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ORIGINAL ARTICLES |
From the Departments of Surgical Oncology (SvR, EJTR, VJV, FANZ), Thoracic Oncology (PB), and Radiotherapy (RLMH), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Correspondence: Address correspondence and reprint requests to: S. van Ruth, MD, Department of Surgical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Fax: 31-20-5122554; E-mail: s.v.ruth{at}nki.nl
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: From August 1998 to August 2001, 22 patients with stage I MPM were included in this study. Two patients were irresectable at operation because of extrathoracic tumor growth. Twenty procedures were performed. After cytoreduction, a perfusion was performed with cisplatin and doxorubicin at 40°C to 41°C for 90 minutes. Adjuvant radiotherapy was given to surgical scars and drainage tracts.
Results: There was no perioperative mortality, but significant morbidity was seen in 13 patients (65%), including bronchopleural fistula, diaphragm rupture, wound dehiscence, persistent air leakage, and chylous effusion. No hair loss or leucopenia was noticed. The median follow-up was 14 months. The median survival (Kaplan-Meier) was 11 months, with a 1-year survival of 42%. A favorable pharmacokinetic ratio was observed for both cisplatin and doxorubicin.
Conclusions: Cytoreductive surgery combined with hyperthermic intrathoracic chemotherapy for stage I MPM is feasible. However, this treatment is accompanied by considerable morbidity. Survival data were less encouraging.
Key Words: Mesothelioma • Cytoreductive surgery • Hyperthermic perfusion • Chemotherapy • Multimodality treatment • HITHOC
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Surgical Cytoreduction
A double-lumen endotracheal tube was used. A posterolateral thoracotomy through the sixth intercostal space was performed. An extrapleural dissection between the chest wall, diaphragm, and mediastinum on one side and the parietal pleura on the other side was continued until the hilar structures were free. The thickened pleural sheets were removed from the underlying healthy tissue, either visceral pleura or pulmonary parenchyma. After this decortication, the viability of the lung was assessed. A pneumonectomy was performed when there was no sufficient viability of the lung after decortication or when the lung was too involved with tumor (when decortication was not possible). Extensive surgical cytoreduction was performed with the aim of reducing the residual tumor to <2.5 mm, which is thought to be the maximum penetration depth of the cytostatic drugs we used. The debulking was considered incomplete when 
2.5 mm of residual tumor was left behind.
Score of Tumor Extent
Before cytoreduction, the tumor extent was scored by assessing the presence of tumor in the upper visceral pleura, lower visceral pleura, upper parietal pleura, sinus/diaphragm, pericardium/mediastinum, and pleural fluid. The tumor extent was again scored after the cytoreduction. We recorded the opening of the pericardium and/or diaphragm and when a pneumonectomy was performed.
Intraoperative HITHOC
After complete cytoreduction, the perfusion system was set up (Fig. 1). A Tenckoff inflow catheter and three silicone outflow catheters were placed in the thoracic cavity—usually one in the pleural cavity top, one in the posterior diaphragm sinus, and one in the anterior diaphragm sinus. A temperature sensor was attached to each catheter. The thoracotomy wound was watertight and closed with sutures for the period of perfusion. The catheters were connected with a fluid filter, roller pump, and heat exchanger. Thereafter, the closed system was filled with an isotonic dialysis fluid (Dianeal PD1; Baxter, Uden, The Netherlands). When a temperature of 40°C to 41°C was reached in all regions, cisplatin and doxorubicin were added to the perfusion fluid. A fixed dose of cisplatin 80 mg/m2 and doxorubicin starting at 20 mg/m2, with increments of 5 mg/m2 per dose step, were used. A different dose method was applied for the last six patients. Cisplatin was given with a fixed dose of 40 mg/L of perfusion liquid. Doxorubicin was given in three patients with a dose of 18 mg/L of perfusion liquid; three other patients were given doxorubicin 21 mg/L of perfusion liquid. The core temperature, measured in the pharynx, was registered. If the core temperature exceeded 39°C, the temperature of the perfusion fluid was decreased to 40°C to maintain the core temperature at <39.5°C. The duration of perfusion was 90 minutes with a flow of 1 L/min. During the perfusion, the contralateral lung was ventilated separately. The ipsilateral lung was inflated at a pressure of 15 cm H2O with oxygen; this kept the lung semi-inflated and allowed sufficient space between the parietal and visceral pleura for adequate perfusion, but limited the possible toxicity of cytostatic drugs to the lung parenchyma. At the completion of perfusion, fluid was removed, and drains were left in the pleural top and sinus. Thereafter, the chest wall was closed in the regular way.
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Follow-Up and Recurrences
Perioperative mortality was defined as death within 30 days after operation. Morbidity consisted of in-hospital and out-of-hospital complications. Chest computed tomograms were performed every 3 months after the operation for 2 years and then every 6 months thereafter. Recurrence of disease was documented by fine-needle aspiration or histological biopsy, if possible.
Statistical Analysis
Survival was determined from the date of operation to the date of death or the date of last follow-up. Overall survival was calculated according to the Kaplan-Meier method. Statistical analysis was performed with SPSS software (SPSS, Inc., Chicago, IL). Differences in survival between the pleurectomy/decortication group and the pleuropneumonectomy group were tested with the log-rank test. A P value of <.05 was considered significant. The area under the curve (AUC) was calculated by using the linear trapezoid rule without extrapolation to infinity (AUC0–90); samples from both perfusate and blood were taken for measurements (perfusate: 1, 30, and 90 minutes; blood: 1, 10, 15, 45, 60, 75, and 90 minutes).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Surgical Procedure and Intraoperative HITHOC
Before cytoreduction, tumor presence was scored: upper visceral pleura, 17 patients (85%); lower visceral pleura, 17 patients (85%); upper parietal pleura, 18 patients (90%); sinus/diaphragm, 20 patients (100%); and pericardium/mediastinum, 19 patients (95%). Pleural fluid was found in 16 patients (80%). After cytoreduction, tumor presence was again scored: upper visceral pleura, five patients (25%); lower visceral pleura, five patients (25%); upper parietal pleura, one patient (5%); sinus/diaphragm, two patients (10%); and pericardium/mediastinum, two patients (10%). Fifteen patients (75%) were optimally debulked (estimated residual tumor <2.5 mm). An example of optimal debulking is shown in Fig. 2. In five patients, resection was incomplete; residual tumor was mostly confined to the visceral pleura and the sinus/diaphragm.
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The median amount of perfusion liquid was 4.8 L (range, 3–7 L). One perfusion was aborted after 80 minutes because of hemodynamic instability. The highest core temperature before perfusion varied from 35.3°C to 38.9°C. During perfusion, the highest core temperature varied from 36.8°C to 39.4°C, a mean increase of .9°C. In three procedures, the temperature of the perfusion fluid had to be decreased to 40°C.
The median blood loss was 1758 mL (range, 400–4615 mL). The median amount of packed red blood cells given was 2 U (range, 0–4 U).
The median hospital stay was 17 days (range, 11–77 days). The median intensive care unit stay was 4 days (range, 1–7 days). There was no mortality. Significant morbidity was noticed in 13 patients (65%). Complications are listed in Table 1. The number of complications in the pleurectomy/decortication group was comparable to the number of complications in the pleuropneumonectomy group. Complications in the pleuropneumonectomy group included pulmonary emboli (n = 2) and bronchopleural fistula (n = 3), indicating that the effect of a complication in the pleuropneumonectomy group seemed larger than in the pleurectomy/decortication group. Well-known chemotherapy-related complications, such as leucopenia or hair loss, were not observed. A transient increase of serum creatinine was noticed in one patient. The maximum dose of doxorubicin reached was 35 mg/m2. After that, the dosage method was changed to one based on the amount of perfusion liquid, as reported in Patients and Methods. The mean AUC perfusate:plasma ratios for cisplatin and doxorubicin were, respectively, 59 and 181; however, these ratios may represent overestimates because no extrapolation to infinity was applied.
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Survival and Recurrences
The median follow-up was 14 months (range, 5–29 months), with a median survival of 11 months (range, 3–19 months). The 1-year overall survival was 42% (Fig. 3). The disease state at last follow-up is listed in Table 2. Fourteen patients developed recurrent disease after a median period of 8 months (range, 2–14 months). Abdominal recurrences were found in four patients. In three (75%) of these patients, the diaphragm was opened during surgery. In 10 of 16 patients without abdominal recurrence, the diaphragm was also opened. Opening of the pericardium did not influence the localization of the recurrence. The calculated median time to progression was 8 months (range, 2–14 months). Eleven patients died of disease after a median period of 9 months (range, 3–16 months). Three patients are alive with signs of disease after 10, 18, and 19 months. One patient died without evidence of disease 4 months after the HITHOC procedure. This patient had a fatal hemorrhage at home, probably caused by acute bleeding from the pulmonary vessels, 1 month after a Clagett procedure for empyema. Five patients are alive without signs of recurrent disease after a median of 7 months (range, 4–8 months). No difference in survival was observed between the pleurectomy/decortication group and the pleuropneumonectomy group (log-rank test; P = .67).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Ratto et al.12 demonstrated that hyperthermic intrathoracic perfusion with cisplatin had pharmacokinetic advantages with limited systemic toxicity. They reported on 10 patients with MPM. A pleurectomy/decortication was performed in three patients, followed by normothermic perfusion. Three other patients had a pleurectomy/decortication with hyperthermic perfusion, and four a pleuropneumonectomy with hyperthermic perfusion. All perfusions were performed with cisplatin alone. Systemic drug concentrations were higher after pleurectomy/decortication than after pleuropneumonectomy. The local tissue/perfusate ratio of platinum concentrations tended to be higher after hyperthermic perfusion rather than with normothermic perfusion. Major postoperative complications included one wound infection and one diaphragmatic prosthesis displacement (which required reoperation), and four patients developed a transient postoperative increase in serum creatinine. No survival data were described.12 Yellin et al.13 treated seven patients with MPM. A combination of surgery and intraoperative hyperthermic pleural perfusion with cisplatin during 60 minutes was used. The technique was feasible, easy to perform, and relatively safe. Three patients had a complication: one late empyema, one gastric herniation, and one late empyema with bronchopleural fistula. A median survival of 15 months was reported. Two patients survived >30 months.13 Carry et al.14 treated three patients with stage I MPM with pleurectomy followed by hyperthermic intrathoracic perfusion with mitomycin C. The only reported complication was pleural clotting, which necessitated surgery. One patient died of hepatic metastasis 4 months after therapy. Another patient died after 11 months because of pleural and systemic recurrent disease. One patient is alive with disease after 22 months.14
In this study, we report the results of 20 patients with stage I MPM who underwent surgery combined with intraoperative HITHOC. Cisplatin and doxorubicin, both direct cytotoxic agents, were applied because MPM is relatively sensitive to these agents.15 A favorable pharmacokinetic ratio was found for both cisplatin and doxorubicin. A pneumonectomy was performed only when the lung was overly involved or was damaged, because survival after pleurectomy seems equal to survival after pleuropneumonectomy; however, performing a pneumonectomy results in a higher morbidity and mortality.16 A pneumonectomy was deemed necessary in 40%, indicating the difficulty of staging correctly before surgery.17 In comparison of the three above-mentioned studies, we found a high complication rate of 65%. However, other large studies18,19 with multimodality treatment for MPM also report high complication rates of approximately 50%. All complications in our study, except one bronchopleural fistula, could be treated successfully. No chemotherapy-related complications were observed. A transient slight increase of serum creatinine was noticed in only one patient. Unfortunately, the survival figures are disappointing. So far, we find a median survival of 11 months, indicating the failure of this treatment modality to significantly improve survival over the natural course of MPM. Most recurrences were in the same hemithorax, despite extensive local treatment. Opening the diaphragm did not seem to influence the development of abdominal recurrence in our study. When we compare our results with those of the multimodality treatment of Sugarbaker et al.,18 we show worse survival. Sugarbaker et al.18 reported a median survival of 21 months and a 2-year survival of 42% in 136 lymph node–negative patients. In that study, the treatment consisted of extrapleural pneumonectomy followed by postoperative systemic chemotherapy and hemithorax radiotherapy. A study of Rusch et al.,20 with a median survival of 17 months, also included hemithorax radiation.20 As to the reasons for failure, three explanations are possible: mesothelioma cells are truly insensitive to doxorubicin and cisplatin, our way of application fails to reach all tumor cells, or both of these. A preliminary study in our center indicates a penetration depth of doxorubicin of only a few cell layers (S. van Ruth, MD, unpublished data, July 2002). The penetration depth of cisplatin is only a few millimeters.2 It seems likely, therefore, that we just did not reach all tumor residue. Possibly further dose increases could improve results. The addition of systemic chemotherapy or hemithorax radiation can also be considered. On the basis of our disappointing results, we conclude that even with extensive surgery, better cytotoxic agents are required to achieve long-term survival. Because of the high morbidity rate, HITHOC cannot be recommended as palliation for MPM.
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Footnotes |
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Received for publication March 15, 2002. Accepted for publication September 17, 2002.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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