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Induction Therapy for Mesothelioma
STATE OF THE ART
Induction Therapy for Mesothelioma Isabelle Opitz, MD, FEBTS, and Walter Weder, MD, FEBTS One particular approach of multimodality treatment for mesothelioma is induction therapy followed by surgery. Among its several advantages, the most important is downstaging of the tumor into a resectable stage, although morbidity and mortality might be increased. In this article we review the principles and outcome of different modalities for induction treatment of mesothelioma. Semin Thoracic Surg 27:240–249 I 2015 Elsevier Inc. All rights reserved. Keywords: induction therapy, MCR, MPM, Pleurectomy and Decortication, Extrapleural Pneumonectomy.
INTRODUCTION Currently multimodality therapy is the most frequently used approach of therapy for malignant pleural mesothelioma (MPM). The best sequence of the different modalities in combination with surgery is unknown. Induction therapy followed by surgery is applied with the intention to achieve downstaging of the tumor — a concept derived from stage III non — small cell lung cancer (NSCLC). In this article we present several approaches to induce malignant pleural mesothelioma (MPM) before resection. PRINCIPLE OF INDUCTION CHEMOTHERAPY The concept of induction chemotherapy has been adapted from stage III NSCLC with the idea to possibly downstage the tumor and herewith render the tumor into a resectable stage. The concept was pioneered in Zürich, Switzerland,1 studied more in detail in a national Swiss multicentre trial,2 and has been adopted by many MPM centers.3 There are several advantages to applying chemotherapy before surgery, the first being that it is better tolerated than after surgery and therefore associated with better compliance. It has been demonstrated for NSCLC that with adjuvant chemotherapy compliance is r50%, the complete dose application can be fulfilled in r60%, and on-time application occurs equally in r50% only.4 Moreover, the efficacy of chemotherapeutic drug delivery might be increased because of intact Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. This study is supported in part by an Swiss National Science Foundation (SNSF), Switzerland, PP00P3_133657. Address reprint requests to Isabelle Opitz, MD, FEBTS, Division of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, Zurich 8091, Switzerland. E-mail: [email protected]
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Survival curves from patients treated with induction chemotherapy followed by pleuropneumonectomy according to response (Opitz I et al. accepted for publication JTO).
blood supply to Central Message the tumor before surgery. Having Induction chemotherapy before surgery in tumor tissue availMPM can lead to improved outcomes with acceptable mortality and morbidity. Future able at the time research is needed for adequate patient point of surgery selection. allows additionally assessing the efficacy of the chemotherapy with chemosensitivity testing. Another theoretical advantage is that microscopic disease might be eradicated early in the treatment course. Ideally, induction chemotherapy downstages the tumor (Fig. 1), leading to improved complete resection, which has been reported from prospective trials to range up to 40%.2,5 Furthermore, patient selection for resection can be based on tumor progression during chemotherapy, which would be assessed by postchemotherapy computed tomography scans. The principal disadvantage of induction chemotherapy is a potentially higher surgical mortality and morbidity and that the delay of surgery may negatively influence resectability, which is discussed in the section Morbidity and Mortality after Induction Chemotherapy.
RESPONSE TO INDUCTION CHEMOTHERAPY In general, MPM does not respond very well to chemotherapy, but still, there are a few reports on chemotherapyinduced complete pathologic responses in the literature.6 However, in our experience of 142 extrapleural pneumonectomy (EPP) after 3 cycles of neoadjuvant chemotherapy with cisplatin and gemcitabine (cis/gem) or cisplatin and pemetrexed (cis/pem) we could not observe a complete response so far. Only a nearly complete response after induction chemotherapy was observed in a (female) patient undergoing 3 cycles of cis/pem chemotherapy (Fig. 2).
1043-0679/$-see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semtcvs.2015.05.003
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Figure 1. CT scan before and after induction chemotherapy showing downstaging of the tumor. CT, computed tomography
The response rates reported in the literature are in the range 30%-40% with the main drawback of lacking reliable response assessment in MPM. The only available tool of modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria7 lacks reproducibility.8 However, patients who do not respond to induction chemotherapy but present with progressive disease after the treatment have indeed a significantly worse prognosis (Opitz et al, accepted for publication) (Fig. 3). To date, no validated biological predictive marker is available to assist patient selection for induction chemotherapy. Pemetrexed is a multitargeted molecule-inhibiting enzyme in folate metabolism, with the main target being thymidylate synthase (TS).9 Thus, the predictive value of TS for outcomes of patients with MPM treated with pemetrexed has been evaluated using both messenger RNA and protein expression. Several studies have reported associations between low TS with longer time to
disease progression, longer overall survival, and better clinical response.10-12 High level of folylpolyglutamate synthetase, an enzyme that facilitates intracellular retention of pemetrexed, was also shown to be associated with better outcomes.10,13 However, 2 studies could not show either prognostic or predictive role of TS13,14; the latter study also could not demonstrate association between folylpolyglutamate synthetase expression and outcomes. The reasons of these discrepancies may stem from differences in patient population and treatment and evaluation methods.15 DNA repair enzymes such as excision repair crosscomplementation group1 (ERCC1) and ribonucleotide reductase M1 (RRM1) were shown to have prognostic and predictive role for patients with cancer receiving platinum-based chemotherapy and gemcitabine.16 We recently identified a prognostic role of immunohistochemical expression of ERCC1 and RRM1 in a cohort of patients with MPM treated
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Figure 2. Microscopic examination of an EPP specimen after 3 cycles of cis/pem chemotherapy demonstrating complete regression. (A) Routine HE-stain showing lung tissue (bottom) and diffuse thickened pleura without infiltrates of mesothelioma, characterized by extensive fibrosis, bleeding, inflammation, and iron depositions (B, C, Perls' iron stain). In this case only minimal remnants of residual tumor cells with regressive changes were detectable using an immunostain for calretinin (D). (Images courtesy of: B. Vrugt et al; Institute of Pathology, the University Hospital Zurich). HE, hematoxylin and eosin. (Color version of figure is available online at http:// www.semthorcardiovascsurg.com.)
with platinum-based induction chemotherapy followed by EPP.17 So far this is the first study showing the prognostic role of RRM1 expression, the enzyme involved in de novo deoxyribonucleotides synthesis and the target of gemcitabine, in MPM. In terms of the prognostic role of ERCC1 in MPM, there have been several studies showing contradictory results.11,18-20 ERCC1 is an enzyme taking part in the nucleotide excision repair of platinum-DNA adducts. Predictive roles of ERCC1 and RRM1 for chemotherapy selection have been evaluated in patients with NSCLC.21,22 Nonetheless, the nonreproducible ERCC1 staining using different batches of 8F1 antibody has hampered the further application of ERCC1 as a predictive biomarker. ERCC1 also exists in 4 different isoforms but only 1 isoform is proficient in platinum-DNA adduct repair.23 RRM1 has several polymorphisms that are associated with gemcitabine treatment efficacy in MPM.24 In
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addition to tumoral markers, ratios of postchemotherapy to prechemotherapy serum N-ERC/mesothelin levels were shown to be associated with response to chemotherapy in a small cohort of patients with MPM.25 Altogether, these markers seem to be useful but further validation is needed, requiring more robust and specific antibodies as well as accurate and reproducible detection techniques. A multiinstitutional effort to validate these markers in a bigger patient cohort is needed. The approach may be further improved by integrating an innovative genomic tool such as next generation sequencing. MORBIDITY AND MORTALITY AFTER INDUCTION CHEMOTHERAPY Morbidity and mortality rates for NSCLC treated with induction chemotherapy followed by surgery,
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Figure 3. Kaplan-Meier curves for overall survival (OS) and chemotherapy (CTX) response from patients being treated between 1999 and 2015 with induction CTX at the University Hospital Zurich. (A) ITT group: patients intended to be treated with induction CTX followed by EPP. (B) EPP group: patients treated with induction chemotherapy followed by EPP (subgroup of the ITT group). CI, confidence interval; CR, complete response; ITT, intention to treat; PR, partial response; SD, stable disease; PD, progressive disease.
as well as the incidence of medical and surgical complications were reviewed in several phase II and randomized trials by Stamatis et al.26 Mortality ranges from 0%-9% and morbidity from 26%-51%. Medical complications after induction treatment are acute respiratory distress syndrome (ARDS; 1.8%-46%), pneumonia (3%-19%), atelectasis (2.7%-16), and arrhythmia (4.4%-18%). Surgical complications after induction treatment are bronchopleural fistula (0%-23%), empyema (1.3%7.4%), bleeding (1%-8.3%), and prolonged air leak (3%-16.6%). After publication of the MARS (Mesothelioma and Radical Surgery) trial results,27 the procedure of EPP was critically discussed for exceedingly high morbidity and mortality rates. This is not supported by recently reported trials for trimodality therapy including EPP (Table 1). In experienced centers, mortality can be reduced to 2%-5%,35 morbidity remains high (22%-82%) but seems to be manageable in terms of improvement in quality of life for all parameters at 3 months after the operation.36 The perioperative mortality and morbidity of extended pleurectomy and decortication (eP/D) and EPP in combination with other treatment modalities were reviewed by Cao et al: mortality rates were significantly lower in the eP/D group compared with EPP (2.9% vs 6.8%) and also morbidity rates were lower after the lungs-sparing procedure (27.9% vs 62% for EPP). However, comparability of morbidity data is complicated by the fact that reporting and definition of morbidity are very heterogeneous. Prolonged air leak is a substantial problem after eP/D as nearly all of these
patients suffer from this problem postoperatively and a substantial part of these patients suffer from persistent air leak over weeks. This is most probably not represented in median morbidity rates of 28%.37 One particular complication after EPP is postpneumonectomy empyema with or without bronchopleural fistula. Whereas it seems to be controversial in lung cancer whether or not the incidence is increased after induction chemotherapy,38-40 the reported empyema rate in MPM can be as high as 16%.34 Several prophylactic measures can be undertaken to decrease the incidence of empyema: irrigation of the chest cavity with povidone iodine solution (diluted 1:10 in NaCl 0.9%) at the end of the resection. Some groups use povidone iodine lavage as an intracavitary cytotoxic agent.41,42 Furthermore standardized intravenous antibiotics with amoxicillin 2.2 g iv should be continued for 5 days after the operation. Bronchial stump coverage can be difficult because a pericardial fat flap is usually not available after radical resection. The quality of an intercostal muscle flap is often poor owing to retraction of the hemithorax, typical for the nature of mesothelioma disease. Alternatively, an extrathoracic muscle flap can be used. Bleeding complications are not very common after MPM surgery, even after induction chemotherapy. But careful hemostasis is certainly important not only to avoid redo surgery but also to prevent later superinfection of persistent hematoma. To reduce the incidence of respiratory complications and here especially of ARDS after platinum-based
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INDUCTION THERAPY FOR MESOTHELIOMA chemotherapy, intraoperative FiO2 should be maintained below 50% if possible to reduce potential oxygen toxicity. ARDS was reported to be higher for induction treatment of lung cancer,43 and is possibly related to an injury of the alveolar-capillary membrane.44 Preservation of the phrenic nerve is important for patients where the diaphragm can be preserved during eP/D. However this is often difficult and not evident, because the pericardial pleura needs to be resected for macroscopic complete resection (MCR) and the phrenic nerve is skeletonized at this point, leading to loss of function. Early extubation should be the aim to decrease the risk of not only ventilator-associated pneumonias but also the extent of air leaks of eP/D patients. Fibrin glue application after P/D can help reduce the duration of air leaks. Thromboembolic complications, such as pulmonary embolism, are frequently observed in most of the series (1.5%-3%)34,45,46 and can be life threatening especially after EPP. Besides the awareness and sensitive clinical attitude to any oxygen desaturations with a low threshold for computed tomography scan with pulmonary embolism protocol, we recommend oral anticoagulation for a period of 3 months after surgery. Overall, surgical mortality and morbidity seem not to be increased after induction chemotherapy (overview of reported literature provided in Tables 1 and 2).
OUTCOME AFTER INDUCTION CHEMOTHERAPY Survival of patients undergoing induction chemotherapy followed by EPP and P/D (median survival time ranging from 10.2-59 months) is comparable to those from other multimodal treatments such as adjuvant chemotherapy after surgery (median survival time in the range of 13-24 months.28 Tables 1 and 2 summarize the reported literature on EPP and P/D after neoadjuvant therapy. Nowadays, the difficulty is the selection of the patients who benefit most from a multimodal approach. All patients with histologically proven mesothelioma and resectable tumor should be considered for a multimodal approach including MCR. For further selection clinical staging and functional assessment is mandatory. Whereas mediastinal lymph node involvement and sarcomatoid histotype are considered as exclusion criteria for multimodal treatment in many protocols, data about the role of mediastinal lymph node involvement of the different case series are conflicting.2,51 However, the results of the International Association for the Study of Lung Cancer and the International Mesothelioma Interest
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Group staging project demonstrate that N2 is not a survival-influencing factor.52 Another criterion to be considered is the volume of the tumor,53,54 which has been shown to be a prognosis-influencing factor. The selection of patients for multimodality treatment should not be based on a single clinical factor or laboratory data but more on a combination of several parameters ideally being available before the treatment starts (Opitz et al, accepted for publication). INDUCTION RADIOTHERAPY The Toronto group (Surgery for Mesothelioma After Radiation Therapy [SMART] protocol) has initiated a different approach by applying induction radiotherapy before surgery55 (Fig. 4). Owing to the delivered doses and the target volume, this approach is so far feasible only in an MCR approach using EPP to avoid severe radiation-induced pulmonary toxicity. The protocol therefore requires a high degree of coordination and cooperation between radiation oncology and thoracic surgery. This may hamper its implementation in centers where this expertise is lacking. However, initial results are very promising; out of 25 patients who received high-dose intensity-modulated radiotherapy followed by EPP, 3-year survival rates reached 84% in epithelioid subtypes and 13% in biphasic subtypes, but 1 patient died of treatmentrelated toxicity (90-day morbidity ¼ 4%). Another benefit of the SMART protocol might be on the immune system by activating the immune system against the tumor and then removing the immunosuppressive environment generated by the tumor. The effect on the immune system of highdose hypofractionated radiation therapy potentially opens the door for new combination therapies in the near future between immunotherapy and radiation to optimize their synergism on the immune system.55-57 TARGETED AGENTS AS INDUCTION THERAPY BEFORE SURGERY A wide range of novel targeted drugs are currently being trialed for use in MPM,58 with most of them focusing on inhibition of tyrosine kinases such as vascular endothelial growth factor receptor, epidermal growth factor receptor, or Focal Adhesion Kinase (FAK). However, most of these trials investigate the respective tyrosine kinase inhibitors (TKIs) in second-line settings or in patients with unresectable disease. But 2 trials specifically address the question of TKIs as novel induction therapy before surgery: NCT02004028 investigates the FAK inhibitor VS-6063 (Defactinib, Verastem Inc) and
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Study Period
No. of Induction CTX Patients
Response Rate
EPP Resectability
Morbidity
Mortality
Adjuvant OS Modalities
PFS
Lauk et al28; 2014
19992012
251
Platinum þ gem: 59 Platinum þ pem: 161 Other: 31
NR
251 NR
Major: 30%
30d: 5% 90d: 8%
NR
NR
NR
Rea et al29; 2013
20052010
54
Cis þ pem: 52
NR
41
NR
Overall: 66.7% Major: NR
30d: 4.4%
RT: 32
15.5 (11.0-NA) (from enrollment)
8.6 (6.3-14.4) (from enrollment)
Treasure et al27; 2011
20052008
50
n ¼ 20: Cis þ gem n ¼ 16: Cis þ pem n ¼ 11: Cis þ mitomycin þ vinblastine n ¼ 3: Cis þ vinorelbine
PR: 5 SD: 34 PD: 7
16
NR
69%
30d: 12.5% In hospital: 18.8%
RT: 8
14.4 (5.3-18.7) (From randomization)
7.6 (5.0-13.4) (from randomization)
Van Schil et al30; 2010
20052007
59
n ¼ 54: Cis þ pem n ¼ 3: Carbo þ pem
CR: 14 PR: 11
42
R0: 30 R1: 10
Overall: 82.6%
30d: 6.5% 90d: 6.5%
RT: 37
ITT: 18.4 (15.6-32.9) EPP: 21.5 (17.6-NR) (unknown)
ITT: 13.9 (10.9-17.2) (unknown)
R0: 6
Major: 37 (80%)
30d and in hospital: 2 (4.3%)
R1: 31
Minor 54%
EBRT:24 EPP: 24 (7.2-30.9) (from diagnosis) IMRT: 14
Missing: 4
SD: 24 PD: 5 Not assessable: 3 Buduhan et al31; 2009
Krug et al32; 2009
19972008
20032006
55
77
n ¼ 24: Cis/ carbo þ pem n ¼ 23: Cis þ methotrexate þ vinblastin n ¼ 5: Cis þ gem n ¼ 3: Other
NR
n ¼ 77: Cis þ pem
Response rate: 32.5% CR: 1 PR: 24 SD: 36 PD: 5 Missing: 11
R2: 3 Unknown: 1 46
R2: 9 54
29.3%
Time to local recurrence IMRT: 12
EBRT: 7 (from diagnosis) Atrial fibrillation (10.5%) Pain (7.0%) Dyspnea (5.3%) Anemia (5.5%) Sepsis (3.5%)
30d: 2 (3.7%)
RT: 40
ITT: 16.8 (13.6-23.2)
ITT: 10.1 (8.6-15.0) (unknown)
EPP: 21.9 (16.8-29.1) EPP þ RT: 29.1 (19.3-NR) (unknown)
De Perrot et al33; 2009
20012007
60
n ¼ 26: Cis þ vinorelbine NR n ¼ 24: Cis þ pem n ¼ 6 Cis þ raltitrexed n ¼ 4: Cis þ gem
45
R0/1: 41 R2: 4
Major: 15
30d And in hospital 3 (6.7%)
RT: 30
ITT: 14 EPP þ RT: 59 (from chemo)
N2: 12 N1: 44 N0: not reached (from chemo)
Weder et al2; 2007
20002003
61
n ¼ 58: Cis þ gem
45
Resectability rate: 61% R0/1: 37 R2: 8
Major: 16 (35%)
In hospital: 1 (2.2%)
RT: 36
ITT: 19.8 (14.6-24.5)
EPP:13.5 (10.2-18.8) (from chemo)
NR
Overall: 39 (62%)
Opitz et al34; 2006
19992005
63
n ¼ 47: Cis þ gem n ¼ 16: Cis þ pem
NR
PR: 20 SD: 32 PD: 11
63
EPP: 23 (16.6-32.9) (from chemo) 30d and in hospital: 3.2%
NR
NR
NR
Overview of reported mortality and morbidity, overall and progression-free survival in extrapleural pneumonectomy (EPP). Studies with less than 50 patients are not considered. CTX, chemotherapy; CR, complete response; EBRT, external beam radiotherapy; IMRT, intensity-modulated radiotherapy; ITT, intention to treat; NR, not reported; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RT, radiotherapy; SD, stable disease.
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Table 1. Induction Chemotherapy Followed by Extrapleural Pneumonectomy (EPP) Study
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Overview of reported mortality and morbidity, overall and progression-free survival in pleurectomy and decortication. Studies with less than 50 patients are not considered. CTX, chemotherapy; NR, not reported; OS, overall survival; PFS, progression-free survival; RT, radiotherapy. * Values based on all patients undergoing P/D (regardless of neoadjuvant chemotherapy).
SP: 8.1* NR TP: 17.2* (from 30d after surgery) NR Major SP: 2.9% * SP: 20%* TP: 0% * TP: 5.9%* Minor SP: 11.8%* TP: 10%* Subtotal P: 34 Total P: 10 Schipper et al50; 2008 19852003
285
n ¼ 29 (NR) NR
NR
Stage I: 32 (17-45)* Stage I: 18 (10-26)* Stage II: 23 (2-40)* (from surgery) Stage II: 10 (5-17)*(from surgery) CTX: 6* Overall: 24%* 30d: 0%* NR 37 n ¼ 31 (NR) NR 19982009 Rena et al49; 2012
77
16 (9-22)* (From surgery) 13.4 (9.7-17.1)*(From diagnosis) CTX: 32* RT: 0 Overall: 43%* 30d: 3%* 90d: 12%* NR 19992010 Nakas et al48; 2012
165
n ¼ 8 (NR)
Total pleurectomy: 67* R0: 33.9%* R1: 62.9%* R2: 3.2%*
NR NR 30d and in hospital: 3.1%* RT: 13 NR NR 130 NR 23 20092011 Burt et al47; 2014
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Resectability Morbidity Response P/D Rate No. of Induction Patients CTX Study Period Study
Table 2. Induction Chemotherapy Followed by Pleurectomy and Decortication (P/D)
Mortality
Adjuvant OS Modalities
PFS
INDUCTION THERAPY FOR MESOTHELIOMA NCT00652574 studies the multi-BCR/ABL and Src kinase family inhibitor Dasatinib (BMS-354825, Bristol-Myers Squibb). Primary objective of both trials is the assessment of biomarker responses in tumor tissue; however, preliminary data regarding safety and efficacy are also being collected. Dasatinib is approved for treatment of both leukemia and Philadelphia chromosome – positive acute lymphoblastic leukemia, both of which harbor the oncogenic BCR/ABL fusion, one of the main kinases targeted by dasatinib.59 Although BCR/ABL has not been implicated in MPM, dasatinib is also a potent inhibitor of members of the Src kinase family, in particular c-Src, which has a key role in the regulation of intracellular signal transduction of, for example, the FAK, vascular endothelial growth factor, and PI3K/Akt pathways.60,61 Tsao et al have shown that c-Src is activated in MPM cells in vitro and that treatment with dasatinib could induce cell cycle arrest and apoptosis as well as a decrease in cell migration and invasion. The study further showed that activated c-Src (p-Src Y419) correlated with higher pathologic stage and presence of metastasis in a series of 46 human MPM tissues.62 Despite these promising in vitro findings, a Phase II trial of singleagent dasatinib in previously treated unresected MPM (CALGB-30601, NCT00509041) did not show any activity of dasatinib in this unselected population.63 The trial, however, also included analyses of potential biomarkers, which revealed that lower pretreatment serum levels of colony-stimulating factor-1 were associated with prolonged overall survival and progression-free survival, suggesting that a subgroup of patients may actually benefit from inhibition of c-Src. The currently still ongoing trial of induction therapy dasatinib in resectable mesothelioma was initiated not long after the Phase II trial by the authors of the initial in vitro study. In this trial, following extended surgical staging with multiple biopsies, patients eligible for radical surgery receive 4 weeks of oral dasatinib (70 mg two times a day) followed by P/D or EPP. In cases of radiographic response to dasatinib, it may be given up to a further 2 years after surgery. Although the primary aim of this phase I trial is to assess the effects of dasatinib on modulation of p-Scr Y419 in tumor tissue, preliminary data presented at the American Society of Clinical Oncology—2010 annual meeting showed stable disease in 12 of 14 patients after 4 weeks of neoadjuvant dasatinib.64 In addition, higher baseline p-Src Y419 as well as significant modulation of p-Src Y419 after dasatinib was significantly associated with improved progression-free survival (P ¼ 0.008 for both). Holding up in the final analysis (final data
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Figure 4. Study schema of SMART protocol. RT, radiotherapy.56
collection expected for March 2016), these promising data could provide the rationale for a novel targeted induction therapy in a subgroup of p-Src Y419positive patients. The second trial investigating a TKI as induction therapy investigates inhibition of FAK by VS-6063 (Defactinib). FAK, like Src a nonreceptor tyrosine kinase, acts as a regulator of cell migration and survival, and has also been shown to be involved in renewal of cancer stem cells. Of great interest in the context of mesothelioma is the fact that the protein Merlin, encoded by the tumor suppressor neurofibromatosis type 2, which is inactivated in 35%40% of MPM tumors, acts as a negative regulator of FAK signaling. A comprehensive study investigating this interesting link in detail has recently shown that merlin deficiency was able to predict sensitivity to the FAK inhibitor VS-4718 both in vitro and in vivo.65 The same study also showed that inhibition of FAK preferentially targeted the cancer stem cells population of MPM xenograft tumors. Together with promising preliminary data on various FAK inhibitors in a range of solid tumors having been presented at a number of conferences, the
observations by Sharipo et al warrant further investigation in clinical trials. The new generation FAK inhibitor VS-6063 is consequently currently being assessed in 2 trials in MPM: the Placebo Controlled Study of VS-6063 in Subjects With Malignant Pleural Mesothelioma (COMMAND) trial of second-line therapy with Defactinib in patients with no progression on first-line platinum and pemetrexed (NCT01870609) as well as a Window-ofopportunity study as induction therapy in patients undergoing radical surgery (NCT02004028). Similar to the dasatinib trial, this phase II trial of induction VS-6063 has assessment of biomarker response in tumor tissue as primary outcome, but again data on safety, pharmacokinetics, and tumor response to the treatment are also being collected. Participants in this trial, whose completion is estimated for early 2015, would have their pretreatment and posttreatment biopsies collected, and they receive 12 days of oral VS-6063 before undergoing EPP or P/D. With the high proportion of MPM cases presenting with inactivated neurofibromatosis type 2, FAK inhibition presents a very promising potential novel option for induction therapy in a subgroup of patients that
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INDUCTION THERAPY FOR MESOTHELIOMA could easily be identified by standard immunohistochemistry methods. SUMMARY The experience from the past decade using induction chemotherapy before surgery in MPM has shown that this multimodal concept is feasible and can lead to improved outcomes with acceptable mortality and morbidity rates, in general being manageable. Nevertheless, patient selection for multimodal treatment is still hampered by a lack of markers able to accurately predict response to chemotherapy, and future research in this field is
1. Weder W, Kestenholz P, Taverna C, et al: Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. J Clin Oncol 22(17): 3451-3457, 2004 2. Weder W, Stahel RA, Bernhard J, et al: Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 18(7):1196-1202, 2007 3. Cao C, Tian D, Manganas C, et al: Systematic review of trimodality therapy for patients with malignant pleural mesothelioma. Ann Cardiothorac Surg 1(4):428-437, 2012 4. Petersen RP, Pham D, Burfeind WR, et al: Thoracoscopic lobectomy facilitates the delivery of chemotherapy after resection for lung cancer. Ann Thorac Surg 83(4):1245-1249, 2007 [discussion 50] 5. Gupta V, Krug LM, Laser B, et al: Patterns of local and nodal failure in malignant pleural mesothelioma after extrapleural pneumonectomy and photon-electron radiotherapy. J Thorac Oncol 4(6):746-750, 2009 6. Bech C, Sorensen JB: Chemotherapy induced pathologic complete response in malignant pleural mesothelioma: A review and case report. J Thorac Oncol 5(5):735-740, 2010 7. Byrne MJ, Nowak AK: Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 15(2):257-260, 2004 8. Oxnard GR, Armato 3rd SG, Kindler HL: Modeling of mesothelioma growth demonstrates weaknesses of current response criteria. Lung Cancer 52(2):141-148, 2006 9. Shih C, Chen VJ, Gossett LS, et al: LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 57(6):1116-1123, 1997 10. Christoph DC, Asuncion BR, Mascaux C, et al: Folylpoly-glutamate synthetase expression is associated with tumor response and outcome from pemetrexed-based chemotherapy in malignant pleural mesothelioma. J Thorac Oncol 7(9):1440-1448, 2012
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urgently needed. But recent developments have also shown that other forms of induction therapy, such as radiotherapy or targeted therapy, present valuable alternative options warranting further investigation.
Acknowledgments The authors thank Dr Martina Friess, Dr Michaela Kirschner, Dr Mayura Meerang, and Dr Chloe Spichiger for manuscript editing. We thank Dr Bart Vrugt for providing images and Swiss National Science Foundation for grant support to IO.
11. Zucali PA, Giovannetti E, Destro A, et al: Thymidylate synthase and excision repair cross-complementing group-1 as predictors of responsiveness in mesothelioma patients treated with pemetrexed/carboplatin. Clin Cancer Res. 17(8):2581-2590, 2011 12. Righi L, Papotti MG, Ceppi P, et al: Thymidylate synthase but not excision repair crosscomplementation group 1 tumor expression predicts outcome in patients with malignant pleural mesothelioma treated with pemetrexedbased chemotherapy. J Clin Oncol 28(9): 1534-1539, 2010 13. Mairinger F, Vollbrecht C, Halbwedl I, et al: Reduced folate carrier and folylpolyglutamate synthetase, but not thymidylate synthase predict survival in pemetrexed-treated patients suffering from malignant pleural mesothelioma. J Thorac Oncol 8(5):644-653, 2013 14. Lustgarten DE, Deshpande C, Aggarwal C, et al: Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma. J Thorac Oncol 8 (4):469-477, 2013 15. Mairinger F, Vollbrecht C, Mairinger T, et al: The issue of studies evaluating biomarkers which predict outcome after pemetrexedbased chemotherapy in malignant pleural mesothelioma. J Thorac Oncol 8(8):e80-e82, 2013 16. Besse B, Olaussen KA, Soria JC: ERCC1 and RRM1: Ready for prime time?J Clin Oncol 31 (8):1050-1060, 2013 17. Frischknecht L, Meerang M, Soltermann A, et al: Importance of ERCC1 and RRM1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum based induction chemotherapy followed by surgery J Thorac Cardiovasc Surg 149(6):1539-1547.e1, 2015. 18. Kao SC, Lee K, Klebe S, et al: Excision repair cross complementation group 1 and thymidylate synthase expression in patients with mesothelioma. Clin Lung Cancer 14(2):164-171, 2013
19. Zimling ZG, Sorensen JB, Gerds TA, et al: Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progressionfree survival. J Thorac Oncol 7(1): 249-256, 2012 20. Ting S, Mairinger FD, Hager T, et al: ERCC1, MLH1, MSH2, MSH6, and betaIII-tubulin: Resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma. Clin Lung Cancer 2013;14(5):558-67, e3. 21. Bepler G, Zinner RG, Moon J, et al: A phase 2 cooperative group adjuvant trial using a biomarker-based decision algorithm in patients with stage I non-small cell lung cancer (SWOG0720, NCT00792701). Cancer 120(15): 2343-2351, 2014 22. Wislez M, Barlesi F, Besse B, et al: Customized adjuvant phase II trial in patients with nonsmall-cell lung cancer: IFCT-0801 TASTE. J Clin Oncol. 32(12):1256-1261, 2014 23. Friboulet L, Olaussen KA, Pignon JP, et al: ERCC1 isoform expression and DNA repair in non–small-cell lung cancer. N Engl J Med 368 (12):1101-1110, 2013 24. Erculj N, Kovac V, Hmeljak J, et al: The influence of gemcitabine pathway polymorphisms on treatment outcome in patients with malignant mesothelioma. Pharmacogenet Genomics 22(1):58-68, 2012 25. Tajima K, Hirama M, Shiomi K, et al: ERC/ mesothelin as a marker for chemotherapeutic response in patients with mesothelioma. Anticancer Res 28(6B):3933-3936, 2008 26. Stamatis G: Risks of neoadjuvant chemotherapy and radiation therapy. Thorac Surg Clin 18(1): 71-80, 2008 27. Treasure T, Lang-Lazdunski L, Waller D, et al: Extra-pleural pneumonectomy versus no extrapleural pneumonectomy for patients with malignant pleural mesothelioma: Clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol 12(8):763-772, 2011
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INDUCTION THERAPY FOR MESOTHELIOMA 28. Lauk O, Hoda MA, de Perrot M, Friess M, Klikovits T, Klepetko W, et al: Extrapleural pneumonectomy after induction chemotherapy: perioperative outcome in 251 mesothelioma patients from three high-volume institutions. Ann Thorac Surg, 2014. 29. Rea F, Favaretto A, Marulli G, Spaggiari L, DePas MT, Ceribelli A, et al: Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma. BMC Cancer 13 (1):22, 2013. 30. Van Schil PE, Baas P, Gaafar R, Maat AP, Van de Pol M, Hasan B, et al: Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. Eur Respir J 36(6):1362-9, 2010. 31. Buduhan G, Menon S, Aye R, Louie B, Mehta V, Vallieres E: Trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 88 (3):870-5(discussion 6), 2009. 32. Krug LM, Pass HI, Rusch VW, Kindler HL, Sugarbaker DJ, Rosenzweig KE, et al: Multicenterp II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009:JCO.2008.20.3943. 33. de Perrot M, Feld R, Cho BC, Bezjak A, Anraku M, Burkes R, et al: Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 27(9):1413-8, 2009. 34. Opitz I, Kestenholz P, Lardinois D, et al: Incidence and management of complications after neoadjuvant chemotherapy followed by extrapleural pneumonectomy for malignant pleural mesothelioma. Eur J Cardio-Thorac 29 (4):579, 2006 35. Cao CQ, Yan TD, Bannon PG, et al: A systematic review of extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Oncol 5(10):1692-1703, 2010 36. Cao C, Krog Andvik SK, Yan TD, et al: Staging of patients after extrapleural pneumonectomy for malignant pleural mesothelioma—institutional review and current update. Interact Cardiovasc Thorac Surg 12(5):754-757, 2011 37. Opitz I: Management of malignant pleural mesothelioma-The European experience. J Thorac Dis 6(suppl 2):S238-S252, 2014 38. Mansour Z, Kochetkova EA, Ducrocq X, et al: Induction chemotherapy does not increase the operative risk of pneumonectomy!. Eur J Cardiothorac Surg 31(2):181-185, 2007 39. Weder W, Collaud S, Eberhardt WE, et al: Pneumonectomy is a valuable treatment option after neoadjuvant therapy for stage III non– small-cell lung cancer. J Thorac Cardiovasc Surg 139(6):1424-1430, 2010
40. Peer M, Stav D, Cyjon A, et al: Morbidity and mortality after major pulmonary resections in patients with locally advanced stage IIIA nonsmall cell lung carcinoma who underwent induction therapy. Heart Lung Circ 24(1): 69-76, 2015 41. Opitz I, Sigrist B, Hillinger S, et al: Taurolidine and povidone-iodine induce different types of cell death in malignant pleural mesothelioma. Lung Cancer. 56(3):327-336, 2007 42. Lang-Lazdunski L, Bille A, Papa S, et al: Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: A 10-year experience. J Thorac Cardiovasc Surg 149(2):558-566, 2015 43. Muraoka M, Oka T, Akamine S, et al: Postoperative complications of pulmonary resection after platinum-based induction chemotherapy for primary lung cancer. Surg Today 33(1): 1-6, 2003 44. Leo F, Solli P, Spaggiari L, et al: Respiratory function changes after chemotherapy: An additional risk for postoperative respiratory complications?Ann Thorac Surg 77(1): 260-265, 2004 [discussion 5] 45. Sugarbaker DJ, Jaklitsch MT, Bueno R, et al: Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies. J Thorac Cardiovasc Surg 128(1):138-146, 2004 46. de Perrot M, McRae K, Anraku M, et al: Risk factors for major complications after extrapleural pneumonectomy for malignant pleural mesothelioma. Ann Thorac Surg 85(4):1206, 2008 47. Burt BM, Cameron RB, Mollberg NM, Kosinski AS, Schipper PH, Shrager JB, et al: Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality. J Thorac Cardiovasc Surg 148(1):30-5, 2014. 48. Nakas A, von Meyenfeldt E, Lau K, Muller S, Waller D: Long-term survival after lung-sparing total pleurectomy for locally advanced (International Mesothelioma Interest Group Stage T3T4) non-sarcomatoid malignant pleural mesothelioma. Eur J Cardiothorac Surg 41(5):10316, 2012. 49. Rena O, Casadio C: Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: A harmful procedure. Lung Cancer 77(1):151-5, 2012. 50. Schipper PH, Nichols FC, Thomse KM, Deschamps C, Cassivi SD, Allen MS, et al: Malignant pleural mesothelioma: surgical management in 285 patients. Ann Thorac Surg 85 (1):257-64(discussion 64), 2008. 51. de Perrot M, Feld R, Cho BC, et al: Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant
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pleural mesothelioma. J Clin Oncol 27(9): 1413-1418, 2009 Rusch VW, Giroux D, Kennedy C, et al: Initial analysis of the international association for the study of lung cancer mesothelioma database. J Thorac Oncol 7(11):1631-1639, 2012 Pass HI, Temeck BK, Kranda K, et al: Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 115(2):310-317, 1998 [discussion 7-8] Gill RR, Richards WG, Yeap BY, et al: Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: Stratification of survival with CT-derived tumor volume. Am J Roentgenol 198(2):359-363, 2012 Cho BC, Feld R, Leighl N, et al: A feasibility study evaluating Surgery for Mesothelioma After Radiation Therapy: The SMART approach for resectable malignant pleural mesothelioma. J Thorac Oncol 9(3):397-402, 2014 Levy A, Chargari C, Cheminant M, et al: Radiation therapy and immunotherapy: Implications for a combined cancer treatment. Crit Rev Oncol Hematol 85(3):278-287, 2013 Ludgate CM: Optimizing cancer treatments to induce an acute immune response: Radiation abscopal effects, PAMPs, and DAMPs. Clin Cancer Res 18(17):4522-4525, 2012 Kotova S, Wong RM, Cameron RB: New and emerging therapeutic options for malignant pleural mesothelioma: Review of early clinical trials. Cancer Manag Res 7:51-63, 2015 An X, Tiwari AK, Sun Y, et al: BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review. Leuk Res 34(10): 1255-1268, 2010 Irby RB, Yeatman TJ: Role of Src expression and activation in human cancer. Oncogene 19(49): 5636-5642, 2000 Levin VA: Basis and importance of Src as a target in cancer. Cancer Treat Res 119:89-119, 2004 Tsao AS, He D, Saigal B, et al: Inhibition of c-Src expression and activation in malignant pleural mesothelioma tissues leads to apoptosis, cell cycle arrest, and decreased migration and invasion. Mol Cancer Ther 6(7):1962-1972, 2007 Dudek AZ, Pang H, Kratzke RA, et al: Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): A brief report. J Thorac Oncol 7(4):755-759, 2012 Tsao AS, Wistuba I, Mehran RJ, et al: Evaluation of Src Tyr 419 as a predictive biomarker in a neoadjuvant trial using dasatinib in resectable malignant pleural mesothelioma. J Clin Oncol 28(15s);28(15s) [abstract 7042] Shapiro IM, Kolev VN, Vidal CM, et al: Merlin deficiency predicts FAK inhibitor sensitivity: A synthetic lethal relationship. Sci Transl Med 6 (237):237ra68, 2014
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Induction Therapy for Mesothelioma Isabelle Opitz, MD, FEBTS, and Walter Weder, MD, FEBTS One particular approach of multimodality treatment for mesothelioma is induction therapy followed by surgery. Among its several advantages, the most important is downstaging of the tumor into a resectable stage, although morbidity and mortality might be increased. In this article we review the principles and outcome of different modalities for induction treatment of mesothelioma. Semin Thoracic Surg 27:240–249 I 2015 Elsevier Inc. All rights reserved. Keywords: induction therapy, MCR, MPM, Pleurectomy and Decortication, Extrapleural Pneumonectomy.
INTRODUCTION Currently multimodality therapy is the most frequently used approach of therapy for malignant pleural mesothelioma (MPM). The best sequence of the different modalities in combination with surgery is unknown. Induction therapy followed by surgery is applied with the intention to achieve downstaging of the tumor — a concept derived from stage III non — small cell lung cancer (NSCLC). In this article we present several approaches to induce malignant pleural mesothelioma (MPM) before resection. PRINCIPLE OF INDUCTION CHEMOTHERAPY The concept of induction chemotherapy has been adapted from stage III NSCLC with the idea to possibly downstage the tumor and herewith render the tumor into a resectable stage. The concept was pioneered in Zürich, Switzerland,1 studied more in detail in a national Swiss multicentre trial,2 and has been adopted by many MPM centers.3 There are several advantages to applying chemotherapy before surgery, the first being that it is better tolerated than after surgery and therefore associated with better compliance. It has been demonstrated for NSCLC that with adjuvant chemotherapy compliance is r50%, the complete dose application can be fulfilled in r60%, and on-time application occurs equally in r50% only.4 Moreover, the efficacy of chemotherapeutic drug delivery might be increased because of intact Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. This study is supported in part by an Swiss National Science Foundation (SNSF), Switzerland, PP00P3_133657. Address reprint requests to Isabelle Opitz, MD, FEBTS, Division of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, Zurich 8091, Switzerland. E-mail: [email protected]
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Survival curves from patients treated with induction chemotherapy followed by pleuropneumonectomy according to response (Opitz I et al. accepted for publication JTO).
blood supply to Central Message the tumor before surgery. Having Induction chemotherapy before surgery in tumor tissue availMPM can lead to improved outcomes with acceptable mortality and morbidity. Future able at the time research is needed for adequate patient point of surgery selection. allows additionally assessing the efficacy of the chemotherapy with chemosensitivity testing. Another theoretical advantage is that microscopic disease might be eradicated early in the treatment course. Ideally, induction chemotherapy downstages the tumor (Fig. 1), leading to improved complete resection, which has been reported from prospective trials to range up to 40%.2,5 Furthermore, patient selection for resection can be based on tumor progression during chemotherapy, which would be assessed by postchemotherapy computed tomography scans. The principal disadvantage of induction chemotherapy is a potentially higher surgical mortality and morbidity and that the delay of surgery may negatively influence resectability, which is discussed in the section Morbidity and Mortality after Induction Chemotherapy.
RESPONSE TO INDUCTION CHEMOTHERAPY In general, MPM does not respond very well to chemotherapy, but still, there are a few reports on chemotherapyinduced complete pathologic responses in the literature.6 However, in our experience of 142 extrapleural pneumonectomy (EPP) after 3 cycles of neoadjuvant chemotherapy with cisplatin and gemcitabine (cis/gem) or cisplatin and pemetrexed (cis/pem) we could not observe a complete response so far. Only a nearly complete response after induction chemotherapy was observed in a (female) patient undergoing 3 cycles of cis/pem chemotherapy (Fig. 2).
1043-0679/$-see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semtcvs.2015.05.003
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Figure 1. CT scan before and after induction chemotherapy showing downstaging of the tumor. CT, computed tomography
The response rates reported in the literature are in the range 30%-40% with the main drawback of lacking reliable response assessment in MPM. The only available tool of modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria7 lacks reproducibility.8 However, patients who do not respond to induction chemotherapy but present with progressive disease after the treatment have indeed a significantly worse prognosis (Opitz et al, accepted for publication) (Fig. 3). To date, no validated biological predictive marker is available to assist patient selection for induction chemotherapy. Pemetrexed is a multitargeted molecule-inhibiting enzyme in folate metabolism, with the main target being thymidylate synthase (TS).9 Thus, the predictive value of TS for outcomes of patients with MPM treated with pemetrexed has been evaluated using both messenger RNA and protein expression. Several studies have reported associations between low TS with longer time to
disease progression, longer overall survival, and better clinical response.10-12 High level of folylpolyglutamate synthetase, an enzyme that facilitates intracellular retention of pemetrexed, was also shown to be associated with better outcomes.10,13 However, 2 studies could not show either prognostic or predictive role of TS13,14; the latter study also could not demonstrate association between folylpolyglutamate synthetase expression and outcomes. The reasons of these discrepancies may stem from differences in patient population and treatment and evaluation methods.15 DNA repair enzymes such as excision repair crosscomplementation group1 (ERCC1) and ribonucleotide reductase M1 (RRM1) were shown to have prognostic and predictive role for patients with cancer receiving platinum-based chemotherapy and gemcitabine.16 We recently identified a prognostic role of immunohistochemical expression of ERCC1 and RRM1 in a cohort of patients with MPM treated
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Figure 2. Microscopic examination of an EPP specimen after 3 cycles of cis/pem chemotherapy demonstrating complete regression. (A) Routine HE-stain showing lung tissue (bottom) and diffuse thickened pleura without infiltrates of mesothelioma, characterized by extensive fibrosis, bleeding, inflammation, and iron depositions (B, C, Perls' iron stain). In this case only minimal remnants of residual tumor cells with regressive changes were detectable using an immunostain for calretinin (D). (Images courtesy of: B. Vrugt et al; Institute of Pathology, the University Hospital Zurich). HE, hematoxylin and eosin. (Color version of figure is available online at http:// www.semthorcardiovascsurg.com.)
with platinum-based induction chemotherapy followed by EPP.17 So far this is the first study showing the prognostic role of RRM1 expression, the enzyme involved in de novo deoxyribonucleotides synthesis and the target of gemcitabine, in MPM. In terms of the prognostic role of ERCC1 in MPM, there have been several studies showing contradictory results.11,18-20 ERCC1 is an enzyme taking part in the nucleotide excision repair of platinum-DNA adducts. Predictive roles of ERCC1 and RRM1 for chemotherapy selection have been evaluated in patients with NSCLC.21,22 Nonetheless, the nonreproducible ERCC1 staining using different batches of 8F1 antibody has hampered the further application of ERCC1 as a predictive biomarker. ERCC1 also exists in 4 different isoforms but only 1 isoform is proficient in platinum-DNA adduct repair.23 RRM1 has several polymorphisms that are associated with gemcitabine treatment efficacy in MPM.24 In
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addition to tumoral markers, ratios of postchemotherapy to prechemotherapy serum N-ERC/mesothelin levels were shown to be associated with response to chemotherapy in a small cohort of patients with MPM.25 Altogether, these markers seem to be useful but further validation is needed, requiring more robust and specific antibodies as well as accurate and reproducible detection techniques. A multiinstitutional effort to validate these markers in a bigger patient cohort is needed. The approach may be further improved by integrating an innovative genomic tool such as next generation sequencing. MORBIDITY AND MORTALITY AFTER INDUCTION CHEMOTHERAPY Morbidity and mortality rates for NSCLC treated with induction chemotherapy followed by surgery,
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Figure 3. Kaplan-Meier curves for overall survival (OS) and chemotherapy (CTX) response from patients being treated between 1999 and 2015 with induction CTX at the University Hospital Zurich. (A) ITT group: patients intended to be treated with induction CTX followed by EPP. (B) EPP group: patients treated with induction chemotherapy followed by EPP (subgroup of the ITT group). CI, confidence interval; CR, complete response; ITT, intention to treat; PR, partial response; SD, stable disease; PD, progressive disease.
as well as the incidence of medical and surgical complications were reviewed in several phase II and randomized trials by Stamatis et al.26 Mortality ranges from 0%-9% and morbidity from 26%-51%. Medical complications after induction treatment are acute respiratory distress syndrome (ARDS; 1.8%-46%), pneumonia (3%-19%), atelectasis (2.7%-16), and arrhythmia (4.4%-18%). Surgical complications after induction treatment are bronchopleural fistula (0%-23%), empyema (1.3%7.4%), bleeding (1%-8.3%), and prolonged air leak (3%-16.6%). After publication of the MARS (Mesothelioma and Radical Surgery) trial results,27 the procedure of EPP was critically discussed for exceedingly high morbidity and mortality rates. This is not supported by recently reported trials for trimodality therapy including EPP (Table 1). In experienced centers, mortality can be reduced to 2%-5%,35 morbidity remains high (22%-82%) but seems to be manageable in terms of improvement in quality of life for all parameters at 3 months after the operation.36 The perioperative mortality and morbidity of extended pleurectomy and decortication (eP/D) and EPP in combination with other treatment modalities were reviewed by Cao et al: mortality rates were significantly lower in the eP/D group compared with EPP (2.9% vs 6.8%) and also morbidity rates were lower after the lungs-sparing procedure (27.9% vs 62% for EPP). However, comparability of morbidity data is complicated by the fact that reporting and definition of morbidity are very heterogeneous. Prolonged air leak is a substantial problem after eP/D as nearly all of these
patients suffer from this problem postoperatively and a substantial part of these patients suffer from persistent air leak over weeks. This is most probably not represented in median morbidity rates of 28%.37 One particular complication after EPP is postpneumonectomy empyema with or without bronchopleural fistula. Whereas it seems to be controversial in lung cancer whether or not the incidence is increased after induction chemotherapy,38-40 the reported empyema rate in MPM can be as high as 16%.34 Several prophylactic measures can be undertaken to decrease the incidence of empyema: irrigation of the chest cavity with povidone iodine solution (diluted 1:10 in NaCl 0.9%) at the end of the resection. Some groups use povidone iodine lavage as an intracavitary cytotoxic agent.41,42 Furthermore standardized intravenous antibiotics with amoxicillin 2.2 g iv should be continued for 5 days after the operation. Bronchial stump coverage can be difficult because a pericardial fat flap is usually not available after radical resection. The quality of an intercostal muscle flap is often poor owing to retraction of the hemithorax, typical for the nature of mesothelioma disease. Alternatively, an extrathoracic muscle flap can be used. Bleeding complications are not very common after MPM surgery, even after induction chemotherapy. But careful hemostasis is certainly important not only to avoid redo surgery but also to prevent later superinfection of persistent hematoma. To reduce the incidence of respiratory complications and here especially of ARDS after platinum-based
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INDUCTION THERAPY FOR MESOTHELIOMA chemotherapy, intraoperative FiO2 should be maintained below 50% if possible to reduce potential oxygen toxicity. ARDS was reported to be higher for induction treatment of lung cancer,43 and is possibly related to an injury of the alveolar-capillary membrane.44 Preservation of the phrenic nerve is important for patients where the diaphragm can be preserved during eP/D. However this is often difficult and not evident, because the pericardial pleura needs to be resected for macroscopic complete resection (MCR) and the phrenic nerve is skeletonized at this point, leading to loss of function. Early extubation should be the aim to decrease the risk of not only ventilator-associated pneumonias but also the extent of air leaks of eP/D patients. Fibrin glue application after P/D can help reduce the duration of air leaks. Thromboembolic complications, such as pulmonary embolism, are frequently observed in most of the series (1.5%-3%)34,45,46 and can be life threatening especially after EPP. Besides the awareness and sensitive clinical attitude to any oxygen desaturations with a low threshold for computed tomography scan with pulmonary embolism protocol, we recommend oral anticoagulation for a period of 3 months after surgery. Overall, surgical mortality and morbidity seem not to be increased after induction chemotherapy (overview of reported literature provided in Tables 1 and 2).
OUTCOME AFTER INDUCTION CHEMOTHERAPY Survival of patients undergoing induction chemotherapy followed by EPP and P/D (median survival time ranging from 10.2-59 months) is comparable to those from other multimodal treatments such as adjuvant chemotherapy after surgery (median survival time in the range of 13-24 months.28 Tables 1 and 2 summarize the reported literature on EPP and P/D after neoadjuvant therapy. Nowadays, the difficulty is the selection of the patients who benefit most from a multimodal approach. All patients with histologically proven mesothelioma and resectable tumor should be considered for a multimodal approach including MCR. For further selection clinical staging and functional assessment is mandatory. Whereas mediastinal lymph node involvement and sarcomatoid histotype are considered as exclusion criteria for multimodal treatment in many protocols, data about the role of mediastinal lymph node involvement of the different case series are conflicting.2,51 However, the results of the International Association for the Study of Lung Cancer and the International Mesothelioma Interest
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Group staging project demonstrate that N2 is not a survival-influencing factor.52 Another criterion to be considered is the volume of the tumor,53,54 which has been shown to be a prognosis-influencing factor. The selection of patients for multimodality treatment should not be based on a single clinical factor or laboratory data but more on a combination of several parameters ideally being available before the treatment starts (Opitz et al, accepted for publication). INDUCTION RADIOTHERAPY The Toronto group (Surgery for Mesothelioma After Radiation Therapy [SMART] protocol) has initiated a different approach by applying induction radiotherapy before surgery55 (Fig. 4). Owing to the delivered doses and the target volume, this approach is so far feasible only in an MCR approach using EPP to avoid severe radiation-induced pulmonary toxicity. The protocol therefore requires a high degree of coordination and cooperation between radiation oncology and thoracic surgery. This may hamper its implementation in centers where this expertise is lacking. However, initial results are very promising; out of 25 patients who received high-dose intensity-modulated radiotherapy followed by EPP, 3-year survival rates reached 84% in epithelioid subtypes and 13% in biphasic subtypes, but 1 patient died of treatmentrelated toxicity (90-day morbidity ¼ 4%). Another benefit of the SMART protocol might be on the immune system by activating the immune system against the tumor and then removing the immunosuppressive environment generated by the tumor. The effect on the immune system of highdose hypofractionated radiation therapy potentially opens the door for new combination therapies in the near future between immunotherapy and radiation to optimize their synergism on the immune system.55-57 TARGETED AGENTS AS INDUCTION THERAPY BEFORE SURGERY A wide range of novel targeted drugs are currently being trialed for use in MPM,58 with most of them focusing on inhibition of tyrosine kinases such as vascular endothelial growth factor receptor, epidermal growth factor receptor, or Focal Adhesion Kinase (FAK). However, most of these trials investigate the respective tyrosine kinase inhibitors (TKIs) in second-line settings or in patients with unresectable disease. But 2 trials specifically address the question of TKIs as novel induction therapy before surgery: NCT02004028 investigates the FAK inhibitor VS-6063 (Defactinib, Verastem Inc) and
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Study Period
No. of Induction CTX Patients
Response Rate
EPP Resectability
Morbidity
Mortality
Adjuvant OS Modalities
PFS
Lauk et al28; 2014
19992012
251
Platinum þ gem: 59 Platinum þ pem: 161 Other: 31
NR
251 NR
Major: 30%
30d: 5% 90d: 8%
NR
NR
NR
Rea et al29; 2013
20052010
54
Cis þ pem: 52
NR
41
NR
Overall: 66.7% Major: NR
30d: 4.4%
RT: 32
15.5 (11.0-NA) (from enrollment)
8.6 (6.3-14.4) (from enrollment)
Treasure et al27; 2011
20052008
50
n ¼ 20: Cis þ gem n ¼ 16: Cis þ pem n ¼ 11: Cis þ mitomycin þ vinblastine n ¼ 3: Cis þ vinorelbine
PR: 5 SD: 34 PD: 7
16
NR
69%
30d: 12.5% In hospital: 18.8%
RT: 8
14.4 (5.3-18.7) (From randomization)
7.6 (5.0-13.4) (from randomization)
Van Schil et al30; 2010
20052007
59
n ¼ 54: Cis þ pem n ¼ 3: Carbo þ pem
CR: 14 PR: 11
42
R0: 30 R1: 10
Overall: 82.6%
30d: 6.5% 90d: 6.5%
RT: 37
ITT: 18.4 (15.6-32.9) EPP: 21.5 (17.6-NR) (unknown)
ITT: 13.9 (10.9-17.2) (unknown)
R0: 6
Major: 37 (80%)
30d and in hospital: 2 (4.3%)
R1: 31
Minor 54%
EBRT:24 EPP: 24 (7.2-30.9) (from diagnosis) IMRT: 14
Missing: 4
SD: 24 PD: 5 Not assessable: 3 Buduhan et al31; 2009
Krug et al32; 2009
19972008
20032006
55
77
n ¼ 24: Cis/ carbo þ pem n ¼ 23: Cis þ methotrexate þ vinblastin n ¼ 5: Cis þ gem n ¼ 3: Other
NR
n ¼ 77: Cis þ pem
Response rate: 32.5% CR: 1 PR: 24 SD: 36 PD: 5 Missing: 11
R2: 3 Unknown: 1 46
R2: 9 54
29.3%
Time to local recurrence IMRT: 12
EBRT: 7 (from diagnosis) Atrial fibrillation (10.5%) Pain (7.0%) Dyspnea (5.3%) Anemia (5.5%) Sepsis (3.5%)
30d: 2 (3.7%)
RT: 40
ITT: 16.8 (13.6-23.2)
ITT: 10.1 (8.6-15.0) (unknown)
EPP: 21.9 (16.8-29.1) EPP þ RT: 29.1 (19.3-NR) (unknown)
De Perrot et al33; 2009
20012007
60
n ¼ 26: Cis þ vinorelbine NR n ¼ 24: Cis þ pem n ¼ 6 Cis þ raltitrexed n ¼ 4: Cis þ gem
45
R0/1: 41 R2: 4
Major: 15
30d And in hospital 3 (6.7%)
RT: 30
ITT: 14 EPP þ RT: 59 (from chemo)
N2: 12 N1: 44 N0: not reached (from chemo)
Weder et al2; 2007
20002003
61
n ¼ 58: Cis þ gem
45
Resectability rate: 61% R0/1: 37 R2: 8
Major: 16 (35%)
In hospital: 1 (2.2%)
RT: 36
ITT: 19.8 (14.6-24.5)
EPP:13.5 (10.2-18.8) (from chemo)
NR
Overall: 39 (62%)
Opitz et al34; 2006
19992005
63
n ¼ 47: Cis þ gem n ¼ 16: Cis þ pem
NR
PR: 20 SD: 32 PD: 11
63
EPP: 23 (16.6-32.9) (from chemo) 30d and in hospital: 3.2%
NR
NR
NR
Overview of reported mortality and morbidity, overall and progression-free survival in extrapleural pneumonectomy (EPP). Studies with less than 50 patients are not considered. CTX, chemotherapy; CR, complete response; EBRT, external beam radiotherapy; IMRT, intensity-modulated radiotherapy; ITT, intention to treat; NR, not reported; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RT, radiotherapy; SD, stable disease.
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Table 1. Induction Chemotherapy Followed by Extrapleural Pneumonectomy (EPP) Study
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Overview of reported mortality and morbidity, overall and progression-free survival in pleurectomy and decortication. Studies with less than 50 patients are not considered. CTX, chemotherapy; NR, not reported; OS, overall survival; PFS, progression-free survival; RT, radiotherapy. * Values based on all patients undergoing P/D (regardless of neoadjuvant chemotherapy).
SP: 8.1* NR TP: 17.2* (from 30d after surgery) NR Major SP: 2.9% * SP: 20%* TP: 0% * TP: 5.9%* Minor SP: 11.8%* TP: 10%* Subtotal P: 34 Total P: 10 Schipper et al50; 2008 19852003
285
n ¼ 29 (NR) NR
NR
Stage I: 32 (17-45)* Stage I: 18 (10-26)* Stage II: 23 (2-40)* (from surgery) Stage II: 10 (5-17)*(from surgery) CTX: 6* Overall: 24%* 30d: 0%* NR 37 n ¼ 31 (NR) NR 19982009 Rena et al49; 2012
77
16 (9-22)* (From surgery) 13.4 (9.7-17.1)*(From diagnosis) CTX: 32* RT: 0 Overall: 43%* 30d: 3%* 90d: 12%* NR 19992010 Nakas et al48; 2012
165
n ¼ 8 (NR)
Total pleurectomy: 67* R0: 33.9%* R1: 62.9%* R2: 3.2%*
NR NR 30d and in hospital: 3.1%* RT: 13 NR NR 130 NR 23 20092011 Burt et al47; 2014
225
Resectability Morbidity Response P/D Rate No. of Induction Patients CTX Study Period Study
Table 2. Induction Chemotherapy Followed by Pleurectomy and Decortication (P/D)
Mortality
Adjuvant OS Modalities
PFS
INDUCTION THERAPY FOR MESOTHELIOMA NCT00652574 studies the multi-BCR/ABL and Src kinase family inhibitor Dasatinib (BMS-354825, Bristol-Myers Squibb). Primary objective of both trials is the assessment of biomarker responses in tumor tissue; however, preliminary data regarding safety and efficacy are also being collected. Dasatinib is approved for treatment of both leukemia and Philadelphia chromosome – positive acute lymphoblastic leukemia, both of which harbor the oncogenic BCR/ABL fusion, one of the main kinases targeted by dasatinib.59 Although BCR/ABL has not been implicated in MPM, dasatinib is also a potent inhibitor of members of the Src kinase family, in particular c-Src, which has a key role in the regulation of intracellular signal transduction of, for example, the FAK, vascular endothelial growth factor, and PI3K/Akt pathways.60,61 Tsao et al have shown that c-Src is activated in MPM cells in vitro and that treatment with dasatinib could induce cell cycle arrest and apoptosis as well as a decrease in cell migration and invasion. The study further showed that activated c-Src (p-Src Y419) correlated with higher pathologic stage and presence of metastasis in a series of 46 human MPM tissues.62 Despite these promising in vitro findings, a Phase II trial of singleagent dasatinib in previously treated unresected MPM (CALGB-30601, NCT00509041) did not show any activity of dasatinib in this unselected population.63 The trial, however, also included analyses of potential biomarkers, which revealed that lower pretreatment serum levels of colony-stimulating factor-1 were associated with prolonged overall survival and progression-free survival, suggesting that a subgroup of patients may actually benefit from inhibition of c-Src. The currently still ongoing trial of induction therapy dasatinib in resectable mesothelioma was initiated not long after the Phase II trial by the authors of the initial in vitro study. In this trial, following extended surgical staging with multiple biopsies, patients eligible for radical surgery receive 4 weeks of oral dasatinib (70 mg two times a day) followed by P/D or EPP. In cases of radiographic response to dasatinib, it may be given up to a further 2 years after surgery. Although the primary aim of this phase I trial is to assess the effects of dasatinib on modulation of p-Scr Y419 in tumor tissue, preliminary data presented at the American Society of Clinical Oncology—2010 annual meeting showed stable disease in 12 of 14 patients after 4 weeks of neoadjuvant dasatinib.64 In addition, higher baseline p-Src Y419 as well as significant modulation of p-Src Y419 after dasatinib was significantly associated with improved progression-free survival (P ¼ 0.008 for both). Holding up in the final analysis (final data
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INDUCTION THERAPY FOR MESOTHELIOMA
Figure 4. Study schema of SMART protocol. RT, radiotherapy.56
collection expected for March 2016), these promising data could provide the rationale for a novel targeted induction therapy in a subgroup of p-Src Y419positive patients. The second trial investigating a TKI as induction therapy investigates inhibition of FAK by VS-6063 (Defactinib). FAK, like Src a nonreceptor tyrosine kinase, acts as a regulator of cell migration and survival, and has also been shown to be involved in renewal of cancer stem cells. Of great interest in the context of mesothelioma is the fact that the protein Merlin, encoded by the tumor suppressor neurofibromatosis type 2, which is inactivated in 35%40% of MPM tumors, acts as a negative regulator of FAK signaling. A comprehensive study investigating this interesting link in detail has recently shown that merlin deficiency was able to predict sensitivity to the FAK inhibitor VS-4718 both in vitro and in vivo.65 The same study also showed that inhibition of FAK preferentially targeted the cancer stem cells population of MPM xenograft tumors. Together with promising preliminary data on various FAK inhibitors in a range of solid tumors having been presented at a number of conferences, the
observations by Sharipo et al warrant further investigation in clinical trials. The new generation FAK inhibitor VS-6063 is consequently currently being assessed in 2 trials in MPM: the Placebo Controlled Study of VS-6063 in Subjects With Malignant Pleural Mesothelioma (COMMAND) trial of second-line therapy with Defactinib in patients with no progression on first-line platinum and pemetrexed (NCT01870609) as well as a Window-ofopportunity study as induction therapy in patients undergoing radical surgery (NCT02004028). Similar to the dasatinib trial, this phase II trial of induction VS-6063 has assessment of biomarker response in tumor tissue as primary outcome, but again data on safety, pharmacokinetics, and tumor response to the treatment are also being collected. Participants in this trial, whose completion is estimated for early 2015, would have their pretreatment and posttreatment biopsies collected, and they receive 12 days of oral VS-6063 before undergoing EPP or P/D. With the high proportion of MPM cases presenting with inactivated neurofibromatosis type 2, FAK inhibition presents a very promising potential novel option for induction therapy in a subgroup of patients that
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INDUCTION THERAPY FOR MESOTHELIOMA could easily be identified by standard immunohistochemistry methods. SUMMARY The experience from the past decade using induction chemotherapy before surgery in MPM has shown that this multimodal concept is feasible and can lead to improved outcomes with acceptable mortality and morbidity rates, in general being manageable. Nevertheless, patient selection for multimodal treatment is still hampered by a lack of markers able to accurately predict response to chemotherapy, and future research in this field is
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urgently needed. But recent developments have also shown that other forms of induction therapy, such as radiotherapy or targeted therapy, present valuable alternative options warranting further investigation.
Acknowledgments The authors thank Dr Martina Friess, Dr Michaela Kirschner, Dr Mayura Meerang, and Dr Chloe Spichiger for manuscript editing. We thank Dr Bart Vrugt for providing images and Swiss National Science Foundation for grant support to IO.
11. Zucali PA, Giovannetti E, Destro A, et al: Thymidylate synthase and excision repair cross-complementing group-1 as predictors of responsiveness in mesothelioma patients treated with pemetrexed/carboplatin. Clin Cancer Res. 17(8):2581-2590, 2011 12. Righi L, Papotti MG, Ceppi P, et al: Thymidylate synthase but not excision repair crosscomplementation group 1 tumor expression predicts outcome in patients with malignant pleural mesothelioma treated with pemetrexedbased chemotherapy. J Clin Oncol 28(9): 1534-1539, 2010 13. Mairinger F, Vollbrecht C, Halbwedl I, et al: Reduced folate carrier and folylpolyglutamate synthetase, but not thymidylate synthase predict survival in pemetrexed-treated patients suffering from malignant pleural mesothelioma. J Thorac Oncol 8(5):644-653, 2013 14. Lustgarten DE, Deshpande C, Aggarwal C, et al: Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma. J Thorac Oncol 8 (4):469-477, 2013 15. Mairinger F, Vollbrecht C, Mairinger T, et al: The issue of studies evaluating biomarkers which predict outcome after pemetrexedbased chemotherapy in malignant pleural mesothelioma. J Thorac Oncol 8(8):e80-e82, 2013 16. Besse B, Olaussen KA, Soria JC: ERCC1 and RRM1: Ready for prime time?J Clin Oncol 31 (8):1050-1060, 2013 17. Frischknecht L, Meerang M, Soltermann A, et al: Importance of ERCC1 and RRM1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum based induction chemotherapy followed by surgery J Thorac Cardiovasc Surg 149(6):1539-1547.e1, 2015. 18. Kao SC, Lee K, Klebe S, et al: Excision repair cross complementation group 1 and thymidylate synthase expression in patients with mesothelioma. Clin Lung Cancer 14(2):164-171, 2013
19. Zimling ZG, Sorensen JB, Gerds TA, et al: Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progressionfree survival. J Thorac Oncol 7(1): 249-256, 2012 20. Ting S, Mairinger FD, Hager T, et al: ERCC1, MLH1, MSH2, MSH6, and betaIII-tubulin: Resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma. Clin Lung Cancer 2013;14(5):558-67, e3. 21. Bepler G, Zinner RG, Moon J, et al: A phase 2 cooperative group adjuvant trial using a biomarker-based decision algorithm in patients with stage I non-small cell lung cancer (SWOG0720, NCT00792701). Cancer 120(15): 2343-2351, 2014 22. Wislez M, Barlesi F, Besse B, et al: Customized adjuvant phase II trial in patients with nonsmall-cell lung cancer: IFCT-0801 TASTE. J Clin Oncol. 32(12):1256-1261, 2014 23. Friboulet L, Olaussen KA, Pignon JP, et al: ERCC1 isoform expression and DNA repair in non–small-cell lung cancer. N Engl J Med 368 (12):1101-1110, 2013 24. Erculj N, Kovac V, Hmeljak J, et al: The influence of gemcitabine pathway polymorphisms on treatment outcome in patients with malignant mesothelioma. Pharmacogenet Genomics 22(1):58-68, 2012 25. Tajima K, Hirama M, Shiomi K, et al: ERC/ mesothelin as a marker for chemotherapeutic response in patients with mesothelioma. Anticancer Res 28(6B):3933-3936, 2008 26. Stamatis G: Risks of neoadjuvant chemotherapy and radiation therapy. Thorac Surg Clin 18(1): 71-80, 2008 27. Treasure T, Lang-Lazdunski L, Waller D, et al: Extra-pleural pneumonectomy versus no extrapleural pneumonectomy for patients with malignant pleural mesothelioma: Clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol 12(8):763-772, 2011
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40. Peer M, Stav D, Cyjon A, et al: Morbidity and mortality after major pulmonary resections in patients with locally advanced stage IIIA nonsmall cell lung carcinoma who underwent induction therapy. Heart Lung Circ 24(1): 69-76, 2015 41. Opitz I, Sigrist B, Hillinger S, et al: Taurolidine and povidone-iodine induce different types of cell death in malignant pleural mesothelioma. Lung Cancer. 56(3):327-336, 2007 42. Lang-Lazdunski L, Bille A, Papa S, et al: Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: A 10-year experience. J Thorac Cardiovasc Surg 149(2):558-566, 2015 43. Muraoka M, Oka T, Akamine S, et al: Postoperative complications of pulmonary resection after platinum-based induction chemotherapy for primary lung cancer. Surg Today 33(1): 1-6, 2003 44. Leo F, Solli P, Spaggiari L, et al: Respiratory function changes after chemotherapy: An additional risk for postoperative respiratory complications?Ann Thorac Surg 77(1): 260-265, 2004 [discussion 5] 45. Sugarbaker DJ, Jaklitsch MT, Bueno R, et al: Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies. J Thorac Cardiovasc Surg 128(1):138-146, 2004 46. de Perrot M, McRae K, Anraku M, et al: Risk factors for major complications after extrapleural pneumonectomy for malignant pleural mesothelioma. Ann Thorac Surg 85(4):1206, 2008 47. Burt BM, Cameron RB, Mollberg NM, Kosinski AS, Schipper PH, Shrager JB, et al: Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality. J Thorac Cardiovasc Surg 148(1):30-5, 2014. 48. Nakas A, von Meyenfeldt E, Lau K, Muller S, Waller D: Long-term survival after lung-sparing total pleurectomy for locally advanced (International Mesothelioma Interest Group Stage T3T4) non-sarcomatoid malignant pleural mesothelioma. Eur J Cardiothorac Surg 41(5):10316, 2012. 49. Rena O, Casadio C: Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: A harmful procedure. Lung Cancer 77(1):151-5, 2012. 50. Schipper PH, Nichols FC, Thomse KM, Deschamps C, Cassivi SD, Allen MS, et al: Malignant pleural mesothelioma: surgical management in 285 patients. Ann Thorac Surg 85 (1):257-64(discussion 64), 2008. 51. de Perrot M, Feld R, Cho BC, et al: Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant
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