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Phase I to II Study of Pleurectomy/Decortication and Intraoperative Intracavitary Hyperthermic Cisplatin Lavage for Mesothelioma

William G. Richards, Lambros Zellos, Raphael Bueno, Michael T. Jaklitsch, Pasi A. Jänne, Lucian R. Chirieac, Beow Y. Yeap, Rene J. Dekkers, Phillip M. Hartigan, Leah Capalbo, David J. Sugarbaker

From the Brigham and Women's Hospital; Dana-Farber Cancer Institute; and Massachusetts General Hospital, Boston, MA

Address reprint requests to David J. Sugarbaker, MD, Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115; e-mail: dsugarbaker{at}partners.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To evaluate morbidity, mortality, maximum-tolerated dose (MTD), and outcome of intraoperative intracavitary hyperthermic cisplatin lavage in patients undergoing pleurectomy for malignant pleural mesothelioma (MPM).

PATIENTS AND METHODS: Sixty-one patients were prospectively registered. Forty-four resectable patients with MPM underwent pleurectomy, followed by a 1-hour lavage of the resection cavity with dose-escalated cisplatin (50, 100, 150, 175, 200, 225, and 250 mg/m²) at 42°C and then intravenous sodium thiosulfate (16 g/m² over 6 hours). Survival estimates were compared using the log-rank test and proportional hazards regression.

RESULTS: Median age was 71 years (range, 50 to 82 years). Twenty-four patients had epithelial tumors, and 20 had sarcomatous or mixed histology. Postoperative mortality was 11% (five of 44 patients). Dose-limiting renal toxicity occurred at 250 mg/m², establishing the MTD at 225 mg/m². Other morbidity included atrial fibrillation (14 of 44 patients, 32%) and deep venous thrombosis (four of 44 patients, 9%). Median survival time of all registered patients was 9 months, and the median survival time of resected patients was 13 months. Survival estimates differed significantly for resectable patients exposed to low doses (50 to 150 mg/m²; n = 9; median, 6 months) versus high doses (175 to 250 mg/m²; n = 35; median, 18 months) of hyperthermic cisplatin (P = .0019); recurrence-free interval also differed significantly (4 v 9 months, respectively; P < .0001). Low dose level (relative risk = 3.418) and nonepithelial histology (relative risk = 2.336) were independent risk factors for poor survival. Twenty patients with epithelial tumors who underwent high-dose cisplatin lavage had a 26-month median survival time.

CONCLUSION: Pleurectomy and high-dose intraoperative intracavitary hyperthermic cisplatin lavage is feasible in this patient population with restricted surgical options. An apparent dose-related survival benefit warrants further study.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Malignant pleural mesothelioma (MPM) is an aggressive, usually fatal tumor of the pleura most often associated with exposure to asbestos. Patients treated with palliative care have a median survival time of 7 months from diagnosis.¹ Doublet therapy with pemetrexed and cisplatin has been demonstrated to improve survival to 12.1 months compared with 9.3 months for cisplatin alone.² Multimodality therapy including cytoreductive surgery with extrapleural pneumonectomy (EPP) followed by adjuvant chemoradiotherapy has been associated with a median survival time of 19 months.³

Patients who are not candidates for EPP as a result of insufficient cardiopulmonary reserve, advanced age, or disease distribution may be candidates for cytoreduction with pleurectomy/decortication (P/D). This procedure spares the lung while providing palliation of dyspnea by removing bulk tumor and pleural effusion.^4,5 Long-term survival benefit has been limited by early disease recurrence.

Hyperthermic intracavitary chemotherapy has been applied after surgical cytoreduction to enhance locoregional control for peritoneal mesothelioma,⁶ as well as other abdominal^7-10 and thoracic^11-13 malignancies including MPM.^12,14 These studies have used cisplatin at 50 to 100 mg/m². No studies to date have investigated the feasibility of intraoperative hyperthermic cisplatin lavage after P/D in MPM or determined the maximum-tolerated dose (MTD).

We used hyperthermic cisplatin as an intraoperative lavage of the ipsilateral hemithorax. Sodium thiosulfate was sequentially administered intravenously after intracavitary lavage to protect against nephrotoxicity^15,16 and to permit escalation of the cisplatin dose to obtain maximal cytotoxic levels of cisplatin within local tissues. An initial dose of 50 mg/m² was used to minimize the likelihood of renal toxicity noted in prior reports of postpleurectomy intrapleural cisplatin administered at 100 mg/m² (normothermic, without sodium thiosulfate).^17,18

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Objectives
The primary objective of this study was to prospectively determine the MTD of intraoperative, intracavitary, hyperthermic cisplatin after P/D and to evaluate the feasibility, safety, morbidity, and mortality of this therapy. Secondary objectives were evaluation of the pattern and timing of disease recurrence and patient survival.

Eligibility and Enrollment
Eligible patients had a diagnosis of MPM confirmed by immunohistochemistry and electron microscopy on an open pleural biopsy. All pathology was examined by a mesothelioma review panel at a single institution. All patients were evaluated with a complete medical history, physical examination, computed tomography of the chest and upper abdomen, magnetic resonance imaging of the chest, serum chemistry and hematology, pulmonary function testing, and doppler echocardiography.¹⁹ Patients were enrolled onto this study if surgical cytoreduction was determined to be tolerable and technically feasible. Patients with clinical or radiographic evidence of Brigham stage III or IV³ MPM were ineligible. Eligible patients were offered enrollment onto the study, and informed consent was obtained in an intent-to-treat design. The protocol and consent form were approved by the Institutional Review Board of the Dana-Farber/Harvard Cancer Center.

Surgery and Intraoperative Hyperthermic Lavage
Patients underwent exploratory thoracotomy, and resectability was determined. Patients in whom a macroscopic complete resection (MCR; < 1.0 cm³ tumor) could not be achieved were considered unresectable and were removed from the study. The operative procedure included resection of the visceral, parietal, and mediastinal pleurae. Involved areas of the pericardium and diaphragm were also resected and reconstructed as necessary.

After tumor resection and hemostasis, a 1-hour intracavitary lavage was completed with a solution of cisplatin in dialysate (Baxter, Deerfield, MA) maintained at 42°C. An Omni retractor (Omni-Tract, Minneapolis, MN) and plastic adhesive drape were used to create a seal around the thoracotomy incision. The inflow and outflow catheters were placed through the open thoracotomy incision in the caudal and cephalad positions, respectively. The resection cavity was continuously bathed with circulating hyperthermic cisplatin solution. Immediately after the 1-hour cisplatin lavage, intravenous sodium thiosulfate was administered as a 4 g/m² bolus in 250 mL of sterile water over 10 minutes followed by 12 g/m² over 6 hours.¹⁶ Perfusate temperature was continuously monitored with thoracic and abdominal probes, and body temperature was monitored with an esophageal probe.

A dose-escalation design was used. The cisplatin dose was sequentially escalated from 50 to 250 mg/m². Three patients were treated at each dose level until a dose-limiting toxicity (DLT; grade 3 renal toxicity or any grade 4 toxicity not definitely related to the surgery) was encountered. When a single patient experienced a DLT, the number of patients treated at that dose level was expanded to six. Dose escalation was continued if none of three or only one of six patients experienced a DLT. If two or more patients experienced a DLT at a given dose level, the MTD was established at the previous lower dose. An additional 10 patients were then treated at the MTD to confirm the absence of toxicity.

Furosemide, low-dose dopamine, mannitol, or intravenous fluid was used to maintain urine output at 100 mL/h during and until 1 hour after the completion of the lavage. At the completion of lavage, the chest was closed in standard fashion with chest drains in place. Patients were maintained on positive pressure ventilation (positive-end respiratory pressure 5 to 12.5 cm H₂O) for at least 24 hours to maximize lung expansion and minimize bleeding after pleurectomy.

Pathology Review
Archival pathologic slides from all resected patients were reviewed by a board of three staff pulmonary pathologists specializing in mesothelioma (Mesothelioma Reference Panel: Joseph M. Corson, MD; John Godleski, MD; and Lucian R. Chirieac, MD). WHO diagnostic criteria were used.

Post-Treatment Follow-Up
Mortality and complications occurring within 30 days of the procedure or before postoperative hospital discharge were considered to be treatment related. Patients were seen in ambulatory follow-up at 1 to 2 weeks and 6 to 8 weeks after discharge and, subsequently, at 4-month intervals. A computed tomography scan of the chest was obtained at the second follow-up and every 4 months to monitor for evidence of recurrence. Date of recurrence was considered to be the date of the first radiographic study on which recurrence was demonstrable. Mortality after documented recurrence was considered to be disease related.

Statistical Analysis
Kaplan-Meier estimates of survival and recurrence-free interval were computed 30 months after the last patient was registered. Survival was calculated from the date of treatment to the date of most recent follow-up or date of death. Recurrence-free interval was defined as the interval between the date of treatment and the earliest clinical evidence of disease recurrence. Patients who died without demonstration of recurrence were censored on the date of their most recent evaluation that did not show evidence of recurrence. The prognostic significance of factors was tested in univariate models using the log-rank statistic and in multivariate models using proportional hazards regression.

	RESULTS

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From August 1999 to April 2002, 61 patients were registered. Forty-four patients determined to be resectable at thoracotomy who underwent an MCR and intraoperative hyperthermic cisplatin lavage followed by intravenous sodium thiosulfate constituted the study cohort. This cohort had a median age of 71 years (range, 50 to 82 years). Thirty-two patients (73%) were male. Thirty-two patients (73%) had right-sided disease. Median preoperative forced expiratory volume in 1 second (FEV₁) was 1.72 L or 60% predicted. Median predicted postpneumonectomy FEV₁ was 0.76 L or 28% predicted. The median postoperative hospital length stay was 11 days (range, 6 to 71 days).

Pathology Review
Tumor was sampled for histologic evaluation in an average of 13 slides (95% CI, 11.1 to 14.2 slides). Comprehensive review of all pathologic specimens by a mesothelioma reference panel who had no knowledge of the therapy or outcome confirmed the diagnosis of MPM in each patient revealed no patients with well-differentiated papillary mesothelioma. Tumor histology was epithelial in 24 patients (55%), mixed in 17 patients (39%), and sarcomatoid in three patients (7%). Pathologic staging is listed in Table 1.

Morbidity
Table 2 lists perioperative complications. Atrial arrhythmias occurred in 14 patients (32%). Major morbidity, which was defined as any grade 3+ complication except atrial fibrillation, occurred in 11 patients (25%). Deep venous thrombosis of the lower extremities occurred in four patients (9%). Four patients developed pneumonia, and five patients developed adult respiratory distress syndrome (ARDS). Other complications included failure of a diaphragmatic patch requiring repair (n = 1), chylothorax (n = 1), pulmonary embolus (n = 1), and ileus (n = 1).

Mortality
Five perioperative deaths (11%) were attributable to the procedure as follows: (1) aspiration pneumonia and respiratory failure (POD 41); (2) ARDS pneumonia and sepsis (POD 20); (3) Klebsiella pneumonia, ARDS, and renal failure (POD 71); (4) multiorgan failure after reoperation for herniation of abdominal viscera into the ipsilateral hemithorax (POD 22); and (5) ARDS and persistent hypoxemia after repeat thoracotomy for thoracic duct ligation (POD 27). Clinical characteristics of these five patients (age, median, 70 years; range, 59 to 78 years; sex, two males and three females; side of disease, right side in two patients and left side in three patients; FEV₁, median, 1.27 L; range, 0.95 to 1.73 L; and histology, nonepithelial in four patients and epithelial in one patient) were not significantly related to mortality.

Survival
Among 61 patients enrolled, 53 patients were deceased, seven patients were known to be alive, and one patient was lost to follow-up at the time of this analysis. The median survival time among all 61 patients enrolled was 9.3 months. Among the 44 patients who underwent resection and intraoperative chemotherapy, median survival time was 13 months compared with 9 months for the 17 patients who did not undergo resection as a result of the determination at thoracotomy that MCR could not be achieved (P = .018; Fig 1A). American Joint Committee on Cancer tumor stage was not significantly related to survival (Fig 1B). Tumor histology and cisplatin dose were each significantly related to survival in univariate analyses. The 24 patients with epithelial histology had a longer median survival time (19 months) than the 20 patients with sarcomatoid/mixed-cell type (8 months; P = .0039; Fig 1C). Patients exposed to low doses (ie, at or less than the middle of the range tested: 50, 100, or 150 mg/m²) of cisplatin had a median survival time of 6 months, and all of these patients died within 15 months. The 35 patients administered high cisplatin doses (175 to 250 mg/m²) had an 18-month median survival time, with seven patients still alive 30 to 50 months after surgery (P = .0019; Fig 1D). Results of multivariate analysis indicated that low cisplatin dose (relative risk = 3.418; P = .0044) and nonepithelial histology (relative risk = 2.336; P = .016) were independently predictive of poor survival. Perioperative mortality occurred in one (11%) of nine patients administered low doses of cisplatin and four (11%) of 35 patients administered high doses.

View larger version (22K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival estimates for (A) all enrolled patients and (B through E) patients undergoing pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage. (A) Log-rank comparison demonstrated significantly longer survival for resected versus unresected patients. (B) Pathologic (American Joint Committee on Cancer) tumor stage did not significantly stratify survival. Significantly longer survival was demonstrated for (C) patients with epithelial versus nonepithelial tumors among all resected patients, (D) patients receiving cisplatin 175 to 250 versus 50 to 150 mg/m2 among all resected patients, (E) patients with epithelial versus nonepithelial tumors among all patients receiving cisplatin 175 to 250 mg/m2.

Patterns of Failure
Radiographic or pathologically confirmed recurrence of mesothelioma was observed in 33 resected patients (75%). The estimated median time to recurrence among all resected patients was 7.2 months. Initial recurrences involved the ipsilateral hemithorax in 25 patients (76%), the abdomen in 10 patients (30%), or the contralateral hemithorax in eight patients (24%). There was one distant metastasis (3%). Four patients (12%) had a bilateral thoracic presentation of recurrent disease, three patients (9%) experienced recurrence in the ipsilateral hemithorax and abdomen, and two patients (6%) presented with simultaneous recurrence in all three cavities. Eight (89%) of nine patients who received low-dose cisplatin lavage experienced disease recurrence compared with 25 (71%) of 35 patients who received high-dose lavage.

Nineteen (54%) of the 35 patients undergoing high-dose cisplatin lavage experienced ipsilateral recurrence, which is similar to the six (67%) of nine patients who underwent low-dose lavage. However, the recurrence-free interval was significantly related to cisplatin dose. Patients treated with high-dose cisplatin had a median recurrence-free interval of 9 months compared with 4 months for low-dose lavage (P < .0001; Fig 2).

View larger version (12K): [in this window] [in a new window]   Fig 2. Recurrence-free interval for resected patients. Log-rank comparison indicated significantly longer recurrence-free interval for patients receiving cisplatin 175 to 250 mg/m2 than for patients receiving cisplatin 50 to 150 mg/m2.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

Previously, P/D as therapy for MPM has primarily been used for palliation of dyspnea associated with lung encapsulation by tumor or pleural effusion^4,5 or in cases of early disease where MCR of tumor seems possible while sparing the patient a pneumonectomy.^17,21 Our study suggests an additional role for P/D, to provide tumor debulking in the context of aggressive local treatment of residual disease.

The present study highlights the potential importance of cisplatin dose to outcome using this treatment strategy. Several prior studies have combined P/D with intrapleural cisplatin^17,18,22 including hyperthermic lavage,¹⁴ but cisplatin was administered at dose levels (50 to 100 mg/m²) that we found, in the present study, to be associated with poor survival. One recent study using high-dose (450 mg/m²) intrapleural liposome-entrapped cisplatin without surgical debulking demonstrated pathologic responses in pleural biopsies but found that viable tumor remained in areas not accessible to the cavitary application, and median survival time was 11 months.²³ Systemic protection with sodium thiosulfate in the present study permitted escalation of cisplatin dose to approximately twice the dose formerly used after resection. Our therapeutic strategy was associated with improved survival relative to historic controls.^14,17,18,22 This result may reflect systemic effects of absorbed platinum in addition to effects of high-dose local application.

However, the procedure has been associated with significant morbidity and mortality in some patients, stressing the need for careful patient selection. The 11% perioperative mortality rate is perhaps not entirely unexpected in an early-phase trial of aggressive therapy in a cohort of high-risk patients. Four of the five deaths occurred in the patients treated at a cisplatin dose of 225 to 250 mg/m². Unfortunately, other factors found to correlate with perioperative death, such as reoperation (two patients), pneumonia (four patients), and ARDS (five patients), are not readily predictable preoperatively.

Although hypercoagulabilty is known to be characteristic of some patients with MPM,²⁴ the significant incidence of deep venous thrombosis in this study is consistent with the demonstrated influence of hyperthermia on the processes of platelet activation,²⁵ fibrin formation,²⁶ and fibrinolysis.²⁷ Our current protocols mandate close monitoring of all patients during hospitalization with noninvasive lower extremity studies and a low threshold for instituting anticoagulation therapy.

Some patients experienced creatinine elevation despite sodium thiosulfate administration. Because renal toxicity is an ever-present concern for some patients in the context of high-dose cisplatin, we have modified our perioperative management of these patients to optimize renal protection. Current protocols include preoperative hydration, 7-day hold of nonsteroidal anti-inflammatory drugs and cyclo-oxygenase 2 inhibitors, a second infusion of sodium thiosulfate, aggressive intraoperative diuresis and blood pressure management, and urine alkalinization.

Tumors with epithelial histology have consistently been associated with improved outcome relative to sarcomatous or biphasic tumors, independent of treatment. This observation, combined with their disparate clinical behavior, leaves the impression that epithelial and sarcomatoid MPM variants represent distinct disease entities. Not surprisingly, most long-term survivors in the current trial had epithelial tumors, and nonepithelial histology was independently predictive of poor survival in multivariate analysis. Interestingly, though, survival among patients with nonepithelial tumors was bimodally distributed. Although most patients with mixed-histology tumors had early recurrence of disease with a maximal survival time of 9 months, five patients treated with cisplatin lavage at 225 or 250 mg/m² survived beyond 18 months, suggesting that a subset of patients with mixed-histology tumors may benefit from cisplatin lavage at the MTD. This observation clearly warrants further investigation.

A significant number of patients in the current study were treated at cisplatin doses that were higher than previously published. Although the current study was designed to address phase I questions and although the possibility of bias as a result of unequal distribution of node stage cannot be ruled out, the favorable survival and recurrence-free interval observed with higher doses compared with lower doses suggest the need to investigate further the efficacy of this approach.

The present study used P/D as an alternative cytoreductive procedure. The pattern of recurrence was predominantly locoregional, despite the additional local treatment with intracavitary cisplatin. Significant differences in the completeness of cytoreduction may exist between EPP and P/D resulting from the potential with P/D for unresected tumor in segmental and lobar fissures, intraparenchymal and infradiaphragmatic lymph nodes, and pericardium. There are cases where meticulous pleurectomy combined with favorable tumor distribution may result in MCR. However, the potential for adjuvant radiation therapy will be much diminished in patients with retained pulmonary parenchyma. We believe that an MCR should be the primary goal of cytoreductive surgery when used in combination with adjuvant therapy. The selection of patients for either EPP or P/D should be determined by the disease distribution, the anticipated physiologic impact of resection on the patient’s cardiopulmonary status, and the availability of effective additional intraoperative and adjuvant therapy.

This study has established the feasibility and MTD of hyperthermic cisplatin when administered intraoperatively after P/D in conjunction with sodium thiosulfate rescue. The observed survival of patients who underwent high-dose lavage is provocative and would seem to warrant further study. The present results establish the parameters for the administration of intraoperative cisplatin, which may provide the foundation for its use in combination with other drugs and biologic therapies.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: William G. Richards, Lambros Zellos, Raphael Bueno, Michael T. Jaklitsch, Rene J. Dekkers, Phillip M. Hartigan, David J. Sugarbaker Financial support: David J. Sugarbaker Administrative support: David J. Sugarbaker Provision of study materials or patients: Lambros Zellos, Raphael Bueno, Michael T. Jaklitsch, David J. Sugarbaker Collection and assembly of data: William G. Richards, Lucian R. Chirieac, Leah Capalbo Data analysis and interpretation: William G. Richards, Raphael Bueno, Lucian R. Chirieac, Beow Y. Yeap, David J. Sugarbaker Manuscript writing: William G. Richards, Lambros Zellos, Raphael Bueno, Michael T. Jaklitsch, Pasi A. Jänne, Beow Y. Yeap, David J. Sugarbaker Final approval of manuscript: William G. Richards, Lambros Zellos, Raphael Bueno, Michael T. Jaklitsch, Pasi A. Jänne, Lucian R. Chirieac, Beow Y. Yeap, Rene J. Dekkers, Phillip M. Hartigan, Leah Capalbo, David J. Sugarbaker

 

	Acknowledgment

 
We thank Emil Frei for guidance in designing this trial, John Godleski and Joseph Corson for participation on the Pathology Review Panel, Jasleen Kukreja for early editorial assistance, Amy Smith for data management, and Bruce Johnson for comments on the manuscript.

	NOTES

 
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted November 11, 2005; accepted January 31, 2006.

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