Ann Thorac Surg 1996;61:969-972
© 1996 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Isolated Lung Perfusion With Doxorubicin Reduces Cardiac and Host Toxicities Associated With Systemic Administration
Bruce Ng, MS,
Steven N. Hochwald, MD,
Michael E. Burt, MDPhD
Thoracic Oncology Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York
Accepted for publication November 3, 1995.
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Abstract
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Background. For patients with malignant neoplasms metastatic to lung, systemic chemotherapy in doses high enough to achieve significant survival improvement is often limited by host toxicity. Isolated single-lung perfusion offers the advantage of delivering high-dose organ-specific chemotherapy while minimizing systemic toxicity. We compared the cardiac and systemic toxicities associated with intravenous administration versus isolated single-lung perfusion with doxorubicin.
Methods. Thirty-three male Fischer 344 rats weighing 275 to 300 g were randomized into three groups: normal control rats (n = 11), intravenous doxorubicin (7 mg/kg) (n = 11), and isolated left lung perfusion with 320 µg doxorubicin/mL (n = 11). Animals undergoing isolated single-lung perfusion were anesthetized with pentobarbital, intubated, and ventilated, and then had left thoracotomy with cannulation of the pulmonary artery and a pulmonary venotomy; pulmonary artery and vein were clamped proximally. Animals were perfused for 10 minutes at a rate of 0.5 mL/min, followed by a 5 minute rinse with buffered hespan solution. Arteriotomy and venotomy were repaired and circulation was restored. Daily weights were recorded. On day 24, cardiac output was determined in all groups by injection of radiolabeled chromium 51 microspheres.
Results. Animals treated with 7 mg/kg intravenous doxorubicin had a significant weight loss as compared with those treated with isolated lung perfusion (209.2 ± 29.9 g versus 302.3 ± 10.1 g; p < 0.01). Animals treated with isolated single-lung perfusion, after recovering from surgical stress, resumed normal growth pattern. Significant cardiac toxicities were seen in intravenously treated animals; cardiac index (27.4 ± 6.9 versus 39.4 +/6.3 mL•min-1•100 g body weight-1) and heart weights (0.56 ± 0.04 versus 0.88 ± 0.09 g) were reduced in the intravenously treated group as compared with the group treated with isolated single-lung perfusion. In addition, severe hematologic toxicities are associated with intravenous doxorubicin administration.
Conclusions. Intravenous administration of doxorubicin is associated with severe host toxicities, which include weight loss, decreased cardiac function, and hematologic toxicity. Isolated lung perfusion with high-dose doxorubicin is well tolerated and is associated with minimal host toxicity.
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Introduction
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Soft-tissue sarcomas metastasize almost exclusively to the lungs [1]. Current surgical therapy yields a 5year survival of approximately 25% [2, 3]. Systemic chemotherapy has not been effective in prolonging survival or rendering patients disease free [3]. Doxorubicin has been used either as single-drug treatment or as part of combination chemotherapy in the treatment of many malignant neoplasms, including sarcomas [4]. One of the major complications of prolonged doxorubicin treatment is congestive heart failure resulting from degenerative cardiomyopathy [5]. Reducing cardiac toxicity associated with systemic doxorubicin treatment is of major clinical importance. Systemic chemotherapy in doses high enough to achieve significant survival improvement is often limited by host toxicity. Recently, we have developed an isolated single lung perfusion (ILP) model in the rat to study regional high-dose chemotherapy delivery. It is effective in increasing lung tissue doxorubicin levels as compared with systemic administration, minimizing systemic doxorubicin uptake [6] and eradicating experimental pulmonary sarcoma metastases in a rat model [7]. This study was designed to compare the functional cardiac and host toxicities of doxorubicin by ILP compared with systemic administration in the rat.
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Material and Methods
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Thirty-three male Fischer F344 rats (Charles Rivers, Kingston, NY) weighing 275 to 300 g were used in this study. Animals were treated in accordance with the Animal Welfare Act and the National Institutes of Health ``Guide for the Care and Use of Laboratory Animals'' (NIH publication 85-23, revised 1985). Experiments were approved by the Institutional Animal Care and Use Committee, Memorial Sloan-Kettering Cancer Center. Animals were kept in a temperature-controlled room with a 12-hour light/dark cycle. They were allowed access to standard laboratory rat food (Purina Rat Chow, St. Louis, MO) and water ad libitum.
Study Design
Thirty-three Fischer 344 rats were randomized into three groups; normal rats (n = 11), rats receiving 7 mg/kg doxorubicin intravenously (IV) (n = 11), and rats receiving 320 µg/mL doxorubicin via ILP (n = 11). The IV group received doxorubicin IV via direct external jugular injection. The ILP group underwent ILP as previously described [6]. Briefly, animals were anesthetized with 50 mg/kg pentobarbital intraperitoneally. Rats were then intubated with a 16F intravenous catheter over a guidewire. Ventilation was maintained with a volume ventilator (Rodent Ventilator model 683; Harvard Apparatus, South Natick, MA) with 100% O2 and a tidal volume of 10 mL/kg at 80 strokes per minute. Anesthesia was supplemented with 0.5% halothane. Left thoracotomy was performed through the fourth intercostal space, and the pulmonary artery and vein were dissected free. A PE-10 catheter (Clay-Adams, Parsippany, NJ) was placed in the pulmonary artery. The pulmonary artery and vein were cross-clamped proximally, preventing leakage of perfusate into the systemic circulation. The left lung was then perfused for 15 minutes at a rate of 0.5 mL/min, and the pulmonary vein effluent was collected through a venotomy. The left lung was perfused with doxorubicin for the first 10 minutes, followed by 5 minutes of hespan washout. At the end of the perfusion, the pulmonary artery and vein were repaired with 9-0 nylon suture, and the pulmonary circulation was restored. The chest was closed in three layers, and the animals were extubated. Daily weights of all animals were recorded for 24 days, and cardiac output was then measured with the radiolabeled microsphere method.
Cardiac Output Measurement
The flow measurements employed radiolabeled microspheres infused into the left ventricle [8]. Nentrac microspheres (New England Nuclear, Boston, MA) that were 15.5 ± 0.1 µm and labeled with chromium 51 were used in this study. The microspheres were suspended in 0.9% saline and 0.01% Tween 80 solution. To prevent aggregation of the spheres, solution containing microspheres was sonicated and vigorously vortexed before injection. The right carotid and left femoral arteries were cannulated with PE-10 catheter welded onto a PE-50 catheter (Clay-Adams). The right carotid line was positioned in the left ventricle. Between 30,000 and 50,000 microspheres were injected into the left ventricle in 0.4 mL over 20 seconds. A reference blood sample was drawn from the femoral artery by a syringe withdrawal pump for 1 minute at a rate of 0.5 mL/min beginning 10 seconds before microsphere injection. Rats were sacrificed 10 minutes after the microsphere injection by exsanguination. Position of carotid cannula in the left ventricle was confirmed. Kidneys and heart were excised and weighed. To ensure uniform distribution of microspheres, radioactivities in both kidneys were counted. Samples were placed in plastic vials and counted on a CompuGamma gamma counter (model 1282; Pharmacia, Turku, Finland). Count rates were corrected for natural background and counter dead time. Cardiac output was calculated from the radioactivity in the reference sample and the total activity after corrections for the residual activity. Cardiac output was determined as follows: cardiac output equals reference flow rate times total injected activity divided by reference activity. Cardiac index was then normalized for body weight and expressed in milliliters per minute per 100 grams of body weight.
Hematocrit and hemoglobin concentrations were determined using an Ortho ELT 8 automated cell counter (Ortho Industries, Braintree, MA).
Statistical Analysis
Data are presented as mean ± standard deviation. Analysis was performed using analysis of variance and where significance was found, individual groups were compared by Student's t test. Significance is defined as p less than or equal to 0.05.
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Results
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Daily Weights
Animals that underwent ILP with 320 µg/mL doxorubicin lost weight for 3 postoperative days and then resumed normal growth pattern. Animals that received IV doxorubicin at a dose of 7 mg/kg failed to thrive throughout the study period. Body weight of the IV doxorubicin group on day 24 was significantly decreased as compared with the ILP doxorubicin group and the normal control group (Fig 1
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Fig 1. . Daily weights of untreated normal controls (CTL) and animals that were treated with isolated lung perfusion (ILP) or intravenous doxorubicin (IV). The IV group has a significant decrease in body weight throughout the study period as compared with the CTL and ILP groups.
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Cardiac Output
In preliminary studies, arterial pressure was not affected by infusion of microspheres. Bilateral symmetry of microsphere distribution to kidneys was consistently demonstrated. Difference in activity per gram of tissue between the two kidneys did not exceed 10%, indicating good mixing of the microspheres in the ventricle. Cardiac index was significantly reduced in the group that received 7 mg/kg doxorubicin IV as compared with the ILP doxorubicin group and the normal control group (Table 1). In addition, heart weights were significantly decreased in the IV doxorubicin group as compared with the ILP doxorubicin group and the normal control group.
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Table 1. . Heart Weights and Cardiac Index for Untreated Animals and Animals After Isolated Lung Perfusion or Intravenous Administration of Doxorubicin
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Hematologic Toxicities
Hematocrit and hemoglobin were significantly decreased in the IV doxorubicin group (14.3% ± 2.7% and 6.3 ± 0.9 g/dL, respectively) as compared with the ILP doxorubicin group (39.6% ± 1.2% and 13.2 ± 0.4 g/dL) and the normal control group (41.1% ± 0.9% and 13.3 ± 0.5 g/dL) (Table 2).
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Comment
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Doxorubicin is one of the most effective single agents in the treatment of sarcoma [4] but has not affected survival in most patients with metastatic sarcoma to the lungs [3]. Systemic doxorubicin administration is associated with a prevalence of dose-limiting side effects, mainly cardiomyopathy [5], which precludes high-dose, effective chemotherapy for the treatment of metastatic sarcoma of the lung. It is likely that doxorubicin displays a dose-response relationship [9], and frequently, this high systemic toxicity prohibits the administration of the most effective dose [5, 9]. Doxorubicin-induced cardiotoxicity was a source of serious morbidity in many of the adjuvant trials. Thus, the role of chemotherapy as an adjuvant to local therapy for patients with soft-tissue sarcoma remains investigational.
Isolated lung perfusion is an attractive way of delivering high-dose chemotherapy [10, 11]. Tissue can be targeted with a high concentration of doxorubicin with minimal systemic toxicity [6, 12]. In our previous studies, we have demonstrated the effectiveness of ILP in various experimental tumor models in the rat [7, 13, 14]. This study was designed to further evaluate the functional toxicities associated with ILP as compared with systemic administration. If safety and antineoplastic efficacy can be demonstrated, a strong argument can be made for human trials in patients in whom standard current antineoplastic therapy has failed.
In the present study, we demonstrated that ILP with doxorubicin (320 µg/mL) is safe, and minimal long-term functional toxicities were seen. Three hundred twenty micrograms per milliliter delivered via ILP for 10 minutes is the maximal tolerated dose and equals approximately 5.1 mg/kg, as compared with the maximal tolerated dose of 7 mg/kg IV [7]. On the other hand, animals that received IV administration of doxorubicin at a dose of 7 mg/kg (LD10, unpublished data) had significant morbidity. Cardiac function and heart mass were significantly reduced by 30% as compared with groups treated by ILP. Hematologic toxicities associated with systemic administration of doxorubicin are severe. Furthermore, the animals tolerated ILP of doxorubicin much better that they did systemic treatment; animals maintained normal growth after ILP, whereas animals that received systemic injections of doxorubicin failed to gain weight.
In summary, we have demonstrated previously that ILP of doxorubicin is pharmacokinetically superior systemic administration [6]. This study demonstrates that ILP with doxorubicin significantly reduces the major morbidity associated with systemic administration of doxorubicin. Even with a tenfold increase in lung doxorubicin concentration after ILP [6], there is minimal long-term cardiotoxicity. In addition, major systemic treatment-associated morbidity such as weight loss and hematologic toxicity can be satisfactorily reduced by ILP. This study further reinforces the viability of ILP as an experimental treatment alternative for pulmonary metastasis.
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Footnotes
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Address reprint requests to Dr Burt, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.
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References
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Abstract
Introduction
