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Ann Thorac Surg 2000;69:1542-1549
© 2000 The Society of Thoracic Surgeons

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Original articles: General thoracic

Isolated lung perfusion for patients with unresectable metastases from sarcoma: a phase I trial

^a Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Address reprint requests to Dr Brennan, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021
e-mail: brennanm{at}mskcc.org

	Abstract

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Background. In patients with unresectable pulmonary metastases from sarcoma, systemic chemotherapy has had limited efficacy possibly because of dose-limiting toxicities. Isolated lung perfusion is an alternative method of delivering high-dose chemotherapy to the lungs while minimizing systemic toxicities. We present the results of our Phase I trial of isolated lung perfusion with doxorubicin hydrochloride in such a group of patients.

Methods. From May 1995 to June 1997, 8 patients with unresectable metastases from sarcoma limited to the lungs underwent isolated lung perfusion with doxorubicin. A dose-escalation schedule starting at 40 mg/m² was used. Seven patients were treated with a dose of 40 mg/m² or less, and 1 patient received 80 mg/m². Blood, tumor, and normal lung samples were obtained at various time points during the operation. Patients were evaluated for cardiac, pulmonary, and other toxicities.

Results. The doxorubicin concentrations in both normal lung and tumor correlated directly with the amount of doxorubicin in the perfusate. The tumors took up less doxorubicin than the lung. All patients had minimal or undetectable systemic levels of doxorubicin at the conclusion of the perfusion. There were no cardiac or other systemic toxicities. In the 7 patients perfused with 40 mg/m² or less of doxorubicin, there was a significant decrease in the forced expiratory volume in 1 second and a trend toward a significant decrease in diffusing capacity. The patient who received 80 mg/m² underwent lung scanning postoperatively, and scans showed no ventilation or perfusion in the perfused lung. There were no perioperative deaths. Two patients are alive with disease, and 6 patients died of disease. The median follow-up is 11 months and the longest, 31 months. There were no partial or complete responses. One patient had stabilization of disease in the perfused lung, whereas the lesions in the untreated lung progressed markedly.

Conclusion. Isolated lung perfusion is well tolerated by patients and effectively delivers high doses of doxorubicin to the lung and tumor tissues while minimizing systemic toxicities. A single dose of 80 mg/m² resulted in substantial injury to the lung. There were no partial or complete responses in patients perfused with doxorubicin at the maximum tolerated dose of 40 mg/m². Isolated lung perfusion remains a model for testing new and innovative therapies for metastatic sarcoma.

	Introduction

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It was estimated that in 1998, there would be an estimated 7,000 new cases of sarcoma in the United States [1]. Accounting for up to 80% of all metastases, the lung is the most common site of distant metastases [2]. Pulmonary resection, when possible, is the standard approach to the management of such patients, and, if resection is complete, yields 5-year survival rates of 20% to 30% [3–6]. However, the majority of patients will have unresectable disease, and chemotherapy remains their only option. Despite the ability of systemic chemotherapy to induce tumor shrinkage in 35% to 50% of patients, systemic therapy has not had a major impact on the survival of these patients [7–12]. The effectiveness of these cytotoxic drugs may be limited by the toxicities that occur before the therapeutic dose is reached.

Isolated lung perfusion (ILP) has been investigated as an alternative method for delivering high-dose chemotherapy to the lungs while minimizing systemic toxicities. Our laboratory found delivery of doxorubicin hydrochloride by ILP to be superior to intravenous injection in minimizing this toxicity in a rodent model [13]. Further, using ILP with doxorubicin, we [14] were able to eradicate sarcoma metastases in the lung in our rodent model. These encouraging results prompted us to initiate a dose-escalating phase I trial evaluating the toxicity of isolated single-lung perfusion with doxorubicin for patients with unresectable pulmonary metastases from sarcomas. We report the findings of this study here.

	Material and methods

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Between May 1995 and June 1997, 25 patients with pulmonary metastases from sarcoma were evaluated for ILP with doxorubicin. Patients were eligible for ILP if they met the following four criteria: multiple pulmonary metastases assessed by radiologic examination to be unresectable; metastatic disease confined to the lungs; adequate pulmonary reserve to tolerate a pneumonectomy; and no comorbid conditions that would preclude an operation. Nine patients met these criteria. The study was approved by the institutional review board, and written, informed consent was obtained from each patient.

Preoperative evaluation
All patients underwent a preoperative workup. This workup included the following: confirmation of the histopathologic diagnosis by a Memorial Hospital pathologist; metastatic workup with a chest roentgenogram, computed tomographic scans of the brain, chest, and abdomen, and bone scan; electrolyte study, complete blood count, and liver function tests; lung ventilation/perfusion scan; pulmonary function tests including carbon monoxide diffusing capacity of the lung; and electrocardiography and radionuclide cineangiography.

Treatment plan
Three patients per group were to be recruited to undergo ILP with doxorubicin at a dose determined by an escalation schedule. The dose escalation was to proceed with the first group of patients undergoing ILP with 40 mg/m² of doxorubicin, the second group with 80 mg/m², the third with 120 mg/m², the fourth with 160 mg/m², the fifth with 250 mg/m², and the sixth with 320 mg/m². If no patient in a group experienced dose-limiting toxicities, then the subsequent 3 patients would be treated at the next higher dose. If 1 patient in a group (ie, 1 of 3) experienced dose-limiting toxicities, then the next 2 patients would be treated at the same dose level. If no other patient experienced dose-limiting toxicities (ie, only 1 of 5 experienced dose-limiting toxicities at a dose level), the next 3 patients would be perfused at the next higher dose level. However, if any 2 patients in a group experience dose-limiting toxicities (ie, 2 of 2, 2 of 3, 2 of 4, or 2 of 5), then no more patients would be treated at that dose level, and the maximum tolerated dose would be established at the previous dose level.

Technique of isolated lung perfusion
All perfusions were performed on the left lung. Patients were anesthetized, intubated with a double-lumen endotracheal tube, and positioned in the lateral decubitus position. A left posterolateral thoracotomy was performed in the standard fashion. The main pulmonary artery and both pulmonary veins were isolated. The ipsilateral lung was collapsed. The bronchial arteries of the main bronchus were temporarily occluded by a clip. The patient was systematically anticoagulated with intravenous administration of heparin sodium. The pulmonary artery and veins were clamped proximally and cannulated by standard techniques. A perfusion circuit containing an oxygenator and heat exchanger was primed with 700 to 800 mL of Hespan (hetastarch) (Fig 1). The remaining volume of the perfusion circuit was contributed by the blood volume of the isolated lung. Perfusion of the collapsed lung was carried out for 20 minutes at a rate of 300 to 500 mL/min at ambient temperatures. In the first 5 patients, doxorubicin was infused into an arterial line leading to the inflow cannula during the course of the perfusion. This resulted in a slow rise to peak doxorubicin concentrations. The last 3 patients had lung perfusion initiated only after the doxorubicin was mixed into the perfusion circuit. This allowed the perfusion to be initiated at the maximum concentration of doxorubicin. After 20 minutes of perfusion, the doxorubicin was washed out of the lungs with Hespan, and the pulmonary vein effluent was discarded. At the end of the perfusion, the lung and pulmonary vein were deaired by sequentially removing the pulmonary artery cannula, repairing the arteriotomy, removing the cannulas in the pulmonary veins, removing the clamp on the pulmonary artery, and allowing the pulmonary veins to bleed until all air had been vented. The venotomies were then repaired and the clamps removed, restoring blood flow to the lung.

View larger version (39K): [in this window] [in a new window]   Fig 1. Technique of isolated lung perfusion. (Reprinted from Liu D, Burt M, Ginsberg RJ. Lung perfusion for treatment of metastatic sarcoma of the lungs. In: Markman M, ed. Regional chemotherapy: clinical research and practice. Totowa, NJ: Humana Press, 1999:94, by permission of the publisher.)

Postoperative evaluation
After perfusion, patients were followed with physical examinations and complete blood counts weekly, chemistry studies and chest roentgenograms every 2 weeks, electrocardiograms and chest computed tomographic scans every 4 weeks, radionuclide cineangiography at week 8, and ventilation/perfusion scans and pulmonary function tests including D at weeks 2 and 8. A paired t test was used to compare the preoperative and postoperative values of various indicators of cardiac and pulmonary functions. A p value of less than 0.05 was considered to be significant.

Criteria for toxicity
Cardiac and pulmonary toxicity were graded according to the following system devised by us:

Cardiac toxicity

Grade 0—Decrease in ejection fraction of 0.10 or less compared with preoperative values; patient asymptomatic

Grade 1—Decrease in ejection fraction of 0.10 to 0.20 compared with preoperative values; patient asymptomatic

Grade 2—Decrease in ejection fraction of 0.20 or more; or patient with congestive heart failure

Pulmonary toxicity

Grade 0—Decrease in D of less than 10%; no significant change in ventilation/perfusion scan; patient asymptomatic

Grade 1—Decrease in D of 10% to 20%; decrease of less than 20% in ventilation or perfusion of treated lung; patient asymptomatic

Grade 2—Decrease in D of more than 20%; decrease of more than 20% in ventilation or perfusion of treated lung; or patient with dyspnea on exertion or rest

All other toxicities were graded on a scale of 0 to 4, using the common toxicity criteria of the National Cancer Institute.

	Results

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Demographics
Nine of the 25 patients screened were deemed eligible for ILP. Eight of them, 6 women and 2 men, underwent successful ILP. One patient was found to have an accessory pulmonary vein at the time of thoracotomy, and perfusion was not performed. The median age of the 8 patients who underwent perfusion was 40 years (range, 26 to 52 years). The primary histologies included two leiomyosarcomas of the uterus, one synovial sarcoma of the extremity, one spindle cell sarcoma of the paraspinal region, one extraosseous chondrosarcoma of the extremity, one alveolar soft part sarcoma of the extremity, one malignant fibrous histiocytoma of the extremity, and one osteogenic sarcoma of the extremity.

Treatment
For technical reasons, the first 2 patients received only 80% and 85% of the planned 40 mg/m² doxorubicin dose. With institutional review board approval, we perfused the next 3 patients with 40 mg/m². The sixth patient received 80 mg/m² as a premature escalation, and pulmonary edema, which required intensive pulmonary care, developed postoperatively. This patient subsequently was found to have a major pulmonary injury at reoperation 2 weeks later for suspected empyema and suppurative pericarditis (Fig 2). The next 2 patients had perfusion at the lower dose of 40 mg/m².

View larger version (72K): [in this window] [in a new window]   Fig 2. (Patient 6.) Chest roentgenograms (A) before operation and (B) 2 weeks after isolated left lung perfusion with 80 mg/m2 of doxorubicin.

Pharmacokinetics and toxicity
The mean perfusate level of doxorubicin in the group of patients who received 40 mg/m² or less was 5.88 µg/mL, corresponding to a mean doxorubicin lung tissue level of 6.51 µg/mg (Table 1). The highest tissue levels were found in patient 6 who received the highest dose (80 mg/m²). The doxorubicin concentrations in both lung and tumor appeared to correlate with the amount of doxorubicin in the perfusate. In general, tumors (three of four) took up less doxorubicin than the lung.

View larger version (51K): [in this window] [in a new window]   Fig 3. (Patient 6.) Chest computed tomographic scans made (A) before operation and (B) 2 months after isolated left lung perfusion with 80 mg/m2 of doxorubicin showing extensive collapse and consolidation in treated lung.

View larger version (68K): [in this window] [in a new window]   Fig 4. (Patient 5.) Roentgenograms show stable disease in perfused left lung and progression of lesions in untreated right lung: (A) before operation; (B) 2 months after isolated lung perfusion; and (C) 4 months after isolated lung perfusion.

	Comment

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In a recent report from the international pulmonary metastases registry [16], soft tissue sarcomas were the most common type of pulmonary metastases resected; they accounted for 42% of all patients undergoing metastasectomy. Forty percent of patients were rendered disease free 3 years after resection. Patients who have recurrence after complete resection of intrathoracic disease rarely survive 5 years [3, 17]. In most patients with recurrence, this takes the form of pulmonary metastases alone. Although not proved, undetectable micrometastases were probably present at the time of the initial operation [18]. However, only approximately 50% of all patients with lung metastases from sarcoma are operative candidates, and of those, approximately 80% will undergo complete resection. It is from this 80% that the 5-year survival rates of 20% to 40% are obtained [6].

One of the most active single agents in the treatment of sarcoma is doxorubicin. However, neither doxorubicin nor doxorubicin-based combination chemotherapy has had a significant impact on survival of patients with primary or metastatic soft tissue sarcoma [7–12]. This may be in part because of dose-limiting toxicities that occur before the effective dose can be reached. Animal and human studies suggest that doxorubicin has a steep dose-response curve. Increasing the doxorubicin dose can be expected to result in a higher tumor response [19]. The major dose-limiting toxicity of doxorubicin therapy is cardiomyopathy, which will be manifest in up to 20% of patients receiving more than 550 mg/m² of doxorubicin [20]. In one study [21], approximately 50% of the patients treated with doxorubicin did not complete the planned treatment course because of cardiac toxicity. Besides the long-term cumulative effects of doxorubicin on the heart, myelosuppression and other systemic toxicities limit the dose of doxorubicin that can be given per course of therapy.

Isolated lung perfusion, first reported by Creech and associates [22] in 1958, is an alternative method of chemotherapy delivery that allows the administration of high doses locally while reducing the incidence of systemic toxicities. Our laboratory found doxorubicin delivery by ILP to be superior to intravenous injection in achieving this goal in a rodent model [13]. We were able to achieve lung levels of doxorubicin that were 20 times higher and heart concentrations that were seven times lower with ILP than those seen with intravenous injection. Using weight as a measure of well-being, the animals that underwent perfusion gained weight normally, whereas the animals that received an equivalent dose intravenously failed to thrive. Further, we [14] were able to eradicate sarcoma metastases in the lung using ILP with 320 µg/mL of doxorubicin. These findings encouraged us to pursue a phase I trial of ILP with doxorubicin for patients with unresectable pulmonary metastases from sarcoma.

Previous animal studies [23, 24] have shown doxorubicin to be toxic to the lungs. In canine studies, Minchin and colleagues [23] demonstrated a dose-related injury to the lungs using biochemical markers such as lactate dehydrogenase and angiotensin-converting enzyme. Contralateral pneumonectomy was performed 2 weeks after ILP to assess the functional status of the perfused lung. It was determined that substantial damage to the lungs occurred with perfusate concentrations of doxorubicin higher than 11.6 µg/mL. Baciewicz and coworkers [24] performed similar perfusion studies and found that significant histologic injury occurred at perfusate concentrations of doxorubicin higher than 7.61 µg/mL. The finding of pulmonary toxicity at lower doses may be related to the perfusions being performed at hyperthermic (39°C) conditions. On the basis of our long-term (> 2 months) toxicity studies in Fischer F344 rats, we determined that for doxorubicin delivered by ILP, the lethal dose for 50% survival was 10 µg/mL (unpublished data). These animal studies corroborate our findings of 40 mg/m², corresponding to a mean perfusate concentration of up to 12.9 µg/mL, as the maximum tolerated dose in humans.

As noted in Table 4, there were no significant differences in rest or exercise ejection fractions or ventilation/perfusion scans obtained before and 8 weeks after ILP with 40 mg/m² or less of doxorubicin. At 8 weeks after perfusion, there was a significant difference in the forced expiratory volume at 1 second and a trend toward significance in the D before perfusion compared with after perfusion. Although these early changes are noted, there have been no clinical signs of dyspnea, shortness of breath, or other clinical variables of decreased pulmonary function in these patients. Part of the decrease in these measurements could be explained by the fact that at the time of perfusion, much manipulation of the lung and eight to ten wedge resections were performed to obtain lung and tumor tissue for analysis, and long-term follow-up was not possible. In the future, we plan to study these variables 2 months postoperatively in patients who undergo wedge resection as standard treatment of metastatic disease and who do not receive chemotherapy, either systemically or by ILP.

There have been a few reports of ILP with doxorubicin in humans. One of the first, by Minchin and coauthors [25], was published in 1984. Three patients underwent 50 minutes of ILP at doxorubicin concentrations ranging from 1 to 2 nmol/mL (0.58 to 1.16 µg/mL). Systemic doxorubicin levels were not detected at any time during or after the perfusions. Tissue doxorubicin levels increased steadily with time of perfusion. However, doxorubicin levels in the tumor nodules (range, 0 to 0.4 nmol/g) were always lower than those in the immediate surrounding pulmonary tissues (range, 0 to 1.2 nmol/g), which was similar to our findings.

Johnston and associates [26] performed single or total lung perfusion with doxorubicin in 6 patients, 3 with sarcoma metastases and 3 with bronchioloalveolar carcinoma of the lung. Escalating doses of doxorubicin, starting with 1 µg/mL and increasing to 10 µg/mL, were used. There were no partial or complete responses to therapy. However, the maximum tolerated dose was never reached. In our study, we used the maximum tolerated dose of 40 mg/m² in all but 1 patient. There were also no partial or complete responses observed in our study. Somewhat encouraging is the fact that in 1 patient, the disease was arrested in the perfused side, whereas the lesions in the unperfused lung progressed markedly.

Although it does not appear that ILP with doxorubicin alone will be an effective treatment of patients with unresectable pulmonary metastases from sarcomas, it may have an adjuvant role as prophylactic therapy to eradicate presumed residual micrometastases before or after resection in patients with resectable pulmonary metastases. Ohno [27] in 1968 performed prophylactic ILP with three anticancer agents, mitomycin C, nitrogen mustard, and 5-fluorouracil, in patients with osteosarcoma limited to the extremities, ie, no evidence of pulmonary metastases. The lung perfusion was performed using the technique of Creech and coworkers [22] 2 weeks before radical operation of the extremity. The control group who underwent only a radical operation on the extremity (n = 41) had a 5-year survival rate of 17.1% compared with 30.1% for the group who had prophylactic ILP (n = 21).

Isolated lung perfusion with doxorubicin is well tolerated by patients and effectively delivers high doses to the lung and tumor tissues while minimizing systemic toxicity. Doses greater than 40 mg/m² result in substantial injury to the lung. Although there were no partial or complete responses in the perfused lung, the method arrested the growth of metastatic lesions in 1 patient. The technique remains a novel way to examine the efficiency of other agents, both biologic and chemotherapeutic, on metastatic disease. Further studies are justified, with the goal of a phase II trial our aim.

	Acknowledgments

 
Dr Burt was supported by US Public Health Service Program Project Grant CA47179. Dr Ross was supported by US Public Health Service Training Grant CA09501.

	References

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