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Eur J Cardiothorac Surg 2002;22:41-46
© 2002 Elsevier Science NL

Technique and results of hyperthermic (41°C) isolated lung perfusion with high-doses of cisplatin for the treatment of surgically relapsing or unresectable lung sarcoma metastasis

^a Division of Cardio-thoracic and Vascular Surgery, Hannover Medical School, Hannover, Germany
^b Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany

Received 2 December 2001; received in revised form 7 March 2002; accepted 25 March 2002.

* Corresponding author. Tel.: +49-511-790-6290; fax: +49-511-790-6266
e-mail: pmacchiarini{at}compuserve.com

	Abstract

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Comment Appendix A. Conference... References

 
Objective: A technique of hyperthermic isolated lung perfusion (ILP) chemotherapy was developed. Methods: Since April 1999, four patients with unilateral (n=2) or bilateral (n=2) sarcoma metastasis confined to a lobe (n=2) or entire lung (n=2) entered into a pilot study of hyperthermic (41°C) ILP with high doses of cisplatin (70 mg/m²). Eligibility included drug resistant metastasis and at least four previous surgical metastasectomies. The ILP of the lung segments was carried out following metastectomy, for 20–40 min at a rate of 0.3–0.5 l/min, a mean perfusion pressure lower than the own mean pulmonary artery pressure, and an inflow temperature of 41°C or higher. Before and following ILP, the isolated lung segments were flushed with normothermic saline (1 l). Flow was continuously maintained by a centrifugal pump. Results: All patients successfully completed 31.7±9 min perfusion time at 41.4±0.3°C, and this time-point corresponded to the maximal platinum lung-uptake (93.8 ng/mg tissue). The total vascular isolation was confirmed by continuously low systemic cisplatin plasma levels. There was no systemic drug-related toxicity but all patients experienced transient pulmonary toxicity as non-cardiogenic edema of the treated lung segments. With a median follow-up of 12 months, three patients are alive and disease-free and one died from cerebral metastasis without autopsy evidence of local recurrence 13 months following ILP. Conclusion: Hyperthermic perfusion chemotherapy can be done safely and effectively. It represents a new treatment modality and deserves further investigations for patients with advanced, drug resistant or surgically refractory, lung sarcoma metastasis. However, further studies are needed to limit the ILP-induced pulmonary toxicity.

Key Words: Hyperthermic isolated lung perfusion • Cisplatin • Lung sarcoma metastasis

	1. Introduction

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Comment Appendix A. Conference... References

 
Metastatis confined to the lung may the sole or life-limiting component of the disease for many patients with primary soft or bony-extrathoracic sarcomas. Their complete surgical resection yields 5-year survival rates between 25 and 40% [1]. Unfortunately, local relapse remains a major issue and despite various (pre- and post-operative) chemotherapy regimens have been used [2,3], none of them have sufficient efficacy to be consider standard therapy.

Pulmonary artery (antero or retrograde)-infusion of chemotherapeutics, using isolated lung perfusion (ILP) techniques [4–7], have been used to provide an opportunity to dose intensify therapy while limiting systemic toxicity in addition to local surgical therapy. Unfortunately, because of their technical complexity, attendant potential morbidity, and lack of documented efficacy, it has not gained widespread application.

It is well known that the therapeutical index of cisplatin, one of the most effective single drugs in the treatment of sarcoma, is limited by its systemic toxicity [4], and that its cytotoxic effects is exponentially enhanced at higher temperatures, e.g. >39.5°C [8]. Based on this rationales, we recently developed a surgical technique for the isolated lobar or lung perfusion with high doses of cisplatin under hyperthermic (41°C) conditions in patients with recurrent or unresectable lung sarcoma metastases, and the preliminary results are presented.

	2. Patients and methods

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Comment Appendix A. Conference... References

 
2.1. Eligibility criteria
Between April 1999 and October 2000, four patients with histologically confirmed sarcoma metastasis to the lung entered this feasibility study (Table 1). Eligibility included no other effective treatment option, controlled primary tumor site, physiological tolerance to the operation(s), anthracycline-refractory metastasis, no previous cisplatin exposure, at least four previous surgical metastasectomies, and normal hepatic, kidney, cardiac and lung function, and no clinically significant peripheral neuropathy.

2.3. ILP technique
Patients were anesthetized, intubated with a double-lumen endotracheal tube, and positioned in the lateral decubitus position. The pleural space was usually opened extrapleurally through a redo posterolateral thoracotomy in the 5th intercostals space, with or without resection of the 5th rib. Initially, the pleural cavity was inspected to exclude the presence of extrapulmonary disease, particularly pleural carcinomatosis or metastatic lymph nodes. The lung was extensively mobilized in preparation for ILP, and care was taken to minimize air leaks. The lobar and/or hilar pulmonary vessels and bronchial artery(ies) were then carefully identified and dissected to insure that there was no leak of perfusate in the systemic circulation. Intrapericardial dissection was unnecessary except for right upper lobe perfusions were the retrocaval pulmonary artery was systematically dissected to adequately perfuse the Boyden pulmonary artery. The pulmonary veins were dissected as for a lung transplantation. Next, the pulmonary artery perfusion pressures were determined. Wedge or segmental resection of the metastases, whenever feasible, was then made and before ILP to reduce the risks of misidentification of the lesions due to the ILP fluid lung overload.

A careful pleural and intrapulmonary hemostastis was made before giving systemic anticoagulation using heparin sodium (100 IU/kg). Next, 4-0 polypropylene (Prolene, Ethicon, Inc., Somerville, NJ) purse-string stitches were placed and used to fix a curve pediatric tube cannula positioned into the isolated right main (n=2) or lobar (n=2) pulmonary artery for pulmonary artery inflow and beyond the pulmonary venous takeoff to drain pulmonary vein blood outflow. Ligatures were then tied around the cannulae. Care was paid to accurately assess that the tips of the inflow and outflow cannulae were able to respectively perfuse and drain the entire lobe or lung. The two cannulae were then connected through connecting tubes to the Computer-Aided-Perfusion-System hyper/hypothermia device (CAPS, Stöckert, Münich, Germany, Fig. 1) . The isolated pulmonary artery and veins were then cross clamped proximally, and the perfusion circuit primed with 800–1000 ml of normothermic saline to wash the isolated lung segments before starting ILP. The ILP (70 mg/m² cisplatin) of the collapsed lung segments was carried out for 20–30 min at a rate of 0.3–0.5 l/min, and a mean perfusion pressure lower than the pre-ILP pressure. An inflow temperature of 41°C or higher was required to maintain the desired temperature. During ILP, the isolated bronchial arteries were left open to give the minimal systemic oxygenated blood required for cisplatin cytotoxic activity. At the end of the ILP, the perfusion circuit was re-primed with 800–1000 ml of normothermic saline to wash out cisplatin from the lung segments. Next, the collapsed lung was ventilated, and the pulmonary vein(s) were allowed to bleed in a standard fashion until complete deairing, preceded by sequential removing the inflow cannula, repair of the arteriotomy (6-0 Prolene), removal of the arterial and venous clamps and venous cannula, and repair of the venotomy, restoring lung circulation.

View larger version (64K): [in this window] [in a new window]   Fig. 1. Drawing of an hyperthermic perfusion of the left upper lobe following staple wedge resection of the metastasis. The inflow is through the left extrapulmonary pulmonary artery, outflow through the extrapericardial left upper pulmonary vein(s) (for more detail see Section 2).

2.5. Pharmacokinetic evaluation
Perfusion parameters were recorded, central venous blood and perfusate samples were taken before, every 10 min during perfusion, and post-operatively. Additional blood samples were collected 6, 12 and 24 h, 7 and 14 days following perfusion. After perfusion, representative peripheral specimens were taken for platinum analysis. The concentrations of platinum in plasma, perfusate and lung tissue were determined by a validated flameless atomic absorption spectrometry method [9] using a Spectraa^TM Zeeman 220 system (Varian, Darmstadt, Germany). For plasma and perfusate analysis a single dilution step with a mixture of Triton X-100 (Serva, Heidelberg, Germany) and Antifoam B (Sigma, Deisenhofen, Germany) 0.2% each in water was sufficient for sample preparation. Tissue samples (20 mg wet weight) were digested with 1 ml 65% nitric acid for 24 h at room temperature. Before analysis the digest was diluted up to 10 ml with the described mixture.

2.6. Follow-up studies
They included physical examinations, chemistry studies and chest roentgenograms every 2 weeks, electrocardiograms and chest computed tomographic scans every 4 weeks, ventilation/perfusion scans, pulmonary function tests including D_LCO, and bronchoscopy at weeks 3, 6, 9 and 12.

	3. Results

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Comment Appendix A. Conference... References

 
The details of the ILP are summarized on Table 2. Stable hemodynamic and perfusion parameters were achieved throughout the ILP, and there was no evidence for cisplatin-related systemic toxicity. However, all patients developed postoperatively a pulmonary toxicity occurring mainly as non-cardiogenic edema (Fig. 2) and ischemic mucosal changes in the treated lung and bronchial segments. In the subsequent 12 weeks these complications gradually improved and no patient had clinical signs of dyspnea, shortness of breath, or other clinical variables of decreased pulmonary function thereafter (Table 3).

View larger version (61K): [in this window] [in a new window]   Fig. 2. Pre-operative (A) chest X-rays showing multiple bilateral metastasis. The patients underwent a right isolated lung perfusion and developed on the post-operative day 1 (B) a non-cardiogenic pulmonary edema which recovered clinically by day 6 but persisted as interstitial injury (C, day 15) at least 1 month.

View larger version (24K): [in this window] [in a new window]   Fig. 3. Platinum concentrations in plasma and perfusate of a representative patient during isolated lung perfusion (ILP) and the post-operative period.

	4. Comment

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Comment Appendix A. Conference... References

 
The clinical application of hyperthermia is attractive because: (i) temperature elevation to 42–45°C for 10–60 min can lethally damage mammalians cells; (ii) both preclinical [11] and clinical [11,12] studies showed that hyperthermia significantly increases tumor growth delay by enhancing antineoplastic drug uptake; and (iii) many chemotherapeutic agents (e.g. doxorubicin, bleomycin, mitomycin C, and cisplatin) have increased cytotoxicity in vivo with increased temperature. There are three potential explanations for the synergism between hyperthermia and cisplatin: (1) an increased drug uptake into cells as a result of enhanced membrane permeability; (2) a significant enhancement of the cisplatin-induced DNA cross-linking effect; and (3) heat-induced inhibition of DNA repair [13]. Other variables such as pH, PO₂, and drug pharmacokinetics can lead in vivo to more complex sequencing. Unsurprisingly, the combination of hyperthermia and cisplatin has been so far used for thymic malignancies with pleural spread [13] and malignant mesothelioma [12].

Although this represents, as far we are aware, the first clinical experience with hyperthermic ILP of high-dose cisplatin via the pulmonary artery and the presented data show that it is feasible and safe in patients with relapsing or unresectable sarcomatous metastasis confined to the lung, further refinements in technique will be necessary in order to optimize patients outcome. First, hyperthermic high-dose cisplatin may be limited to the perfusion of a lobe, as there is an increased risk for the development of pulmonary edema and severe pulmonary toxicity beyond the lobar perfusion. The only patient having an ILP of the entire right lung experienced a pulmonary toxicity lasting for 9 weeks postoperatively that fully recovered by week 12 and allowed a left upper lobe ILP without major complications, intraoperatively (one-lung ventilation) and post-operatively (pulmonary toxicity). Although part of the pulmonary toxicity could be explained by the fact that at the time of perfusion, extensive lung manipulation and several wedge resections were performed, the limited lung tissue uptake of cisplatin observed and the previous evidence that significant histological injury occurs when doxorubicin [11] or cisplatin [12] is perfused at hyperthermic (39 and 43°C, respectively) conditions, suggest that these drugs may not be the optimal agents for ILP. Therefore, clinical attempts must be made to limit perfusion-related toxicities by using agents with improved therapeutic profiles as well as compounds that specifically protect normal parenchyma without affecting the tumoricidal activity of chemotherapeutic agents. Despite digitonin can increase platinum uptake into the lung [14] and inhalative (e.g. nitric oxide) or systemic (e.g. nitroglycerin) vasodilatation agents can improve the homogenous distribution of the chemotherapeutic agent [15,16], the most promising way to reduce ILP-toxicity seems to be the recent in vitro evidence that moderate hyperthermia significantly enhances paclitaxel-mediated cytotoxicity in cancer cell lines but not in normal human bronchial epithelial cells [17].

Second, in patients with resectable metastasis, surgery should be made before ILP. Our clinical experience clearly showed that following priming and ILP, the treated lung segments are edematous and this may reduce the ability to re-identify all known disease. Since this combination was not given to treat the clinically known metastatic deposits but the residual clinical undetectable micrometastasis, and complete resection remains the only hope for cure, we strongly recommend to resect first all known and resectable disease completely and then start the priming and hyperthermic cisplatin ILP. Third, during ILP the nourishing bronchial arteries were left untied to allow the perfusate to perfuse them retrogradely, and this because the: (i) the cisplatin-cytotoxicity is increased if its metabolites have an oxygen substrate; and (ii) bronchial, and not the pulmonary, circulation has angiogenic potential after the lung stops growing in late adolescence. For antiagiogenic purposes, there were tied following ILP. One may argue that this contributed to enhance the pulmonary toxicity since the functions of the bronchial circulation are to provide nutrition to the airways and larger blood vessels, to warm and add water vapor in order to condition inspired air, and to provide substrate for airway cellular metabolism and secretions. However, in the present study, the perfusate temperature, cisplatin dose, timing and uptake, and perfusion technique were almost constant suggesting that the total amount of treated capillary surface area plays a triggering role in the genesis of the observed pulmonary toxicity. One may further claim that the different tumor burden may have had a playing role since areas of low blood perfusion in tumors can reach preferentially higher temperatures than normal tissue and can therefore enhance the differential effects of heat. Again, among the two patients (# 1 and 4) with the major tumor burden, only the one whose entire lung was perfused developed a significant pulmonary toxicity.

In conclusion, hyperthermic isolated lung perfusion deserves further investigations for patients with advanced, drug resistant and/or surgically refractory lung sarcoma metastasis. It will definitely remain a palliative treatment but it offers the chance of slowing down the disease progression. Although we demonstrated the feasibility of the perfusion technique, further experimental and clinical studies are warranted to limit perfusion-related toxicities by using agents with improved therapeutic profiles as well as compounds that specifically protect normal lung parenchyma without affecting the drug-related cytotoxicity.

	Footnotes

 
Presented at the joint 15th Annual Meeting of the European Association for Cardio-thoracic Surgery and the Annual Meeting of the European Society of Thoracic Surgeons, Lisbon, Portugal, September 16–19, 2001

¹ Present address: Department of Cardiac and Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232-5734, USA.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Comment Appendix A. Conference... References

 
Dr T. Krueger (Lausanne, Switzerland): Do you know if you do a systemic administration of the drug which lung level you could achieve? Of course you gave us well your 18 or 19 mcg/mg. Do you know the level which can be reached in the lung by systemic administration?

Dr Schroeder: It is around 5 ng/mg in the lung tissue after systemic administration. There are other groups that achieved higher levels. They also obtained higher levels in the liver, up to 200 ng/mg.

But our point is the hyperthermic effect, and cisplatin is one of the drugs which really works well with the hyperthermia, and you can really intensify with each degree of Celsius the effect. So in the end how much cisplatin you have in the lung is not the main point. The toxicity at the time of perfusion is the interesting part. And in the end it does not correlate with the real drug level.

Dr Krueger: I have just a second question. There are probably two possible indications to do isolated lung perfusion: one is if you have non-resectable lung metastases and the second one if you do surgery and you would like to treat residual disease or microscopic disease you can't palpate or you can't visualize on the CT.

You described that you did lobar perfusion, selective perfusion of lobe. Wouldn't it be better to perfuse the complete lung in order to treat your disease to do even a sequential bilateral procedure?

Dr Schroeder: In these patients where we did the lobar approach, there had always been metastases in that same lobe in the past. Therefore, to get low toxicity for the remaining lung we decided to just perfuse the lobe where the cancer had been in the past and where the current metastases were.

Dr T. Grodzki (Szczecin, Poland): It is really a very interesting paper and I wonder why it is almost the last during the Congress, but that's by the way.

Dr Ginsberg has tried this without hyperthermia and Dr Sugarbaker with hyperthermia but regarding mesothelioma, but I discussed with Dr Ginsberg once and I am interested in what you described as lung reperfusion injury. Was it only reperfusion injury or was it kind of local toxicity, anyway, and what were the further observations regarding infused lung?

Dr Schroeder: One of the obvious side effects was edema, which responded well to diuretics. We performed also a VQ scan and we saw a decrease to 10% in both perfusion and ventilation on these patients, but it came up. We had one case where we did bilateral sequential perfusions, first the left side and then the right side. We had to wait 1 month between each perfusion, that's usual in the literature, until the VQ scan comes up, so then it is equal again.

Dr Grodzki: It was a result, anyway?

Dr Schroeder: It went up to 45%, both ventilation and perfusion.

Mr G. Ladas (London, UK): It is really a very exciting paper. The data from the International Registry of Lung Metastases does suggest that patients who come back for a second or third time metastasectomy actually do much better than those with just one operation. So in that sense, what would you comment on whether this particular subgroup, people coming back with relapse to the same parts of the lung, are really the best group of patients to test your hypothesis? That's one question.

The major question in treating specific soft tissue sarcomas is whether they are indeed sensitive to chemotherapy or not, and that's why we would normally give two cycles of chemotherapy preoperatively, then operate to see if there is any response or not. In that sense, do you have any thoughts as to how one could possibly select people who are most likely to benefit from what is obviously a toxic intervention?

And finally, we normally allow four to 6 weeks between operating on one side and then going to do the other side. In your experience do you have to modify that or would you still keep these guidelines?

Dr Schroeder: We used the interval of 4 weeks, because only when the VQ scan comes up again do you have the possibility to operate on the other side. Otherwise you have this edema and the patients are in the intensive care unit and you have big problems. Mr Ginsberg published a study in which he did both sides at the same time and had big problems with this. So sequential for sure, even if the disease is progressing.

If you do a metastasectomy and perform it repeatedly in patients, it is a pilot study and the decision to treat must be individualized. Actually we just offered this treatment to young patients who had no other possibility for survival, so I am not the person to have a good really guideline for the future. I think we have to have more studies about this. The other problem is, you say ‘sarcomas’, but we have different types of it, and we don't have the figures to get really the right chemotherapy treatment for each type.

And the third question, we took cisplatin because the patients had never been treated with it before, so the cells were not selected, hopefully, and it works well in combination with hyperthermia. There are just four drugs out which work synergistically with hyperthermia. For example if you take doxorubicin, it is not that synergistic. Also, if you compare our approach using 70 mg/m² to Mr Ratto's approach, he did this in 1996 using 200 mg/m², he had more problems with toxicity. So we decided to use the lower level of cisplatin with a higher temperature. We used 41 degrees. You can go up to 43 but we didn't do this.

Dr M. Furrer (Chur, Switzerland): We did some experimental work also together with the group of Michael Burt and Robert Ginsberg with isolated lung perfusion, and in these studies we had the impression that the lung edema, as you showed in your patients, is dependent from the pressure of the circulating system. So my question is, did you measure the pressure of perfusion and what was the pressure limit?

Dr Schroeder: It was 15–20 mmHg.

	References

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Comment Appendix A. Conference... References

 

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