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Ann Thorac Surg 1997;64:181-184
© 1997 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Isolated Lung Perfusion With Doxorubicin Prolongs Survival in a Rodent Model of Pulmonary Metastases

Amir Abolhoda, MD, Ari Brooks, MD, Sumihiko Nawata, MD, Yoshikazu Kaneda, MD, Huiming Cheng, MS, Michael E. Burt, MD, PhD

Thoracic Oncology Laboratory/Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York


   Abstract
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Introduction
 Material and Methods
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Background. We developed a rodent model of unilateral pulmonary metastases to evaluate long-term survival after isolated lung perfusion with doxorubicin.

Methods. In the model development study, on day 0, two groups of F344 rats (n = 15) underwent transient right pulmonary artery occlusion for either 5 or 10 minutes at the time of intravenous injection of methylcholantrene-induced sarcoma cells. On day 14, all animals were sacrificed and lung nodules counted. In the survival study, on day 0, 21 rats received intravenous injection of sarcoma cells with concomitant 10-minute right pulmonary artery occlusion. On day 7, eight rats underwent left isolated lung perfusion with doxorubicin (6.4 mg/kg); five rats underwent perfusion with buffered Hespan; six untreated rats were studied as controls.

Results. Ten of fifteen animals (67%) in the model study with 5-minute pulmonary artery occlusion had right-sided tumor nodules. Ten-minute occlusion resulted in a tumor-free right lung in all animals. In the survival study, all animals in the Hespan and control groups died of massive tumor replacement of the left lung, with median survival times of 20 and 18 days, respectively. The median survival time of 36 days for the animals undergoing isolated lung perfusion with doxorubicin was significantly longer (p < 0.00001). The left lung of two of the doxorubicin perfused rats was tumor-free at 6 weeks.

Conclusions. Isolated lung perfusion with doxorubicin results in a durable response and prolongs survival in the treatment of experimental sarcoma pulmonary metastases.


   Introduction
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Material and Methods
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Complete resection of pulmonary metastases remains the mainstay of treatment in patients with soft tissue sarcoma metastases to the lung. However, there is an approximately 70% failure rate after pulmonary metastasectomy [1–3], with the lungs being the most frequent and commonly the only site of tumor recurrence [4, 5]. Recurrence is presumably caused by subclinical micrometastases present at the time of the initial resection of the metastatic nodules [4]. Neoadjuvant or adjuvant systemic chemotherapy have had disappointing results in treatment of disseminated sarcoma, with virtually no impact on long-term survival [6, 7]. Isolated lung perfusion (ILP) has been developed as a technique for delivering high-dose organ-specific chemotherapy, the primary goal of which is to target and treat the pulmonary micrometastatic disease. Previous reports from our laboratory have demonstrated the safety and the superior pharmacokinetics of cytotoxic drug delivery by ILP [8, 9]. Furthermore, we have shown the ability of left ILP with doxorubicin at a concentration of 320 µg/mL (~6.4 mg/kg) to completely eradicate metastatic nodules in the perfused lungs of 9 of 10 rats with bilateral sarcoma pulmonary metastases [10]. However, our existing tumor model is of limited value for evaluation of durability of response and long-term survival after isolated single lung chemoperfusions. The perfused animals succumb approximately 2 to 3 weeks after perfusion to uncontrolled progression of disease in the untreated right lung. The objectives of the present study were (1) to establish a rodent model of unilateral sarcoma pulmonary metastases and (2) to investigate long-term survival after a one-time isolated single lung perfusion with doxorubicin in this tumor model.


   Material and Methods
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Animal Care
Male F344 rats (Charles River Laboratories, Kingston, NY), weighing 225 to 275 grams, were used in all experiments. Animals were treated in accordance with the Animal Welfare Act and the "Guide for the Care and Use of Laboratory Animals" (NIH Publication 86-23, revised 1985). All experiments were approved by the Institutional Animal Care and Use Committee of Memorial Sloan-Kettering Cancer Center. Animals were allowed access to standard laboratory rat food (Purina Rat Chow; Ralston Purina, St. Louis, MO) and water ad libitum. Housing was temperature controlled and provided a 12-hour light/dark cycle.

Development of a Model of Unilateral Pulmonary Metastases
OPERATIVE TECHNIQUE.
Each animal was anesthetized with intraperitoneal injection of pentobarbital 50 mg/kg and was orotracheally intubated, as previously described [11]. The animal's neck was prepared with 10% povidone-iodine solution. A right longitudinal cervical incision was performed and the external jugular vein was identified and isolated with silk ligatures. The right chest was then shaved and prepared, and the animal was connected to a volume ventilator (rodent ventilator model 683; Harvard Apparatus, South Natick, MA). A right thoracotomy incision was performed through the fourth intercostal space. The right upper lobe was covered with a moist sponge gauze and packed inferior and anterior to the chest incision to accommodate a posterior approach to the hilar structures. With the use of an operating microscope (magnification x16, OpMi-1; Carl Zeiss, Wotan, Germany), a longitudinal incision was made in the mediastinal pleura along the posterior border of the superior vena cava. The right main pulmonary artery (PA) was identified in its epibronchial course. A 3-0 silk ligature was passed around the vessel and was used to facilitate placement of an occluding microvascular clamp on the proximal right PA (Fig 1Go). At this time, the animal was repositioned to access the neck incision, while maintained on the ventilator. A single tumor cell suspension, prepared in advance, was then injected via the external jugular vein cutdown. At specified time intervals after the tumor cell injection, the PA clamp was removed, the right lung was allowed to reexpand, and the chest incision was closed in layers after placement of a 16-gauge catheter as a tube thoracostomy. The neck incision was subsequently closed and the animal was allowed to recover from anesthesia on a 37°C thermal barrier (Vetko, Model No. V-21, Denver, CO).



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  		Fig 1. . Anterior view of the right (R.) lung hilar structures showing placement of a microvascular clamp to occlude the proximal right pulmonary artery. (n. = nerve.)

 
EXPERIMENTAL DESIGN.
On day 0, 30 F344 rats were randomized into two groups of 15 animals each. All animals underwent right thoracotomy, transient right PA occlusion, and intravenous injection of 3 x 106 viable methylcholanthrene-induced (MCA) sarcoma cells through the right external jugular vein, as described above. Duration of PA occlusion was 5 minutes for group 1 and 10 minutes for group 2. On day 14, all animals were sacrificed and their lungs were stained with India ink for identification of metastatic nodules by the method of Wexler [12]. The duration of right PA occlusion necessary for complete exclusion of the tumor cells from the right lung was used in the long-term survival experiments.

Survival Experiments After Doxorubicin ILP
On day 0, 21 F344 rats were injected with 1.5 x 106 methylcholanthrene-induced sarcoma cells (ie, half of the tumor inoculum used in the model experiments) through the right external jugular vein with concomitant 10-minute right PA occlusion. This cohort of animals, with presumably unilateral pulmonary metastases, were randomized on day 7 into three groups. Eight rats underwent left ILP with doxorubicin at 6.4 mg/kg (ie, 320 µg/mL for 10 minutes at a rate of 0.5 mL/min for a 250-g rat), followed by 5-minute washout with buffered Hespan (6% hetastarch in 0.9% sodium chloride, Dupont Pharma, Wilmington, DE). Five rats underwent left ILP with buffered Hespan for 15 minutes at a rate of 0.5 mL/min. The remaining eight untreated rats were studied as controls. The end point of the study was death owing to disease. Those animals surviving more than 6 weeks after tumor injection were sacrificed and their censored survival times were used in the Kaplan-Meier calculations. In each case, an initial in situ autopsy was performed with special attention to the lungs, both chest cavities, and the abdominal viscera. Subsequently, the lungs were harvested and stained.

Isolated left lung perfusion was performed by the methods previously described [13, 14]. Briefly, after establishment of pentobarbital anesthesia and endotracheal intubation, a left thoracotomy was performed through the fourth intercostal space. With the use of the operating microscope, the left pulmonary artery and vein were identified, isolated, and occluded with microvascular clamps. An arteriotomy was performed and the artery was cannulated with a PE-10 catheter (Beckton Dickinson & Co, Parsippany, NJ) and secured in place with a 4-0 silk tie. Perfusate was instilled through this catheter. A pulmonary venotomy was created to allow egress of the effluent. Homogeneous distribution of the perfusate was confirmed by uniform blanching of the entire left lung throughout the duration of the perfusion. At the completion of the perfusion, the arteriotomy was repaired with a single 9-0 Ethilon suture (Ethicon, Somerville, NJ). The microvascular clamps were removed, point pressure was used to tamponade the bleeding from the venotomy site, and the chest incision was closed in layers after placement of a 16-gauge catheter as a chest tube.

Statistical Analysis
Survival plots were generated using the Kaplan-Meier method. Statistical comparisons between the treated and untreated groups were made using the log-rank test with survival estimated from the time of intravenous tumor injection; a p value less than 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Material and Methods
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Comment
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Model Experiments
All animals had confluent tumor infiltration of the left lung, with heavier seeding of the apex. Ten of fifteen (67%) of the animals in group 1 (5-minute right PA occlusion) had between 2 and 10 discrete right lung tumor nodules. On gross inspection, there was no evidence of right lung parenchymal injury and the PA appeared intact and patent. Two of the animals in group 2 (10-minute PA occlusion) were excluded at the time of thoracotomy based on inadvertent PA injury and, thus, the potential for tumor cell spillage into the pleural cavity. The remaining 13 rats were sacrificed 2 weeks after tumor cell injection and their right lungs were free of tumor nodules at this time. Ten-minute PA occlusion was employed in the subsequent long-term survival experiments.

Survival Experiments
All the animals in the untreated and the buffered Hespan ILP groups died as a result of massive tumor replacement of their left lungs with median survival times of 18 and 20 days, respectively. The median survival time of the doxorubicin ILP group (36 days; range, 21–43 days) was significantly longer than the controls (p < 0.00001) (Fig 2Go). Three of the rats survived for up to 43 days after tumor cell injection, two of which had tumor-free left lungs (Fig 3Go). The third animal had a centrally located tumor nodule and postobstructive atelectasis, along with a unilateral adrenal metastasis. The cause of death in two of the animals in the doxorubicin ILP group was attributed to the presence of bilateral tumor replacement of the adrenal glands and the resulting addisonian crisis (Fig 4Go). Both of these animals had residual left lung tumor nodules. The pattern of failure in the doxorubicin treatment group was progressive growth of a single dominant tumor mass extending to the parietal pleura and the chest wall. The remaining portion of the perfused lung was free of tumor nodules.



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  		Fig 2. . Survival after intravenous (i.v.) injection of methylcholanthrene-induced sarcoma cells with concomitant right PA occlusion. The animals undergoing isolated left lung perfusion with doxorubicin had significantly longer survival than the animals receiving buffered Hespan perfusion or no treatment (p < 0.00001). (BHE ILP = buffered Hespan isolated lung perfusion; DOX. ILP = doxorubicin isolated lung perfusion; No Tx. = no treatment).

 


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  		Fig 3. . Posterior view of the lungs of one control and two treatment animals. Normal lung tissue stains black; tumor stains white. (A) Lungs of an untreated rat on day 18 after tumor injection and right pulmonary artery occlusion. Right lung is free of tumor nodules. Left lung is confluently infiltrated by metastatic sarcoma. (B) Lungs of a rat that had received doxorubicin isolated lung perfusion and survived for 33 days after tumor injection. Notice the large apical lung mass and clear base representing a partial tumor response. This animal was discovered to have bilateral adrenal metastases. (C) Lungs of a doxorubicin-perfused rat 6 weeks after intravenous tumor injection. Both lungs are free of tumor.

 


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  		Fig 4. . Complete tumor replacement of right (A) and left (B) adrenal glands.

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
Isolated lung perfusion in large animals has been shown to be a feasible and safe modality for delivery of organ-specific chemotherapy [15–18]. However, lack of an implantable tumor model in these animals has hampered formulation of efficacy trials using ILP. Availability of several rodent implantable tumor cell lines has allowed us to conduct efficacy experiments using various chemotherapeutic and biological agents in our ILP model. We have primarily used the methylcholanthrene-induced sarcoma cell line for establishment of pulmonary metastases. This cell line has been extensively characterized and shown to reproducibly result in bilateral pulmonary metastases after intravenous injection [19, 20]. However, the aggressive growth characteristics of this sarcoma cell line have limited the observation period in which to evaluate long-term outcome after isolated single lung perfusion. We developed a model of unilateral sarcoma pulmonary metastases to investigate the potential survival advantage of ILP with doxorubicin.

Transient PA occlusion was used to exclude tumor inoculation of the right lung. We discovered that right PA occlusion was effective in preventing tumor cell seeding of the right lung. This observation confirmed our presumption that physical entrapment of tumor cells on first pass through the pulmonary capillary bed is the primary mechanism of tumor implantation following intravenous injection, and that systemic (ie, bronchial arterial) contribution is negligible. For the same reason, we believe that the adrenal metastases identified in the survival experiments are true secondary metastases from the primary metastatic lung implant overgrowth and eventual erosion into a tributary of the pulmonary vein rather than systemic dissemination at the time of initial intravenous tumor injection.

Our experiments demonstrate the survival advantage of ILP with doxorubicin in the treatment of experimental sarcoma pulmonary metastases. We have shown a near twofold increase in the median survival time for the animals receiving doxorubicin ILP after intravenous tumor inoculation, compared to the ILP groups receiving either no treatment or buffered Hespan. Furthermore, we observed a 25% (2/8) rate of complete durable response in the doxorubicin-perfused rats, with no evidence of intrathoracic disease up to 5 weeks after ILP. In our experience, no other single therapeutic modality has produced similar results in treatment of this aggressive pulmonary metastatic tumor model. Our tumor model is in several ways analogous to the clinical situation in which, following pulmonary metastasectomy, the patient is left with unresectable micrometastatic disease with approximately 70% chance of subsequent clinical recurrence. Our encouraging findings form an optimistic foundation for the upcoming human trials in which ILP will be used as an adjuvant therapy at the time of surgical resection of the pulmonary metastases, targeting the micrometastatic disease, with hopefully similar results.


   Footnotes
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Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 
Presented at the Poster Session of the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Feb 3–5, 1997.

Address reprint requests to Dr Burt, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.


   References
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 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Gadd MA, Casper ES, Woodruff JM, McCormack PM, Brennan MF. Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma. Ann Surg 1993;218:705–12.[Medline]
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  6. Casper ES, Gaynor JJ, Hajdu SI, et al. A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high grade extremity soft tissue sarcoma and an analysis of prognostic factors. Cancer 1991;68:1221–9.[Medline]
  7. Lanza LA, Putnam JB, Benjamin RS, Roth JA. Response to chemotherapy does not predict survival after resection of sarcomatous pulmonary metastases. Ann Thorac Surg 1991;51:219–24.[Abstract]
  8. Ng B, Hochwald SN, Burt ME. Isolated lung perfusion with doxorubicin reduces cardiac and host toxicities associated with systemic administration. Ann Thorac Surg 1996;61:969–72.[Abstract/Free Full Text]
  9. Weksler B, Ng B, Lenert JT, Burt ME. Isolated single-lung perfusion with doxorubicin is pharmacokinetically superior to intravenous injection. Ann Thorac Surg 1993;56:209–14.[Abstract]
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