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Ann Thorac Surg 2004;78:1919-1927
© 2004 The Society of Thoracic Surgeons
a Department of Thoracic and Vascular Surgery, University Hospital Antwerp, Edegem, Belgium
b Department of Cardiac Surgery, University Hospital Antwerp, Edegem, Belgium
c Department of Anesthesiology, University Hospital Antwerp, Edegem, Belgium
d Department of Medical Oncology, University Hospital Antwerp, Edegem, Belgium
e Department of Pathology, University Hospital Antwerp, Edegem, Belgium
f Department of Pulmonary Medicine, Antonius Hospital, Nieuwegein, The Netherlands
g Department of Cardiothoracic Surgery, Antonius Hospital, Nieuwegein, The Netherlands
h Department of Anesthesiology, Antonius Hospital, Nieuwegein, The Netherlands
i Department of Clinical Pharmacy, Antonius Hospital, Nieuwegein, The Netherlands
j Department of Pathology, Antonius Hospital, Nieuwegein, The Netherlands
Accepted for publication May 19, 2004.
* Address reprint requests to Dr Van Schil, Department of Thoracic and Vascular Surgery, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium
paul.van.schil{at}uza.be
Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.
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Abstract |
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METHODS: From May 2001 to August 2003, 16 patients underwent isolated lung perfusion with MN, followed by surgical resection of lung metastases. Patients were treated with increasing MN doses (15, 30, 45, and 60 mg). For each dose level, normothermia (37°C) and hyperthermia (42°C) were evaluated (n = 3 per level). Serum samples were obtained during the procedure. Pulmonary, hematologic, and nonhematologic toxicities were recorded. The primary tumor was colorectal in 7 patients, renal in 5, sarcoma in 3, and salivary gland in 1. Isolated lung perfusion was performed unilaterally in 11 patients, and staged bilaterally in 5.
RESULTS: In total, 21 procedures of isolated lung perfusion with complete metastasectomy were performed without technical difficulties. Operative mortality was 0%, and no systemic toxicity was encountered. Grade 3 pulmonary toxicity developed at a dose of 60 mg of MN at 37°C in 2 of 3 patients at this dose, terminating the trial.
CONCLUSIONS: Isolated lung perfusion with MN combined with pulmonary metastasectomy is feasible. Dose-limiting toxicity occurred at a dose of 60 mg of MN at 37°C, and the maximum tolerated dose was set at 45 mg of MN at 42°C.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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The study was approved by the ethical committee of Antonius Hospital in March 2001 and of the University Hospital Antwerp in September 2001, and written informed consent was obtained from each patient.
Inclusion Criteria
Patients with pulmonary metastases from melphalan-sensitive tumors were included if general and specific criteria were met. General criteria to perform a procedure were fourfold: all metastatic disease assessed by radiologic examination was resectable, metastatic disease was confined to the lungs, patients had adequate pulmonary and cardiac reserve, and no comorbid conditions that preclude an operation were present. All inclusion criteria are listed in Table 1.
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Dose-Escalation Scheme
Isolated lung perfusion with melphalan was performed at a dose determined by an escalation schedule. For each dose level, 3 patients underwent perfusion at 37°C and 3 patients at 42°C. The different levels are depicted in Table 2.
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Preoperative Examinations
All patients underwent a workup consisting of electrolyte studies, complete blood count, tumor markers if indicated, and liver and renal function tests; chest roentgenogram; computed tomographic scan of the brain, chest, and abdomen; bone scan; and positron emission tomography scan if available. Pulmonary function was analyzed by means of quantitative lung perfusion scintigraphy and pulmonary function tests including spirometry and diffusion capacity, whereas cardiac function was tested by electrocardiography and transthoracic cardiac ultrasound. If indicated, a colonoscopy was also performed in case of colorectal metastases. Pathologic diagnosis of suspected lung metastases was obtained preoperatively or during the operation by frozen-section analysis.
Surgical Procedure
Complete metastasectomy was performed after ILuP. In case of bilateral disease, staged thoracotomies were planned with an interval of 4 to 8 weeks. This interval allowed adequate observation of (sub)acute toxicity, leaving time for the patient to recover. All patients were intubated with a double-lumen endotracheal tube and turned to a lateral position. An anterolateral or posterolateral thoracotomy was performed in a standard fashion. After inspecting the thoracic cavity, contraindications for a complete metastasectomy were excluded. All nodules were palpated before perfusion, and their anatomic localization was documented before perfusion. Isolated lung perfusion can induce pulmonary edema, making accurate identification after perfusion more difficult. However, we choose to perform ILuP before surgical resection as perfusion is more homogeneous throughout the lung tissue and no bleeding will occur at the sites of resection because heparin is corrected with protamine. In case no preoperative histologic diagnosis was present, frozen section of one of the tumor nodules was performed to obtain pathologic confirmation of metastatic disease.
Next, the main pulmonary artery and both pulmonary veins were isolated. The pericardium was opened to clamp the pulmonary artery and veins centrally. The patient was systemically anticoagulated with IV administration of heparin sodium up to an activated clotting time of greater than 200 seconds. The pulmonary artery and veins were clamped proximally and cannulated by standard techniques; the main bronchus was snared to occlude bronchial arterial blood flow. A perfusion circuit consisting of a centrifugal pump, a heat exchanger, and special extracorporeal circuit tubing was primed with a mixture of 6% Voluven (6% hydroxyethyl starch 130/0.4) and 2% heparin. The total volume of this circuit was less than 300 mL. Isolated lung perfusion was carried out for a period of 30 minutes during which the lung was ventilated with warmed (38°C) room air. The flow rate was calculated preoperatively (0.7 L/m2) but adjusted to achieve a mean pulmonary artery pressure of less than 30 mm Hg. After stabilization of temperature and flow and no signs of leakage (loss of priming volume out of the circuit), melphalan was injected into the perfusion circuit through the pulmonary artery cannula. After 30 minutes of perfusion, melphalan was washed out of the lung with a balanced fluid consisting of 3 L of the priming solution. The flushed volume was collected in a waste bag. At the end of the washout period, air was removed from the lung and pulmonary veins by sequentially removing the pulmonary artery cannula, repairing the arteriotomy, removing the cannulas from the pulmonary veins, and removing the pulmonary artery clamp until bleeding from the pulmonary veins had vented all the air. The venotomies were repaired and the clamps removed, restoring blood flow to the lung.
After correcting the activated clotting time with protamine, a complete metastasectomy was performed. Metastases were resected with a margin of 5 mm of normal lung tissue. Subsequently, a hilar and mediastinal nodal sampling were performed. Before the start of ILuP, at 5, 15, 30 minutes during ILuP, and at 30 minutes off bypass, systemic arterial blood samples were collected in serum tubes and directly stored at 0°C. Samples were spun at 4,000 rpm for 5 minutes in a cooled (4°C) centrifuge, and sera were stored at –70°C until analysis was performed.
Postoperative Evaluation
Clinical examination and recording of CTC were performed on days 1 to 7, 14, 28, and 180 by means of electrolyte studies, complete blood count, chest roentgenogram, arterial blood gasses, and electrocardiography. A transthoracic cardiac ultrasound was performed on day 2, and pulmonary function testing (forced expiratory volume in 1 second, diffusing capacity of the lung for carbon monoxide) and a high-resolution computed tomographic scan of the thorax were performed on day 28. Further follow-up was performed according to the specific scheme of the primary tumor.
Measurement of Melphalan
High-performance liquid chromatographic assay with fluorescence detection based on the assay of Wu and colleagues [5] was used for the quantification of melphalan. Plasma samples were stored at –70°C until required for analysis. Samples were clarified by centrifugation before the supernatant was brought on the column. After the samples were completely absorbed by the column, the columns were washed and dried. Finally, the compounds of interest were eluted and the extract was evaporated to a volume of approximately 200 µL. Finally, the extract was filtered and ready for injection. A calibration curve was prepared using blank plasma. Dilutions of 100, 10, and 1 µg/mL for melphalan were prepared. Calibration standards of 50, 100, 300, 500, 1,000, 3,000, 5,000, 10,000 and 30,000 ng/mL were prepared by mixing an appropriate volume of the melphalan dilutions to 50 to 500 µL of blank plasma and 100 µL of the internal standard solution (10 µg/mL).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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All metastatic nodules were resected by a wedge resection in all patients but 1. This patient, with complete replacement of the right lower lobe by a large metastasis of a colorectal tumor, had a lobectomy followed by perfusion of the right upper and middle lobes. Tumor nodules were located in the right upper lobe in 5 patients, the right middle lobe in 5, the right lower lobe in 7, the left upper lobe in 6, and the left lower lobe in 6.
Toxicity
In total, seven levels of ILuP were completed (Tables 4 and 5). There was no operative or postoperative mortality. In 1 patient postoperative bleeding required reintervention (level 6).
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The mean duration on intensive care was 2 days (range, 2 to 6 days) and the mean hospitalization was 14 days (range, 9 to 23 days).
Melphalan Levels
In the first four levels all patients but 1 had undetectable systemic levels of melphalan at 30 minutes after perfusion (Table 6). At the final three levels all patients had systemic leakage, but far below the levels known from IV therapy [6]. These systemic levels were not different among the groups, with a range from 0.16 to 0.57 µg/mL. Although limited systemic exposure was present, no systemic toxicity was seen up to the dose of 60 mg.
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Tumor-eradicating studies were started in 1994 with the development of rodent models of ILuP [10, 11]. Several agents were tested with success, and these studies showed that ILuP is superior to IV infusion [3, 4, 12–15]. Some of these agents, such as doxorubicin, tumor necrosis factor-
(TNF-), and cisplatin, were subsequently tested in human phase I trials, and in some studies the MTD levels were defined (Table 7). One of the first reports of clinical ILuP was published in 1958 by Creech and associates [16]. They investigated ILuP as a prophylactic therapy before radical operation of extremity sarcoma, but no further studies followed although a survival difference was seen. Next, Minchin and coworkers [7] reported on ILuP with doxorubicin in 3 patients. No systemic leakage was present, although increasing lung levels of doxorubicin with time of perfusion were seen. Minchin and colleagues [7] and Johnston and coworkers [8] continued experimental work with doxorubicin, and performed both single-lung and total-lung perfusion in patients with inoperable pulmonary metastases and primary lung cancer. Drug concentrations in normal lung and tumor increased with higher doses, although lung levels were higher than tumor levels. Two major complications occurred in 8 patients: 1 patient experienced pneumonia with a subsequent sternal dehiscence, and 1 patient had respiratory failure several days after lung perfusion and died at postoperative day 81.
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More recently, Putnam and coworkers [18] presented their phase I study of isolated single-lung perfusion of doxorubicin in 16 patients with unresectable pulmonary metastatic disease. Systemic levels were minimal or undetectable, although 2 patients experienced a grade 4 pulmonary toxicity at a dose of 75 mg/m2, therefore defining the MTD at 60 mg/m2 of doxorubicin.
Results of ILuP with TNF- were published by Pass and colleagues in 1996 [19]. Nineteen patients underwent a 90-minute perfusion with TNF- combined with 
-interferon and moderate hyperthermia. No deaths occurred and no significant systemic changes in systemic blood pressure or cardiac output were seen. Isolation of the lung was complete in 10 patients with 0% leak. For a dose up to 6 mg of TNF-, maximal systemic TNF- level was 3 ng/mL, which is far below the systemic MTD of 150 µg/m2 in humans.
Isolated lung perfusion with cisplatin was tested by Ratto and coworkers in a series of 6 patients [9], and by Schröder and associates in a series of 4 patients [20]. Ratto and colleagues [9] showed that ILuP combined with surgical excision of sarcoma lung metastases was technically feasible. The dose was fixed at 200 mg/m2 of cisplatin while ILuP was performed for 60 minutes at normothermia. No deaths were seen, but in 2 patients diffuse lung edema developed 48 hours after treatment. Schröder and associates [20] tested the combination of hyperthermic ILuP with cisplatin at a fixed dose of 70 mg/m2 for both resectable and unresectable disease. Perfusion was variable between 21 and 40 minutes, and surgical resection of lung metastases was performed after ILuP. No deaths were seen, although all patients experienced noncardiogenic edema and ischemic changes in the treated lung.
Melphalan, an alkylating agent used for the treatment of many tumors such as ovarian cancer, rhabdomyosarcoma, pancreatic carcinoma, osteogenic sarcoma, and multiple myeloma, has rendered its attractiveness for local organ perfusion after being investigated with success in isolated limb perfusion for melanoma when combined with TNF- [21, 22]. Experimental work of ILuP in rodent models was able to achieve lung levels of melphalan that were several times higher, and systemic concentrations were significantly lower, with ILuP compared with IV injection [3, 4]. In addition, ILuP with 2 mg/kg was able to eradicate carcinoma and sarcoma metastases in the lung, which also resulted in a prolonged survival compared with control animals [23, 24].
No other human or large animal trials of ILuP with melphalan have been published so far, and therefore the initial dose to start with was unknown. The starting dose of 15 mg of melphalan was calculated from rat studies and estimated to result in one third of the effective melphalan concentration of the rat studies in the human perfusion circuit [4]. Because it was of utmost importance to avoid leakage into the systemic circulation, which could result in gastrointestinal and bone marrow toxicity, any level increase was only performed after the results of systemic melphalan levels were analyzed.
If systemic melphalan levels were detected after ILuP, these were much lower compared with the levels obtained after IV infusion or after high-dose IV melphalan combined with bone marrow substitution [6, 25]. For a dose of 10 to 20 mg/m2 of melphalan given IV, reported systemic levels are 0.5 to 7.2 µg/mL. For high-dose melphalan (180 mg/m2) with bone marrow eradication, systemic levels are 4.8 to 11.5 µg/mL.
No systemic, hematologic, or nonhematologic DLT was seen in this study up to a dose of 60 mg at 37°C. All patients were scored a cardiac CTC grade 1 because the pericardium was opened for central clamping. This resulted in an asymptomatic pericardial effusion.
Only for a dose of 60 mg at 37°C were severe pulmonary changes seen in 2 of 3 patients. The radiographic picture resembled a vascular leakage syndrome or chemical pneumonitis and was controlled with oxygen and diuretics. This picture was similar to the one seen in the studies by Ratto and coworkers [9] and Burt and associates [17], although permanent extensive collapse and consolidation as seen by Burt and coworkers was not present in our 2 patients, who fully recovered.
Schröder and colleagues [20] recommended that surgery be performed before ILuP based on their experience with 4 patients. They had difficulty identifying metastatic nodules owing to the edematous lung tissue after ILuP. In our experience, we chose to identify and record all metastatic disease before cannulating the pulmonary artery and veins. Next, ILuP was performed to have a homogeneous perfusion throughout the lung. Pharmacokinetic analysis of experimental work of ILuP in rats [4], of isolated liver perfusion [26], and of isolated limb perfusion [27], showed that melphalan is only slowly removed from the perfused tissue after an initial high uptake phase that extends up to 30 to 40 minutes.
Clinical follow-up results presented in this paper have to be interpreted with caution. In this phase I trial, survival is not a secondary end point, and responses in the perfused lung cannot be assessed because macroscopic disease was completely resected at the time of perfusion. In addition, in each dose level there were only 3 patients with different primary tumors, lacking uniformity. Because ILuP is a local therapy, recurrent disease outside the lung or disease in the nontreated lung cannot be prevented. From this point of view, only 1 of the 16 patients developed recurrent disease within the perfused lung, 9 months after perfusion.
In conclusion, hyperthermic ILuP with melphalan followed by surgical resection of pulmonary metastatic disease is feasible. A dose of melphalan of 45 mg given at a temperature of 42°C was defined as the MTD. A higher dose of 60 mg of melphalan at 37°C resulted in substantial but reversible injury to the lung. Further clinical studies of ILuP with melphalan in patients with sensitive lung metastases are justified to determine its long-term efficacy and possible survival benefit.
Discussion
DR ARA VAPORCIYAN (Houston, TX): I wanted to commend you on a tremendous amount of work. I can imagine coordinating at two centers and doing all this work.
You mentioned that as part of your postoperative evaluation you performed pulmonary function testing, but I did not see that data. We had done some phase I studies as well with Adriamycin perfused in an isolated fashion with Dr Putnam, and we found that there was progressive deterioration of the pulmonary function as we followed the patients out to 6 months. I was wondering if you had any information on that or could share those results with us.
DR VAN SCHIL: For the moment our follow-up is rather short. As you have seen, the study was terminated in August 2003. In the patients who had severe lung injury, there was a decrease in the perfusion of the operated lung from 50% to almost 20%, so a 30% decrease, and this resulted in a decline of the diffusing capacity of carbon monoxide in those patients. For the others, there was only a minimal grade 1 or sometimes grade 2 toxicity when analyzing the pulmonary function tests on day 28.
DR BENNY WEKSLER (Rio de Janeiro, Brazil): I was just wondering why you picked that particular drug and that particular study design with the different temperatures and all. Did you do any previous laboratory work on that particular drug and that is why you continued it to humans?
DR VAN SCHIL: Yes, we did extensive experimental laboratory work in the rat model described by Dr Burt, who unfortunately died. Especially useful for survival studies is the left unilateral model, in which carcinoma or sarcoma cells are injected intravenously, while the right pulmonary artery is clamped. So this is a unique model of unilateral lung metastases in which we had very good results with the use of melphalan for lung metastases from adenocarcinoma cells. Other drugs were also tested, especially in the United States, the most important being doxorubicin, tumor necrosis factor, cisplatin, and interferon. So we have chosen melphalan for our clinical study because of the fact that it provided excellent results in our laboratory work, and it had never been tested before in a clinical phase I study.
DR ROBERT J. KORST (New York, NY): I am sure a lot of thought went into the study design in terms of the patient selection, and you chose patients that I believe you resected at the same time as the perfusion or in the same setting as the perfusion.
DR VAN SCHIL: Exactly.
DR KORST: Why not perfuse patients with unresectable pulmonary metastases? This would be not only be more appropriate for a phase I study, but you could also look at the radiographic response as well, as a secondary end point.
DR VAN SCHIL: Regarding the clinical experience until now, the first study of isolated lung perfusion was reported by Johnston in 8 patients with unresectable lung metastases or primary lung cancer. There were no objective responses in this trial.
Harvey Pass published a phase I trial including 15 patients with lung metastases who underwent 16 lung perfusions. This phase I trial showed that it was feasible to perform a unilateral or bilateral lung perfusion. There were no deaths, and there was an excellent separation between the systemic and the pulmonary circulation. However, there were only three partial responses, which were short-term.
In another study from Italy 6 patients with resectable lung metastases were perfused with cisplatin followed by surgical excision of the lung metastases.
Michael Burt reported on 8 patients with sarcoma lung metastases undergoing isolated lung perfusion with doxorubicin. There were no partial or complete responses.
And, lastly, Dr Putnam from Houston reported a phase I dose-escalating trial of patients with unresectable lung metastases of sarcoma. The lungs were also perfused with doxorubicin. There was no systemic toxicity. Mortality was 3 of 16 patients. Regarding the clinical response, there were no complete responses and only one major response, and 5 patients had stabilization of the disease.
So until now it has never been shown that isolated lung perfusion for patients with unresectable lung metastases yields a lasting clinical response. For this reason we thought it would be better to include patients undergoing a thoracotomy for resectable lung metastases and consider the isolated lung perfusion as a kind of adjuvant therapy to treat remaining micrometastases. Indeed, most patients with sarcoma and adenocarcinoma metastases will recur intrathoracically without any other metastases during follow-up. For this reason we thought it would be more ethical to apply this procedure in patients with resectable lung metastases.
DR STEVEN R. DEMEESTER (Los Angeles, CA): A number of reports have described a relatively surprising high incidence of lymph node metastases in these patients with pulmonary metastases. You did dissect out some lymph nodes. Were there lymph node metastases present in these patients? And in future trial designs, would you exclude them from lung perfusion or not?
DR VAN SCHIL: It has been shown that prognosis is poor when there are lymph node metastases while operating on patients with lung metastases. In our series there were no patients with positive lymph node metastases. Personally, I would exclude patients with mediastinal lymph node metastases in future trial designs owing to poor prognosis and the fact that you do not reach the mediastinal lymph nodes by isolated lung perfusion.
DR RICHARD H. FEINS (Rochester, NY): Thank you very much, Dr Van Schil.
I think that may actually be the first perfusion study that did not have significant toxicity to the pulmonary vasculature and such.
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Acknowledgments |
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References |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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