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Ann Thorac Surg 1996;61:1609-1617
© 1996 The Society of Thoracic Surgeons
Thoracic Oncology Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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Abstract |
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, interferon-
, and moderate hyperthermia for patients with unresectable pulmonary metastases.
Methods. Twenty patients with lung metastases (Ewing's, 2; sarcoma, 8; melanoma, 6; other, 4) were considered for single-lung isolation perfusion with 0.3 to 6.0 mg of tumor necrosis factor- and 0.2 mg interferon- delivered through an oxygenated pump circuit. Sixteen perfusions were performed in 15 patients (bilateral in 1). Metastases were completely resected (no single-lung isolation perfusion) in 3 patients, 1 patient had extrapulmonary disease, and one single-lung isolation perfusion was aborted for mechanical reasons.
Results. There were no significant changes in systemic arterial blood pressure or cardiac output during perfusion. Systolic pulmonary artery pressure increased with isolation, but returned to pre-single-lung isolation perfusion levels after clamp release. The maximum systemic tumor necrosis factor- level was 8 ng/mL, whereas pump-circuit levels ranged from 200 to 10,976 ng/mL. There were no deaths, and the mean hospitalization period was 9 days (range, 5 to 34 days). A short-term (6 to 9 month) unilateral decrease in perfused nodules was noted in 3 patients (melanoma in 1, adenoid cystic carcinoma in 1, renal cell carcinoma in 1).
Conclusions. Future studies using a combination of biologic modifiers, chemotherapy, and hyperthermia should be pursued to define active cytotoxic agents that will preserve underlying pulmonary function.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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The lung is the site of many neoplasms including sarcoma, melanoma, renal cell cancer, and metastatic gastrointestinal disease that, because of location, size, or multiplicity, are unresectable. Even with complete resection of pulmonary metastases from soft-tissue sarcoma, only a 25% 3-year survival is possible. Moreover, this is in a select group of patients, and the majority of these patients will have recurrence with nodules that cannot be resected, eventually leading to their death from pulmonary failure. Despite a variety of regimens, response rates of only 25% to 50% are noted for the chemotherapy of pulmonary metastases, and these responses are usually brief. Innovative therapies are desperately needed for this unfortunate population of patients, who, in many instances, will die with disease confined solely to the lungs.
There has been a resurgence of interest in the regional delivery of chemotherapy, using perfusion techniques after isolation of the involved organ. At our institution, the concept of isolated lung perfusion has been explored using naturally occurring cytokines, ie, interferon- and tumor necrosis factor- (TNF). Tumor necrosis factor is a protein that derives its name from the activity demonstrated against subcutaneous methylcholanthrene-induced tumors in mice [1]. Although preclinical murine studies demonstrated excellent antitumor activity against a variety of subcutaneous tumors, phase I trials of systemic recombinant TNF in patients have been discouraging, with response rates of 4% and considerable toxicity [2]. The difference between murine and human efficacies is most likely related to the dose intensity: The maximally tolerated dose in most human trials ranged between 5 and 10 µg/kg, whereas the doses of TNF required for antitumor effects in the murine studies were 200 to 400 µg/kg [3]. An isolated perfusion of the lung that could achieve high local concentrations of TNF while limiting systemic toxicity may have important therapeutic consequences for selected patients.
A large series of animal experiments was performed initially to familiarize the perfusion team with the isolated lung circuit and to define the tolerance of the normal lung to high-dose TNF with and without hyperthermia. The goal of these experiments, however, was to discover potential problems that could be life-threatening if isolated lung perfusion with TNF were used in humans. When there was incomplete isolation, either during the perfusion or at its completion, severe systemic toxicity led to life-threatening complications [4]. Although no animal model system can precisely define the human tolerance to any drug, the perfusion method using standard cardiopulmonary bypass equipment and cannulas lent itself readily for adaptation to human trials.
The purpose of the phase I trial reported here was to evaluate the single lung and systemic toxicity, and the possible therapeutic efficacy of hyperthermic single-lung isolation perfusion (ILuP) with TNF and interferon- in patients with unresectable cancer limited to the lung(s). We also assessed the technical aspects of the surgical procedure, including hemodynamic changes associated with single-lung perfusion, the completeness of the isolation, and the methodology for monitoring pulmonary to systemic leak rates.
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Material and Methods |
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The clinical and functional evaluation included complete history and physical examination, routine blood work, and chest roentgenogram; computed tomography of the chest, head, and abdomen; and radionuclide bone scan. Pulmonary function testing, arterial blood gas determination, and quantitative ventilation-perfusion scanning were performed. A forced expiratory volume in 1 second of less than 1 L or a maximal voluntary ventilation of less than 35% were exclusion criteria, as was an arterial blood gas determination on room air revealing a partial pressure of carbon dioxide greater than 48 mm Hg or a partial pressure of oxygen tension less than 55 mm Hg. Patients with a history of coronary artery disease, previous transmural myocardial infarction, or congestive heart failure had full cardiac evaluation, including stress nuclear angiograms as deemed necessary.
Patient Population
From December 1992 to November 1994, 20 patients were registered for the phase I trial, and all were prepared (see later) and explored for lung perfusion. Of these, 5 patients did not receive lung perfusion (three resections, one procedure aborted for mechanical reasons, and one aborted because of extraparenchymal, pleural involvement). Sixteen lung perfusions (six left, ten right) were performed in the remaining 15 patients (1 patient had bilateral, staged perfusions). The mean age was 39 years (range, 24 to 59 years), and there were 8 men and 7 women. Histologic categories of the pulmonary metastases were soft-tissue sarcoma (5 patients), melanoma (5), Ewing's sarcoma (2), adenoid cystic carcinoma (1), renal cell carcinoma (1), and colon cancer (1). Fourteen of the 15 patients had prior systemic therapy (8, chemotherapy; 6, immunotherapy). All patients were essentially asymptomatic with regard to pulmonary symptoms, and preoperative forced expiratory volume in 1 second and forced vital capacity were both 95% of predicted values (3.2 ± 0.24 L/min and 4.2 ± 0.34 L, respectively).
Trial Schema
The doses of human recombinant TNF (kindly supplied by Knoll Pharmaceutical, Whippany, NJ) proposed in this protocol were based on the maximally tolerated dose of TNF given systemically in humans, the dose of TNF used in isolated limb perfusion protocols, and the dose of TNF tolerated in preclinical isolated lung perfusions in pigs. The dose of TNF evaluated at each treatment level, in cohorts of three patients, was not based on body weight or body surface area because for each patient, the active drug concentration was determined by the dilution of the TNF in the prime volume of the perfusion circuit. The initial TNF dose was 0.3 mg, which is 2- to 3-fold lower than the maximally tolerated dose given by systemic intravenous bolus injection [2], 8 times lower than the dose tolerated in isolated lung perfusions in pigs in preclinical studies, and 13 times lower than the dose of TNF used clinically in isolated limb perfusions. As mandated by the Institutional Review Board, the initial 2 patients were treated with TNF and interferon under normothermic conditions. In the original protocol, patients would then be treated with moderate hyperthermia, and dose escalation would be performed in cohorts of 3 patients each to 1.0, 3.0, and 6.0 µg of TNF. However, after completion of the 0.3-mg cohort, an addendum to the protocol was approved by the Institutional Review Board requesting permission to treat at least 1 patient at an intermediate level of 0.6 mg with hyperthermia.
Toxicity Recording
If grade III or IV major organ toxicity occurred at any dose in any individual and was not reversible within 24 hours, as many as 5 patients were to be treated at that dose level to determine the degree of toxicity at that dose. Pulmonary toxicity due to vascular manipulation of the lung that occurred within 7 days of the procedure and that was reversible was excluded from the definition of dose-limiting toxicity. However, pulmonary toxicity (grade III/IV) that was not reversible within 7 days was considered dose limiting. Before advancing to a new dose level, at least 1 week had elapsed from the previous perfusion.
Preparation and Technique for Single-Lung Isolation Perfusion
Patients received 0.2 mg of recombinant interferon- subcutaneously on each of the 2 days before the operation, and a Swan-Ganz catheter was placed in the pulmonary artery contralateral to the ILuP. The incision used was a standard posterolateral thoracotomy. Once the chest was opened, the position of the Swan-Ganz catheter was confirmed by palpation to be in the lung opposite the tumor, or else the catheter was manipulated into that position. The pericardium was opened, and a complete dissection of the posterior mediastinum was performed by ligating all possible systemic-pulmonary collaterals. The main pulmonary artery was dissected free so that it could be encircled with a vascular tape. A Rommel occluder was placed around the main bronchus for occlusion of the bronchial arteries during the perfusion. Two pursestring sutures of 5-0 Prolene (Ethicon, Somerville, NJ) were placed in the pulmonary artery, one at the base of the first branch to the upper lobe, and the other just distal in the continuation of the main artery. The superior and inferior pulmonary veins were isolated either intra- or extrapericardially. If there was involvement of the pulmonary artery or either pulmonary vein with tumor, such that pursestring sutures could not be safely placed, or if the atrial side of the veins could not be clamped with the appropriate vascular clamp or Rommel tourniquet for pulmonary systemic isolation, the case was terminated. The patient was given systemic heparin, 200 U/kg, before pulmonary artery and pulmonary vein occlusion with vascular clamps. For perfusions 1 to 5, one large, metal, curved DLP (Grand Rapids, MI) cannula (16 to 24F) was placed in the pulmonary artery. The technique was changed in perfusions 6 to 16, in which an appropriate-sized arterial cannula was placed in the first branch to the upper lobe (usually a 10 to 12F DLP metal curved cannula) and in the main pulmonary artery (14F) and secured to the extracorporeal circuit. The superior and inferior pulmonary veins were then cannulated individually using 14 to 16F DLP metal curved cannulas and secured to the extracorporeal circuit to drain into the venous reservoir. Temperature probes were secured to the upper and lower lobes.
The Isolated Perfusion Circuit and Leak Detection
The extracorporeal circuit, which is analogous to the circuit used in cardiac procedures, consisted of a roller pump, membrane oxygenator, and heat exchanger. The perfusate was a balanced salt solution (1,000 mL) prime. Flow rates were determined by the perfusion pressure, which was kept at levels compatible with physiologic pulmonary artery pressures (<20 to 30 mm Hg). Perfusate temperature was initially heated to 42°C using a Hemotherm cooler/heater, model 400 (Cincinnati SubZero Products, Cincinnati, OH), and lung temperature was monitored by 22-gauge thermistor probes placed in the lung parenchyma. The target tissue temperature for the perfusion was between 38° and 39.5°C. Early in the protocol, warm laparotomy pads were placed on the surface of the lung for additional thermal effects (perfusions 2 to 5).
After establishing a stable baseline, we injected 20 µCi of 131I human albumin into the systemic circuit, and a 500-µL aliquot of blood was counted in a gamma counter. Then 200 µCi of 131I human albumin was injected into the perfusion circuit. An aliquot of blood (500 µL) from the circuit was then removed and counted in a gamma counter for 1 minute, simultaneously with the removal of 500 µL of blood from the systemic circulation from the arterial line. The ratio of these counts represented a first-order approximation of the degree of leak rate. If there was greater than a 1% leak for 10 minutes, adjustments were made to identify the source of the leak before administering TNF. When the leak rate was less than 1% for 10 minutes and the tissue temperature had reached 38°C, the interferon and TNF were given as slow injections into the pulmonary artery line over a period of one complete circulation of the perfusate to allow adequate mixing. Perfusion with interferon- and TNF continued for 90 minutes. Blood samples were taken from the systemic circulation and the perfusion circuit at 0, 15, 30, 45, 60, and 90 minutes to assay for TNF levels. Random lung biopsy specimens were taken during bypass, before TNF, 45 minutes after TNF delivery, and 30 minutes off bypass. At the completion of the perfusion, the lung was flushed with 2.0 L of saline and 1 L of Hespan solution (Du Pont, Wilmington, DE). Samples during the washout period were taken from the venous return line to assess whether the volume of washout was adequate. The cannulas were removed and the vessels were closed only after minimal radioactivity was noted in the pulmonary washout samples.
Postoperative Care and Follow-Up
Postoperatively, the patients were monitored in the intensive care unit, primarily to evaluate systemic toxicity due to TNF. If needed, extra fluids, dopamine, and possibly phenylephrine hydrochloride were used to treat hypotension after the TNF ILuP. Pulmonary complications such as pulmonary edema and adult respiratory distress syndrome were treated with standard intensive care unit techniques, including positive-pressure ventilation, positive end-expiratory pressure, and high inspired oxygen fraction as needed. Research blood samples were drawn for measurement of cytokine levels.
All perfused patients were followed up at monthly intervals after the procedure with complete history and physical examination, blood work, chest roentgenogram, and repeat chest computed tomography. Pulmonary function testing and quantitative ventilation-perfusion scanning were repeated. A response to therapy was graded as a partial response only if the sum of the products of the perpendicular diameters of all lesions had decreased by 50% from measurements before perfusion. Decreases of 25% to 50% were considered marginal responses, and if any lesion increased or new lesions appeared while other lesions were decreasing, it was termed a mixed response.
Circuit and Systemic Tumor Necrosis Factor Determinations
Quantitative determination of human TNF- was performed using a commercially available enzyme-linked immunoassay (Quantikine; R & D Systems, Minneapolis, MN). Samples of the perfusate as well as the patients' serum were collected before perfusion, every 15 minutes during perfusion, and during the washout period. Serum samples were obtained every hour for 6 hours after perfusion and then every 24 hours for 2 days.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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lists the hemodynamic changes associated with TNF ILuP for all 16 perfusions. There were no differences seen between the groups receiving differing doses of TNF. In general, the 90-minute perfusion period was accompanied by a mild elevation of heart rate and cardiac output, without significant changes in filling pressures. After the initial increase in pulmonary artery systolic pressure with clamping, the pulmonary artery pressure remained the same until declamping, at which time it returned to pre-ILuP levels. There was a trend toward decreased mean systemic blood pressure during the perfusion. Cardiac output and oxygen extraction were unchanged during the procedure. Arterial blood gases were equivalent before and after perfusion (partial pressure of oxygen 326 ± 37 mm Hg, partial pressure of carbon dioxide 35 ± 2 mm Hg, pH 7.4 ± 0; versus partial pressure of oxygen 385 ± 29 mm Hg, partial pressure of carbon dioxide 36 ± 1 mm Hg, and pH 7.4 ± 0, respectively), and during the perfusion, arterial oxygenation was greater than 400 mm Hg.
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The highest leak rate of 10% was recorded in perfusion 4, which also achieved temperatures higher than the rest of the perfusions. For the majority of the perfusions, the ``radioactive'' leak rate was 0%, and this was confirmed by examination of the systemic TNF levels by enzyme-linked immunosorbent assay (see later).
A mild bronchorrhea coming from the perfused side was noted during the majority of the perfusions, but abated in the early postoperative period. Analysis of these secretions revealed them to be predominantly neutrophils. No consistent changes were seen in the color or consistency of the nodules visualized on the surface of the lung after the perfusion, and at the termination of bypass and unclamping, all patients had a minimal decrease in systolic blood pressure, which was easily resuscitated with fluids. No abnormal clotting problems or hemodynamic changes were noted with administration of the protamine for heparin reversal.
Toxicity and Course in the Hospital
All patients except in perfusion 8 had the endotracheal tube removed either in the operating room or within 24 hours of the procedure. The patient undergoing perfusion 8, despite fulfilling the eligibility criteria, had a 2 pack-per-day smoking history, multiple large metastases, and multiple large parenchymal lung cysts, possibly related to either his smoking or preoperative chemotherapy for his Ewing's sarcoma. This patient's course was complicated by the development of hepatitis A and pancreatitis, necessitating an intensive care unit stay of 17 days and a total hospital course of 34 days. At no time did he exhibit TNF-related complications (ie, hypotension, fever, renal dysfunction, thrombocytopenia, or leukopenia), and his peak serum TNF levels were below the limits of detection of the enzyme-linked immunosorbent assay. He recovered completely.
One patient (perfusion 4), as mentioned earlier, exhibited the sequelae of a TNF leak. He was originally extubated in the operating room, but evidence of TNF toxicity developed with: (1) decreased blood pressure requiring phenylephrine, (2) transient rise in the creatinine from 1.5 to 1.9 mg/dL, and (3) pulmonary insufficiency with bilateral infiltrates and neutrophilic bronchorrhea. This symptom complex may have been amplified by excessive hyperthermia to the lung (peak of 45.3°C). Nevertheless, after reintubation, his pulmonary toxicity was reversed in 6 days and he was discharged on the 11th postoperative day. His systemic levels of TNF were the highest recorded in the series (see later).
In the remainder of the patients at any dose of TNF, the postoperative convalescence was similar to that with an exploratory thoracotomy. The length of stay in the intensive care unit for all 16 perfusions was 4 ± 1 days (range, 2 to 17 days), of which 3 days were obligatory for epidural catheter maintenance. Chest tubes were removed 2.6 ± 0.3 days (range, 2 to 5 days) after the procedure despite the lung biopsies. On the night of operation, the majority of patients had a temperature of 39°C; however, the maximum temperature decreased from 38.4° ± 0.1°C on the first postoperative day to 37.3° ± 0.2°C by the fifth postoperative day. There were no unexpected findings in the serum chemistries, hematologic indices, or clotting profiles in the 14 uncomplicated perfusions.
Evidence of immediate perfusion effects on the lung were seen on the first postperfusion roentgenogram, which revealed asymmetric infiltrates, swelling of the metastatic nodules, and minimal effusion. These infiltrates resolved with induced diuresis by the time of discharge, which was at 9 ± 2 days (range, 5 to 34 days) for all patients.
Tumor Necrosis Factor Levels
Figures 1 and 2 demonstrate the levels of TNF attainable in the pump circuit as well as the systemic levels during and after ILuP. Progressive increases in TNF levels in the prime were recorded as the dose was escalated. Despite the high levels, the washout at the conclusion of the perfusion was very efficient, minimizing systemic exposure to TNF upon release of the pulmonary veins. The only group of perfusions that had evidence of systemic TNF during the perfusion was the 0.3-mg dose, which included perfusion 4, as discussed earlier.
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) revealed a 90% decrease in the size of this metastasis, but he did not reach the criteria for a partial response.
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Three partial responses, all seen within 8 weeks of the perfusion, occurred in 1 patient each with melanoma (0.3 mg TNF), adenoid cystic carcinoma of the breast (1.0 mg TNF) (Fig 4), and renal cell cancer (6.0 mg TNF). These responses were short-lived, however, with regrowth or development of new nodules on the perfused side within 7, 6, and 9 months after the procedure, respectively. In all patients, the nonperfused side exhibited either stable disease (3) or progressive disease by 8 weeks after ILuP.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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, and melphalan in isolated limb perfusions for extremity melanomas or sarcomas [13, 14]. For each of these two histologic entities, 100% overall response rates and greater than 90% complete response rates have been reported in patients from several European groups. It is important to note, however, that these series combined TNF with cytotoxic chemotherapy. We believed that as an initial phase I trial, the tolerance to the cytokines given in this fashion should be investigated before adding any other agent.
The theoretic basis for this use of TNF with interferon- and hyperthermia for regional therapy is supported by several preclinical observations. Tumor necrosis factor clearly has substantial toxicity in human trials at the concentrations that can cause a response, but the antitumor effect of TNF is very rapid, with histologic changes in the tumor occurring as early as 30 minutes [3]. This short time of action could obviate the major disadvantage of isolated perfusion, which is the very limited exposure of the tumor to the active agent. Moreover, the combination of TNF with interferon- and hyperthermia has shown augmented cytotoxicity compared with TNF administration alone [15, 16], and hyperthermia augments the activity of TNF both in vitro and in vivo [17].
How the normal lung would tolerate these high doses of TNF was unknown, but it has been documented that a major component of the TNF toxicity-besides reversible cardiac, renal, and hepatic dysfunction-has been a pulmonary response similar to that seen in endotoxemia. Intravenous administration of TNF injures pulmonary arterioles, venules, and capillaries, resulting in alveolar epithelial injury, alveolar exudation, alveolar neutrophil accumulation, and capillary endothelial injury [18–20]. Changes compatible with pulmonary edema and adult respiratory distress syndrome have been described with large-dose intravenous administration of TNF to rats. Thrombosis of small and medium-size pulmonary blood vessels occurs, and wet lung weight ratios are increased with time. There are increases in pulmonary vascular permeability as well as vasoconstriction, probably mediated through platelet-activating factor and thromboxane.
This trial demonstrates that it is feasible to deliver naturally occurring cytokines to the lung in doses that would probably result in irreversible multiorgan failure if distributed systemically. Few hemodynamic changes are seen during the perfusion, and if there is no leak of the perfusate, the patient should recover from the procedure as if he or she simply had an exploratory thoracotomy. With regard to the technique of the perfusion, it is impossible to comment whether the system of perfusion that is described in this phase I trial-ie, a continuous closed circuit for a given length of time-has any advantage over a first-pass, low-pressure, isolated perfusion as described by Weksler and associates [12]. We used a standard cardiopulmonary bypass circuit, which allowed easy control of flow rates and perfusion pressure and optimal temperature control. At least at our institution, this requires a fully trained perfusionist and may not be as cost-effective as first-pass techniques. These perfusions were performed with the lung partially expanded because we believed that this would allow the greatest flow to the periphery of the lung, where the majority of pulmonary metastases are found. By monitoring the temperature of the lung and noting the ease with which the hyperthermic conditions could be sustained, we believe that we achieved as uniform a perfusion of the organ as possible. The importance of perfusion pressure in distributing perfusate is largely undetermined, but previous studies have shown that greater delivery is achieved with higher perfusion pressures, and to minimize vasoconstriction, flow was maintained at physiologic pressures and high oxygen tensions.
The importance of instantaneous monitoring for leak when using these agents cannot be overemphasized. Small leaks at small doses can lead to toxicity, as demonstrated by perfusion 4. The only way to prevent such leaks is a compulsive dissection of the posterior mediastinum with lysis of all adhesions to the chest wall, division of vagal branches to the lung in the subcarinal region, division of the inferior pulmonary ligament, and pericardiotomy at the hilum. There have been no leaks documented, either in the operating room or postoperatively, by the immunoassay in the patients having such an isolation. The ability to free the lung completely from the chest wall, diaphragm, and mediastinum could also have implications on eligibility for ILuP. Patients who have had previous thoracotomy or median sternotomy for metastasis resection may not be candidates for this procedure because the dissection may cause many small, peripheral parenchymal bronchopleural fistulas, which will not allow the lung to retain the perfusate.
Despite the high flows and the high concentrations of TNF, the perfused lung tolerated the treatment well. By treating the radiographic findings as a lung contusion, ie, with induced diuresis and fluid restriction, we quickly reversed the radiographic picture, and for the majority of patients, oxygen requirements lasted only 3 to 4 days. At least with the follow-up radiographic, nuclear medicine, and physical examinations, we were not able to detect any functional decrease caused by the perfusion. Indeed, 11 patients who had progression of their metastases after ILuP were treated under the auspices of other phase I trials or salvage chemotherapy.
The responses seen in this study, although fulfilling the criteria for a partial response, were disappointingly low and short lived. Moreover, there does not seem to be a dose-dependent correlation with these responses. We have no data regarding the vascularity of these lesions or the TNF receptor status of the metastases, and both of these factors may be crucial for TNF-mediated tumor responses. There did not seem to be a size or location predilection for responses, in that both large and small nodules as well as central, peripheral, upper-zone, and lower-zone nodules had short-term regression.
Only 1 patient (with pulmonary metastases from melanoma) had sequential perfusions after achieving a stable response, but she progressed bilaterally shortly after her second perfusion. In reflecting on future considerations for the use of this therapy, one must explore, as Johnston did, the ability for simultaneous perfusion of both lungs using two circuits, ie, total cardiopulmonary bypass and a dedicated lung circuit. This would be more relevant for the majority of patients who present with bilateral metastases.
Tumor necrosis factor will probably be only one component of future regimens for ILuP, in combination with standard chemotherapeutic agents such as adriamycin, melphalan, cisplatin, or 5-fluorouracil, and the combination used may be dependent on histologic characteristics. It will be necessary, however, to document responses using a given cocktail for a given histologic process, and such studies will have to be performed as part of a cooperative group or international study.
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Pass, Thoracic Oncology Section, NCI/NIH, Bldg 10, Rm 2B07, Bethesda, MD 20892.
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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in combination with IFN-gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 1992;10:52–60.[Abstract]
in combination with interferon-gamma and melphalan in isolation perfusion. World J Surg 1992;16:234–40.[Medline]
. Circ Res 1990;67:68–77. depends on the route of administration. Diagn Microbiol Infect Dis 1990;13:397–404.[Medline]Related Article
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D. S. Schrump, S. Zhai, D. M. Nguyen, T. S. Weiser, B. A. Fisher, R. E. Terrill, B. M. Flynn, P. H. Duray, and W. D. Figg Pharmacokinetics of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques J. Thorac. Cardiovasc. Surg., April 1, 2002; 123(4): 686 - 694. [Abstract] [Full Text] [PDF]
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T. Tanaka, Y. Kaneda, T.-S. Li, T. Matsuoka, N. Zempo, and K. Esato Digitonin enhances the antitumor effect of cisplatin during isolated lung perfusion Ann. Thorac. Surg., October 1, 2001; 72(4): 1173 - 1178. [Abstract] [Full Text] [PDF]
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H. R. Alexander, S. K. Libutti, D. L. Bartlett, M. Puhlmann, D. L. Fraker, and L. C. Bachenheimer A Phase I-II Study of Isolated Hepatic Perfusion Using Melphalan with or without Tumor Necrosis Factor for Patients with Ocular Melanoma Metastatic to Liver Clin. Cancer Res., August 1, 2000; 6(8): 3062 - 3070. [Abstract] [Full Text]
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