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Right arrow Lung - cancer

Ann Thorac Surg 2001;72:234-242
© 2001 The Society of Thoracic Surgeons

Original article: general thoracic

Percutaneous venovenous perfusion-induced systemic hyperthermia for advanced non–small cell lung cancer: initial clinical experience

Joseph B. Zwischenberger, MDa,c, Roger A. Vertrees, PhD, CCPa,d, Lee C. Woodson, MD, PhDb, Eric A. Bedell, MDb, Scott K. Alpard, BAa, Christopher K. McQuitty, MDb, Jill M. Chernin, RNe a Department of Surgery, The University of Texas Medical Branch, Galveston, Texas, USA
b Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, USA
c Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas, USA
d Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, USA
e Department of Critical Care Nursing, The University of Texas Medical Branch, Galveston, Texas, USA

Accepted for publication March 27, 2001.

Address reprint requests to Dr Zwischenberger, Division of Cardiothoracic Surgery, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-0528
e-mail: jzwische{at}utmb.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Venovenous perfusion-induced systemic hyperthermia raises core body temperature by extracorporeal heating of the blood. Five patients with advanced non–small cell lung carcinoma stage IV (4.4 ± 1 months after initial diagnosis) received venovenous perfusion-induced systemic hyperthermia to 42.5°C (core temperature) to assess technical and patient risks.

Methods. After general anesthesia and systemic heparinization (activated clotting time > 300 seconds), percutaneous cannulation of the right internal jugular vein (15F) for drainage and common femoral vein (15F) for reinfusion allowed extracorporeal flow rates up to 1,500 mL/min (20 mL · kg-1 · min-1) with the ThermoChem System. This device uses charcoal-based sorbent for electrolyte homeostasis. Six monitored sites (rectal, bladder, tympanic x2, nasopharyngeal, and esophageal) determined average core temperature.

Results. All patients achieved a core target temperature of 42.5°C for 2 hours. Electrolyte balance was maintained throughout hyperthermia (mean) in mmol/L: Na+, 136.2 ± 2.2 mmol/L; K+, 4.0 ± 0.3 mmol/L; Ca2+, 4.1 ± 0.2 mg/dL; Mg2+, 1.9 ± 0.1 mg/dL; PO4-, 4.5 ± 0.9 mg/dL). Plasma cytokine concentration revealed significant heat-induced activation of proinflammatory and antiinflammatory cascades. All patients exhibited systemic vasodilation requiring norepinephrine infusion, 4 of 5 patients required vigorous diuresis, and 3 of 5 required intubation for 24 to 36 hours because of pulmonary edema or somnolence, with full recovery. Average length of hospital stay was 5.4 days. Serial tumor measurements (1 patient withdrew) revealed a decrease (64.5% ± 18%) in tumor size in 2 patients, no change in 1, and enlargement in 1, with no 30-day mortality. Median survival after hyperthermia treatment was 172 days (range, 40 to 271 days).

Conclusions. Venovenous perfusion-induced systemic hyperthermia is feasible and provides the following potential advantages for better tumoricidal effect: (1) homogeneous heating, and (2) a higher sustained temperature.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Non–small cell lung carcinoma (NSCLC) remains the leading cause of cancer death in both men and women in the United States [1]. The majority of patients with NSCLC present with advanced regional (stage III) or metastatic disease (stage IV). Survival without treatment for stage IV is 6 months [2]; with current treatment options including radiation therapy, chemotherapy, and surgery for palliation, average survival is still extended to only 9 months [3].

All known mammalian cells and tissues are thermosensitive, as manifested by protein denaturation and tissue destruction at critically elevated temperatures [4]. At less than critical temperatures, response (recovery or apoptosis) depends on the thermal dose received and the type of cell or tissue involved [5, 6]. Thermal dose is the product of the temperature differential (Televated - Tnormal [in °C]) and the time interval at the elevated temperature [7]. Neoplastic as opposed to normal tissues are vulnerable to destruction by heat at 41°C to 43°C [8–11]. The potential exists for exploiting this vulnerability by using hyperthermia to selectively destroy neoplastic tissue. Exogenously induced heat (hyperthermia) has attained a measure of success in the treatment of isolated and regional tumors [12, 13].

Systemic or whole-body hyperthermia (WBHT) is currently under investigation as a treatment for patients with metastatic cancer [14]. Whole-body hyperthermia for metastatic disease is controversial [15] because of the difficulty in administering and monitoring the thermal dose and an incomplete knowledge of thermal pathophysiology [16]. Previous techniques of WBHT have demonstrated substantial morbidity and mortality (approximately 12%), especially in debilitated elderly cancer patients [17, 18].

We have developed an extracorporeal method of WBHT (venovenous perfusion-induced systemic hyperthermia [VV-PISH] with multipoint temperature monitoring) in which the core body temperature is raised to 42.5°C for 2 hours. We have shown in adult swine heated with VV-PISH to 43°C for 2 hours that no adverse changes occur in cardiac function or serum enzymes (lactate dehydrogenase, creatine phosphokinase, or creatine kinase-MB) [19], and when temperatures return to normal, hemodynamic stability was maintained [20]. Venovenous perfusion-induced systemic hyperthermia delivers a thermal dose that exceeds published data from all other methods [21].

The purpose of this investigator-initiated phase I clinical trial was to evaluate the feasibility as well as immediate technical and patient-related risks of VV-PISH (42.5°C for 120 minutes) in patients with stage IV NSCLC. All patients achieved the core target temperature of 42.5°C for 2 hours with no 30-day mortality, 50% of measured tumors decreased in size, and median survival after hyperthermia treatment was 172 days (range, 40 to 271 days).


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Study subjects
Between February 1998 and April 1999, 5 patients with stage IV NSCLC were treated with VV-PISH to a core temperature of 42.5°C for 2 hours. This study was approved by the Institutional Review Board of The University of Texas Medical Branch as well as the US Food and Drug Administration for patients with histologic or cytologic documentation of stage IV (metastatic) NSCLC (squamous cell, adenocarcinoma, or large cell carcinoma) for a phase I study. Patients were reviewed by The University of Texas Medical Branch multiple disciplinary lung cancer working group consisting of attending faculty from Thoracic Surgery, Medical Oncology, Radiation Oncology, Pulmonary Medicine, Radiology, Pathology, and Medical Ethics. For informed consent of the VV-PISH protocol, standard and alternative treatment modalities were explained independently by the principal investigator, a disinterested physician, and a nurse coordinator. In addition, all patients received a neuropsychological evaluation before VV-PISH. Inclusion criteria were (1) stage IV NSCLC after conventional therapy failed or was refused, (2) one focus of measurable disease (in two dimensions), (3) Karnofsky score more than 60 and performance status 0 to 2, and (4) informed consent. Exclusion criteria included (1) congestive heart failure, coronary disease, cardiomyopathy, severe chronic obstructive pulmonary disease, (2) brain metastasis, (3) within 3 weeks of operation or 30 days of chemotherapy and radiation, (4) white blood cell count less than 4,000/µL, platelet count less than 75,000/µL, creatinine clearance less than 60 mL/min, serum bilirubin and serum glutamic-oxaloacetic transaminase more than 2x normal, (5) concurrent hormonal, biologic, or radiation therapy, and (6) pregnant or nursing women.

All patients underwent one hyperthermia treatment. Venovenous perfusion-induced systemic hyperthermia elevated average body temperature to 42.5°C and maintained this temperature for 120 minutes, followed by cooling to return the patient’s temperature to normal. All patients were followed in clinic weekly for 30 days at which time a computed tomographic scan was used to reevaluate tumor size. Patients were then followed monthly until death.

Pretreatment preparation
Patients were pretreated with intravenous glycopyrrolate (0.2 mg). General anesthesia was induced using thiopental (3 to 5 mg/kg intravenously) and incremental fentanyl (500 to 1000 µg/dose). Succinylcholine (1 to 1.5 mg/kg intravenously) facilitated intubation. Anesthesia was maintained with isoflurane (0.5 to 1.0% inspired) in nitrous oxide/oxygen, and mechanical ventilation was used briefly until the patient established a spontaneous breathing pattern. Arterial access allowed continuous pressure monitoring and blood sampling. A urinary bladder catheter with a temperature probe was inserted. A pulmonary artery thermodilution catheter measured continuous mixed venous oxygen saturation (Opticath, Abbott Labs, Mountain View, CA). Cefazolin (1 g), heparin, and methylprednisolone (100 mg intravenously) were given. Immediately before VV-PISH, isoflurane was discontinued, and the patient received assisted ventilation (Puritan-Bennett 7200; Mallinckrodt, St. Louis, MO). The inspired oxygen fraction maintained the arterial partial pressure of oxygen at 85 to 110 mm Hg. Infusions of thiopental (3 mg/min), fentanyl (5 to 10 µg · kg-1 · h-1), and lorazepam (1 mg/dose, to a maximum of 6 mg) were titrated to achieve a respiratory rate of 14 to 20 breaths/min. Volume administration was limited to albumin (5%) solution and packed red blood cell transfusion to maintain central venous, pulmonary artery diastolic, and pulmonary capillary wedge pressures within normal limits. Transesophageal echocardiograph was used intraoperatively for evaluation of cardiac function and detection of regional wall motion abnormalities.

Arterial blood samples were obtained every 30 minutes. Systemic heparin was infused before cannulation (5,000 to 10,000 U of beef lung heparin, Upjohn, Kalamazoo, MI), and 1,000 to 2,000 U were administered if the activated clotting time fell below 300 seconds. For VV-PISH, a 15F perfusion cannula (15F Arterial, 96530-15, Biomedicus, Eden Prairie, MN) was percutaneously inserted by Seldinger technique into the right internal jugular vein and positioned in the proximal superior vena cava or inserted into the left common femoral vein and positioned in the distal inferior vena cava for drainage of blood. A 15F cannula was then positioned in the proximal inferior vena cava (immediately below the diaphragm) by means of the right common femoral vein for reinfusion of blood. A sheet of aluminized Mylar wrapped around the patient to minimize radiant heat loss.

Temperature was monitored and recorded from the distal esophagus, bilateral auditory canals, rectum, bladder, airway, pulmonary artery blood, and skin. Core body temperature was defined as the mean value of the esophagus, right and left auditory canals, rectum, pulmonary artery blood, and bladder. The hyperthermia extracorporeal circuit consisting of the ThermoChem System (ViaCirQ Corp, Pittsburgh, PA) was connected to the cannulas, and blood was withdrawn, heated, and then pumped back into the proximal inferior vena cava at up to 1,500 mL/min (20 mL · kg-1 · min-1) (Fig 1) [21]. During the initial heat-induction phase, the maximum water temperature did not exceed 52°C and maximum blood temperature did not exceed 48°C (Fig 1).



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  		Fig 1. Schematic diagram of venovenous perfusion-induced systemic hyperthermia circuit used in this study.

 
The ThermoChem System machine (Fig 1) contains a heat exchanger and a cellulose plate dialyzer with membranes that expand and contract (in response to dialysate pressure changes) to propel blood through the dialyzer. The heat exchanger is regulated by a computer program feedback loop based on the six measured temperatures that determine core body temperature. The dialysate side contains a 2-L suspension of powdered sorbents (charcoal and cation exchanger): (1) 200 g of cation exchanger preloaded with sodium, calcium, potassium, hydrogen, and magnesium (maintains equilibrium with normal blood concentrations, (2) 140 g of powdered activated charcoal with 80 mmol of calcium phosphate precipitated on the surface to dissociate when surrounding solubility product is lower than normal, (3) sodium bicarbonate and sodium chloride in physiologic concentrations, (4) flow-inducing agents (1 liter DsW, 1 liter 0.45 NS), and (5) glucose absorbed to the powdered charcoal (maintains normal or slightly elevated blood glucose). Additional calcium chloride was infused into the venous return line of the ThermoChem System to maintain normal blood calcium concentration [2]. A norepinephrine infusion was used to control the peripheral vasodilatation seen with initiation of VV-PISH, and fluid administration was titrated to maintain a target systolic blood pressure of more than 100 mm Hg. When the target core body temperature of 42.5°C was achieved, the water temperature was reset to 30°C until the average body temperature was below 37°C. Venovenous perfusion-induced systemic hyperthermia was terminated, and heparin was reversed with protamine sulfate (1:1).

All patients recovered in an intensive care unit setting, monitored by femoral arterial catheter, the Foley catheter, and the pulmonary artery catheter. At completion of VV-PISH, the patient received intermittent propofol infusion for sedation. Diuresis was initiated with furosemide (40 mg intravenously every 8 to 12 hours) and mannitol (50 g). The patients remained in the intensive care unit for at least 24 hours until extubated and responsive.

Plasma levels of interleukin (IL)-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor-{alpha} were measured in duplicate and averaged using quantitative sandwich enzyme immunoassay (ELISA, R&D Systems, Minneapolis, MN) for the following time points: after anesthesia, before VV-PISH, after 60 minutes of stable hyperthermia, and after decannulation.

Statistics
Values are expressed as mean ± standard error of the mean. Significance was determined when p less than 0.05 in all comparisons. Between group comparison was accomplished with Student’s t test, comparison before and after hyperthermia treatment was done with a paired Student’s t test, and analysis of variance was used for repeated measures.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Table 1 shows the demographics of this patient population. All patients had stage IV lung cancer and had failed or refused alternate therapies including radiation or chemotherapy. The average length of time between the initial diagnosis of stage IV NSCLC and the hyperthermia treatment was 4.4 ± 1 months (range, 2 to 7 months).


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  		Table 1. Demographics: Pretreatment

 
During VV-PISH an average of 67 ± 2.4 minutes was needed to reach the target temperature of 42.5°C, which was maintained for 120 minutes (Fig 2). It took an average of 37 ± 1.4 minutes to return the average core temperature to 37.5°C. The average perfusion interval was 224 ± 3 minutes. The average thermal isoeffect dose (dose of heat theoretically received by the tumor [7]) was 210 ± 80 minutes [22]. Figure 3 shows the relationship between the temperature exiting the heat exchanger, the blood entering the patient, and the corresponding average body temperature. Figure 4 illustrates the temperature recorded at all monitored sites in a representative patient (No. 4) (rectal, bladder, esophageal, nasopharyngeal, left tympanic, and right tympanic). Figure 5 demonstrates the relationship between the average body temperature and the directly measured tumor temperature (patient 5).



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  		Fig 2. The average body temperature in all 5 patients reached the target temperature of 42.5°C. Each patient was maintained at this level for 120 minutes before cooling returned the average body temperature to 37°C.

 


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  		Fig 3. Comparison among water, blood, and average body temperatures.

 


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  		Fig 4. Temperatures recorded in six sites used to determine the average body temperature in patient 4.

 


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  		Fig 5. Relationship between average body temperature and directly measured intratumor temperature in patient 5.

 
Figure 6 demonstrates the relationship between the heart rate, mean arterial blood pressure, mean pulmonary artery blood pressure, central venous pressure, and venous blood oxygen saturation in these 5 patients. Heart rate, cardiac output, and central venous pressure increased and mean arterial blood pressure decreased. All patients exhibited systemic vasodilation requiring norepinephrine infusion to maintain the mean arterial pressure more than 60 mm Hg. All patients, documented by transesophageal echocardiography, displayed hyperdynamic hemodynamic changes in cardiac function with left ventricular cavity obliteration and a midventricular pressure gradient responsive to ß-blockers and an increased preload.



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  		Fig 6. Demonstration of effect of hyperthermia on hemodynamic variables. In all patients, the heart rate (HR) and cardiac output (CO) increased immediately with heating. The patients’ mean arterial blood pressure (mABP) decreased, requiring fluid administration subsequently causing the central venous pressure (CVP) to rise. Hemodynamic stability returned during cooling. (mPA = mean pulmonary arterial pressure; PvO2 = venous partial pressure of oxygen.)

 
During heating (22.7 ± 3 mL/min) and maintenance (18.3 ± 2.8 mL/min), significant volume was required while urine output decreased significantly (< 1 mL/min in all patients). This additional volume had to be eliminated during cooling, and 4 of 5 patients required vigorous diuresis. Hematocrit dropped from 33% ± 3% to 29.2% ± 5% secondary to hemodilution. Arterial blood gases were maintained within normal limits, with a mild respiratory acidosis present in all patients during the hyperthermia maintenance interval.

Electrolyte balance was maintained, with only serum glucose outside the normal values. Significant increases were noted in creatine kinase, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase. Significant decreases were noted in lymphocytes, platelet count, and fibrinogen (to within normal range; Table 2).


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  		Table 2. Comparison of Variables

 
Table 3 shows plasma concentrations of all cytokines, which were higher at time points 2 and 3, indicating significant activation of both the proinflammatory (tumor necrosis factor, IL-6, IL-8, and IL-1ß) and antiinflammatory (IL-10) systems.


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  		Table 3. Comparison of Cytokine Plasma Levelsa

 
Intubation was required 24 to 36 hours after hyperthermia in 3 of 5 patients because of pulmonary edema or somnolence, with full recovery. Average length of stay was 5.4 days; all 5 patients survived more than 30 days. Table 4 shows all patient-related variables that were affected by the treatment. For changes in tumor size, 2 of 4 patients had tumor enlargement at 30-day follow-up; but tumors of 2 of 5 patients were increased in size. No major complications attributable to hyperthermia were seen. Minor complications included vasodilation requiring norepinephrine infusion in 5 of 5 patients, decreased platelet count (resolved by discharge) in 5 of 5 patients, elevated lactate dehydrogenase and serum glutamic-oxaloacetic transaminase (resolved by discharge) in 5 of 5 patients, vigorous diuresis in 4 of 5 patients, intubation 24 to 36 hours because of pulmonary edema or somnolence in 3 of 5 patients, red blood cell transfusion in 2 of 5 patients, and superficial burns at pressure points in 2 of 5 patients.


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  		Table 4. Outcomes

 
At 30 days after hyperthermia, 1 patient (No. 2) had a worse Karnofsky score and functional class rating, whereas 2 patients (Nos. 4 and 5) had improvement in functional class. Three patients completed neuropsychological testing at 30 days after VV-PISH. No abnormalities referable to hyperthermia were noted [23]. Median survival after VV-PISH was 172 days (range, 40 to 271 days). All deaths were judged secondary to tumor burden with none attributable to the hyperthermia treatment. At time of death for all observable tumors, three of six had decreased in size and three of six had increased in size. At autopsy (patients 1 and 2), the pathologist stated, "The amount of necrosis observed in the neoplastic tissue appeared to be significantly greater than that commonly seen. The core is necrotic with a thin viable rim. This possibly represents the effect of hyperthermia treatment on the tumor cells."


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
This study evaluated VV-PISH for (1) feasibility, (2) immediate technical risks, and (3) patient-related risks in patients with stage IV NSCLC. We demonstrated that (1) VV-PISH is feasible, (2) the delivered isoeffect thermal dose far exceeded other published thermal doses, (3) electrolyte balance was maintained, (4) all patients exhibited systemic vasodilation, (5) tumors received substantial thermal doses, and (6) all patients experienced full recovery.

The rationale for hyperthermia in cancer treatment is the variation in response to heat between normal and cancerous tissue. At the molecular level, hyperthermia has been shown to be a stimulus for apoptotic cell death in cancer cells [24]. Effects at the cellular level include damage caused by heat-induced lipid peroxidation, reduced mitotic rate [25], destabilized cellular membranes [26], and an increase in tumor necrosis factor-{alpha} and IL-1ß [27]. At the tumor level, decreased tumor blood flow facilitates preferential heating of tumors. Within the tumor, hyperthermia causes an elevated rate of glycolysis, acidosis, and oxygen utilization [28]. Heat also has a well-known stimulatory effect on the immune system, causing both increased production of interferon-{gamma} and increased immune surveillance [29].

Complications from hyperthermia are the result of (1) the elevated temperature and (2) the technique of inducing the elevated temperature. Temperatures more than 41.8°C increase vascular compliance [30], increase intrinsic heart rate (7.1 beats · min-1 · C°-1) [31], decrease afterload [32], and increase cardiac output [6]. Additionally, if hypovolemia results, electrolyte concentrations become altered, resulting in arrhythmias and further impairing cardiac performance [32]. Electrolyte concentrations were maintained within normal ranges throughout the treatment period, and no arrhythmias were seen. These phenomena disappeared quickly when cooling commenced. Our patients showed an immediate increase in heart rate and cardiac output and decrease in afterload (Fig 6). Central venous pressure increased steadily throughout the treatment period. Phenylephrine, norepinephrine, and vigorous diuresis returned these values to normal in the early postoperative period.

The significantly elevated levels of tumor necrosis factor-{alpha} and IL-1ß are a serendipitous finding warranting further study and suggesting a possible mechanism for tumor cell kill. Oxygen free radicals, byproducts of cellular metabolism, can be mitigated by a family of superoxide dismutases, particularly manganese superoxide dismutase [33]. Manganese superoxide dismutase levels are induced by tumor necrosis factor and can result in apoptosis in tumor cells [34]. Additionally, upregulation of IL-1ß has been linked to increased apoptosis in tumor cells [35]. Paradoxically, both cytokines offer a protection against oxidative stress in normal cells by upregulation of cytoprotective mechanisms [27]. The elevated levels documented in this study may offer both a protective effect to normal cells and a cytotoxic effect to tumor cells.

Whole-body hyperthermia is also associated with consumptive coagulopathy [36, 37]. However, Parks and associates [18], when using perfusion-induced systemic hyperthermia with systemic anticoagulation, reported no hemolysis, clotting, or bleeding, although they experienced a 32% drop in platelet count. In our studies, activated clotting times returned to normal after heparin reversal with protamine. We also observed a 44% decrease in platelet count, but the resultant number was still greater than 150,000/dL. No hemostatic derangements were experienced from perfusion-induced systemic hyperthermia in the HemoCleanse human immunodeficiency virus clinical trials [38]. Alterations in coagulation profiles with WBHT are probably the result of hyperthermia combined with the primary disease state without the protection offered by heparin used in perfusion-induced systemic hyperthermia studies.

Our VV-PISH technique has three unique aspects in delivering WBHT. First, we use a venovenous approach, allowing us to deliver blood at 42.5°C in a more rapid and homogeneous manner than other methods (Fig 3). Heated blood is introduced back into the venous circulation, mixes in the pulmonary circulation, then the heat is evenly distributed by the systemic circulation [20]. The rate of heat induction is of critical importance because the faster the rate, the better the cancer cell kill [39]. Venovenous perfusion-induced systemic hyperthermia requires only 52 ± 2.4 minutes (Fig 2) to reach target temperature, whereas other methods of WBHT may require up to 2.8 hours [18]. The therapeutic effects of hyperthermia are dependent on the actual temperature of the target tissues. Because we have targeted systemic metastatic disease, homogeneous distribution of heat and precise control of temperature gradients are critical. The heterogeneous temperature distribution seen with other techniques may explain the inconsistent results in previous clinical trials using hyperthermia for the treatment of tumors. We have documented a redistribution of blood flow favoring the thoracoabdominal organs and resulting in a homogeneous temperature elevation [40]. The second unique aspect of this technique is temperature management, which involves multipoint temperature monitoring and use of average body temperature for feedback control of heat induction [20]. Excessive temperature elevations or excessive time at an elevated temperature may damage nontarget tissue, whereas insufficient temperature or thermal dose may have no therapeutic effect on target tissue. Venovenous perfusion-induced systemic hyperthermia delivers a thermal dose that is both predictable and substantial [20]. We measured intratumor temperature directly (2 patients with accessible tumor burden, supraclavicular nodes). The measured thermal dose exceeded that received by the body. The third unique aspect we have is the incorporation of a sorbent-based plate-membrane dialyzer system [2], which controls the chemical composition of the dialysate and helps to maintain normal electrolyte values [19].

All 5 patients had stage IV NSCLC and had failed or refused other therapeutic trials. All patients had multiple solid-organ metastases with cachexia on entry into the trial. The target of 42.5°C for 2 hours was achieved for average core temperature and 42.5 ± 0.2°C at all monitored sites. Percutaneous cannulation, hyperthermia induction, maintenance, and cooling were free of significant complications. Although all patients required critical care management in the intensive care unit for 2 to 3 days, all were discharged with an average length of stay of 5.4 days and all survived longer than 30 days. In the 3 patients in whom neuropsychic testing was completed before hyperthermia and at 30 days afterward, no central nervous system abnormalities were detected [23]. During this safety trial of 5 patients, no assessment of therapeutic efficacy is possible; however, serial tumor measurement revealed a decrease in tumor size in 2 patients (Nos. 2 and 4) and no change in another (No. 5) at 30 days after hyperthermia. Two aspects of these studies are particularly intriguing: (1) the pathology reports in 2 patients (Nos. 1 and 2) showed near-complete tumor necrosis (viable rim only) in some tumors at the time of patients’ death, and (2) the median survival for the group was 172 days after hyperthermic treatment. This may reflect a therapeutic advantage considering that the average time from initial diagnosis to hyperthermia treatment was an additional 4.4 ± 1 months.

In summary, VV-PISH is feasible with potentially better tumoricidal effects by homogeneous heating to achieve a target core and site-specific temperature of 42.5°C. Our technique of percutaneous VV-PISH provides potential advantages both in terms of safety and efficiency of thermal delivery over other external methods [9, 41, 42]. Venovenous perfusion-induced systemic hyperthermia provides more precise control of tumor temperature, maintenance of electrolyte homeostasis, distribution of blood flow favoring the thoracoabdominal organs, and a higher sustained temperature providing better tumoricidal effects.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This study was conducted in the General Clinical Research Center at The University of Texas Medical Branch at Galveston. It was supported by grants (M01 RR-00073) from the National Center for Research Resources, National Institutes of Health, US Public Health Service, and ViaCirQ, Inc, Pittsburgh, PA.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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