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A Phase I Trial of Surgical Resection and Intraoperative Hyperthermic Cisplatin and Gemcitabine for Pleural Mesothelioma

Open ArchivePublished:May 09, 2018DOI:https://doi.org/10.1016/j.jtho.2018.04.032

      Abstract

      Introduction

      The primary objective of this single-institution phase I clinical trial was to establish the maximum tolerated dose of gemcitabine added to cisplatin and delivered as heated intraoperative chemotherapy after resection of malignant pleural mesothelioma.

      Methods

      The extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) treatment arms were based on investigators’ assessment of patient fitness and potential for macroscopic complete resection. Previously established intracavitary dosing of cisplatin (range 175–225 mg/m2) with systemic cytoprotection was used in combination with escalating doses of gemcitabine, following a 3-plus-3 design from 100 mg/m2 in 100-mg increments.

      Results

      From 2007 to 2011, 141 patients were enrolled and 104 completed treatment. The median age of those completing treatment was 65 years (range 43–85 years), and 22 (21%) were female. In the EPP arm (n = 59), 31 patients (53%) had the epithelioid histologic type and the median radiographic tumor volume was 236 cm3 (range 16–4285 cm3). In the P/D arm (n = 41), 29 patients (71%) had the epithelioid histologic type and the median tumor volume was 79 cm3 (range 6–1107 cm3). The operative mortality rate was 2%, and 35 and 22 serious adverse events were encountered among 27 patients (46%) and 16 patients (39%) in the EPP and P/D arms, respectively. Dose-limiting toxicity (grade 3 leukopenia) was observed in two patients who were receiving 1100 mg/m2 of gemcitabine, thus establishing the maximum tolerated dose at 1000 mg/m2, in combination with 175 mg/m2 of cisplatin. The median overall and recurrence-free survival times in treated patients were 20.3 and 10.7 months, respectively.

      Conclusions

      Combination cisplatin and gemcitabine heated intraoperative chemotherapy can be administered safely and feasibly in the context of complete surgical resection of malignant pleural mesothelioma by EPP or P/D.

      Keywords

      Introduction

      Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy of the pleura that is fatal in most cases and has defied standard approaches to treatment. The median survival of patients treated with standard-of-care chemotherapy (pemetrexed and cisplatin) is only 12 months.
      • Vogelzang N.J.
      • Rusthoven J.J.
      • Symanowski J.
      • et al.
      Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
      Multimodality protocols that include cytoreductive surgery combined with systemic treatment with or without radiotherapy have been associated with extended survival for selected patients, with median survival times ranging from 18 to 23 months,
      • Sugarbaker D.J.
      • Richards W.G.
      • Bueno R.
      Extrapleural pneumonectomy in the treatment of epithelioid malignant pleural mesothelioma: novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients.
      • Weder W.
      • Strahel R.A.
      • Bernhard J.
      • et al.
      Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma.
      • Rusch V.W.
      • Giroux D.
      • Kennedy C.
      • et al.
      Initial analysis of the international association for the study of lung cancer mesothelioma database.
      Approximately half of these patients (54%), however, will experience locoregional recurrence after treatment.
      • Baldini E.H.
      • Recht A.
      • Strauss G.M.
      • et al.
      Patterns of failure after trimodality therapy for malignant pleural mesothelioma.
      Local recurrence may arise from microscopic tumor deposits that are either retained at surgical margins or shed from the resected specimen during surgery and are not eradicated by adjuvant treatment. Thus, there is rationale for more aggressive local measures to better control the local disease that is so characteristic of mesothelioma.
      A number of centers that use surgery-based multimodality treatment have investigated adjunctive strategies to help eradicate minimal residual disease at the time of resection, including brachytherapy,
      • Hilaris B.S.
      • Nori D.
      • Kwong E.
      • Kutcher G.J.
      • Martini N.
      Pleurectomy and intraoperative brachytherapy and postoperative radiation in the treatment of malignant pleural mesothelioma.
      • Lee T.T.
      • Everett D.L.
      • Shu H.K.
      • et al.
      Radical pleurectomy/decortication and intraoperative radiotherapy followed by conformal radiation with or without chemotherapy for malignant pleural mesothelioma.
      • Rosenzweig K.E.
      • Fox J.L.
      • Zelefsky M.J.
      • Raben A.
      • Harrison L.B.
      • Rusch V.W.
      A pilot trial of high-dose-rate intraoperative radiation therapy for malignant pleural mesothelioma.
      photodynamic therapy,
      • Pass H.I.
      • Temeck B.K.
      • Kranda K.
      • et al.
      Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma.
      • Friedberg JSCulligan M.J.
      • Mick R.
      • et al.
      Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma.
      and intracavitary hyperthermic lavage with chemotherapeutic agents,
      • 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.
      • Richards W.G.
      • Zellos L.
      • Bueno R.
      • et al.
      Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.
      • Zellos L.
      • Richards W.G.
      • Capalbo L.
      • et al.
      A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic cisplatin with amifostine cytoprotection for malignant pleural mesothelioma.
      • Tilleman T.R.
      • Richards W.G.
      • Zellos L.
      • et al.
      Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study.
      or povidone iodine.
      • Lang-Lazdunski L.
      • Bille A.
      • Belcher E.
      • et al.
      Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine followed by adjuvant chemotherapy in patients with malignant pleural mesothelioma.
      We have investigated hyperthermic intraoperative chemotherapy (HIOC) with single-agent cisplatin in a series of early-phase prospective trials
      • Richards W.G.
      • Zellos L.
      • Bueno R.
      • et al.
      Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.
      • Zellos L.
      • Richards W.G.
      • Capalbo L.
      • et al.
      A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic cisplatin with amifostine cytoprotection for malignant pleural mesothelioma.
      • Tilleman T.R.
      • Richards W.G.
      • Zellos L.
      • et al.
      Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study.
      that demonstrated the feasibility and safety of HIOC. Among patients at low risk for early recurrence, HIOC with single-agent cisplatin extended time to recurrence from 13 to 27 months and extended overall survival (OS) from 23 to 35 months.
      • Sugarbaker D.J.
      • Gill R.R.
      • Yeap B.Y.
      • et al.
      Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection.
      Effective systemic chemotherapy for unresectable MPM typically combines two or more agents
      • Vogelzang N.J.
      • Rusthoven J.J.
      • Symanowski J.
      • et al.
      Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
      • Zalcman G.
      • Mazieres J.
      • Margery J.
      • et al.
      Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
      rather than a single agent, and we reasoned that the same may be true for an intracavitary regimen. Herein, we report the results of a single-institution phase I study extending this strategy by investigating the maximum tolerated dose (MTD), toxicity, and initial efficacy of gemcitabine added to cisplatin HIOC after either extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D) for MPM.

      Methods

      Each patient consented to this prospective, single-institution, investigator-initiated protocol (NCT00571298), which was approved by the Dana-Farber/Harvard Cancer Center Scientific Review Committee and Institutional Review Board (protocol No. 07-091). The study schema is presented in Figure 1A. The design is a phase I trial with an expansion cohort and three concurrent treatment arms with initial nonrandom preoperative assignment by the surgeon to either the EPP or P/D arm as appropriate to the patient’s disease burden, physiologic fitness, and potential for macroscopic complete resection (MCR). A third “tumor-debulking” arm accommodated intraoperative crossover for some patients for whom MCR could not be achieved by EPP or P/D and who underwent substantial but incomplete tumor resection. Dose escalation proceeded independently for each arm on the basis of the potential for different rates of systemic drug absorption in the presence versus absence of a lung on which pleurectomy has been performed.
      Figure thumbnail gr1
      Figure 1(A) Trial design. (B) CONSORT diagram. EPP, extrapleural pneumonectomy; P/D, pleurectomy/decortication; HIOC, hyperthermic intraoperative chemotherapy.
      Patients who were being evaluated for surgery-based treatment at the Brigham and Women’s Hospital and met eligibility criteria were offered participation. The eligibility criteria were similar to those of prior trials utilizing single-agent cisplatin HIOC at a dose of 175 to 225 mg/m2 with systemic cytoprotection.
      • Richards W.G.
      • Zellos L.
      • Bueno R.
      • et al.
      Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.
      • Zellos L.
      • Richards W.G.
      • Capalbo L.
      • et al.
      A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic cisplatin with amifostine cytoprotection for malignant pleural mesothelioma.
      • Tilleman T.R.
      • Richards W.G.
      • Zellos L.
      • et al.
      Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study.
      Briefly, patients were eligible for inclusion if they were men or nonpregnant women age 18 years or older and had histopathologically confirmed MPM, potentially resectable disease without distant metastases (according to computed tomography and magnetic resonance imaging), no mediastinal lymph node involvement (according to mediastinoscopy), adequate cardiopulmonary function (according to echocardiogram and spirometry), and good functional status with no significant comorbidities or cancer other than MPM. The exclusion criteria included receipt of chemotherapy and/or radiation therapy within the last 3 years at the time of study entry. The primary end point was the MTD of gemcitabine when added to cisplatin at a fixed and established dose and administered (as intraoperative, hyperthermic intracavitary lavage after EPP, P/D, or tumor debulking) with intravenous amifostine and sodium thiosulfate cytoprotection as previously described.
      • Richards W.G.
      • Zellos L.
      • Bueno R.
      • et al.
      Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.
      • Zellos L.
      • Richards W.G.
      • Capalbo L.
      • et al.
      A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic cisplatin with amifostine cytoprotection for malignant pleural mesothelioma.
      • Tilleman T.R.
      • Richards W.G.
      • Zellos L.
      • et al.
      Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study.
      Secondary end points included the feasibility and toxicity of administering this combination chemotherapy and indications of potential efficacy based on OS and recurrence-free survival (RFS).
      Participants underwent EPP, P/D, or tumor debulking. After the specimen was removed, 910 mg/m2 of amifostine was infused intravenously over 15 minutes. Thirty minutes after completion of the amifostine infusion, a 1-hour lavage of intraoperative chemotherapy at the current dose level for the assigned arm was administered to the hemithorax at 40°C to 42°C and to the peritoneal cavity if the diaphragm had been resected. At the conclusion of the lavage, the chemotherapy perfusate was evacuated and a sodium thiosulfate bolus of 4 g/m2 was administered and followed by a sodium thiosulfate infusion of 12 g/m2 over 6 hours. Two hours after the first dose of amifostine, a second dose of amifostine (500 mg/m2) was given.
      The initial dose level was single-agent gemcitabine at 100 mg/m2 to establish its safety when administered by the intracavitary route. The second and all subsequent dose levels included concurrent intracavitary cisplatin at a fixed dose of 225 mg/m2, which was the MTD established in prior phase I trials.
      • Richards W.G.
      • Zellos L.
      • Bueno R.
      • et al.
      Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.
      • Zellos L.
      • Richards W.G.
      • Capalbo L.
      • et al.
      A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic cisplatin with amifostine cytoprotection for malignant pleural mesothelioma.
      • Tilleman T.R.
      • Richards W.G.
      • Zellos L.
      • et al.
      Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study.
      The dose escalation followed a 3-plus-3 design from 100 mg/m2 of gemcitabine at levels 1 and 2, thereafter increasing the dose in 100-mg/m2 increments. A serious adverse event (SAE) was defined as an adverse event (AE) of grade 3 or higher. Dose-limiting toxicity (DLT) was defined as an SAE related to study treatment. Dose escalation occurred if none of three or one of six participants experienced DLT at a given dose level in one arm. DLT experienced by two patients at any dose level in any arm was used to define the MTD as the previous (lower) dose level.
      Participants were monitored for occurrence of AEs for 30 days postoperatively. Thereafter, disease status was monitored by follow-up clinic visits and vital status was updated at least annually. Adjuvant chemotherapy was permitted at the discretion of each participant’s oncologist, but adjuvant hemithoracic radiation therapy was not recommended. Fisher’s exact and Mann-Whitney tests were respectively used to compare categorical and continuous covariates. OS was calculated from date of registration to date of death or censored at date of the most recent documented live encounter. RFS was defined as the time from date of registration until first recurrence or death. Kaplan-Meier and Cox regression analyses were used to estimate survival functions and account for prognostic covariates. Statistical analyses were performed with Stata 13.1 software (StataCorp LP, College Station, TX).

      Results

      A total of 141 participants were enrolled between November 2007 and October 2011; a CONSORT diagram for this study is displayed in Figure 1B. In all, 104 evaluable participants completed all study interventions in one of the three protocol arms. Of the 37 patients who were enrolled but did not receive HIOC per the study protocol, one did not undergo surgery, 28 were determined at thoracotomy to have an unresectable tumor, five underwent successful MCR but without protocol-specified HIOC, and three had a change of surgical procedure that was decided on intraoperatively (but crossover to the appropriate arm was not possible because it was not open to accrual).
      Table 1 summarizes the demographic, clinical, and disease characteristics of the evaluable patients. Because participants were not randomly assigned to study arms, known prognostic factors were compared between the EPP and P/D arms to assess balance. An insufficient number of participants were enrolled in the tumor debulking arm to support comparative analysis. The evaluable cohort had a median age of 65 years (range 43–85) and included 82 males (79%) and 22 females (21%). In all, 59 patients were treated in the EPP arm and 41 patients were treated in the P/D arm. Four patients were treated in the tumor debulking arm. The distributions of tumor histologic type, participant age, and sex were not significantly different between EPP and P/D arms. However, participants enrolled in the EPP arm demonstrated a significantly larger radiographic tumor volume (p = 0.003), were more likely to be at a more advanced pathologic stage (p = 0.007), and were more likely to undergo adjuvant radiotherapy (p = 0.005) than were those enrolled in the P/D arm.
      Table 1Patient and Tumor Characteristics of the Evaluable Patients (n = 104)
      CharacteristicArmp Value (EPP vs. P/D)
      DebulkingEPPP/D
      Number45941
      Sex, n (%)0.219
       Male4 (100)49 (83)29 (71)
       Female0 (0)10 (17)12 (29)
      Median age, y, (range)4 67 (47–73)59 64 (43–81)41 69 (48–85)0.095
      Histologic type, n (%)0.083
       Epithelioid2 (50)31 (53)29 (71)
       Biphasic1 (25)24 (41)8 (20)
       Sarcomatoid1 (25)4 (6)4 (9)
      AJCC stage, n (%)0.007
       I0 (0)2 (3)10 (24)
       II0 (0)7 (12)4 (10)
       III3 (75)31 (53)21 (51)
       IV1 (25)19 (32)6 (15)
      Adjuvant chemotherapy1 (50)27 (46)17 (42)0.688
      Adjuvant radiotherapy0 (0)10 (17)0 (0)0.005
      Tumor volume, cm325839
      Median (range)617 (262–972)236 (16–4285)79 (6–1107)0.003
      EPP, extrapleural pneumonectomy; P/D, pleurectomy/decortication; AJCC, American Joint Committee on Cancer.
      The primary objective of this study was to establish the MTD of gemcitabine added to cisplatin HIOC after resection of MPM. Supplementary Table 1 displays the doses of cisplatin and gemcitabine administered in each trial arm, and Figure 2 demonstrates these data in graphic form relative to SAEs and DLTs. A total of 60 SAEs were experienced by 39 participants (38%) and included 35 SAEs (58%) in the EPP arm and 22 SAEs (37%) in the P/D arm (p = 0.1). Most of the SAEs were expected in the context of the participants’ disease and thoracic surgery, including two deaths during the study (one from acute respiratory distress syndrome and one from multisystem organ failure [both of which occurred in the EPP arm]), acute respiratory distress syndrome (in 3.8% of participants), atrial fibrillation (4.8%), dyspnea (7.8%), and deep venous thrombosis (2.9%) (Table 2). Figure 3 shows the categories of AEs in the EPP and P/D arms. Supplementary Table 2 provides the distribution of less than severe AEs, all of which were expected in the context of the participants’ disease and thoracic surgery, with the most common being atrial fibrillation (4.8%), dyspnea (3.8%), and pneumothorax (2.9%).
      Figure thumbnail gr2
      Figure 2Graphic representation of trial elements. cc, cm3; EPP, extrapleural pneumonectomy; P/D, pleurectomy/decortication; SAE, serious adverse event; MTD, maximum tolerated dose.
      Table 2SAEs among Treated Patients
      Arm (n)EPP (n = 59)P/D (n = 41)Debulking (n = 4)Any (n = 104)
      Grade345345345Any
      Acute kidney injury11
      Adult respiratory distress syndrome314
      Atrial fibrillation3115
      Bilirubin11
      Bronchopulmonary hemorrhage11
      Calcium elevation11
      Cardiac infarction11
      Congenital cardiac defect11
      Cerebrovascular ischemia11
      Colitis11
      Creatinine112
      Deep vein thrombosis112
      Dehydration11
      Diarrhea11
      Dyspnea2518
      Increased LFT results11
      Empyema11
      Hemoglobin11
      Hypotension112
      Hypoxia112
      Laryngeal nerve dysfunction11
      Leukopenia134
      Multisystem organ failure11
      Optic disc edema11
      Pain, abdomen NOS11
      Pleural effusion11
      Pneumothorax112
      Pulmonary embolism11
      Renal failure44
      Respiratory insufficiency22
      Thrombosis/embolism213
      Upper respiratory infection11
      Total SAEs14192148021060
      Total participants10152115021039
      Total participants (%)17253271205025038
      SAE, serious adverse event; EPP, extrapleural pneumonectomy; P/D, pleurectomy/decortication; LFT, liver function test; NOS, not otherwise specified.
      Figure thumbnail gr3
      Figure 3Categories of serious adverse events (SAEs) in the extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) arms. CI, confidence interval.
      Grade 4 renal failure (occurring in three patients) and grade 3 leukopenia (occurring in two patients) were the HIOC-related and DLTs encountered for cisplatin and gemcitabine, respectively, during the dose escalation phase of this trial (see Fig. 2). The protocol had been designed to add dose-escalated gemcitabine to cisplatin at the previously established single-agent MTD of 225 mg/m2 by using appropriate systemic cytoprotection/rescue.
      • Richards W.G.
      • Zellos L.
      • Bueno R.
      • et al.
      Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.
      • Tilleman T.R.
      • Richards W.G.
      • Zellos L.
      • et al.
      Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study.
      Grade 4 renal toxicity, which was encountered in three of 19 participants receiving 225 mg/m2 of cisplatin in combination with low-dose (100–300 mg/m2) gemcitabine prompted protocol review and amendment to reduce the dose of cisplatin to 175 mg/m2 for all subsequently administered gemcitabine dose levels. No further grade 3 or higher renal toxicity was encountered among 50 participants treated with cisplatin at a dose of 175 mg/m2 and gemcitabine doses between 100 and 900 mg/m2. Among 29 participants treated at 175 mg/m2 cisplatin in combination with 1000 to 1200 mg/m2 of gemcitabine, two cases of grade 2 and one case of grade 4 increases in creatinine level were encountered (the grade 4 increase in creatinine level was deemed unlikely to be related to the study drugs). Of the six patients who received single-agent gemcitabine at a dose of 100 mg/m2, none had gradable renal toxicity or an increased creatinine level. DLT attributed to gemcitabine (grade 3 leukopenia) was observed in two participants at a dose of 1100 mg/m2 of gemcitabine in the P/D arm, establishing the gemcitabine MTD as 1000 mg/m2 in combination with 175 mg/m2 of cisplatin.
      A secondary objective of this study was assessment of OS and RFS. At the time of analysis, 26 patients were alive, 115 had died, and one patient was lost to follow-up, leaving 27 participant survival times censored at a median of 51 months of follow-up. Among the participants treated per protocol (n = 104), the median OS was 20.3 months (Fig. 4A). Also among the participants treated per protocol (n = 104), 74 (71%) had a recurrence and the median RFS was 10.7 months (Fig. 4B). Seventy percent of recurrences were in the ipsilateral chest. The median OS in the EPP and P/D arms among all patients were 17.7 and 38.8 months, respectively (p = 0.001); among patients with the epithelioid histologic type, the median OS were 25.6 and 41.6 months (p = 0.067); and among patients with the nonepithelioid histologic type, the median OS was 10.7 and 20.9 months (p = 0.006). The median RFS in the EPP and P/D arms among all patients were 10.3 and 13.1 months, respectively (p = 0.059); among patients with the epithelioid histologic type, the respective RFS were 11.7 and 14.7 months (p = 0.725), and among patients with the nonepithelioid histologic type, they were 4.2 and 11.7 months (p = 0.013). Univariable Cox regression analyses demonstrated that the following variables were associated with decreased OS: male sex, older age, larger tumor volume, EPP procedure, nonepithelioid histologic type, advanced pT descriptor, advanced pN descriptor, advanced pathologic stage, and occurrence of an SAE. In multivariable analyses, older age, EPP procedure, nonepithelioid histologic type, advanced pathologic stage, and occurrence of an SAE were associated with decreased OS (Table 3). Univariable Cox regression analyses demonstrated that the following variables were associated with decreased RFS: male sex, older age, larger tumor volume, nonepithelioid histologic type, advanced pT descriptor, advanced pN descriptor, advanced pathologic stage, and occurrence of an SAE. In multivariable analyses, older age, nonepithelioid histologic type, advanced pathologic stage, and occurrence of an SAE were associated with decreased RFS (Table 4).
      Figure thumbnail gr4
      Figure 4Overall survival (OS) (A) and recurrence-free survival (RFS) (B) in treated patients (n = 104).
      Table 3Univariable and multivariable Cox regression analysis of overall survival
      VariablesUnivariableMultivariable
      Hazard Ratio (95% CI)p ValueHazard Ratio (95% CI)p Value
      Sex (male vs. female)2.07 (1.16–3.72)0.0141.45 (0.78–2.72)0.242
      Age (y)1.04 (1.01–1.06)0.0111.05 (1.01–1.08)0.005
      Tumor volume (cm3)1.00 (1.00–1.001)0.0021.00 (1.00–1.00)0.730
      Surgery type (EPP vs. P/D)2.16 (1.33–3.49)0.0021.81 (1.07–3.09)0.028
      Histologic type (nonepithelioid vs. epithelioid)2.18 (1.39–3.41)0.0013.30 (1.95–5.58)<0.001
      pT stage
       1Reference
       25.72 (1.88–17.36)0.002
       35.83 (2.05–16.59)0.001
       49.14 (3.13–26.67)<0.001
      pN stage
       0Reference
       11.32 (0.61–2.87)0.484
       21.55 (0.96–2.50)0.074
       35.03 (1.16–21.79)0.031
      TNM staging
       I–IIReferenceReference
       III2.78 (1.43–5.42)0.0035.36 (2.52–11.40)<0.001
       IV3.98 (1.92–8.25)<0.0015.06 (2.24–11.46)<0.001
      Adjuvant chemotherapy (yes vs. no)1.05 (0.67–1.64)0.836
      Adjuvant radiotherapy (yes vs. no)1.25 (0.62–2.51)0.539
      SAE (yes vs. no)1.87 (1.20–2.93)0.0061.98 (1.27–3.26)0.007
      Note: Variables with a p value less than 0.05 in univariable analysis were considered for multivariable analysis.
      CI, confidence interval; EPP, extrapleural pneumonectomy; P/D, pleurectomy/decortication; SAE, serious adverse event.
      Table 4Univariable and multivariable Cox regression analysis of recurrence-free survival
      VariablesUnivariableMultivariable
      Hazard Ratio (95% CI)p ValueHazard Ratio (95% CI)p Value
      Sex (male vs. female)1.70 (1.01–2.87)0.0461.31 (0.75–2.31)0.347
      Age (y)1.03 (1.01–1.06)0.0111.04 (1.01–1.07)0.012
      Tumor volume (cm3)1.00 (1.00–1.001)0.0271.00 (1.00–1.00)1.000
      Surgery type (EPP vs. P/D)1.52 (0.98–2.35)0.061
      Histologic type (nonepithelioid vs. epithelioid)2.09 (1.37–3.19)0.0013.10 (1.89–5.08)<0.001
      pT stage
       1Reference
       23.99 (1.57–10.17)0.004
       34.72 (1.99–11.21)<0.001
       47.42 (3.00–18.32)<0.001
      pN stage
       0Reference
       11.02 (0.48–2.19)0.952
       21.41 (0.91–2.20)0.128
       34.35 (1.00–18.83)0.049
      TNM staging
       I–IIReferenceReference
       III2.18 (1.21–3.89)0.0093.42 (1.79–6.53)<0.001
       IV3.48 (1.80–6.74)<0.0014.67 (2.25–9.68)<0.001
      Adjuvant chemotherapy (yes vs. no)1.07 (0.70–1.63)0.767
      Adjuvant radiotherapy (yes vs. no)1.19 (0.61–2.31)0.607
      SAE (yes vs. no)1.76 (1.15–2.70)0.0091.75 (1.10–2.78)0.018
      Note: Variables with a p value less than 0.05 in univariable analysis were considered for multivariable analysis.
      CI, confidence interval; EPP, extrapleural pneumonectomy; P/D, pleurectomy/decortication; SAE, serious adverse event.

      Discussion

      Here, we have reported the completion of a phase I trial of combination cisplatin-gemcitabine HIOC for after surgical resection of MPM, with determination of the MTD as 175 mg/m2 in the case of cisplatin and 1000 mg/m2 in the case of gemcitabine. Morbidity and mortality were consistent with our prior trials of single-agent cisplatin HIOC in patients with MPM, which demonstrated the safety of and suggested the efficacy of this approach. The decision to evaluate combination cisplatin-gemcitabine in the current trial was made with consideration of their pharmacological compatibility, their nonoverlapping toxicity profiles, and their mechanisms of action. Although single-agent gemcitabine is not active in MPM when delivered systemically,
      • van Meerbeeck J.P.
      • Baas P.
      • Debruyne C.
      • et al.
      A phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.
      • Kindler H.L.
      • Millard F.
      • Herndon 2nd, J.E.
      • Vogelzang N.J.
      • Suzuki
      • Green M.R.
      Gemcitabine for malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B.
      intravenous combination of cisplatin (75–100 mg/m2) with gemcitabine (1000–1250 mg/m2) shows activity with partial response rates of 16% to 33%, effective disease control, and manageable toxicity.
      • Byrne M.J.
      • Davidson J.A.
      • Musk A.W.
      • et al.
      Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study.
      • Nowak A.K.
      • Byrne M.J.
      • Williamson R.
      • et al.
      A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma.
      • van Haarst J.M.
      • Baas P.
      • Manegold Ch
      • et al.
      Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma.
      For example, Byrne et al.
      • Byrne M.J.
      • Davidson J.A.
      • Musk A.W.
      • et al.
      Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study.
      evaluated the effectiveness of intravenous gemcitabine-cisplatin in the treatment of MPM in a multicenter phase II study. A total of 53 patients with advanced MPM received 100 mg/m2 of cisplatin on day 1 and 1000 mg/m2 of gemcitabine on days 1, 8, and 15 of a 28-day cycle, for a maximum of six cycles. Although no complete responses were observed, partial response was observed in 33% of patients and 60% had stable disease with significant improvement in symptoms and pulmonary function. Toxicity was mainly gastrointestinal (17% of patients had grade 3 nausea and emesis) and hematologic (56% of patients had grade 3 or 4 neutropenia and 49% had grade 3 or 4 thrombocytopenia).
      Intraperitoneal normothermic cisplatin-gemcitabine has been evaluated in the past for treating ovarian carcinoma after varying degrees of surgical debulking, which prompted us to consider this regimen in mesothelioma.
      • Sabbatini P.
      • Aghajanian C.
      • Leitao M.
      • et al.
      Intraperitoneal cisplatin with intraperitoneal gemcitabine in patients with epithelial ovarian cancer: results of a phase I/II trial.
      To our knowledge, no prior report of intrathoracic cisplatin-gemcitabine has been published. We sought to establish whether this regimen could be administered safely through the intrathoracic route, in the presence of hyperthermia, and in the context of the common surgical approaches to MPM. Unanticipated renal toxicity was encountered with the addition of even low-dose gemcitabine at the previously determined single-agent MTD for cisplatin HIOC (225 mg/m2) despite systemic pharmacologic protection. When the cisplatin dose was reduced to 175 mg/m2, gemcitabine was successfully escalated to its MTD without further renal toxicity. The MTD combination of cisplatin, 175 mg/m2, and gemcitabine, 1000 mg/m2, was administered to 18 participants (12 in the EPP arm and six in the P/D arm) without increasing mortality or morbidity relative to the historical experience with single-agent cisplatin HIOC.
      The most common SAEs encountered in this trial were acute respiratory distress syndrome (3.8%), atrial fibrillation (4.8%), dyspnea (7.8%), and deep venous thrombosis (2.9%), all of which were expected in the context of the participants’ disease and thoracic surgery. The DLT of cisplatin in cases of renal failure occurred despite an intraoperative renal protection program of intravenous sodium thiosulfate and amifostine, as well as aggressive preoperative and early postoperative volume loading (to offset cisplatin-induced diuresis). Aggressive monitoring of serum creatinine level is warranted after cisplatin-containing HIOC regimens, as it has been shown that sustained kidney injury can be predicted by a 59% or greater increase in serum creatinine level within 48 hours of resection of MPM (in a cohort in which 79% received HIOC cisplatin).
      • Mizuguchi K.A.
      • Mitani A.
      • Waikar S.S.
      • et al.
      Use of postoperative creatinine to predict sustained kidney injury in patients undergoing mesothelioma surgery.
      Consultation with the inpatient renal medicine service is recommended early in such cases, which can occasionally require renal replacement therapy. The leukopenia that accounted for the DLT of gemcitabine occurred within the first several postoperative days. When it is encountered, evaluation by the hematology inpatient service is recommended and may require administration of agents such as filgrastim (granulocyte colony-stimulating factor) to treat neutropenia.
      This trial was designed with nonrandom assignment to surgical treatment arms to permit parallel and independent phase I evaluation of cisplatin-gemcitabine HIOC in the context of EPP and P/D rather than to compare the two surgical procedures. Although there has been debate as to a preferred surgical procedure for MPM, we and others have contended that the multiple factors considered by the surgeon (often intraoperatively) in selecting the most appropriate procedure for an individual patient render randomization unfitting.
      • Rusch V.
      • Baldini E.H.
      • Bueno R.
      • et al.
      The role of surgical cytoreduction in the treatment of malignant pleural mesothelioma: meeting summary of the International Mesothelioma Interest Group Congress, September 11-14, 2012, Boston, Mass.
      In the current study, P/D was favored in analyses of OS and RFS, which may reflect well-documented differences in morbidity and mortality between these procedures
      • Burt B.M.
      • Cameron R.B.
      • Mollberg N.M.
      • et al.
      Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality.
      that were reconfirmed in the current study. Participants with tumors of the epithelioid histologic type had longer survival with cisplatin-gemcitabine HIOC after the EPP (25.6 months) than the survival demonstrated in our prior protocol of single-agent cisplatin HIOC after EPP (17.1 months).
      • Tilleman T.R.
      • Richards W.G.
      • Zellos L.
      • et al.
      Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: a phase II prospective study.
      Similarly, participants with epithelioid tumors in the P/D arm had longer survival in the current trial (59 months) than did those in our prior trial of P/D followed by single-agent cisplatin HIOC (26 months).
      • Richards W.G.
      • Zellos L.
      • Bueno R.
      • et al.
      Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.
      Although this is an encouraging result, these data should be interpreted with caution, as comparisons of these cohorts is likely confounded by group imbalances of patients with low risk profiles, who are the most likely to respond favorably to HIOC.
      • Sugarbaker D.J.
      • Gill R.R.
      • Yeap B.Y.
      • et al.
      Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection.
      We continue to advocate a personalized approach to surgery for MPM that is based on the surgeon’s assessment of the minimal degree of resection necessary to achieve MCR.
      The results of our trial should be considered in the context of the variability in multimodality treatment programs for MPM at centers around the world. Although it can be reasonably stated that a true standard-of-care for the treatment of patients with MPM has not been established, resection is recommended only in the context of systemic therapy and/or radiation. As such, intraoperative therapies can be considered to add another dimension to the treatment approach. One limitation of our trial is the nonrandom assignment to the treatment arms, the rationale for which has already been discussed. It should be noted that the patients for whom P/D is indicated may have included both fit patients with limited disease burden and less fit patients who lack the cardiopulmonary reserve to tolerate pneumonectomy, and this variability may influence comparison among cohorts. Similarly, although it is possible that the MTD for cisplatin-gemcitabine HIOC may differ between the EPP and P/D arms, the design of our trial does not allow for this assessment. A related limitation is that the potential role of HIOC for patients who undergo incomplete resection could not be addressed, because only four participants were assigned to that arm. Lastly, the assessments of efficacy in this study are limited to exploratory analyses.
      In summary, both the former and current trials have demonstrated the safety and feasibility of HIOC as a platform for local drug delivery. The current trial demonstrates the safety and feasibility of doublet therapy with cisplatin and gemcitabine intraoperative heated lavage, and it has established the MTD for this combination. These data provide a strong rationale for both single-agent versus double-agent comparison trials and phase II and III trials of doublet HIOC in MPM.

      Acknowledgments

      The authors would like to thank the following individuals for their gracious contributions to this project: Juliann Barlow, Leah Capalbo, Hannah Eisen, Sarah Rogers, Olivia Winfrey, Ellie Biaghoshi, and Lambros Zellos.

      Supplementary Data

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