Current Treatment Options in Oncology (2014) 15:683–699 DOI 10.1007/s11864-014-0314-4

Lung Cancer (HA Wakelee, Section Editor)

Local and Systemic Therapies for Malignant Pleural Mesothelioma Daniel Gomez, MD1 Anne S. Tsao, MD2,* Address 1 Department of Thoracic Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA 2,* Department of Thoracic/Head & Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 432, Houston, TX 77030, USA Email: [email protected]

Published online: 30 September 2014 * Springer Science+Business Media New York 2014

Keywords Malignant pleural mesothelioma I Radiation I Neoadjuvant I Systemic therapy

Opinion statement Malignant pleural mesothelioma (MPM) is a challenging disease to treat with median overall survival times ranging between 9-17 months for all stages of disease. Recent clinical trials have improved our understanding of the biology of MPM. However, survival results are still not ideal. For early-stage MPM, patients should be evaluated for trimodality therapy in an experienced cancer center. If treating off-protocol, MPM patients should receive a surgical staging evaluation. The decision to proceed with surgical resection also should be considered after an extensive and thorough pulmonary and cardiac evaluation. If deemed a good surgical candidate, patients should receive surgical resection (pleurectomy/decortication or extrapleural pneumonectomy), adjuvant radiation therapy (hemithoracic external beam or intensity modulated radiation therapy), and either neoadjuvant or adjuvant chemotherapy (cisplatin-pemetrexed for 4 cycles). The optimal precise sequence of the trimodality is unclear and should be decided upon by a multidisciplinary consensus for each individual patient. In general, clinical trial participation should be encouraged. Several trials are currently underway to examine intraoperative therapies, vaccines, immunotherapy additions, and novel radiation therapy techniques. Advances in the field of MPM are reliant on participation in clinical trials and identifying biomarkers that are predictive for response to systemic therapies and prognostic for survival benefit.

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Lung Cancer (HA Wakelee, Section Editor)

Introduction Malignant pleural mesothelioma (MPM) occurs in approximately 2,000-3,000 new individuals each year in the United States [1]. MPM remains a difficult disease to treat with median overall survival rates remaining between 9–17 months, regardless of stage [2–4]. Due to the rarity of the disease, clinical trials in the localregional setting are limited with small numbers of eligible patients and progress in this field has been slow.

Earlier-stage or resectable MPM is commonly treated with trimodality therapy inclusive of surgery with or without radiation, and systemic chemotherapy as neoadjuvant or adjuvant therapy. This review article will focus on the latest updates in the local-regional setting of resectable mesothelioma and discuss future directions for clinical research.

Surgical approaches Surgical intervention can be diagnostic or therapeutic (palliative or curative intent). Video-assisted thoracotomy (VATS) commonly involves drainage of the pleural effusion, biopsy of the tumor, and can include a talc pleurodesis for palliative purposed. Recently, the MesoVATS trial was reported to evaluate the clinical benefit of video-assisted thoracoscopic partial pleurectomy (VAT-PP) compared with best supportive care [5•]. MesoVATS was a randomized trial of VAT-PP compared with talc pleurodesis in 120 mesothelioma and 76 suspected malignant pleural mesothelioma (MPM) patients throughout 12 centers in the United Kingdom. VAT-PP involves thoracoscopic debulking with pleurectomy (visceral and parietal pleura) and decortication. Patients were stratified by EORTC prognostic scores (high vs. low risk). Postprocedure, both arms had similar rates of immediate chemotherapy (32 % VAT-PP vs. 28 % pleurodesis group) for a mean number of 4.4 to 4.5 cycles. Rintoul et al. reported that although the overall survival (the primary endpoint) in the MPM patients was not significantly different between the 2 arms (hazard ratio [HR] 1.11, p=0.51), there was an improvement in control of pleural effusion and in quality of life as defined by EuroQol EQ-5D, which surveyed patients at baseline, 1, 3, 6, and 12 months posttherapy. In EQ-5D, VAT-PP at 6 (p=0.042) and 12 months (p= 0.006) improved quality of life (QOL) but not at month 1 where the QOL was rated worse (p=0.065). VAT-PP improved pleural effusions (p=0.008) at 1 month and 6 months (p=0.028). However, there was no improvement at 3 or 12 months. Two other QOL surveys (EORTC QLQ-C30 and QLQ-LC13) did not reach statistical significance for any QOL difference. There was no difference in serious adverse event rates between the two arms, although VAT-PP had longer hospital stays (pG0.0001) and postoperative air leaks (p=0.001). There were more respiratory complications in the VAT-PP arm, although the difference did not reach statistical significance. VAT-PP was more expensive than talc pleurodesis. The authors concluded that some MPM patients may be better served with talc pleurodesis, because there is a shorter hospital stay with fewer complications. VAT-PP therefore was recommended for low-risk patients who are likely to survive more than 6 months. From this study, it appears that VAT-PP is unlikely to provide any survival benefit or clinical advantage over talc pleurodesis in advanced stage

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unresectable MPM [5•]. However, these results are not applicable in earlier stage MPM patients (I-II) where surgical debulking in this population remains an important research focus. The MesoVATs trial only included 23-24 % of earlier stage patients in this trial; and it is reasonable to assume that these patients (if their performance status was sufficient) would have a different clinical course with improved survival with more extensive surgical intervention. The MesoVATs trial is limited, because it did not report the survival subgroup analysis by stage or the number of post-study systemic therapies, which could have impacted the overall survival outcomes. MPM survival benefit is associated with additional lines of therapy. It is therefore unlikely that this trial will alter our current clinical practice in the United States. There are two main surgical therapeutic or debulking options for MPM: pleurectomy/decortication (P/D) and extrapleural pneumonectomy (EPP). P/D consists of an open thoracotomy, removal of the visceral and parietal pleura, the mediastinal pleura, the pericardium, and the diaphragm. It is believed that this procedure leaves residual tumor cells and is therefore considered a palliative rather than curative-intent approach [6]. The first site of recurrence in patients who receive a P/D often will be local recurrence where the primary tumor was. However, retrospective studies have shown that trimodality therapy, including P/D, can lead to long-term clinical benefit [7]. Flores et al. [7] evaluated 663 MPM patients who received multimodality therapy, including surgical resection (P/D or EPP), and reported that the EPP procedure led to a worse survival outcome (HR=1.4, pG0.001). Thoracic surgeons often will choose to perform P/D in borderline patients who would likely not tolerate an EPP. The EPP is reported to be the only surgical treatment for MPM that is curative intent. EPP consists of en bloc removal of the parietal and visceral pleura, involved lung, mediastinal lymph nodes, diaphragm, and pericardium. It has a significant morbidity with close to 76 % of patients experiencing postoperative complications, primarily cardiac, and pulmonary complications [8–10]. The 30-day mortality rate ranges from 3.4–8 % in experienced cancer centers with high volumes of patients [9, 11]. It is recommended to perform EPP only in epithelioid histology, good performance status, and negative nodal disease [9, 12–14]. In most studies to date, the 2-year overall survival rate for EPP alone is 10– 37 % but is higher when a multimodality regimen is prescribed [2, 4, 7, 8, 12, 14, 15]. Several critics in recent years have suggested that EPP is not beneficial to MPM patients [16•, 17•]. The Mesothelioma and Radical Surgery trial (MARs) [16•, 18], which compared 50 randomized MPM patients to EPP (n=24) versus “no EPP” (n=26), reported that receipt of EPP led to worse survival (HR 1.90, 95 % confidence interval [CI] 0.92–3.93, p=0.082). In this study, only 16 of the 24 patients in the EPP arm actually received the EPP and 19 % (n=3) had postoperative deaths. After accounting for prognostic factors (stage, histology, gender, age), the HR for EPP was reported as 2.75 (p=0.016). The median overall survival was 14.4 months for patients in the EPP arm compared with 19.5 months for the patients in the “no EPP” arm. This trial, although limited in numbers of patients, suggested that at worst, EPP can harm patients and at best, there was no clinical benefit for MPM patients. Lang-Lazdunski et al. [17•] conducted a nonrandomized study of consecutive MPM patients and compared 25 who received neoadjuvant chemotherapy followed by EPP and radiation to 54 patients with P/D, hyperthermic lavage,

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Lung Cancer (HA Wakelee, Section Editor) adjuvant radiation, and chemotherapy. The study reported that the P/D arm was superior to the EPP arm for compliance, toxicity, and survival. Patients in the P/D arm had 100 % compliance to complete trimodality treatment versus 68 % in the EPP arm. The P/D arm also had a higher median overall survival of 23 months versus 12.8 months [17•]. These small trials have led to significant controversy in the surgical realm on the topic of which surgical procedure to perform. It is clear that the optimal debulking method remains unknown. In the United States, EPP is still being offered as a curative intent procedure with multimodality treatment for MPM.

Systemic therapy for resectable disease It is currently recommended to use trimodality therapy in resectable MPM. The current guidelines for systemic therapy in the United States consists of 4 cycles of cisplatin-pemetrexed, given as either neoadjuvant or adjuvant therapy. In other areas of the world, common practice is to use platinum-gemcitabine, platinum-vinorelbine, or platinum-raltitrexed. A retrospective analysis [14] of 60 MPM patients who received multimodality therapy reported that there was no significant difference in survival outcomes based on the type of induction therapy; this study compared cisplatin-vinorelbine, platinum-pemetrexed, cisplatin-raltitrexed, and cisplatin-gemcitabine. The optimal neoadjuvant chemotherapy regimen has not been compared in a prospective, randomized trial due to the limited number of patients who are candidates for these multimodality studies. It also is unknown whether the sequencing of the different modality treatments impacts clinical outcome. There is some concern that neoadjuvant chemotherapy can adversely affect patient outcome by delaying surgical resection or causing complications before resection. Some experts believe that adjuvant chemotherapy is better suited to this MPM population with similar survival outcomes. One trial (n=20) reported using adjuvant platinum-gemcitabine or platinum-pemetrexed as part of multimodality therapy after EPP and had a median overall survival of 17 months [19]. However, there is the risk of being unable to administer adjuvant chemotherapy in patients undergoing surgical resection and adjuvant hemithoracic radiation therapy. Several trimodality studies have been performed in MPM (Table 1). All of these listed trials were single-arm trials with a platinum-doublet regimen. Taken together, the reported median overall survival ranges between 16.6 to 25 months [4, 20–25]. An EPP after systemic chemotherapy was able to be completed between 42-84 % in the studies but had a higher completion rate (67–76 %) in some of the larger trials [4, 17•, 18–22]. The largest neoadjuvant EPP trial completed to date treated 75 MPM patients with neoadjuvant cisplatinpemetrexed chemotherapy [4]. The resp\onse rate to neoadjuvant chemotherapy was 29 %, the median time to progression was 13.1 months, and the overall survival was 16.6 months [4]. There is some speculation that the neoadjuvant chemotherapy had an adverse impact in compliance with surgery, as in the larger trials, the completion EPP rate ranged between 67–76 % [4, 24, 25]. However, it is unknown whether these patients had poor prognostic factors that would have led to a worse surgical outcome. The use of neoadjuvant chemotherapy is thought to be

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Table 1. Selected prospective induction chemotherapy and EPP clinical trials in resectable malignant pleural mesothelioma Author

Year

Neoadjuvant regimen

Completed EPP

Response rate

Adjuvant XRT

Median PFS (mo)

Median OS (mo)

Krug [4] (n=75)

2009

Cisplatinpemetrexed

50

29.3

42

13.1

16.6

Van Schil [24] (n=59)

2010

Cisplatinpemetrexed

42

% 43.9

37

13.9

18.4

Federico [25] (n=54) Weder [20] (n=61) Flores [22] (n=21)*

2013

Cisplatinpemetrexed Cisplatingemcitabine Cisplatingemcitabine

41

% NR

32

8.6

15.5

37

NR

36

13.5

19.8

8

26

8

NR

19

2007 2006

able to provide prognostic information. Krug et al. did show in a subgroup analysis that patients who had a complete or partial response to neoadjuvant chemotherapy had a higher median overall survival (29.1 compared with 13.9 months for patients with stable or progressing disease, p=0.076) [4]. This indicates that sensitive MPM patients can achieve survival benefit from multimodality therapy. Based on the neoadjuvant studies reported to date, it can be hypothesized that improvements in systemic therapy can increase survival benefit in MPM patients. These advances are needed to focus on improving efficacy while limiting toxicity that could negatively impact compliance with surgery and radiation therapies. Several investigational approaches to neoadjuvant therapy with novel agents are underway and have been explored. At M.D. Anderson Cancer Center, a clinical trial of neoadjuvant dasatinib was performed based on preclinical studies that showed that the multi-kinase inhibitor dasatinib has in vitro efficacy against MPM cell lines, which overexpress active Src kinase [26]. In this study, patients undergo an extended surgical staging with multiple biopsies of the primary tumor followed by 4 weeks of neoadjuvant dasatinib therapy and then EPP or P/D. Patients who respond to the dasatinib therapy (as determined by radiographic or pathologic evaluation) were given an additional 2 years of maintenance dasatinib treatment. All patients will be offered adjuvant radiation therapy or chemotherapy at the discretion of the investigators. The primary endpoint is biomarker modulation of SrcTyr419 (an active Src kinase), and the secondary endpoints include survival, response rate, safety, and various downstream and antiangiogenic biomarkers identified through analysis of tumor tissue, plasma/serum, and pleural effusion specimens. This trial has completed accrual and the biomarker evaluations are underway. The role of immunotherapy in resectable mesothelioma also is being explored. Mesothelioma is considered an immunogenic disease and it is surmised

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Lung Cancer (HA Wakelee, Section Editor) that the addition of an anti-PDL1 inhibitor to cisplatin-pemetrexed in the neoadjuvant setting would be clinically beneficial. After surgical resection and adjuvant radiation treatment, maintenance immunotherapy to enhance t-cell activation against microscopic disease would potentially increase overall survival outcomes. At ESMO 2014, Mansfield et al. [27] reported a 40 % PD-L1 immunohistochemical (IHC) expression in pleural mesotheliomas (n=224) using a mouse monoclonal anti-human B7-H1 (clone 5H1-A3). A score G5 % IHC expression was considered negative. PD-L1 IHC expression was associated with more disease burden and less offers of surgery to the patient. Also, PD-L1 IHC expression was associated with a worse survival 6 months versus 14 months, pG0.0001) [27]. Southwest Oncology Group (SWOG) is therefore initiating a neoadjuvant trial with cisplatin-pemetrexed with and without MPDL3280A, a PD-L1 inhibitor, in resectable MPM patients. At Memorial Sloan Kettering and M.D. Anderson, a DOD sponsored adjuvant trial using WT-1 vaccine is currently open for enrollment. WT-1, a transcription factor, is commonly expressed on mesothelioma tumor cells and is typically processed and presented to the immune system. This peptide vaccine induced T cell recognition to attack WT-1 expressing mesothelioma tumor cells.

Intrapleural strategies Several research programs have investigated the use of intrapleural strategies in MPM. To date, it is not recommended to perform these procedures unless on a clinical trial and in experienced hands. Intrapleural therapies are hypothesized to have antitumor activity as the investigational agent would be in direct contact with the tumor and could be delivered with an increased concentration (presuming minimal systemic absorption). The majority of intracavitary chemotherapy trials are older have used platinum-based regimens in conjunction with P/D, with some studies continuing additional systemic platinum-based chemotherapy (cisplatin paired with mitomycin, cytarabine) [28–33]. The median progression-free survival ranges between 7.5 to 13.6 months and overall survival ranges between 11.5 to 18.3 months [28–33]. The greatest toxicity identified in these studies was renal failure, presumed to be secondary to systemic absorption of cisplatin. One phase II study using intrapleural liposomeentrapped cis-bisneodecanoato-trans-R-R-1,2-diaminocyclohexane platinum (II) or L-NDDP [34] (450 mg/m2) once every 3 weeks unfortunately demonstrated severe toxicity that precludes its use to treat MPM patients. Hyperthermic intrapleural perfusion of chemotherapy during a P/D or an EPP also has been investigated. The premise is that the elevated temperatures (42 °C) enable chemotherapy to penetrate the tumor cells. Clinical studies have demonstrated that this is a feasible approach and have reported the maximum tolerated dose of cisplatin at 225–250 mg/m2 [29, 33–37]. The usual doselimiting toxicity was renal insufficiency, although atrial fibrillation also was a common adverse event [32, 35]. In general, the median overall survival for hyperthermic intrapleural chemotherapy perfusion with P/D ranges between 9 to 13 months [32, 35–37]. Due to the small number of trials, high risk of toxicity, limited centers with experience, and lack of significant survival benefit, intrapleural chemotherapy perfusions with or without hyperthermia are not

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considered standard of care and should only be considered for well-designed clinical trials. Intrapleural gene therapy is a novel approach to treating resectable MPM [38]. A phase I trial with intrapleural adenovirus vectors containing the herpesvirus thymidine kinase (Ad-HSVtk) suicide gene were given to 21 MPM patients followed by 2 weeks of gancyclovir [39–41]. Eleven patients were able to show adequate transfer of the HSVtk gene into the superficial layers of the tumor. Two patients were reported to have long-term survival benefit over 6.5 years [39]. A subsequent phase I trial was designed using an adenoviral vector containing an immune stimulant, interferon-β (Ad.hu.IFN-β) injected into the pleural space [42]. Seven of ten patients showed successful gene transfer with three mesothelioma patients having disease stability [42]. The patients tolerated the procedure well with only transient hypoxia and reversible elevation of the liver enzymes reported. Intrapleural interferon-α2b gene transfer mediated by an adenoviral vector (Ad.IFN-α2b) also has been studied in a phase I trial [38]. Ad.IFN-α2b had similar toxicities with limited fever and tachycardia but appeared to lead to higher IFN levels in the pleura compared with Ad.hu.IFN-β. The Ad.IFN-α2b also had more prolonged expression time [38]. Additional studies are ongoing with gene therapy, but this therapy appears to be most beneficial in patients with smaller volume disease. There have been a small number of intrapleural immunotherapy studies [43–46]. Intrapleural gamma-interferon (40 x 106 U) solution administered twice per week for 2 months was reported to cause tumor regression in 5 of 19 patients [45]. The main adverse events included all patients with a fever and one reported pleural empyema [45]. Intrapleural interleukin-2 (IL-2) also has been evaluated, with small numbers of responses and median overall survival ranges of 15.6 to 18 months [44, 46]. Fever, flu-like symptoms, and catheter infections are the main adverse events. Astoul et al. [44] noted in their subgroup analysis that the IL-2 responders had a superior median overall survival of 28 months versus 8 months (p=0.01), suggesting that the immune system modulation is an important strategy in MPM treatment. In an aggressive approach, Lucchi et al. treated 49 MPM patients with intrapleural IL-2 (18 x 106 IU/day for 3 days) followed by a P/D, intrapleural postoperative epidoxorubicin therapy (25 mg/m2 for 3 days), postoperative systemic IL-2 therapy (18x 106 IU/day for 3 days), adjuvant radiation therapy (30 Gy), adjuvant systemic chemotherapy (cisplatin, 80 mg/m2 on day 1; gemcitabine, 1250 mg/m2 on days 1–8 for 6 cycles), and maintenance therapy with subcutaneously administered IL-2 (3 x 106 IU/day, 3 times per week) [43]. The initial results were impressive with a median overall survival of 26 months. However, at last follow-up, 37 of 49 patients had local relapse and 7 patients had both local and distant relapse. It is clear that the use of immune modulatory agents is a viable strategy in resectable MPM. However, the optimal method of delivery (intrapleural, systemic, or both) remains to be defined. Also, identifying better management algorithms of the immune toxicities is needed to further this field. Further study in the evaluation of the cytokine and host immune response is needed in MPM.

Radiation therapy advances in MPM Because MPM is a malignancy that involves the pleura, it is widely accepted that even when discrete regions are found to be involved with imaging, the entire

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Lung Cancer (HA Wakelee, Section Editor) pleural cavity is at risk for disease. Therefore, attempts to control localized disease with radiation have focused on hemithoracic approaches, often defined as the entire external pleural bed. Specifically, this target volume begins at the thoracic inlet, extends inferiorly to the last rib and encompasses all surgical regions of risk. Surgical incision and drain sites are boosted at the treating physician’s discretion. In addition, radiation has primarily been used in the adjuvant setting (after EPP or P/D), although we will discuss below that recently hemithoracic approaches have been utilized in unresectable MPM.

Adjuvant radiation therapy with an extrapleural pneumonectomy Several published reports, mostly retrospective, describe outcomes after EPP followed by hemithoracic radiation therapy. Before the advent of conformal techniques, radiation therapy was delivered with “conventional” approaches, consisting of two fields and with appropriate blocks placed over critical normal structures, such as the heart, spinal cord, and lungs. In one report, investigators from Memorial Sloan-Kettering Cancer Center reported their outcomes after EPP and conventional radiation techniques at doses of 50.4 Gy in 28 fractions. Radiation therapy was reasonably well tolerated, with approximately 85 % of patients experiencing nausea/vomiting and a 10-15 % rate of Grade 2 lung toxicity [47]. A study from the Brigham and Women’s Hospital reported 3-year freedom from disease-free progression at 33 % with this approach [48]. However, limitations of this technique include substantial dose heterogeneity within the treatment field and the reduced capacity to conform the radiation field to the region at risk, which often leads to dose outside of the target volume. In the past decade, technologic advances in radiation therapy have made it possible to increase precision and better quantitate radiation dose to the target volume and surrounding critical structures, through the advent of intensity modulated radiation therapy (IMRT). With this approach, the treatment plan can be designed to better “shape” around the target volume of interest, which reduces normal structure dose and increases radiation dose homogeneity within the target volume. Figure 1 demonstrates an example of a radiation plan after EPP demonstrating the conformality of this technique. Our institution reported initial results in 28 patients undergoing EPP+IMRT. Patients were treated to the involved hemithorax to 45-50 Gy, with boosts given to 60 Gy in selected patients. The treatment was relatively well tolerated, with the most common toxicities being mild nausea/vomiting (89 %) and increases in dyspnea (80 %). Seventeen percent of patients had Grade 3 dyspnea, and 24 % had Grade 3 fatigue. At a median follow-up of 9 (range 5-27) months, in-field local control was 100 %, and 20 of 28 patients were alive with no evidence of disease [49]. We have since updated these results in 136 patients who underwent surgical resection with planned IMRT. We found that approximately one-third of patients were not ultimately eligible for this approach due to treatmentrelated complications, low performance status, or the development of metastatic disease. However, control rates were promising. Locoregional recurrencefree survival at 2 years was 71 %, and 2-year overall survival was 32 %. Five of 86 patients experienced a grade 5 pulmonary toxicity, and pretreatment respiratory function was associated with survival. We concluded that locoregional control is high, although patients need to be well selected based on postoperative performance status and baseline respiratory function [50•].

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Fig. 1. Dose distribution and dose volume histogram of patient treated with IMRT after EPP for locally advanced mesothelioma. Contralateral lung sparing is critical to minimize the risk of high-grade pneumonitis.

These results are in line with those that have been reported at other centers, such as Duke University and in a phase II study of trimodality therapy performed at Memorial Sloan-Kettering Cancer Center [4, 51]. In the latter study, 77 patients with operable stage T1-3 N0-2 MPM were treated with neoadjuvant pemetrexed plus cisplatin (PC) followed by EPP and hemithoracic radiation therapy to a total dose of 54 Gy. IMRT was allowed but not required. With a median OS of 17 months, the authors found that a radiographic response to induction chemotherapy doubled survival times, from 13 to 26 months (pG0.05). In contrast, a pathologic complete response did not predict for longterm survival. Only one grade 5 pneumonitis and five grade 3 or higher radiation-related toxicities were noted in patients completing radiation therapy [4]. It should be emphasized that when using IMRT in this setting, it is of critical importance to adhere to dose constraints to the contralateral lung. In a widely cited study, investigators at Dana-Farber Cancer Institute/Brigham and Women’s Hospital treated 13 patients with EPP and adjuvant IMRT from 20042005. Eleven of 13 patients also received heated intraoperative cisplatin. All patients received adjuvant IMRT to a dose of 54 Gy to the involved hemithorax.

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Lung Cancer (HA Wakelee, Section Editor) Contralateral lung dose constraints were used that were in alignment with those in lung cancer, including a volume of lung receiving at least 20 Gy (V20) G20 % and a mean lung dose (MLD) G15 Gy. The investigators observed that 6 of 13 patients (46 %) died of fatal pneumonitis. Among those patients with Grade 5 pulmonary complications, the V20 ranged from 15 % to 22 %, the V5 ranged from 81 % to 100 %, and the MLD ranged from 13.3 to 17 Gy [52]. In editorials written regarding these results, several factors were thought to have potentially contributed to these suboptimal outcomes, including heated intraoperative cisplatin that was delivered in most patients. However, the most significant factor was thought to be the dose to the contralateral (and only functioning) lung. As a result, recommendations based on these outcomes included a lung dose constraint of V20G10 %, with closer attention to V5 as well (G35-40 %) [53].

IMRT after lung-sparing techniques As noted above, EPP has historically been preferred for fit patients with localized tumors and particularly without nodal involvement. However, unfortunately, a minority of patients with MPM are appropriate candidates for this approach. In multiple comparisons that have been performed between the two techniques, most studies demonstrate increased rates of local recurrence with P/D, at approximately 60-70 %, but similar overall survival and decreased morbidity and mortality [7, 16•]. As a result, recently there has been a shift at many centers away from EPP and towards lung-sparing procedures, such as P/D. Hemithoracic radiation therapy has been explored with the lung intact (after P/D or unresectable disease), although it presents unique issues compared with RT after EPP. First, the presence of functional lung tissue on the same side as the target volume exposes the patient to the risk of radiation pneumonitis in this lung. Second, presuming that the ipsilateral lung is functional, patients can theoretically experience significant functional decline due to the difficulty in sparing this structure. Finally, if much of the ipsilateral lung is nonfunctional after RT, a “shunting” effect can occur whereby patients continue to perfuse to the ipsilateral lung, yet air exchange does not occur. For these reasons, hemithoracic radiation treatment with two functional lungs can paradoxically be more challenging than with only one lung intact, and we recommend that this approach primarily be done primarily in the context of a clinical trial. Figure 2 demonstrates our institution’s technique of delineating a target volume using IMRT after P/D. In contrast to the target after EPP, we place a “rind” on the inner and outer pleural surface to attempt to spare the ipsilateral lung. However, the entire external pleural surface is covered. Experience with hemithoracic RT in an intact lung has been explored on a more limited basis than after EPP. One early report from Memorial-Sloan Kettering Cancer Center (MSKCC utilizing nonconformal techniques concluded that the relatively low efficacy of this approach did not justify the associated toxicity [54]. However, these results have been improved in select centers that have utilized IMRT. Between 2005 and 2010, 36 patients from the MSKCC with malignant pleural mesothelioma who were unable to undergo pneumonectomy underwent induction chemotherapy (89 % of patients) and then P/D with adjuvant IMRT (56 %) or IMRT with biopsy only (44 %). All patients were treated to the pleural surface of the involved hemithorax to a median dose of

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Fig. 2. IMRT after pleurectomy/decortication, with the dose distribution and the dose volume histogram (bottom right). The “rind” structure is used to spare the ipsilateral lung, and contralateral lung sparing remains of great importance, as it is after an EPP.

46.8 Gy. Seven (20 %) patients developed high-grade pneumonitis (including 1 death). For patients who underwent PL/D prior to IMRT, the 1- and 2-year survival rates were 75 % and 53 %, and the median survival was 26 months. For patients who did not undergo surgical resection, the 1- and 2-year survival rates and median survival trended lower at 69 % and 28 %, and 17 months respectively [55•]. These investigators also recently examined patterns of failure when treating the external pleural hemithorax in 67 patients to a similar volume as Fig. 2. The rate of in-field local failure was 64 %, with 1- and 2-year total failure rates of 56 % and 74 %, respectively. Interestingly, the authors also found that failure within the fissures was 16 %, and only 1 patient had an incisional failure despite the practice of not routinely boosting the incisional sites [56].

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Lung Cancer (HA Wakelee, Section Editor) Other institutions also have reported their results on this regimen. Investigators from Australia published results on the treatment of 3D conformal therapy or IMRT in MPM with the lung intact. Of the 14 patients treated with 45-60 Gy to the hemithorax, only 1 had previously undergone an EPP. In this analysis, the in-field local control rate was 71 %, with no grade 4 or higher toxicities. The median survival of patients in their cohort was 25 months, and 17 months after RT. [57] In another recently published prospective study from Italy, 20 patients with MPM patients underwent radical P/D followed by IMRT to the entire hemithorax but attempting to exclude the intact lung to a prescribed dose of 50 Gy with a simultaneous integrated boost to 60 Gy to areas concerning for residual disease. Nineteen patients received cisplatin/ pemetrexed. At a median follow-up of 27 months, the median overall survival and progression-free survival were 33 and 29 months, respectively. Overall survival at 2 and 3 years was 70 % and 49 %, respectively. Local-regional control at 2 and 3 years was 68 % and 59 %, respectively. The predominant pattern of failure was distant, with 7 patients developing distant metastases as the first site of relapse. Three patients experienced an isolated locoregional recurrence. Five patients experienced grades 2-3 pneumonitis, but no fatal pulmonary toxicity was noted [58]. Finally, in a recent report from MDACC, 22 patients (11 prospectively enrolled in an institutional protocol and 11 studied off protocol) with MPM underwent P/D followed by adjuvant IMRT to the involved hemithorax. Patients were treated to 45 Gy in 25 fractions with 9 patients receiving a simultaneous boost to 60 Gy to high-risk areas. Twenty patients received chemotherapy (15=induction, 2=adjuvant, 3=both). Median follow-up was 14.7 months after surgery (range 4.1-37.1 months). The therapy was well tolerated. No grade 4-5 pulmonary toxicity was noted. One case of grade 4 thrombocytopenia was observed. Progressive decreases in pulmonary function were noted after surgery and IMRT. Median baseline % predicted FVC, FEV1, and DLCO were 90 %, 84 %, and 87 %. The change in % predicted FVC, FEV1 and DLCO was −18 %, −11 %, and −17 % after surgery and −25 % (p=0.02), −18 % (p=0.01), and −27 % (p=0.01) after IMRT. Rates of overall survival and progression-free survival were 73 % and 60 % at 1 year, respectively, and 52 % and 32 % at 2 years, respectively. Outcomes for IMRT after P/D were compared to 22 matched patients who underwent IMRT after EPP. The patients who underwent P/D had less grade 4-5 toxicity (0/22 vs. 3/22, p=0.23) and a trend toward improved median overall survival (28.4 vs. 14.2 months, p=0.14), median disease-free survival (15.4 vs. 10.2 months, p=0.18), and median time to distant metastasis (not reached vs. 11.8 months, p=0.15). Finally, the median time to local regional failure (20.5 months vs. not reached, p=0.06) appeared better in the EPP cohort. [59] Indeed, while attempts are made to spare the ipsilateral lung in this context, many patients do ultimately experience a significant decline in function on the side that is treated, which can develop into a “functional” pneumonectomy. However, the clinical effects of such changes, as manifested by high rates of Grade 3 radiation pneumonitis or high-grade dyspnea often are disproportionally low. This discrepancy may occur for multiple reasons. First, the ipsilateral lung is typically substantially smaller than the uninvolved lung, with much less perfusion to that side. As a result, treating to the ipsilateral hemithorax rarely is synonymous with delivering radiation to 50 % of the lung

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Fig. 3. Comparison of IMRT (left) vs. proton beam (right) dose distribution of a patient who has received an extrapleural pneumonectomy. With intensity modulated proton beam therapy (IMPT), it is possible to limit low-dose “spillover” to the contralateral lung and reduce dose to the heart, particularly for left-sided tumors, as depicted by the color wash extending to the contralateral lung.

volume. Second, with IMRT, the dose to the target can be made more homogenous, and hot spots within normal lung parenchyma can be avoided to a greater extent. If the region of lung receiving high-dose radiation also is important in the development of radiation pneumonitis, as prior studies have suggested [60]. Then, although in most cases the ipsilateral lung receives a lowdose radiation “bath,” sparing this region from high doses that would be present with conventional, nonconformal techniques also may reduce the rates of this toxicity.

Future directions – proton beam therapy for MPM While IMRT has provided a substantial dosimetric benefit over 3D-conformal and two-dimensional techniques in the adjuvant setting for MPM, as noted above, one major limitation is the requirement for a large number of beams. Because of the dose distribution properties of photons, which deliver a high dose at the surface and then have a period of dose fall-off, low doses are spread out over wide volumes and it remains difficult to completely spare adjacent normal tissue. With proton beam therapy, or more specifically intensity modulated proton therapy (IMPT), it is possible to combine the benefits of conformality that can be achieved with IMRT and to improve the dose distribution through the delivery of protons, which deliver low doses proximal and distal to the region of interest for any individual beam in what is termed the “Bragg Peak.” While several studies have now reported proton beam therapy in the setting of lung cancer, data pertaining to proton therapy in the context of MPM is sparse [61–63]. At our institution, we have recently begun investigations on the delivery of IMPT in the adjuvant setting for MPM, both after EPP as well as lung-sparing surgery. Figures 3 and 4 demonstrate the differences in dose distribution between IMRT and IMPT in both of these scenarios. The primary benefit is total sparing (elimination of the low-dose bath) to the contralateral lung, as well as reductions in low to moderate doses delivered to adjacent structures, such as the heart, liver, and kidneys. Studies on this approach are ongoing, with ongoing challenges being the size of the radiation field, the

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Fig. 4. Comparison of IMRT (left) vs. IMPT (right) in a patient with a right-sided pleurectomy/decortication. In the patients treated with IMPT, we have observed a modest capacity to spare the ipsilateral lung and more substantial improvements in the dose distribution to the heart, liver (right sided tumors), kidneys, and contralateral lung.

constant and sometimes irregular respiratory motion, and the heterogeneity of the tissue involved. The latter limitation is of particular import with a proton beam, as changes in tissue density can substantially affect dose distribution. Our institution has currently treated a limited number of select patients with this approach and data collection is ongoing. Given the sharp increase in the number of proton therapy centers nationally, if this treatment could be standardized, patients would have another option in the adjuvant setting that may further reduce toxicity and improve outcomes in this aggressive and oft-deadly malignancy. Further clinical trials are encouraged.

Conclusions Improved strategic design of clinical studies for the treatment of resectable MPM is crucial. This will require integration of improved systemic therapies, immune modulation, identification of predictive and prognostic biomarkers, investment in genetic profiling, and novel advances in radiation therapy technique. MPM patients with resectable disease should be encouraged to participate in clinical trials at experienced centers with dedicated mesothelioma multimodality programs..

Compliance with Ethics Guidelines Conflict of Interest Daniel Gomez declares that he has no conflict of interest. Anne Tsao is on the advisory board for Genentech, Roche, Lilly, Medimmune, Astellas, and Boeringer Ingelheim and has received grants from Medimmune. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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