage. The procedure is performed under hyperthermic conditions (38.5–40°C). After the desired limb temperature is reached and there is no evidence of systemic leakage (<0.5%), the intended chemotherapeutic regimen is administered.
Melphalan is the drug of choice for HILP and dosage is calculated according to the liter-volume method. Although several different cytotoxic regimens have been investigated for use in regional therapy for extremity STS, including cisplatin and dacarbazine, none have exceeded the outcomes observed using melphalan. Actinomycin D, when used in combination with melphalan, has shown favorable response rates and is currently the regimen used for ILI regional therapy in many centers in the United States. European centers initially used a three-drug regimen with recombinant tumor necrosis factor (TNF)-α (2–4 mg), recombinant interferon (IFN)-γ (0.2 mg), and melphalan (10 mg/L for lower limb and 13 mg/L for upper limb) when treating advanced melanoma and patients with STS with HILP. However, early results showed that most of the tumor-related response was TNF-α–related and INF-γ use was subsequently abandoned.
The perfusion is performed for a total of 90 minutes. At the completion of the procedure, the limb is flushed with 2 to 4 L of isotonic saline solution, tourniquets are released, and vascular anatomy is reconstructed. Postoperatively, patients are observed in an intensive care setting for hydration and monitoring for systemic toxicity and reperfusion injury. Average postoperative hospital length of stay ranges from 8 to 10 days.
Technique of HILP
First reported in the 1950s for treating melanoma patients with regional disease, HILP was the first established therapy to gain acceptance for regional chemoperfusion to improve limb salvage rates in patients with extremity STS. The technique has been extensively described in the literature. Briefly, HILP requires surgical exposure and cannulation of the iliac or femoral vessels for lower-extremity tumors or subclavian or axillary vessels for upper-extremity tumors. Cannulae are connected to an extracorporeal circuit that contains a membrane oxygenator and heat exchanger. The circuit is primed with blood, Ringer’s lactate solution, and heparin. To ensure complete vascular isolation and target tumor perfusion, a pneumatic cuff or Esmark tourniquet is applied proximally on the affected extremity. Systemic leakage is measured continuously during the procedure by a precordial Geiger counter that monitors 99 Tc radiolabled human serum albumin or red blood cells previously injected into the perfusate. Flow rates are set as high as possible, generally 35 to 40 mL/L of limb volume per minute, and are adjusted based on the percentage of leakage. The procedure is performed under hyperthermic conditions (38.5–40°C). After the desired limb temperature is reached and there is no evidence of systemic leakage (<0.5%), the intended chemotherapeutic regimen is administered.
Melphalan is the drug of choice for HILP and dosage is calculated according to the liter-volume method. Although several different cytotoxic regimens have been investigated for use in regional therapy for extremity STS, including cisplatin and dacarbazine, none have exceeded the outcomes observed using melphalan. Actinomycin D, when used in combination with melphalan, has shown favorable response rates and is currently the regimen used for ILI regional therapy in many centers in the United States. European centers initially used a three-drug regimen with recombinant tumor necrosis factor (TNF)-α (2–4 mg), recombinant interferon (IFN)-γ (0.2 mg), and melphalan (10 mg/L for lower limb and 13 mg/L for upper limb) when treating advanced melanoma and patients with STS with HILP. However, early results showed that most of the tumor-related response was TNF-α–related and INF-γ use was subsequently abandoned.
The perfusion is performed for a total of 90 minutes. At the completion of the procedure, the limb is flushed with 2 to 4 L of isotonic saline solution, tourniquets are released, and vascular anatomy is reconstructed. Postoperatively, patients are observed in an intensive care setting for hydration and monitoring for systemic toxicity and reperfusion injury. Average postoperative hospital length of stay ranges from 8 to 10 days.
Technique of ILI
ILI, a less invasive approach for administering regional chemotherapy, was developed and first reported on by the Sydney Melanoma Unit. Initially described for the treatment of in-transit metastases in melanoma patients, ILI is a less complex, less invasive procedure that has been shown to have overall response rates close to those observed after conventional HILP. ILI is essentially a low-flow HILP performed under hyperthermic, nonoxygenated conditions by percutaneously placed catheters. ILI was first described in patients with advanced extremity STS using doxorubicin (0.7 mg/kg upper limb, 1.4 mg/kg lower limb) in conjunction with preoperative radiotherapy and delayed surgical resection with the aim of improving limb preservation. Since that time, several other institutions have reported on their experience using ILI for advanced extremity STS.
On the day of the procedure, high-flow 5F to 6F arterial and 6F to 8F venous catheters are inserted by way of the uninvolved lower extremity (femoral artery and vein, respectively) using the Seldinger technique and advanced under fluoroscopic guidance into the involved extremity. After the induction of general anesthesia, heparin is given to achieve full systemic anticoagulation with a target activated clotting time greater than or equal to 350 seconds. The arterial and venous catheters are then connected to an infusion circuit that consists of a heat exchanger and bubble excluder. After subcutaneous temperatures of greater than 37°C are achieved, a pneumatic tourniquet (inflated to 250–300) or an Esmark wrap is placed on the proximal aspect of the limb to be infused, isolating the limb from the systemic circulation. Papaverine (60 mg) is injected into the arterial catheter and chemoperfusion is initiated. Depending on the chemotherapeutic regimen used (frequently actinomycin D and melphalan), cytotoxic agents are typically circulated for 30 minutes. After 30 minutes of infusion, the limb is manually flushed with 750 to 1000 mL of isotonic crystalloid solution. After the washout period, the tourniquet is removed, heparinization is reversed with protamine if necessary, and the catheters are removed when the activated clotting time is at or near baseline. Patients are monitored daily for regional toxicity with serial creatine phosphokinase (CPK) measurements and are discharged home when CPK levels peak and then fall back toward the baseline, generally within 4 to 6 days.
Toxicity
The toxicity profile for HILP and ILI is described in acute and long-term side effects and is further classified as either systemic or regional toxicities. In general, the toxicity of HILP is more severe than that experienced by patients who undergo ILI procedures.
Systemic Toxicity After HILP or ILI
Systemic toxicities, in particular, are seen more frequently with HILP procedures and are related to the type of chemotherapy used and amount of leakage of the chemotherapeutic into the systemic circulation. Leakage rates less than 3% to 4% are generally well tolerated. However, higher flow rates may result in increased systemic leakage, producing gastrointestinal, hematopoietic, or other constitutional side effects. Continuous precordial monitoring for systemic leakage is mandatory for patients undergoing HILP therapy. To minimize potential systemic toxicity post-HILP, some authors have suggested that prolonged washout during the termination portion of the perfusion may also further help reduce systemic toxicity complications.
The potential systemic toxicities described after HILP include the hematologic, gastrointestinal, genitourinary, cardiac, pulmonary, neurologic, and integumentary systems. TNF-α, which is commonly used in many European centers, is thought to be responsible for many of the systemic toxicities experienced with HILP. TNF-α targets tumor microvasculature, which results in coagulative and hemorrhagic necrosis of tumors. Systemic leakage of TNF-α can induce a severe systemic inflammatory response syndrome with hypotension and shock-like symptoms, which necessitates aggressive hydration and vasopressor resuscitation. Eggermont and colleagues, in a multicenter HILP trial treating 186 patients with locally advanced extremity STS using TNF-α and melphalan, found only a mild to moderate systemic toxicity profile attributable to high-dose TNF-α (2–4 mg). This was easily managed and associated with no toxicity-related deaths. Most patients had mild fever or chills, controlled with antipyretics. Only 3% of patients developed grades III to IV cardiovascular toxicity, managed with vasopressor agents and hydration. In another report of 217 HILP procedures using TNF-α and melphalan for limb-threatening STS, there were minimal sequelae for patients with leak rates less than 10% (88% of patients). Six patients had leak rates greater than 20%. Their procedures were subsequently terminated, but none went on to develop severe complication or require intensive care unit monitoring for more than 24 hours. These results suggest that appropriate monitoring and supportive care may offset much of the TNF-α–induced toxicity without significant long-term sequelae.
Systemic toxicity related to ILI is much less common than that experienced after HILP. Early reports of ILI in advanced extremity STS noted no specific systemic toxicity. Symptoms experienced by most patients are mild (eg, nausea) and self-limiting, often resolving by postoperative Days 1 or 2. Rhabdomyolysis, as measured by serum CPK, is commonly encountered in patients undergoing this form of regional therapy. CPK levels often rise greater than 1000 IU/L and require daily blood urea nitrogen and creatinine level monitoring to avoid myoglobin-induced renal failure. Aggressive hydration with isotonic saline, maintaining a urine output of greater than 0.5 mL/kg/h, may reduce the risk of renal failure caused by myoglobinuria. Patients with CPK levels greater than 1000 IU/L are hydrated, given corticosteroids to decrease muscle edema or inflammation, and monitored until CPK levels have peaked and fallen less than 1000 IU/L. In a multicenter report of 12 patients with locally advanced STS undergoing ILI, CPK levels peaked around Day 3 with median levels of 127 for the upper extremity and 93 for the lower extremity. No patient developed any short- or long-term sequelae because of CPK-related toxicity.
Regional Toxicity After HILP or ILI
Regional toxicity after HILP or ILI is common and results in short- and long-term morbidity. A commonly used classification system characterizing acute tissue reactions after HILP or ILI was first reported by Wieberdink and colleagues. Briefly, it characterizes acute regional toxicity on a one to five scale with grade I toxicity representing no injury. Grade II toxicity is described as a soft tissue reaction manifesting as slight erythema or edema of the extremity. Grade III toxicity consist of considerable erythema or edema with some blistering. Grade IV injury involves extensive epidermolysis, which may cause definite functional disturbance with the threat or manifestation of compartment syndrome requiring fasciotomy. Grade V toxicity is characterized by severe tissue necrosis or vascular catastrophe that results in amputation. This classification system has standardized regional toxicity reporting for patients undergoing HILP or ILI therapy ( Table 1 ).
| Grade | Clinical Characteristics |
|---|---|
| I | No subjective or objective evidence of reaction |
| II | Slight erythema or edema |
| III | Considerable erythema or edema with some blistering; slightly disturbed motility permissible |
| IV | Extensive epidermolysis or obvious damage to the deep tissues causing definite functional disturbances; threatened or manifest compartmental syndromes |
| V | Reaction that may necessitate amputation |
Acute regional toxicity-related symptoms are seen within the first 48 hours after HILP or 72 to 96 hours after ILI. Typical reactions to therapy are mild erythema, edema, and pain (Wieberdink grades II–III). Mild or moderate blistering is not uncommon and is seen up to several days posttherapy. Mild erythema or edema, when present, may persist for months after treatment. Other acute complications including vascular injury, thrombosis, compartment syndrome, and tissue loss leading to amputation have also been reported. In the first description of ILI therapy for limb-threatening STS, no significant regional toxicity-related complications were reported. Forty patients underwent preoperative ILI with doxorubicin followed by external-beam radiation and delayed resection. Only 30% of patients experience grades II or III toxicity. In a multicenter study of ILI for nonmelanoma cutaneous and STS malignancies, Turaga and colleagues reported on 22 patients undergoing 26 ILI treatments with melphalan and D-actinomycin over a 5-year period. Most patients (96%) had grade III toxicity or less; only one (4%) developed grade IV toxicity. The authors concluded that ILI offers good extremity function preservation with only minimal morbidity.
Long-term regional toxicity is less frequently reported for patients undergoing regional therapy with HILP. In the largest HILP multicenter experience for STS to date, most patients (92%) had mild perfusion reaction (grades II and III), whereas 14 patients experienced grade IV toxicity. The authors noted that 20% developed transient distal extremity parasthesias, whereas 3% developed long-term peroneal nerve dysfunction. Similar findings were reported in 49 patients undergoing HILP with TNF-α and melphalan for unresectable STS; short- and long-term complications were described in detail. Most patients (71%) had mild acute regional toxicity (grade II). Three patients (6%) developed major complications after ILP: two patients developed arterial thrombosis treated with thrombectomy, another developed a life-threatening clostridial wound infection and died 2 days after ILP. Long-term functional morbidity was also described: 31% had some sort of extremity malfunction 1 year post-HILP, whereas four patients suffered permanent nerve dysfunction.
Outcome after HILP for extremity STS
In one of the earliest reports of regional therapy for STS, Lienard and colleagues performed 25 HILPs in 23 patients with advanced melanoma or STS (N = 4). Using a multidrug regimen of high-dose TNF-α (2–4 mg), IFN-γ (0.2 mg), and melphalan (10 mg/L for lower limb, 13 mg/L for upper limb), 21 patients (89%) developed a complete response (CR) and 2 had a partial response (PR), essentially no treatment failures. Overall survival was 76% at 12 months of follow-up. Although most patients in this study were treated for advanced melanoma, these findings confirmed the proof of concept for the successful treatment of recurrent STS using regional therapy while avoiding amputation with acceptable outcomes. This early work was later supplanted by a larger multicenter European HILP trial treating specifically patients with nonresectable extremity STS. Fifty-five patients with primary (N = 30) or recurrent (N = 25) STS were treated with HILP using a similar multichemotherapeutic regimen. The clinical CR rate, as defined by gross tumor disappearance, was 18%; a clinical PR rate of 64% and no change was observed in 18%. When determined by the clinical and pathologic response to treatment, outcomes were much better: 36% CR, 51% PR, and 13% no change, respectively.
Although these initial experiences showed promising results, additional studies using melphalan with TNF-α formed the foundation for the role of regional therapy in patients with advanced extremity STS previously only considered for amputation. Tumor response rates ranging from 68% to 91% have been reported from several centers using TNF-α and melphalan irrespective of the dose of TNF-α used. From the largest reported series of HILPs in patients with limb-threatening STS, Grunhagen and colleagues noted a 75% overall response rate (CR in 26% and PR of 49%). Rossi and colleagues, investigating the combination of other cytotoxic agents with TNF-α, reported on their experience with HILP using doxorubicin (8.5 mg/L limb volume) for patients with limb-threatening STS. Doxorubicin, an active antiblastic agent, was found to be synergistic with low-dose TNF-α (1 mg) in early phase I and II study by the same authors. Building on their prior experience, a major histologic response for doxorubicin–TNF-α was identified in 90% of 21 patients treated. Clinical responses were 5% CR and 57% PR. Although several cytotoxic combinations have been studied to optimize tumor response rates with HILP, TNF-α with melphalan remains the most frequently used regimen at many European centers.
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