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Ann Thorac Surg 2009;88:385-391. doi:10.1016/j.athoracsur.2009.04.101
© 2009 The Society of Thoracic Surgeons
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Right arrow Lung - cancer

Original Articles: General Thoracic

Thoracoscopic Organ Suffusion for Regional Lung Chemotherapy (Preliminary Results)

Todd L. Demmy, MDa,*, Garin Tomaszewski, MDb, Grace K. Dy, MDc, Sai Yendamuri, MDa, Chukwumere Nwogu, MDa, Lakshmi Pendyala, PhDc, Nithya Ramnath, MDc, Alex A. Adjei, MD, PhDc

a Department of Thoracic Surgery, Roswell Park Cancer Institute, Buffalo, New York
b Department of Radiology, Roswell Park Cancer Institute, Buffalo, New York
c Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York

Accepted for publication April 21, 2009.

* Address correspondence to Dr Demmy, Department of Thoracic Surgery, Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263 (Email: todd.demmy{at}roswellpark.org).

Presented at the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
Background: After promising preclinical studies using a thoracoscopic regional lung chemotherapy technique less morbid than open perfusion methods, we initiated a Phase I clinical study.

Methods: Four performance status 0 to 1 patients with oligometastatic stage IV lung cancer underwent unilateral thoracoscopic lung suffusion targeting the bulk of primary disease and regional lymph nodes. We used the term suffusion (permeation of an organ) to describe the total lung distribution of chemotherapy afforded by venous distention akin to retrograde cardioplegia physiology. This was obtained by temporary thoracoscopic pulmonary vein occlusions and fluoroscopy-guided transfemoral intravascular balloon occlusion, drainage, and cisplatin distention of the main pulmonary artery. Single-lung ventilation allowed atelectasis that helped to drain the blood under pulmonary artery occlusion, then cisplatin (5% systemic dose) was instilled during venous occlusion and lung reexpansion. Chemotherapy dwelled for 30 minutes before lung reperfusion.

Results: All four suffusions were successful (three right, one left). Cisplatin remained concentrated in the pulmonary circulation by the end of the dwell (1,124 versus 236 ng/mL systemic). There were no changes in the postsuffusion pulmonary function tests or lung perfusion scans. All patients were discharged early (24 to 48 hours) without chest tubes, began standard chemotherapy without delay, and completed follow-up. After two systemic chemotherapeutic cycles primary tumors had volume reductions of 96%, 88%, 64%, and 14%, with the latter showing a 100% volume increase in a nonsuffused osseous metastasis.

Conclusions: Our initial clinical experience of thoracoscopic lung suffusion suggests that this approach is safe and merits future study with higher dose levels.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
The promise of selectively delivered chemotherapy has long been recognized. This approach has been used most notably in isolated limb perfusion for melanoma and sarcoma as well as hepatic perfusion for unresectable liver tumors and metastases from colorectal cancer [1, 2]. In adopting this technology for the effective treatment of pulmonary tumors, similar techniques have been explored using isolated lung perfusion. These required thoracotomy incisions for cannulation of delicate pulmonary vessels or risked toxic chemotherapy leakage into the systemic circulation [3–5]. Advances in minimally invasive technologies allowed the development of a reproducible, safe, and less cumbersome alternative for selective pulmonary chemotherapy. As this technique is quite different from earlier methodologies and involves permeation of the chemotherapeutic agent throughout the lung without use of perfusion apparatus, we have termed the procedure lung suffusion.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Discussion
 Acknowledgments
 References
 
Background Experiments
The regional delivery methodology was established in a large canine model using limited access incisions and, finally, thoracoscopic vascular control [6]. Radiopaque contrast (replacing blood drained from a lung whose arteries and veins were occluded) rapidly permeated the organ. Tracer experiments showed that 75% of the drug remained in the lung for 30 minutes [6]. Then immature beagle dogs underwent unilateral lung suffusion of cisplatin (n = 16) or saline (n = 3). The left bronchus, pulmonary artery (PA), and pulmonary veins were occluded selectively by minithoracotomy, trapping the PA-delivered cisplatin for 30 minutes while bilateral lung, serum, and suffusate samples were taken. The lungs were reperfused and the animals were allowed to recover for 30 days' observation. First, 4 dogs were given high doses (≥1 mg/kg) to show uniform drug delivery (Fig 1A). Platinum remained segregated between serum and tissues during high-dose testing: suffusate, 62,100 ng/mL; treated lung, 29,150 ng/g; contralateral (non-infused) lung 1,518 ng/g; and serum, 387 ng/mL (p = 0.01, one-way analysis of variance). The other dogs were treated in groups of 4 to estimate safe starting human dose range (0.125, 0.25, or 0.5 mg/kg). Serum levels rose while lung levels fell during reperfusion (Fig 1B). All dogs survived until study completion except for 2 (0.5 and 2 mg/kg) that developed early surgical or drug-related toxicities. Toxic behavior signs and histopathologic evidence of fibrosis or inflammation increased proportionally with infused platinum, but a dose of 0.125 mg/kg was tolerated well with no histologic changes. Diffuse ipsilateral lung injury in the high-dose group indicated uniform delivery. Draining tracheobronchial lymph nodes also demonstrated lymphoid atrophy in 10 of 11 survivors of the low-dose experiments.


Figure 1
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  		Fig 1. A. Photograph of beagle lung block 30 days after suffusion with the equivalent of a systemic dose of cisplatin. The photo compares the fibrotic remnant of the suffused side that was devoid of functional parenchyma on histologic evaluation with the normal pink contralateral lung. B. This graph shows the mean serum concentrations of cisplatin for each dose level in dogs before the suffusion (Pre), at the end of the suffusion (End), and then minutes (2' and 30') and hours (1, 2, and 24) after the procedure.

 
Because physiologic and histologic evidence of lung or other systemic injury disappeared when approximately 5% of the systemic dose was suffused for 30 minutes, this dose (which happens to approximate the normal ratio of lung to systemic blood volume) was chosen as the starting point for the Phase I clinical trial. Cisplatin was also chosen because it is a familiar agent with efficacy in lung malignancy and tissue uptake kinetics that would be suitable for a 30-minute delivery.

Phase I Clinical Trial Design
This nonblinded, prospective dose-escalation trial was approved by the Institutional Review Board at Roswell Park Cancer Institute on May 8, 2007, and individual consent was obtained for all participants. The objective of the study is to determine the dose-limiting toxicities (DLT) of a single infusion of cisplatin administered directly to the PA to the lung in patients with advanced non–small cell lung cancer. The cisplatin dose is assigned at registration. Lung circulation is controlled surgically (thoracoscopy) to isolate the cisplatin to the desired side for 30 minutes (see below). The starting dose was 5% of systemic dose (3.75 mg/m2). Administration of standard systemic chemotherapy for stage IV disease begins approximately 2 weeks thereafter. Cohorts of 3 to 6 patients are used for each infusion dose. Doses are escalated to the next dose level (ie, at 5.625 mg/m2, 7.5 mg/m2, 11.25 mg/m2, 15 mg/m2, and so on) until DLT is reached (Fig 2). A standard platinum-based combination regimen (eg, cisplatin 75 mg/m2 plus docetaxel 75 mg/m2 on day 1 every 21 days) is used and managed by medical oncologists as per current standard of care and administered about 2 weeks after suffusion. Serum samples for platinum are measured (1) before PA release (at which time samples will be from the isolated pulmonary circulation and systemic circulation) and then (2) 15 minutes and (3) 1 hour from the first draw. Pulmonary arterial blood and 2 x 2-cm lung samples are obtained approximately 30 minutes after infusion just before control release. Chest roentgenogram, pulse oximetry, and dyspnea scale at days 2, 3, 7 (each ±1) and 30 ± 5 after infusion are performed. A 6-minute walk is performed at days 7 ± 1 and 30 ± 5. Mediastinal irradiation is permitted sequentially after 30 days provided a restaging chest computed tomographic scan is obtained.


Figure 2
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  		Fig 2. Phase I study schema.

 
Eligibility
Eligibility requirements are biopsy-proven stage 4 non–small cell lung cancer with the bulk of disease in one lung, no clinical central nervous system disease, Eastern Cooperative Oncology Group performance status 0 or 1, no previous radiation for lung cancer, nonpregnant, no uncontrolled comorbid disease, no antiretroviral therapy for human immunodeficiency virus disease, no prior chemotherapy for metastatic disease (prior adjuvant therapy for lung cancer allowed), no supplemental oxygen requirements, Borg dyspnea scale less than 5, 6-minute walk greater than the lower limit of normal, forced expiratory volume in 1 second at least 50% predicted, diffusing capacity of carbon monoxide at least 50% predicted, vital capacity at least 50% predicted, and an ambulatory and resting oxygen saturation greater than 88%.

Study End Points
Acute pulmonary toxicities are assessed using National Cancer Institute common toxicity criteria, version 3 [7]. A grade 3 or above nonhematologic toxicity is considered a DLT in this study if attributed to the isolated lung suffusion procedure. In addition, grade 4 hematologic toxicity and any suffusion complications that prevent starting systemic chemotherapy within 2 weeks of the infusion are considered DLT.

Statistical Considerations
If 1 of 3 patients exhibit a DLT, the cohort is expanded to 6 patients. If 2 of 3 patients exhibit a DLT, no further dose escalation will occur and the previous dose level would be the maximally tolerated dose. The maximum tolerated dose was defined as one dose level below that which induced DLT in more than one third of patients (at least 2 of a maximum of 6 patients).

Suffusion Technique
Double-lumen endotracheal general anesthesia is initiated, a femoral venous access sheath is placed, and the targeted lung is collapsed with the patient in a lateral decubitus position. Three 1- to 2-cm ports are placed to dissect the pulmonary veins and are sufficiently anterior to access later when the patient is supine. The superior and inferior pulmonary veins are dissected at the pleural reflection level and encircled with silicone vessel loops (Aspen Surgical Products, Caledonia, MI). Each loop is circled around again so when retracted it snares and occludes the pulmonary vein (Fig 3). Generally, only one loop per major vein is needed; however, sometimes it is necessary to separately loop the lower lobe superior segmental vein or the middle lobe vein. Once the entire venous drainage can be controlled, the slack loop ends are brought out through nearby ports, secured using ties or clips and sutured to the subcutaneous tissue. A chest tube is placed through the former camera port, the other ports are closed temporarily, and the lung is reventilated. The patient is then placed supine, a small pad is placed beneath the operative side to facilitate access to the port incisions, and moderate rotation of the C-arm fluoroscopy compensates for angulation of the patient's torso.


Figure 3
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  		Fig 3. Intraoperative photo shows silicone snares around pulmonary veins. (L = lower; M = middle; P = phrenic nerve; R = right lung; U = upper.)

 
If not already established, venous access is attained; typically, we prefer femoral over jugular vein cannulation. The main PA is occluded by a 9F Arndt bronchial occlusion balloon (Cook Medical, Bloomington, IN). This catheter has a tapered low-pressure balloon, a central channel large enough to drain the distal PA, and a girth that requires placement through a 16F sheath. The desired main PA is selected with a J-tip or tip-deflecting wire and pigtail catheter. Over this wire, the 9F catheter is threaded and positioned in the proximal PA of the targeted lung. Angiographic contrast may be injected to confirm placement. Once positioned, the catheter channel is connected to a pressure transducer in an analogous fashion to flow-directed PA catheters. The balloon is test inflated to ensure safe, wedge positioning for the later chemotherapeutic injection. Next, the port sites are opened and the silicone vessel loops are extracted in preparation for venous occlusion. After intravenous infusion of 5,000 units of heparin, the following sequence is performed:
1 Pulmonary artery occlusion: The Arndt catheter balloon is inflated with air (5 to 10 mL) to occlude the targeted main PA. Air rather than fluid inflation allows balloon identification on fluoroscopy, prevents vascular injury, and permits easy catheter deflation.
2 Snaring of the pulmonary veins: The pulmonary veins are occluded by gentle retraction on the vessel loops. The loops are clamped near the hinge of standard hemostats thereby bridging the skin edges at the port site to provide stable tension. Pulmonary vein occlusion was confirmed visually during test snaring during the dissection phase. If needed to confirm just before chemotherapeutic injection, occlusion can also be shown by slow arterial transit with stasis in the venous phase after a small test radiographic contrast injection through the PA catheter.
3 Deflation of lung and aspiration of PA: Ipsilateral lung ventilation is ceased and the chest tube is vented. As the lung collapses, the PA catheter is aspirated to drain at least enough blood for the planned chemotherapeutic infusion and immediately reinfused through the side port of the femoral sheath. The unilateral lung blood volume is approximately 5% of the systemic volume but aspirating more than 1 to 2 mL/kg is unnecessary.
4 Reventilation and installation of chemotherapeutic agent: The lung is then ventilated to expand the vascular space while simultaneously injecting the chemotherapeutic agent. Ventilation is performed throughout the entire dwell time to enhance tissue permeation.
5 Dwell and reperfusion: Throughout the 30-minute dwell time, PA pressures are monitored. Early venous release should be considered if wedge pressure exceeds 50% systemic, although the balloon should pop out before that happens. Near dwell termination (immediately before releasing vascular control) the distal PA blood is sampled for residual chemotherapeutic concentration and vascular leak identification. The pulmonary veins are then released, followed by deflation of the PA balloon. If one limb of the slick vessel loop is cut, the silicone device will slide out without thoracoscopic assistance. To exclude vascular injury or obtain lung biopsies, repeat thoracoscopy is performed by removing the chest tube without shifting patient position. We use the former inferior anterior working port to place the camera, the superior port to grasp the lung, and the previous camera port to pass the stapler for lung biopsy.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Discussion
 Acknowledgments
 References
 
Between February and November 2008, 4 patients (3 female) ages 46 to 69 years underwent the procedure without complications and were discharged on the first or second postoperative day without chest tubes. Because there were no toxicities greater than grade 3 in the first 3 patients, the fourth case was performed at the next dose level and the study is ongoing. All patients continued on to standard chemotherapy and had some minor toxicity or adverse event (grades 1 through 3) not related to the suffusion.

Achieving surgical venous control consistently took less than 1 hour, and interventional venous access and PA control half that time except it was tedious assuring proper PA catheter position fluoroscopically in the lateral position for the first patient. Thereafter, the balloon occluder was placed after vein control while the patient was supine. Because this made it difficult to quickly reintroduce the thoracoscopic equipment to do the lung biopsy at the end of the suffusion as in the preclinical experiments, the lung biopsies were performed several minutes after reperfusion, reducing the levels below the assayable limits for the first 3 patients. No patient had any rise in the distal PA pressure during the dwell time.

Complete platinum concentration data were processed in batch for the 3 patients in dose level one. Cisplatin remained concentrated in the pulmonary circulation by the end of the dwell (mean, 1,124 versus 236 ng/mL systemic). Table 1 shows the separation of platinum followed by a soft peak and fall as seen in the preclinical experiments save for the first case in which catheter positioning was difficult. Split lung function testing showed unchanged perfusion for the 4 patients postoperatively, and lung forced vital capacity and diffusion capacities have shown minor fluctuation (Table 2). At 6 weeks, the patients' primary target lesions (after additional systemic chemotherapy) generally sustained considerable volumetric reductions whereas the other systemic metastases such as regional adenopathy were stable or improved. Two patients had metastatic lesions in the upper lobe of the suffused side that approached partial responses, but much less than the lower lobe primaries. Although the second patient had a slight reduction in the primary tumor, the tumor volume of bony metastases doubled within the first 6 weeks despite systemic chemotherapy (Fig 4). This patient's performance status declined because of dissemination of painful skeletal metastases, and he expired 8 months after the procedure as a result of disease progression. No postmortem lung examination was performed.


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  		Table 1 Serum Platinum Concentrations (ng/mL)
 

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  		Table 2 Study Group Update (as of March 2009)
 

Figure 4
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  		Fig 4. Representative computed tomographic images from first 3 patients. The middle panel shows the growth of the pelvic metastases (arrows) in patient 2 despite stable disease in suffused lung.

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Discussion
 Acknowledgments
 References
 
Despite the limited number of relatively frail patients with advanced malignancy, our results so far indicate safety and potential benefit from administration of regional chemotherapy with thoracoscopic lung suffusion, and further study is warranted. We did not observe differential pulmonary toxicity (split lung function remained stable); however, we saw a reduction in overall diffusing capacity that is similar to reductions we see from generalized chemotherapy at our institution.

Because the maneuvers described in this report are similar to commonly performed procedures, specifically pulmonary catheterization and pulmonary vein dissection, it should be feasible for others to replicate this work. We also believe that this technique may prove to be another therapeutic option for patients with unresectable tumors owing to either unfavorable anatomic location or inadequate postresectional reserves. Suffusion may be particularly useful to treat micrometastases within the lung as well as debulk the primary or metastatic tumors for resection.

Moreover, the scope of these treatments could be widened for lung tumors and other pulmonary maladies to delivery of agents that radiosensitize or enhance immune therapies. Cytokines such as interleukin 12 that are not well-tolerated by systemic infusion could be introduced locally by means of suffusion to induce a salutary immune response both in the primary tumor and in distant metastases [8]. Targeted gene therapy is also conceivable.

The lung's unique low-pressure vascular supply and low metabolic needs make suffusion possible without ischemic compromise of the organ; it is thus theoretically possible to amplify a safe systemic dose by 20-fold or reduce peripheral distribution reciprocally. It is possible that some elements of the suffusion procedure, such as temporary lung collapse by selective ventilation, could be eliminated for simplification. Also, because it was cumbersome from the supine position to obtain the lung biopsy thoracoscopically before the cisplatin was washed out (more important measurements were necessary at the end of dwell time), we amended the protocol to compare ipsilateral and contralateral bronchoalveolar lavage specimens at the end of suffusion. The protocol has also been expanded to allow metastasectomy patients who will provide tumors for assay as well as larger lung samples.

The morbidity of this procedure may be lessened further by atrial transseptal interventional techniques to eliminate thoracoscopy, or implantable venous occluders could enable repetitive treatments. Currently, because the vascular loops can slide out at the bedside, it is possible to shorten the operating room time and allow the suffusion to be carried out in the angiographic suite if desired.

Although our human experience is early and limited, isolated lung suffusion appears to be a safe, promising, and reproducible technique with numerous potential applications. We are continuing this trial with higher dose levels, and expanding inclusion criteria to patients with metastatic pulmonary disease from other primary sites.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
Acknowledgments
 References
 
DR ROBERT J. CERFOLIO (Birmingham, AL): Tell me about withdrawing the blood, and what made you get the idea that you needed to withdraw the blood? Did you have problems? And how do you know when the lung is really empty and bloodless?

DR DEMMY: In all these patients, we're monitoring the PA (pulmonary artery) pressure throughout the entire dwell time and it doesn't fluctuate. Based on the pulmonary thromboembolectomy experience, there's enough collateral flow between the systemic and the pulmonary circulations that you may not have to withdraw. The original concept was to make some room for the chemo, and that's what we did in the canine model. But it's possible that you wouldn't have to. We only draw enough to reach a certain level, about twice the volume of chemo that we're going to give.

DR CERFOLIO: So your plan is to keep doing that step or not?

DR DEMMY: I'm going to continue to do it until we finish the trial.

DR JOSEPH B. SHRAGER (Stanford, CA): Very impressive work and a smart idea.

I have another technical question. Do you have to occlude the veins? Have you taken any measures of drug concentrations when you do or don't occlude the veins?

DR DEMMY: The early research simply placing a catheter and just doing infusions didn't work well. I got the idea for this because retrograde cardioplegia is very important for heart surgery.

DR SHRAGER: I've heard of it.

(Laughter.)

DR DEMMY: Right. It turns out if you give antegrade but you occlude the vein, the coronary sinus, you get the same sinusoidal filling of the entire heart. That was basically the idea behind this, and it seems to work. So I think the venous control is very important, because the chemo basically fills the lung and then it just slowly suffuses the organ and then leaks out slowly into the systemic circulation.

DR SHRAGER: And how far did Mike Burt get doing similar stuff? I don't really know the literature on this, but I know he was working on whole-lung vascular perfusion in sarcoma. Did that only get as far as animal models?

DR DEMMY: Yes, and they did a human trial with doxorubicin, but that led to pump physiology with issues of interface with plastic biosurfaces and then a big reservoir full of chemo to potentially leak systemically. So this offers a lot of advantages because you're only going to give a safe dose, but amplify it 20 times by the volume of distribution. Or you can take what would ordinarily be a safe systemic dose, reduce it to 5%, to deliver the same proportional amount to the tumor in a patient who is frail and can't tolerate chemo.

DR W.J.P. VAN BOVEN (Zeist, Netherlands): We have some experimental experience also infusing chemotherapy selectively in the pulmonary artery in pig models, and what we did was routinely take samples after infusion of this chemotherapy and measure the concentration of the chemotherapy in the parenchyma. Did you do samples in your experimental setting or during your VATS (video-assisted thoracoscopic surgery) procedure taking little wedges from the parenchyma of the lung and measure concentrations?

DR DEMMY: In the experimental data, we have the platinum washout curves for the various dosage levels. It does also concentrate, though some of it seems to be in the interstitium and washes out quickly when you take off the tapes because the normal lung doesn't hold quite as much of the platinum. When we started this experiment, we wanted to do the biopsy in the lateral position, but it wasn't practical. So we've done lung samples, but we've done them after we release because of the difficulty putting the scope in and getting it in the time allotted. So I think we're not going to be able to document as much of that platinum separation like we did in our preclinical experiments.

DR VAN BOVEN: Did you take these samples from different parts of the lung? I think that information about distribution and diffusion of chemo into the healthy parenchyma and also into tumor tissue is important. It should be equally distributed.

DR DEMMY: Right, it does. The interesting thing is that the ipsilateral lymphatics showed a lot of atrophy in the preclinical experiments. So if you're interested in minimal residual disease, it's kind of cool. What we observed was very reproducible in the preclinical work. The whole lung was affected by the chemotherapy dose diffusely, both histologically and grossly.

DR MICHAEL LANUTI (Boston, MA): Thank you for this interesting work.

Why not use the PA catheter as your infusion catheter?

DR DEMMY: We do. Maybe I didn't make that clear, but it goes through the femoral vein. We found the femoral route was the easiest. You could use a Swan, but the balloon is too small for main pulmonary artery occlusion in many patients.

DR LANUTI: Yes, but you could navigate the catheter into a lobar pulmonary artery under fluoroscopy or under direct thoracoscopic assistance. If you were in the main pulmonary artery, I agree, the balloon may be too small.

DR DEMMY: Yes. We wanted to do the whole lung to get the whole effect, but I think you could do regional just to do that lobe. If you want to really get the whole draining lymphatic basin, you might have to do the whole lung. That's why we used that different catheter off-label.

DR CERFOLIO: But that part commits you to go into the groin.

DR DEMMY: Because you need a big sheath to use that floppy balloon, but I think that's just device development issue.

DR JESSICA S. DONINGTON (New York, NY): I actually participated in a lot of the isolated lung perfusion work. We often added heat in our isolated perfusions. Does this system have that ability?

DR DEMMY: I suppose, yes, that the lung would be more susceptible to topical heat-exchange with its circulation impeded. Through these port sites, you probably could circulate warm fluid, just like in the abdominal heated chemotherapy that's being used clinically.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 Acknowledgments
References
 
The authors wish to thank Michele Cooper, Jonah H. Patel, Reema Mallick, Peter Kanter, DVM, PhD, Dongfeng Tan, MD, Thaer Khoury, MD, Jorge Gomez, MD, and the rest of the Clinical Research Services staff involved with this project.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 

  1. Bartlett DL, Libutti SK, Figg WD, Fraker DL, Alexander HR. Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer Surgery 2001;129:176-187.[Medline]
  2. Lienard D, Ewalenko P, Delmotte JJ, Renard N, Lejeune FJ. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma J Clin Oncol 1992;10:52-60.[Medline]
  3. Grootenboers MJ, Heeren J, Van Putte BP, et al. Isolated lung perfusion for pulmonary metastases, a review and work in progress Perfusion 2006;21:267-276.[Abstract/Free Full Text]
  4. Pass HI, Mew DJ, Kranda KC, Temeck BK, Donington JS, Rosenberg SA. Isolated lung perfusion with tumor necrosis factor for pulmonary metastases Ann Thorac Surg 1996;61:1609-1617.[Abstract/Free Full Text]
  5. Weksler B, Burt M. Isolated lung perfusion with antineoplastic agents for pulmonary metastases Chest Surg Clin N Am 1998;8:157-182.[Medline]
  6. Demmy TL, Wagner-Mann C, Allen A. Isolated lung chemotherapeutic infusions for treatment of pulmonary metastases: a pilot study J Biomed Sci 2002;9:334-338.[Medline]
  7. [No authors listed] Common terminology criteria for adverse events (CTCAE) v3National Cancer Institute; 2009Available at: http://www.fda.gov/cder/cancer/toxicityframe.htm. Accessed May 26, 2009.
  8. Hess SD, Egilmez NK, Bailey N, et al. Human CD4+ T cells present within the microenvironment of human lung tumors are mobilized by the local and sustained release of IL-12 to kill tumors in situ by indirect effects of IFN-gamma J Immunol 2003;170:400-412.[Abstract/Free Full Text]




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