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Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3495-3501 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.00.802 Phase II Study of a Liposome-Entrapped Cisplatin Analog (L-NDDP) Administered Intrapleurally and Pathologic Response Rates in Patients With Malignant Pleural MesotheliomaFrom the Departments of Thoracic/Head & Neck Medical Oncology, Thoracic and Cardiovascular Surgery, Pathology, Bioimmunotherapy, Experimental Therapeutics, Diagnostic Radiology and Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, and New York University, New York, NY Address reprint requests to Dong M. Shin, MD, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Rd, Room 3090, Atlanta, GA 30322; e-mail: dong_shin{at}emoryhealthcare.org
PURPOSE: To determine pathologic response rates to liposome-entrapped cis-bisneodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (L-NDDP) administered intrapleurally in patients with malignant pleural mesothelioma. PATIENTS AND METHODS: Thirty-three patients with malignant pleural mesothelioma and free-flowing pleural effusions received intrapleural L-NDDP once every 3 weeks at a dose of 450 mg/m2. Thoracoscopic evaluation with pleural biopsies was performed before therapy and then after every two cycles. The primary end point was pathologic response as determined by thoracoscopic biopsy. RESULTS: After at least two cycles, post-treatment pleural biopsy analysis was negative in 14 patients for a pathologic response rate of 42% (95% CI, 25% to 61%). Median survival was 11.2 months. There were three treatment-related deaths secondary to peritonitis, cellulitis at the thoracoscopy site, and empyema. Grade 3 nonhematologic toxicities included infection, fever, dyspnea, and anorexia, which occurred in five (15%), one (3%), one (3%), and one (3%) patients, respectively. There were no grade 4 nonhematologic toxicities. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in five (15%), three (9%), and two (6%) patients, respectively. Two patients with pathologic responses subsequently underwent pleural decortication. Both surgical specimens revealed residual tumor in regions that were not in direct communication with the pleural space. CONCLUSION: Intrapleural L-NDDP therapy in this patient population is feasible with significant but manageable toxicity. Although pathologic responses are highly encouraging, areas of mesothelioma that are not in direct communication with the pleural space will evade drug exposure and limit efficacy in some patients. The optimal role of intrapleural L-NDDP therapy currently remains to be determined.
Malignant pleural mesothelioma (MPM) is an uncommon neoplasm with an annual estimated incidence of 2,000 to 3,000 new cases in the United States.1,2 Most cases of MPM are associated with prior asbestos exposure. Researchers have estimated that the mortality rate for MPM will continue to increase in Western Europe and the United States at least until 2020.3 MPM is characterized by progressive local tumor invasion and poor median survival durations ranging from 4 to 18 months in various series.4 A standard treatment strategy for MPM remains elusive. Although a multimodality surgical approach is feasible in highly selected patients,5,6 most patients are not candidates for this type of therapy due to advanced stage and/or comorbid conditions. Palliative single-agent chemotherapy and combination regimens have been evaluated in MPM. Drugs with consistently modest antitumor activity include platinum agents, doxorubicin, and antimetabolites, with response rates typically in the range of 10% to 15%.7 A recent phase II study of the multitargeted antifolate permetrexed in chemotherapy-naive patients yielded a response rate of 14.1% and median survival duration of 10.7 months.8 Although a subsequent large phase III trial comparing cisplatin plus permetrexed with cisplatin alone demonstrated a significant survival benefit in the combination arm (12.1 months v 9.3 months),9 more effective therapies for MPM are clearly needed. Liposome-entrapped cis-bisneodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (L-NDDP) is a lipophilic cisplatin analog that has been formulated in multilamellar liposomes measuring from 1 to 3 µm in diameter.10,11 L-NDDP has been demonstrated to be non–cross-resistant with cisplatin in several in vitro and in vivo models.12 In a phase I study of intravenous L-NDDP, the maximum-tolerated dose (MTD) was 300 mg/m2 and the dose-limiting toxicity was myelosuppression.13 Nausea and vomiting were mild, and no nephrotoxicity was observed. Several studies have demonstrated favorable depot properties of liposomes after subcutaneous or intracavitary administration.14 Preclinical studies have examined plasma and peritoneal fluid pharmacokinetics of rats treated with intravenous and intraperitoneal cisplatin and L-NDDP.15 Absorption of L-NDDP from the peritoneal cavity was much slower than that of cisplatin, and the peritoneal fluid levels of L-NDDP were several times higher than those of cisplatin. These results suggested that L-NDDP possessed a more favorable pharmacokinetic profile for intraperitoneal therapy, and, possibly, other intracavitary therapy when compared with cisplatin. In consideration of the aforementioned observations, a phase I clinical and pharmacologic study of L-NDDP administered intrapleurally in patients with malignant pleural effusions was conducted.16 The recommended MTD for future phase II study was 450 mg/m2, which was 50% higher than the MTD administered intravenously. At this MTD, the only toxic effects were grade 1 to 2 nausea and vomiting; grade 1 to 2 fever was observed in 18% of treatment cycles. The dose-limiting toxicity observed at 550 mg/m2 was chest pain secondary to chemical pleuritis. Absorption of L-NDDP into the systemic circulation was much slower than that of the parent compound cisplatin. Among five patients with MPM, one had complete resolution of the pleural effusion for at least 21 months and two patients had a greater than 50% reduction of the effusion for 8 and at least 6 months, respectively. Based on these encouraging results, we conducted a phase II trial of L-NDDP administered intrapleurally in patients with MPM with free-flowing pleural effusions. In light of the inherent difficulties in accurately assessing MPM response with standard imaging,17-19 the primary end point for this trial was the pathologic response rate based on post-treatment thoracoscopic pleural biopsy analysis.
Patient Population To be eligible for this study, patients had to be at least 19 years old and have pathologically confirmed MPM (with an epithelial, sarcomatoid, or mixed histology) in a pleural biopsy, a free-flowing pleural effusion, a Zubrod performance status of 0 to 2, a life expectancy of more than 12 weeks, a serum total bilirubin level  1.5 mg/dL, an ALT level 1.5x the upper limit of normal, a serum creatinine level 1.5 mg/dL, a granulocyte count  1,500/mm3, a platelet count 100,000/mm3, no prior or concomitant malignancies, and no serious medical or psychiatric illnesses. Also, they must have gone more than 3 weeks since their last major surgery and more than 4 weeks since undergoing systemic chemotherapy. Prior pleurodesis or chest surgery on the same side of the effusion was allowed. The protocol was approved by the institutional review board of each participating center. All patients gave their written informed consent to participate.
Prestudy Evaluation
Evaluation During Study
Evaluation of Response
Preparation of L-NDDP
Study Design and Treatment After the first eight patients, however, the protocol was amended as a result of two treatment-related fatal toxicities. One patient died after developing peritonitis and disseminated intravascular coagulation; the other died after the development of cellulitis at the thoracoscopy site and sepsis. Starting with the ninth patient, L-NDDP was no longer administered at the time of baseline thoracoscopy and placement of the intrapleural Denver catheter. Instead, patients received the first dose 1 week after the baseline thoracoscopy to ensure that the intrapleural catheter site was well healed and without signs of infection. L-NDDP was infused over a longer period of 30 to 60 minutes in the outpatient clinic. After the drug infusion, patients were observed for 4 hours. During this observation period, they were placed in eight different positions to facilitate exposure of the entire pleural surface to L-NDDP. While supine, patients were placed in Trendelenburg's and reverse-Trendelenburg's positions and tilted to the left and right. This was repeated while the patients were in a prone position. Subsequent intrapleural L-NDDP infusions were given once every 3 weeks in the outpatient clinic. Before each infusion, pleural fluid was drained; a volume at least equal to that of L-NDDP to be infused was removed.
The starting dose of L-NDDP was 450 mg/m2 (6,750 mg lipid/m2). The L-NDDP concentration was 2 mg/mL saline, resulting in a fluid volume of 225 mL/m2. Dose reductions were required for granulocyte and platelet nadir counts of less than 500/mm3 and less than 50,000/mm3, respectively. Intrapleural infusions were held for granulocyte counts of less than 1,500/mm3 or platelet counts of less than 100,000/mm3. A delay of more than 2 weeks required a one-level dose reduction or removal from the study if the patient was treated at dose level –2. For nonhematologic toxicity, dose reductions or cessation of therapy was required for grade 3 or higher toxicities. The first two dose-reduction levels were 350 mg/m2 (dose level –1) and 250 mg/m2 (dose level –2). When necessary, further reductions were continued at 25% decrements. A single dose-escalation to 550 mg/m2 was allowed in patients with nadir granulocyte and platelet counts of more than 1,000/mm3 and more than 100,000/mm3, respectively, and nonhematologic toxicity
Statistical Analyses Descriptive statistics were used to characterize response and toxicity rates. The response rate was estimated as the proportion of responders among patients who received any therapy. Survival time was measured from the first day of treatment until the date of death or last follow-up, and survival probabilities were estimated by the Kaplan-Meier method.21
From November 1996 to July 2000, 38 patients were registered onto this phase II study at two institutions (The University of Texas M.D. Anderson Cancer Center, Houston, TX, and New York University, New York, NY). Five patients did not undergo therapy and thus were not included in this analysis. In three of these patients, therapy was not delivered due to lack of a free-flowing pleural effusion after placement of the intrapleural catheter. The characteristics of the 33 patients who underwent therapy are listed in Table 1. Stage was not an eligibility criterion, and the International Mesothelioma Interest Group stage22 was available for 28 patients (85%). Five patients received prior chemotherapy, including four patients who received platinum-based regimens. In total, 72 cycles of intrapleural L-NDDP were administered. The median number of cycles was two (range, one to four). Five patients (nine cycles) required dose reductions, whereas six patients (eight cycles) underwent dose escalations.
Nonhematologic toxic effects are listed in Table 2, which includes any toxic effects grade 3 and all effects observed in 10% of patients. There were three deaths on study, all considered to be as a result of treatment. The first patient entered onto the trial died from peritonitis and disseminated intravascular coagulation 7 days after receiving his third cycle of therapy. Cellulitis developed at the thoracoscopy site in the eighth patient entered onto the trial; he died of sepsis 29 days after receiving his first cycle of therapy. As described in Patients and Methods, the protocol was subsequently amended to require that patients begin treatment 1 week after the baseline thoracoscopy to ensure that the intrapleural catheter site was well healed and without signs of infection. The twenty-second patient entered onto the trial experienced empyema and respiratory failure and died 32 days after receiving her second cycle of therapy. The most common grade 3 nonhematologic toxic effect was infection, which occurred in five patients (four with intrapleural catheter infections, one with empyema). These catheter-related infections occurred despite waiting 1 week after placement of the intrapleural catheter to ensure that the catheter site was well healed and without signs of infection before beginning therapy. There were no grade 4 nonhematologic toxic effects. Frequent nonhematologic toxic effects (any grade) occurring in more than 25% of patients were fever (52%), dyspnea (42%), pleuritic chest pain (42%), fatigue (39%), nausea (30%), infection (30%), and anorexia (27%).
Hematologic toxic effects are listed in Table 3 and were considered to be mild. Grade 3 or higher neutropenia, thrombocytopenia, and anemia occurred in five (15%), three (9%), and two (6%) patients, respectively. As indicated in the table, one third of the grade 3/4 hematologic toxic effects were observed in a single patient who developed peritonitis, disseminated intravascular coagulation, and pancytopenia. It is likely that this patient's pancytopenia was not a result of direct myelosuppression from intrapleural L-NDDP.
The trial's primary end point was pathologic response as determined by thoracoscopy with pleural biopsy analysis. In addition, pleural fluid was also collected at the time of thoracoscopy for cytologic evaluation. Post-treatment thoracoscopic pleural biopsy results are listed in Table 4. Post-treatment biopsies were available for 21 (64%) of 33 patients. Patients for whom post-treatment biopsy samples were not available were primarily those who were taken off study early after the first or second cycle of therapy. The reasons for early removal from the study included early death, disease progression, lack of a free-flowing pleural effusion, and intrapleural catheter infection. In 14 patients, pleural biopsy analysis was negative for MPM after treatment, yielding a pathologic response rate of 42% (95% CI, 25% to 61%). A representative case with a complete pathologic response to intrapleural L-NDDP therapy is illustrated in Figures 1A and 1B. Significant changes were seen after intrapleural L-NDDP therapy at the time of thoracoscopy. Pleural tumor was noted to be necrotic and softer in texture, often associated with fibrinous debris. Two patients with MPM-negative post-treatment biopsies underwent pleural decortication. Although some prior areas of tumor demonstrated necrosis and inflammation, there were regions not in direct communication with the main pleural cavity that contained residual mesothelioma. These regions included areas of loculated effusions, chest wall invasion, and the mediastinum. Both of these patients subsequently underwent irradiation of the chest.
Pretreatment pleural fluid cytology data were available for 32 patients (97%; Table 5). Among 23 patients with MPM-positive pretreatment pleural fluid cytology, 18 patients (78%) had MPM-negative post-treatment cytology (Figs 1C and 1D), two patients (9%) had MPM-positive post-treatment cytology, and three patients (13%) did not have post-treatment cytology specimens. Among the nine patients with MPM-negative pretreatment cytology, eight patients (89%) had MPM-negative post-treatment cytology and one patient did not have a post-treatment cytology specimen. Thirteen (93%) of the 14 patients with pathologic responses had negative post-treatment cytology (cytology was not available for one patient). Among the 26 patients with negative post-treatment cytology, 13 patients (50%) and six patients (23%) had positive and negative post-treatment pleural biopsies, respectively (post-treatment biopsies not available for seven patients (27%).
Conventional tumor response was not a primary end point for this trial. However, tumor response data were recorded for patients treated at one site (The University of Texas M.D. Anderson Cancer Center, Houston, TX) using a modified response evaluation criteria in solid tumors (RECIST).18 Among the 23 patients treated at this site, tumor response was determined for 22 patients (one patient was not assessable because of an early death after cycle 1). The number of patients with partial response (PR), stable disease (SD), and progressive disease (PD) were one (5%), eight (36%), and 13 (59%), respectively. At this site, 17 of 23 patients had post-treatment thoracoscopic biopsies performed, with 12 biopsies (52%) negative and five biopsies (22%) positive for MPM. Among the 12 patients with negative post-treatment biopsies, PR, SD, and PD occurred in one patient (8%), six patients (50%), and five patients (42%), respectively. Among the five patients with positive post-treatment biopsies, SD and PD occurred in one patient (20%) and four patients (80%), respectively. Pathologic response rates were 78% for those patients achieving a PR or SD and 38% for those with PD. The overall survival curve for all 38 patients enrolled onto this study is shown in Figure 2. Thirty-four patients have died and four patients have been censored (two patients alive, two lost to follow-up). The median survival duration was 11.2 months (95% CI, 8.3 to 19.2 months). The median survival for the 33 patients who received intrapleural L-NDDP was 13.2 months (95% CI, 6.5 to 24.2 months). Median time to disease progression was 5.0 months (95% CI, 3.2 to 13.4 months).
This trial was conducted in an attempt to exploit the favorable depot effect, direct tumor exposure, and low systemic toxicity of intrapleural L-NDDP therapy in patients with MPM and free-flowing pleural effusions. The results of our study demonstrate that this novel approach is feasible in this patient population. A multidisciplinary clinical team is required for effective monitoring of these patients in light of the toxic effects observed. These effects include infectious complications such as intrapleural catheter infections and empyema. One of the three treatment-related deaths occurred after the development of a cellulitis at the thoracoscopy site. This fatal complication did not recur after the protocol was amended to require that the first dose of therapy be given 1 week after thoracoscopy and placement of the intrapleural catheter, allowing additional time for the catheter site to heal and be monitored for any signs of infection. Similar to the results of the prior phase I experience with L-NDDP, hematologic toxicity was mild and there was no appreciable renal toxicity. Three patients did not receive therapy after placement of their intrapleural catheter due to subsequent lack of a free-flowing effusion. The overall pathologic response rate of 42% and 13.2 months median survival rate among treated patients are encouraging in this patient population. However, our clinical impression is that efficacy may be limited in patients with areas of mesothelioma that are not in direct communication with the pleural space. This is supported by our observation that viable tumor was present in these regions in two patients who underwent pleural decortication after intrapleural L-NDDP treatment. Both of these patients had MPM-negative thoracoscopic pleural biopsies before pleural decortication. Based on this experience, a trial of induction intrapleural L-NDDP before extrapleural pneumonectomy and postoperative radiotherapy was begun. The development of significant postoperative wound infections in the first two patients, however, lead to the early closure of this study. Verschraegen et al23 conducted a phase I and pharmacologic study of intraperitoneal L-NDDP in patients with peritoneal carcinomatosis or sarcomatosis. Drug was administered after laparoscopy for the first two cycles and subsequently through a peritoneal catheter with a subcutaneous port. Fifteen patients were treated, and dose-limiting toxicities were fatigue and abdominal pain. Perioperative complications included a colonic perforation requiring primary closure, a port-site hematoma, a peritoneal catheter malfunction, and an ascites leak requiring resuture. Pharmacokinetic studies demonstrated prolonged peritoneal cavity exposure with limited systemic absorption, and five patients survived at least 3 years. To our knowledge, this trial is the first report of intrapleural liposomal platinum therapy in patients with MPM. Several groups have demonstrated the feasibility of intrapleural cisplatin immediately following pleurectomy or decortication in these patients, though toxicities included renal failure and myelosuppression.24-26 Intrapleural immunotherapy with interleukin-2 has been studied by other investigators, who have reported objective tumor responses with manageable toxicity.27,28 How these intrapleural therapies compare with standard systemic chemotherapy approaches is unclear. In summary, intrapleural L-NDDP therapy in patients with malignant pleural mesothelioma with free-flowing pleural effusions is feasible with significant but manageable toxic effects. Although pathologic responses were observed, areas of mesothelioma that were not in direct communication with the pleural space evaded drug exposure, limiting efficacy in some patients. The optimal role of intracavitary L-NDDP therapy remains to be determined.
The authors indicated no potential conflicts of interest.
Supported by grant No. K12 CA088084 from the National Cancer Institute (C. L.) and FD-R-00167 from the U.S. Food and Drug Administration Orphan Product Grant (D.M.S.) and Antigenics Inc, New York, NY (formerly Aronex Pharmaceuticals, Houston, TX). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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24. Rusch V, Saltz L, Venkatraman E, et al: A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 12:1156-1163, 1994 25. Lee JD, Perez S, Wang HJ, et al: Intrapleural chemotherapy for patients with incompletely resected malignant mesothelioma: The UCLA experience. J Surg Oncol 60:262-267, 1995[Medline] 26. Colleoni M, Sartori F, Calabro F, et al: Surgery followed by intracavitary plus systemic chemotherapy in malignant pleural mesothelioma. Tumori 82:53-56, 1996[Medline] 27. Castagneto B, Zai S, Mutti L, et al: Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients. Lung Cancer 31:303-310, 2001[CrossRef][Medline] 28. Astoul P, Picat-Joossen D, Viallat JR, et al: Intrapleural administration of interleukin-2 for the treatment of patients with malignant pleural mesothelioma: A Phase II study. Cancer 83:2099-2104, 1998[CrossRef][Medline] Submitted September 7, 2004; accepted March 8, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
