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Ann Thorac Surg 1995;59:127-131
© 1995 The Society of Thoracic Surgeons

Intrapleural Perfusion Hyperthermo-Chemotherapy for Malignant Pleural Dissemination and Effusion

Yasunori Matsuzaki, MD, Koichiro Shibata, MD, Makoto Yoshioka, MD, Masakuni Inoue, MD, Ryo Sekiya, MD, Toshio Onitsuka, MD, Isao Iwamoto, MD, Yasunori Koga, MD

Second Department of Surgery, Miyazaki Medical College, Miyazaki, Japan

Accepted for publication July 13, 1994.


   Abstract
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 Footnotes
 Abstract
Introduction
 Patients
 Material and Methods
 Results
 Comment
 References
 
Taking advantage of the antitumor effect of hyperthermia, we administered intrapleural perfusion hyperthermo-chemotherapy for the treatment of malignant pleural seeding or pleural effusion. This consists of irrigating the pleural space for 2 hours with 43°C saline solution containing cis-platinum using specially devised extracorporeal circuits. From January 1988 through December 1993, we performed this technique in 12 patients with malignant disseminated lesions stemming from lung cancer who also underwent surgical resection of the primary lesions and in 7 patients with malignant pleural effusions who did not undergo thoracotomy or surgical resection. There were no serious clinical complications associated with this procedure. The pharmacokinetics showed that a high concentration of cis-platinum (more than 17.6 µg/mL in the free form) was retained in the pleural cavity during perfusion. After this therapy, the cancer cells showed marked degeneration with fibrosis in the pleural wall. The pleural effusion was well controlled in 100% of the patients. The median survival time in the 12 patients with pleural disseminated lesions who were treated with intrapleural perfusion hyperthermo-chemotherapy was 20 months. On the other hand, the median survival time in 7 patients with similar lesions who did not receive IPHC was only 6 months. Intrapleural perfusion hyperthermo-chemotherapy seems to have considerable value as an adjuvant therapy for patients with pleural dissemination who have had their primary lesions removed.


   Introduction
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 Introduction
Patients
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 References
 
Attempts to treat intrapleural disseminated lesions and malignant pleural effusion in patients with advanced lung cancer by pleurotomy and the intrapleural injection of sclerosing drugs have not met with success [1]. In an experimental study, we investigated the antitumor effect of regional hyperthermia [2, 3]. We subsequently introduced the technique of intrapleural perfusion hyperthermo-chemotherapy (IPHC), which involved the use of a hyperthermic perfusion method, as a new therapy for patients with intrapleural disseminated lesions and malignant pleural effusion. This technique, combined with the administration of cis-platinum (CDDP), achieved enhanced antitumor effects in combination with hyperthermic therapy.

We carried out IPHC in 12 patients with malignant pleural disseminated lesions detected at thoracotomy for the treatment of lung cancer and in 7 patients with malignant pleural effusion who did not undergo thoracotomy. The effectiveness of IPHC was then evaluated from the standpoint of the recurrence of effusion and the survival rate.


   Patients
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 Patients
Material and Methods
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During January 1988 through December 1993, IPHC was carried out in 12 patients with lung cancer who had intrapleural disseminated lesions recognized at thoracotomy and who also underwent resection of their primary lesions (group A) and in 7 patients with malignant pleural effusions detected by chest x-ray studies, computed tomography, or thoracentesis who did not undergo thoracotomy (group B), as shown in Table 1Go. There were 9 male and 10 female patients, and the ages ranged from 33 to 79 years (mean, 59.7 years). Seventeen patients had primary adenocarcinoma of the lung and 2 had lesions metastatic to the lung, one was an adenocarcinoma stemming from breast cancer and the other was a submaxillar osteosarcoma. To assess the effect of IPHC, the survival rate was compared with those in 7 patients with intrapleural dissemination found at thoracotomy (group C) and in 9 patients with a malignant pleural effusion (group D) who did not receive IPHC. Informed consent was obtained in all patients before instituting IPHC.


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  		Table 1. . Patients Who Received Intrapleural Perfusion Hyperthermo-Chemotherapy
 

   Material and Methods
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 Patients
 Material and Methods
Results
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 References
 
When the disseminated lesions were noted at thoracotomy for the treatment of lung cancer, the primary lesions were locally resected followed by intrapleural hyperthermic perfusion administered through the thoracotomy space, as shown in Figure 1Go. Two tubes connected with a specially devised circuit (modified CRPH-3000C; Mera, Tokyo, Japan) were placed in the pleural cavity using a double-lumen tracheal tube with the patient under general anesthesia. In the patients with pleural effusion (group B), IPHC was performed by inserting two intrapleural tubes without thoracotomy.



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  		Fig 1. . Schema of intrapleural perfusion hyperthermo-chemotherapy during thoracotomy. (CDDP = cis-platinum.)

 
As combined chemotherapy, 200 mg/m2 of CDDP was perfused in 19 patients because it has been shown both in vitro [4] and in vivo [5] to have an enhanced effect in combination with hyperthermia. The CDDP was perfused through the circuit while the temperature was increased. All fluid in the thoracic cavity was removed at the end of perfusion. Before this protocol was tried, the absorption of CDDP by blood when delivered to the intrapleural space at a concentration of 200 mg/m2 in 2 L of saline solution was examined to evaluate its toxicity, as shown in Figure 2Go. The platinum concentration in serum peaked 2 hours after the beginning of perfusion; it was 1.8 µg/mL in total and 0.5 µg/mL in the free form. These values were approximately half and one-quarter the levels obtained with the systemic administration of CDDP (80 mg/m2). No significant changes were noted in the blood chemistry test results, such as the creatinine, blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, and hemoglobin concentrations and the white blood cell, red blood cell, and platelet counts because its passage into blood was insignificant. Neither nausea nor vomiting developed. To measure the temperature of the intrapleural cavity during IPHC, temperature monitoring probes were fixed on the surface of the pleura, the irrigation inlet and outlet, and the thoracic esophagus by means of transnasal insertion. We carefully controlled the pump flow and heat exchanger of our specially devised circuit to maintain a temperature of 43°C at the pleural surface.



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  		Fig 2. . Platinum concentration in serum. (IPHC = intrapleural perfusion hyperthermo-chemotherapy; SD = standard deviation.)

 
In animal experiments, we observed that pulmonary edema could develop after hyperthermia at 43°C for 3 hours of perfusion, and that the administration of methylprednisolone decreased such pulmonary edema [6]. Therefore, we administered 1,000 mg of methylprednisolone intravenously to prevent pulmonary edema from developing during IPHC.

The effectiveness of IPHC was evaluated in terms of (1) the hemodynamic and temperature changes at the monitored sites during IPHC; (2) the accumulation of pleural fluid and the cytologic changes in the cancer cells after IPHC; (3) the platinum concentration in the pleural effusion and serum during IPHC; (4) the platinum concentration in the pleural metastatic tissue biopsied during IPHC; and (5) the survival rate based on comparison of groups A and B with C and D. The survival rate for each group was calculated by the Kaplan-Meier method.


   Results
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 Abstract
 Introduction
 Patients
 Material and Methods
 Results
Comment
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With a pump flow rate of 1 L/min, the temperature at the pleural surface stabilized at 43°C in about 5 minutes. Figure 3Go shows the changes in the temperature at each measured site. The maximum temperature in the thoracic esophagus was less than 38.3°C compared with the rise in temperature on the pleural surface. Changes in blood pressure and the pulmonary artery pressure were mild, with the exception of a slight increase in cardiac output during IPHC. Blood gas analysis and blood biochemistry testing revealed a slight metabolic acidosis and a decline in the serum albumin levels (Table 2Go). The systemic influence of IPHC was considered mild. Histologically, cancer cells in the pleural effusion immediately after 2 hours of perfusion showed degenerative findings such as swelling of cells and intracellular vacuoles, characteristics not seen in the cancer cells before IPHC, as shown in Figure 4Go.



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  		Fig 3. . Temperature changes during intrapleural perfusion hyperthermo-chemotherapy (IPHC).

 

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  		Table 2. . Laboratory Data in 10 Patients Receiving Intrapleural Perfusion Hyperthermo-Chemotherapya
 


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  		Fig 4. . Microscopic findings of cancer cells (x400 before 53% reduction.) (A) Before intrapleural perfusion hyperthermo-chemotherapy. (B) After therapy, cancer cells showed degenerative characteristics, such as swelling of cells and intracellular vacuoles (arrows).

 
From the standpoint of complications, 2 patients showed transient pulmonary infiltrates on the affected side on chest x-ray films postoperatively. These shadows disappeared spontaneously by the following day. A high platinum concentration in the pleural effusion was obtained during IPHC (Fig 5Go). As to the level of platinum in the free form, which is considered the active form, it was maintained at more than 33.7 µg/mL during perfusion and was 4.1 µg/mL 24 hours after IPHC. The level of free-form platinum in metastatic tissue on the surface of the pleura was 16.7 µg/g 2 hours after IPHC. Reaccumulation of the pleural effusion was not observed in any of the 19 patients who received IPHC. Control of the pleural effusion was 100% effective.



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  		Fig 5. . Platinum concentration in perfusate. (IPHC = intrapleural perfusion hyperthermo-chemotherapy; SD = standard deviation.)

 
The median survival times in the various groups of patients were as follows: group A, 20 months; group B, 6 months; group C, 6 months; and group D, 11 months. The survival rates of group A versus group C and group B versus group D are shown in Figures 6 and 7GoGo, respectively.



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  		Fig 6. . Survival rates in the patients in group A (pleural disseminated lesions treated by intrapleural perfusion hyperthermo-chemotherapy) and group C (similar lesions not treated with intrapleural perfusion hyperthermo-chemotherapy). Group A versus group C: p < 0.01.

 


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  		Fig 7. . Survival rates in the patients in group B (malignant pleural effusion treated by intrapleural perfusion hyperthermo-chemotherapy) and group D (malignant pleural effusion not treated with intrapleural perfusion hyperthermo-chemotherapy). Group B versus group D: not significant.

 

   Comment
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 Footnotes
 Abstract
 Introduction
 Patients
 Material and Methods
 Results
 Comment
References
 
There have been a few reports on the use of radiofrequency hyperthermia in the treatment of lung cancer [7–11]. These radiofrequency hyperthermia methods have involved some problems, such as (1) extensive loss or radiation of heating energy due to respiratory ventilation and abundant pulmonary blood flow; (2) poor thermal conduction by radiofrequency because of the air in the lung; and (3) differing heat distribution according to the physique of the patient and the location of the tumor. The present hyperthermic perfusion technique is excellent, in that the entire inner cavity can be heated uniformly by collapsing one lung, but this requires general anesthesia. The temperature in the thoracic esophagus did not exceed 38.3°C during IPHC for 2 hours, with 43°C measured at the pleural surface, and this technique could be employed safely because its systemic effects were slight. This suggests that thermal conduction by IPHC does not penetrate more than 10 mm from the surface of the pleural wall. These results suggest that this technique would be appropriate for the treatment of pleural disseminated lesions.

Furthermore, the effectiveness of the conventional drug injection technique could be enhanced. Cis-platinum was perfused during IPHC because it is currently the most effective agent for the control of non–small cell lung carcinoma, and we have found its antitumor effect to be enhanced by hyperthermia. Based on the findings from the phase I study conducted by Zimm and associates [12], we used a 200-mg/m2 dose of CDDP for intrapleural perfusion. At this dose, there were low levels of CDDP in the serum, suggesting that the dose in the perfusate could be increased beyond 200 mg/m2. We plan to do a dose escalation study using our procedure. Intrapleural perfusion hyperthermo-chemotherapy produced marked degenerative changes in the cancer cells. A total cell kill has been reported to be achieved by a 10-µg/mL concentration of CDDP (free platinum) in vitro [13]. We were able to maintain levels of more than 33.7 µg/mL of CDDP (free platinum) in the perfusate and of 16.7 µg/g of CDDP (free platinum) in pleural metastatic tissue during 2 hours of perfusion, without any side effects. The pleural effusion was well controlled in all patients, probably through the antitumor effect of IPHC.

Because of the pulmonary infiltration shadows that appeared on the chest x-ray films in 2 patients after IPHC, this suggests that the lung is sensitive to heat and that one must be careful with the lung during IPHC. On the basis of Yoshioka's report [6] of the protective effect of steroids against heat damage to the lung, we administered 1,000 mg of methylprednisolone intravenously during IPHC. However, it is well known that methylprednisolone can also blunt the effects of chemotherapy. Further in vivo studies of the effect of methylprednisolone on the cytotoxic response under conditions of hyperthermia in combination with CDDP therapy are necessary.

We have described a new technique of IPHC for patients with pleural dissemination whose primary lesions are resected. This technique is safe and can be carried out in conjunction with routine lung cancer operations whenever pleural dissemination is found. The patients in group A (pleural disseminated lesions treated by IPHC) showed prolonged survival compared with those in group C (similar lesions not treated by IPHC); however, group B (malignant pleural effusion treated by IPHC) and group D (malignant pleural effusion not treated by IPHC) patients showed almost the same survival curve. In the absence of randomized studies, we could not determine whether the prolonged survival in these patients was significant. However, our results do suggest that the primary indication for IPHC is in patients with malignant pleural disseminated lesions resulting from lung cancer who also undergo surgical resection of their primary lesions.


   Footnotes
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Abstract
 Introduction
 Patients
 Material and Methods
 Results
 Comment
 References
 
Address reprint requests to Dr Matsuzaki, Second Department of Surgery, Miyazaki Medical College, 5200 Kihara, Kiyotake-Cho, Miyazaki-Gun, Miyazaki, 889-16, Japan.


   References
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 Footnotes
 Abstract
 Introduction
 Patients
 Material and Methods
 Results
 Comment
 References
 

  1. Albain KS, Hoffman PC, Little AG, et al. Pleural involvement in stage III M0 non–small cell bronchogenic carcinoma. Am J Clin Oncol 1986;9:255–61.[Medline]
  2. Matsuzaki Y. Experimental studies of hyperthermia against MH134 tumor on mice-antitumor effects under various conditions of heating. J Jpn Surg Soc 1984;85:633–42.
  3. Matsuzaki Y, Yoshioka M, Yonezawa T, Onitsuka T, Shibata K, Koga Y. Thermotolerance in regional hyperthermia in vivo-an experimental study using MH134 tumor. Jpn J Surg 1990;21:69–74.
  4. Herman TS, Teicher BA, Collins LS. Effect of hyperthermia and acidosis on the cytotoxicity of four platinum complexes at normal and hyperthermic temperatures. Cancer Res 1988;48:2342–7.[Abstract/Free Full Text]
  5. Yatvin MB, Muhlensiepen H, Porschen W, et al. Selective delivery of liposome-associated cis-dichlorodiammineplatinum (II) by heat and its influence on tumor drug uptake and growth. Cancer Res 1981;41:1602–7.[Abstract/Free Full Text]
  6. Yoshioka M, Shibata K, Matsuzaki Y, Yonezawa T, Koga Y. Experimental study on acute heat injury of the lung induced by whole body hyperthermia. Jpn J Hypertherm Oncol 1986;2:181–90.
  7. Baker HW, Snedecor PA, Goss JC, et al. Regional hyperthermia for cancer. Am J Surg 1982;143:586–90.[Medline]
  8. LeVeen HH, Ahmed N, Piccone VA, Shugaar S, Falk G. Radiofrequency therapy: clinical experience. Ann NY Acad Sci 1980;335:362–71.[Medline]
  9. Matsuda T, Tanaka Y, Takeshita N. Hyperthermia in the treatment of lung cancer and mediastinal tumor. Saishinigaku 1985;40:2558–63.
  10. Hiraoka M, Jo S, Akuta K, et al. Radiofrequency capacitive hyperthermia for deep-seated tumors: I. Study on thermometry. Cancer 1987;60:121–7.[Medline]
  11. Kodama K, Doi O, Tatsuta M, Kuriyama K, Tateishi R. Development of postoperative intrathoracic chemo-thermotherapy for lung cancer with the objective of improving local cure. Cancer 1989;64:1422–8.[Medline]
  12. Zimm S, Cleary SM, Lucas WE, et al. Phase I/pharmacokinetic study of intraperitoneal cisplatin and etoposide. Cancer Res 1987;47:1712–16.[Abstract/Free Full Text]
  13. Kodama K, Doi O, Kurokawa E, Terasawa T. Local chemohyperthermotherapy for lung cancer. J Jpn Lung Cancer Soc 1987;27:133–40.



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