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A. Scherpereel
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ORAL 26 - Clinical Trials 2 (ID 127)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 8
- Moderators:A. Scherpereel, C. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 702+704+706
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ORAL26.01 - Initial Analyses of the IASLC Malignant Pleural Mesothelioma (MPM) Database: Implications for the 8th Edition AJCC and UICC Staging Manuals (ID 1734)
10:45 - 10:56 | Author(s): V. Rusch, K. Chansky, A. Nowak, D. Rice, H.L. Kindler, H.I. Pass
- Abstract
- Presentation
Background:
This report is on behalf of the Mesothelioma Domain (MD) of the IASLC International Staging and Prognostic Factors Committee (ISC). The ISC MD previously developed the largest international staging database in MPM and analyzed outcomes and prognostic factors. (JTO 2012:1631-1639 and 2014:856-864).These results indicated the need for more granular TNM data to inform revisions of the staging system for the upcoming 8th edition of the AJCC/UICC staging manuals. We report analyses of this new MPM database.
Methods:
The MD established a new data dictionary with more detailed information about TNM descriptors and permitting electronic data capture. Minimum case submission requirements: complete clinical and/or post-surgical TNM stage with anatomical descriptors to support stage designation, accurate survival information, no conflict between descriptors and reported stage, and node positivity recorded by individual station. Overall survival analyzed by Kaplan-Meier and significance of individual T,N, and M descriptors evaluated by logrank and Cox regression.
Results:
3,519 cases treated 1995-2014 were submitted from 31 centers or consortia. 1,069 cases were excluded due to timing of presentation (244), missing dates (196), conflicting or incomplete stage information (615) or incorrect cell type (14). Geographic source for remaining 2,450 cases was: Europe 33%, North America 36%, Turkey 12%, Asia 10%, Australia 9%. Stage available: clinical (cTNM) only 34%; post-surgical (pTNM) only 33%; both 34%. A total of 1,982 cases (81%) underwent surgery (43% EPP, 23% PD, 8% partial pleurectomy, 26% exploration without resection). 5 year overall survival (OS) for any N, M0 showed no difference for T1a versus T1b or for post-surgical T2 versus T3. 5 year OS for any T, M0 showed no difference for N1 versus N2 (Table 1). Median and 5 year OS by stages I-IV were similar to those reported from original database. Table 1. Median overall survival times (MST), 2-year, and 5-year overall survival rates for pre-treatment and post-surgical stage categories. Figure 1
Conclusion:
While additional analyses are ongoing, these initial results suggest some changes in the current MPM staging system are warranted, especially regarding T categories.
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ORAL26.02 - What Are the Risks and Benefits of Extended Pleurectomy Decortication for Mesothelioma? A Review of the Largest Institutional Series in the UK (ID 2925)
10:56 - 11:07 | Author(s): A.J. Sharkey, S. Tenconi, A. Nakas, D. Waller
- Abstract
- Presentation
Background:
Uncertainty surrounds the long term benefits of extended pleurectomy decortication(EPD). In the absence of randomized controlled evidence enabling informed consent for such a major procedure with little prospect of cure is challenging. We have reviewed the largest series of EPD procedures in the UK to provide existing selected evidence for decision making and future research surrounding radical surgery for mesothelioma.
Methods:
We retrospectively analysed the case notes and pathological reports of 266 patients who underwent EPD over the last 15 years to determine length of hospital stay, complication rates and survival.
Results:
Overall survival was: 48.0% at 1 year, 10.3% at 3 years and 2.7% at 5 years. In the most favourable subgroup, those with epithelioid pN0 pathology, the 1, 3 and 5 year survivals were 64.9%, 17.5%, and 5.2% respectively. Overall median survival was 12.2 months, ranging from 23.1 months in those with epithelioid pN0 disease to 6.2 months in those with non-epithelioid, node positive tumours. Post-operative mortality was 3.8% at 30-days and 9% at 90 days. Median length of hospital length of stay was 13 (5-70) days. Re-operation was required in 20 patients (11.9%). A significant increase in postoperative hospital stay was associated with: postoperative atrial fibrillation(14 vs. 20 days p=0.037); persistent air leak(19 vs. 13 days p<0.001); postoperative empyema(40 vs.14 days p<0.001) and subsequent removal of the prosthetic neodiaphragm(21 vs. 14 days p=0.013). Postoperative 30-day mortality was significantly higher in those patients who developed pneumonia(15.8% vs. 3.2% p=0.048). Postoperative 90-day mortality was significantly increased in those who developed a pleural empyema(71.4 v. 8.6% p=0.001), similarly overall survival was reduced in this group(3.1 vs. 12.7 months p=0.072). Duration of intercostal drainage was significantly associated with the development of an empyema(p<0.001) and with the incidence of prosthetic dehiscence of the neodiaphragm(p=0.042). Revisional surgery to remove an infected prosthesis had no detrimental effect on 30 or 90-day mortality, or on overall survival Adjuvant chemotherapy significantly increased overall survival (18.1 vs. 8.2 months p<0.001), but 22.7% patients with neodiaphragm dehiscence, and 28% of those with empyema, did not receive this due to these complications.Complication Rate (%) Persistent air leak 31.0 Atrial Fibrillation 16.7 Pneumonia 8.7 Diaphragmatic patch dehiscence 8.7 Mechanical 22.9 % Infection 77.1 % Empyema 4.8 Wound infection 4.4 Thromboembolic 6.3 Chylothorax 3.6
Conclusion:
Extended pleurectomy decortication(EPD) can be performed in high volume centres with acceptable risk. In all but a selected subgroup it remains a palliative procedure. Thus, reducing postoperative air leak, which increases pleural sepsis and perioperative risk and decreases adjuvant chemotherapy, is paramount. The true role of EPD can only be answered by a prospective randomized comparison with non-surgical treatment.
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ORAL26.03 - Predictive and Prognostic Value of Clinical TNM Staging for Patients with Malignant Pleural Mesothelioma Undergoing Surgery (ID 3127)
11:07 - 11:18 | Author(s): R.R. Gill, R. Bueno, W. Richards
- Abstract
- Presentation
Background:
Clinical staging of malignant pleural mesothelioma (MPM) is challenging due to the unique morphology of the tumor, macroscopic resolution and lack of radiographic contrast between tumor and adjacent structures and the number and complexity of anatomic features comprised by the descriptors. Recent analysis of a large IASLC MPM database revealed discrepancy between clinical (cTNM) and pathological (pTNM) staging (J Thorac Oncol 2012;7: 1631–1639). The current study examined in a retrospective cohort the concordance between cTNM and pTNM stage, the accuracy of individual clinical T and N features in predicting corresponding pathological features, and the prognostic significance of each feature.
Methods:
An IRB approved MPM registry was queried to identify patients who had undergone extrapleural pneumonectomy with complete pathological evaluation and who had preoperative CT or PET-CT scans available for review. All scans were assigned binary scores at the level of individual features by a single chest radiologist (R.G.) with significant experience with MPM. Corresponding scores for pathological features were obtained from the registry database along with histological subtype and overall survival (OS). cTNM and pTNM stage were assigned according to AJCC/UICC 7[th] edition criteria. Taking pTNM as gold standard, each case was scored as concordant, understaged or overstaged by cTNM. Sensitivity, specificity and univariate hazard ratio (HR) for death were determined for individual cT and cN features.
Results:
Inclusion requirements were met for 390 patients. Available preoperative imaging comprised CT scan for 240 (62%) and integrated PET-CT for 150 (38%) patients. MPM was left-sided in 196 (50%) cases. Histology was epithelioid in 234 (60%), biphasic in 141 (36%), sarcomatoid in 13 (3%) and desmoplastic in 2 (<1%) cases. Staging by pTNM was: I, 7 (2%); II, 33 (8%); III, 225 (58%); IV, 125 (32%). Staging by cTNM was: I, 30 (8%); II, 39 (10%); III, 250 (64%); IV, 71 (18%). cTNM was concordant with pTNM staging in 188 (48%), overstaged in 139 (36%), and understaged in 63 (16%) cases. Concordance rate was not substantially modulated by type of scan, use of contrast, prior sclerosis or presence of pleural effusion. The most predictive and prognostic features included (N, sensitivity, specificity, HR, p-value): T2: Interlobar fissures (297, 85%, 71%, 1.4, 0.02); T3: Endothoracic fascia (158, 48%, 64%, 1.4, 0.004), Mediastinal fat (105, 28%, 73%, 1.8, <0.0001); T4: Diffuse/multifocal chest wall (21, 12%, 96%, 1.8, 0.01).
Conclusion:
Data-driven modification of cTNM criteria may improve concordance between cTNM and pTNM staging. Despite inherent sensitivity limitations of cTNM, improved prognostic performance may be achievable by 1) incorporating a size criterion (e.g. radiographic tumor volume), and 2) emphasizing features with high specificity and significant prognostic value when defining T descriptors.
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ORAL26.04 - Discussant for ORAL26.01, ORAL26.02, ORAL26.03 (ID 3362)
11:18 - 11:28 | Author(s): M. de Perrot
- Abstract
- Presentation
Abstract not provided
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ORAL26.05 - Symptom Study of Radiotherapy in Mesothelioma (SYSTEMS), a Phase II Study (ID 390)
11:28 - 11:39 | Author(s): N. Macleod, N. O'Rourke, A. Price, J. Hicks, K. Moore, L. McMahon, J. Stobo, C. Bray, A. Chalmers, M. Fallon, B. Laird
- Abstract
- Presentation
Background:
There is little evidence to support the use of radiotherapy in treating pain in malignant pleural mesothelioma (MPM), however it is widely used. The aim of the present study was to assess the role of radiotherapy in palliating pain in MPM.
Methods:
A multi-centre, single arm, phase II study was conducted in the UK. Eligible patients met the following criteria: a diagnosis of MPM; worst pain score of > 4/10; performance status 0-2; CT scan within eight weeks of radiotherapy; due to receive radiotherapy for pain. Patients who had received anti-cancer therapy in the previous 6 weeks were ineligible. The following key assessments were performed at study baseline: pain (Brief Pain Inventory), Quality of Life (EORTC QLQ-C30) and inflammation (CRP). Following this, all patients were treated with 20 Gray in five fractions to the area of tumour felt to be responsible for the pain. The primary endpoint was a 30% drop in the BPI score five weeks after radiotherapy. Patients were followed up for 12 weeks after radiotherapy.
Results:
Forty patients were recruited between June 2012 and December 2013. Mean age was 71 with a male to female ratio of 7 : 1. Histological diagnosis was present in 85% of patients; 52.5% epithelioid, 25% sarcomatoid, 7.5% biphasic and 15% unspecified. The mean response to radiotherapy at five weeks was 35% (95% CI 20.6-51.7%). 37 patients started radiotherapy and 35 patients completed the full course. Fourteen patients had received prior chemotherapy. No association between baseline CRP and response was observed (p=0.958). Only one patient had a radiological response on CT with stable disease seen in a further 13 patients. There was no significant change in quality of life (QoL) score at any timepoint (p=0.680 week 1, p=0.765 week 5, p=0.384 week 12).
Conclusion:
Radiotherapy provides effective pain relief in a proportion of patients with MPM and should be considered for all patients with MPM related pain. Randomised dose escalation studies are now warranted and funding has been secured for such a study, SYSTEMS 2.
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ORAL26.06 - Prospective Assessment of Proton Therapy for Malignant Pleural Mesothelioma (ID 3071)
11:39 - 11:50 | Author(s): Y.R. Li, E.W. Alley, J. Friedberg, M. Culligan, T.M. Busch, S. Hahn, K.A. Cengel, C.B. Simone
- Abstract
- Presentation
Background:
Use of radiotherapy (RT) to treat malignant pleural mesothelioma (MPM) has been limited due to reported significant morbidity and risk of fatal pneumonitis when treating large pleural volumes. To date, RT for MPM has generally been limited to palliation, prophylaxis of surgical tract sites, and adjuvant therapy generally after extrapleural pnuemonectomy. Reports of RT for MPM have employed photons and electrons nearly exclusively. Proton therapy (PT) can significantly reduce irradiation to lung and other critical organs, possibly reducing treatment toxicities and enabling novel RT indications. To date, only a single case series of 4 patients has reported on PT for MPM. We report our prospective experience using PT as adjuvant or definitive therapy for MPM and hypothesized that PT will have low rates of esophagitis and pneumonitis, while providing excellent local control.
Methods:
All consecutive patients diagnosed with MPM from 2011-2015 and treated at the Penn Mesothelioma and Pleural Program with PT on a prospective registry study were included for this Institutional Review Board-approved analysis. Local control, defined as lack of tumor progression in the RT portal, and overall survival were measured from PT completion to last follow-up or death. Toxicities were scored using CTCAEv4.
Results:
Sixteen patients treated to 17 PT courses were included. Patients were predominantly male (81%) and Caucasian (100%) with epithelial histological subtype (82%) and stage III-IV disease (94%). Patients were a median of 69.8 years old at PT start, which was delivered at a median of 11.1 months (range 3.5-69.3 months) after diagnosis. All patients received pemetrexed plus cisplatin or carboplatin prior to (n=15) or concurrent with (n=1) PT. PT was administered as adjuvant therapy following lung-sparing radical pleurectomy (n=8), to sites of gross disease following progression on systemic therapy (n=8), or as initial definitive therapy with concurrent chemotherapy (n=1). Patients were treated to a median dose of 51.75Gy (CGE) in 2.0Gy daily fractions (range 50.0-75.0Gy/1.8-2.5Gy). At a median follow-up of 5 months from PT completion, all patients had durable local control throughout the study period. Five patients died at a median of 5.4 months following PT. Median overall survival for the cohort has not yet been reached, and 6- and 12-month survival rates were 35% and 24%, respectively. No patients experienced grade ≥3 acute or late toxicity. Across the 17 PT courses, acute grade 2 toxicities included radiation dermatitis (n=8), dysphagia/esophagitis (n=4), anorexia (n=3), fatigue (n=2), and cough (n=1). Late grade 2 toxicity included a single patient with radiation pneumonitis (6%). Overall, patients experienced no significant change in ECOG performance score from PT beginning to end (mean 0.82 to 0.88).
Conclusion:
This is the largest report of PT for MPM and demonstrated PT is well tolerated with a favorable toxicity profile compared with photon reports. As such, PT may better allow for integration of RT in multimodality therapy for MPM. This study also demonstrated the efficacy of PT, with local control achieved following all 17 treatment courses. Longer follow-up and additional patients are needed to assess late toxicities and overall survival after PT.
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ORAL26.07 - Early Signs of Clinical Activity of a MicroRNA-Based Therapy in a Phase I Study in Recurrent Malignant Pleural Mesothelioma (ID 1101)
11:50 - 12:01 | Author(s): N. van Zandwijk, N. Pavlakis, S. Kao, S. Clarke, A. Linton, H. Brahmbhatt, J. Macdiarmid, S. Pattison, F. Leslie, Y. Huynh, G. Reid
- Abstract
- Presentation
Background:
Recently we demonstrated that members of the miR-15/16 family of microRNAs are implicated as tumor suppressors in malignant pleural mesothelioma (MPM) (Reid et al, Ann Oncol, 2013). MesomiR 1 is a first-in-man study testing TargomiRs (miR-15/16-derived mimics packaged in EDV[TM]nanocells [EDVs] targeted with EGFR antibodies) in MPM patients.
Methods:
In this phase I study (ClinicalTrials.gov: NCT02369198) a standard 3-6 patient dose escalation cohort design examining weekly/twice weekly administration of TargomiRs is followed. Patients tolerating weekly/twice weekly TargomiR infusions well are allowed to continue experimental therapy for at least 8 weeks. Fifty percent of the MTD previously established for EDVs was chosen as the first dose level to be studied and corresponded to 5 billion EDVs containing 1.5 μg miR-15/16 mimics. Based on prior experience with EDVs, patients who presented with elevated IL-6 levels were given a dose adaptation period of two weeks before receiving phase I doses. Premedication consisted of dexamethasone, promethazine and paracetamol and patients were monitored for a minimum period of 3 hours after TargomiR infusion. Response assessment (CT, FDG-PET, pulmonary function) was scheduled for patients completing 8 weeks of treatment. Quality-of-Life (QoL) questionnaires (EORTC) were requested on a weekly basis.
Results:
Ten MPM patients have enrolled to date. The majority of patients receiving 5 billion TargomiRs experienced a period of shivering/rigor 80-90 minutes after the start of the infusion, sometimes associated with burning/painful sensations in the area of disease. Overall TargomiR treatment was well tolerated and no patient failed to complete the first (8 weeks) treatment period. Laboratory examination revealed a steep but transitory rise in inflammatory cytokines, neutrophilia and lymphopenia shortly after TargomiR infusion, sometimes accompanied by mild elevation of liver enzymes. QoL assessment (9 patients) showed improving scores in 3 patients, stabilization in 4 and slightly lower scores in 2 patients. Response assessment (modified RECIST) in the 6 patients completing 8 weeks of treatment to date: 1 PR (see Figure 1, reconfirmed after 12 and 16 weeks), 4 SD and 1 PD. Figure 1. FDG-PET scintigraphy before (left) and after (right) 8 weeksFigure 1 of TargomiR treatment (patient 5)
Conclusion:
Early MesomiR 1 data revealed that infusions with 5 billion TargomiRs were well tolerated. Transient inflammatory (cytokine-mediated) reactions were noted shortly after TargomiR administration. One objective response was recorded while stable disease and stable QoL scores were noted in the majority of patients completing 8 weeks of experimental treatment.
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ORAL26.08 - Discussant for ORAL26.05, ORAL26.06, ORAL26.07 (ID 3363)
12:01 - 12:11 | Author(s): A. Rimner
- Abstract
- Presentation
Abstract not provided
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Author of
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MTE 22 - Diagnosis and Treatment of MPM: Overview (Ticketed Session) (ID 74)
- Event: WCLC 2015
- Type: Meet the Expert (Ticketed Session)
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 07:00 - 08:00, 205+207
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MTE22.01 - Diagnosis and Treatment of MPM: Overview (ID 2009)
07:00 - 08:00 | Author(s): A. Scherpereel
- Abstract
- Presentation
Abstract:
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor issued from the mesothelial surface of the pleural space. A previous exposure to asbestos is the main risk factor of mesothelioma. Clinical signs are most of time late and unspecific. Chest CT-scan, a key imaging procedure, usually shows pleural effusion ±pleural thickening. PET-CT may help to differentiate MPM from pleural benign tumors, as well for distal tumor staging. But PET-CT is not recommended for the diagnosis of MPM, as well as soluble biomarkers, including mesothelin. A diagnosis of MPM based on pleural biopsies best obtained by thoracoscopy is recommended with compulsory immunohistochemistry (1, 2). The treatment of MPM is so far quite deceptive with median overall survival (OS) around 12 months, and relies mostly on chemotherapy and best supportive care (BSC). To date, only first line chemotherapy by cisplatin/carboplatin+pemetrexed is recommended by all guidelines for patients fitted for chemotherapy (3). The optimal duration of first line chemotherapy is unknown but a maximum of 6 cycles is recommended. There is no evidence supporting a maintenance treatment including by pemetrexed. Therapeutic options beyond first line treatment are presently highly limited despite nearly half of patients are clinically fitted for. According to guidelines, pemetrexed alone may be proposed again if patients did have tumor progression at least 3 to 6 months after stopping chemotherapy (1, 2). Other options exhibited deceptive response rates (4). Therefore, it is recommended in the other cases to propose patients to join clinical trials. Pathogenesis of MPM includes overexpression of growth factors (VEGF…), many genetic and epigenetic alterations and/or mutations of malignant cells (p16 INK4A/CDKN2A, BAP-1, NF-2…) responsible for cell proliferation and resistance to apoptosis, pleural inflammation and local immunosuppression induced by the tumor and favoring its growth. These elements provide the rationale for many targeted therapies and immunotherapy. But so far, very few drugs exhibited sufficient value to deserve further trials. Thus, first trials assessing anti-angiogenic drugs in MPM did not support their use in this cancer despite the key role of VEGF. A phase II trial of bevacizumab (anti-VEGF antibodies) combined with cisplatin+gemcitabine was negative (5). But other phase II trials evaluating bevacizumab with cisplatin+pemetrexed were promising with PFS of 6.9, 7.9 and 9.2 months, and DCR of 40, 57 and 88%, respectively. Therefore a phase III randomized (1:1) trial (« MAPS ») recruited 448 unresectable MPM patients to test cisplatin+pemetrexed with (arm B) or without (arm A) bevacizumab (6). Arm B non-progressive patients received bevacizumab maintenance until progression or toxicity. Median OS was significantly longer in the B arm: 18.8 [95%CI: 15.9-22.6] vs. 16.1 months [14.0-17.9] in the A arm, (adj.HR= 0.76, p=0.012). Thus bevacizumab addition to pemetrexed+cisplatin provided a significantly longer survival in MPM patients with acceptable toxicity, making this triplet a new treatment paradigm for this cancer. Pro-apoptotic agents such as proteasome inhibitors (bortezomib) or histones deacetylases inhibitors (HDACi) were also assessed with discordant results. In 2[nd]/3[rd] line treatment, vorinostat (HDACi) failed to show any significant OS gain versus placebo in a large phase III trial (7). Focal adhesion kinase (FAK) is a tyrosine kinase with multiple roles in tumor growth and resistance to chemotherapy. FAK is overexpressed with increasing activity in many human cancers, associated to a low tumor expression of the Merlin molecule, a potential predictive biomarker of FAK inhibitors. An inhibition of FAK may induce tumor cells apoptosis, reduce cancer stem cells, and modulate the activity of NF-2, frequently mutated in MPM. Thus, a trial is currently assessing FAK inhibitors (VS-6063/Defactinib) as maintenance treatment after 1[rst] line chemotherapy by platinum+pemetrexed. Phase I-II trials assessed antibodies targeting mesothelin, a mesothelial cell surface molecule overexpressed in (epithelioïd) MPM, alone or combined with Listeria toxin, showing promising results (8). Other innovative techniques including gene therapy, cellular therapy or oncovirotherapy, are also currently evaluated with first promising results. But, as in melanoma or in lung cancers, checkpoint inhibitors represent presently the most exciting tool. First results with anti-CTLA4 Ab (tremelimumab) were recently published: the main goal (RR) was not achieved but several prolonged response or stable disease were observed, justifying a larger phase II trial (n=564), assessing tremelimumab versus placebo in 2[nd]/3[rd] line treatment of MPM. Early data of a phase Ib basket trial with anti-PD-1 (Pembrolizumab) in the same setting found promising RR of 28% and DCR of 76% in PD-L1 positive MPM (2015 AACR meeting). Other trials with checkpoint inhibitors are underway. To date, the place of radiotherapy is limited in MPM, mostly with palliative intent (1). Prophylactic irradiation of chest scars and drains is highly discussed. A definitive answer on this controversial indication is hoped with a current randomized UK trial. Adjuvant radiotherapy is not validated yet as well. Limitations due to technical reasons and toxicities may be answered in the future by new modalities of radiotherapy such as IMRT. Multimodal treatment of MPM patients, whatever the surgery is (i.e. extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D)) is not recommended outside clinical trials (1). Recent trials, even the highly controversial “MARS” trial, and meta-analysis undeniably plead for stopping EPP and to continue P/D only in clinical trials to find the best multimodal treatment for potentially resecable MPM patients, fitted for surgery (9). Additional intrapleural treatments (chemotherapy, photodynamic therapy (PDT) or immunotherapy) seem needed to improve significantly the post-surgery outcome, mostly as now targeted therapies such as bevacizumab may increase median OS close to 19 months in patients less selected than surgical patients! Thus, Friedberg and al found exciting OS over 31 months in patients treated by multimodal treatment including extensive P/D and intrapleural PDT (10). In conclusion, many research studies presently assess the value of targeted therapies and biomarkers, opening new perspectives in the management of MPM. Remaining questions are how to target the best patients for each drug or technique, and how to combine the different current and future therapeutic tools in MPM. But real hopes seem close now for our patients after a long dark age. References Scherpereel A, Astoul P, Baas P, Berghmans T, Clayson H, de Vuyst P, et al. Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. Eur Respir J 2010 ;35:479-95. van Zandwijk N, Clarke C, Henderson D, Musk AW, Fong K, Nowak A, et al. Guidelines for the diagnosis and treatment of malignant pleural mesothelioma. J Thorac Dis. 2013; 5(6): E254-E307. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636-44. Zucali PA, Simonelli M, Michetti G, Tiseo M, Ceresoli GL, Collovà E, et al. Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. Lung Cancer 2012;75:360-7. Kindler HL, Karrison TG, Gandara DR, Lu C, Krug LM, Stevenson JP, et al. Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma. J Clin Oncol 2012;30:2509-15. Zalcman G, Mazières J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, Molinier O, Corre R, Monnet I, Gounant V, Janicot H, Gervais R, Locher C, Milleron B, Tran Q, Lebitasy MP, Morin F, Creveuil C, Parienti JJ, and Scherpereel A. Bevacizumab 15mg/kg plus cisplatin-pemetrexed (CP) triplet versus CP doublet in Malignant Pleural Mesothelioma (MPM): Results of the IFCT-GFPC-0701 MAPS randomized phase 3 trial. ASCO 2015 annual meeting (Chicago, USA) Abstract #150191. Krug LM, Kindler HL, Calvert H, Manegold C, Tsao AS, Fennell D, Öhman R, Plummer R, Eberhardt WE, Fukuoka K, Gaafar RM, Lafitte JJ, Hillerdal G, Chu Q, Buikhuisen WA, Lubiniecki GM, Sun X, Smith M, Baas P. Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol. 2015; 16(4): 447-56. Hassan R, Kindler HL, Jahan T, Bazhenova L, Reck M, Thomas A, Pastan I, Parno J, O'Shannessy DJ, Fatato P, Maltzman JD, Wallin BA. Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma. Clin Cancer Res. 2014; 20(23): 5927-36. Cao C, Tian DH, Park J, Allan J, Pataky KA, Yan TD. A A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma. Lung Cancer. 2014; 83(2): 240-5. Friedberg JS. Radical pleurectomy and photodynamic therapy for malignant pleural mesothelioma. Ann Cardiothorac Surg. 2012; 1(4): 472-80.
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ORAL 11 - Clinical Trials 1 (ID 100)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:A.K. Nowak, F. Detterbeck
- Coordinates: 9/07/2015, 10:45 - 12:15, 702+704+706
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ORAL11.01 - Bevacizumab 15mg/kg Plus Cisplatin-Pemetrexed (CP) vs CP in Malignant Pleural Mesothelioma (MPM): IFCT-GFPC-0701 MAPS Randomized Phase 3 Trial (ID 2142)
11:07 - 11:18 | Author(s): A. Scherpereel
- Abstract
Background:
MPM median overall survival (OS) did not exceed 13 months with pemetrexed-platinum doublet, with virtually no surviving patients at 5 years. Vascular endothelial growth factor is a potent mitogen for MPM cells.
Methods:
In this French multicenter randomized phase 3 trial, eligible patients had unresectable, histologically proved MPM, age < 76, no prior chemo, PS 0-2, no thrombosis, nor bleeding. Randomized patients (1:1) received pem 500 mg/m2, CDDP 75 mg/m2 at D1, with (arm B) or without bevacizumab (arm A), 15 mg/kg Q21D, for 6 cycles. Arm B non-progressive patients received bevacizumab maintenance therapy until progression or toxicity. Primary endpoint was OS. 445 patients were to be randomized, and 385 events observed, to show a significant OS improvement, with 80% statistical power, 5% a-risk.
Results:
From Feb. 2008 to Jan. 2014, 448 patients were included in 73 centers. Males: 75.4%, median age: 65.7 years (range 34.7-75.9), PS 0-1: 96.7%. The IDMC recommended a second interim analysis after 85% of events. On 01-Jan-2015, the duration since last news was < 30 days in 105 out of 106 still living patients. Overall survival was significantly longer in the experimental arm (median: 18.8 months, 95%CI[15.9-22.6] vs. 16.1 months, 95%CI[14.0-17.9] for the reference arm, (adj.HR = 0.76, 95%CI[0.61; 0.94], p = 0.012). With only 46/448 non-progressive patients at the date of analysis, median PFS was 9.6 months, 95%CI[8.5-10.6] in bevacizumab arm vs. 7.5 months, 95%CI[6.8-8.1] (adj.HR = 0.62, 95%CI[0.50-0.75], p < 0.0001). G3-4 hematological toxicities did not significantly differ in the two arms (49.5% vs. 47.3%). Significantly more G3 proteinuria (0.0 vs. 3.1%), G3 hypertension (0.0 vs. 23%), G3-4 arterial thrombotic events (0.0 vs. 2.7%) were observed in bevacizumab arm. QOL and exploratory biomarkers studies will be also presented at time of the meeting.
Conclusion:
Bevacizumab addition to pemetrexed/cis-platin provides a significantly longer survival in pts with MPM, with acceptable toxicity, making this triplet a new treatment paradigm.
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ORAL 27 - Care (ID 123)
- Event: WCLC 2015
- Type: Oral Session
- Track: Advocacy
- Presentations: 1
- Moderators:M.N. Mountain, J. Freeman-Daily
- Coordinates: 9/08/2015, 10:45 - 12:15, 708+710+712
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ORAL27.06 - Disparities in Lung Cancer Incidence and Management Care in France: A Nationwide Cohort Study (the TERRITOIRE Study) (ID 1177)
11:39 - 11:50 | Author(s): A. Scherpereel
- Abstract
- Presentation
Background:
Reducing health inequalities in oncology is a major public health priority in France, particularly in terms of social and geographic exclusion and equity of access to health care services. However, no specific registry currently exists for patients with lung cancer allowing description and comparison of local situations. Our aim was to use available National medico-administrative databases to constitute a nationwide population-based cohort study to analyze disparities among French areas (the TERRITOIRE study).
Methods:
We included all patients who had a first diagnosis of lung cancer between January 1rst and December 31th 2011 in the National hospitals databases (PMSI, Programme de Médicalisation des Systèmes d'Information). Patients’ data were linked to create a retrospective cohort study with a two-year follow-up period. The 22 administrative regions were considered in this analysis. In addition of demographic characteristics, metastatic status, comorbidities and treatment procedures, we assigned each patient to socioeconomic deprivation and urbanization scores based on their postcode of residence.
Results:
We identified 41,715 patients newly diagnosed for lung cancer. Mean age at diagnosis was 66.4(±11.9) years and most of patients were men (71.8%). Patients from socioeconomic deprived areas represented 27.5% of the whole lung cancer population, ranging from 9.6% to 55.2% according to the region. Incidences of lung cancer were 35.1 per 100,000 in women and 95.3 per 100,000 in men. Age-standardized incidences showed important disparities between French regions ranging from 27.5 to 55.0 and from 82.4 to 118.2 per 100,000 in women and men, respectively. Higher incidences were found in the northern and eastern regions for men and in the southern and eastern regions for women. Although patients living in rural areas were the larger group (34.5%), Age-standardized incidence significantly increased with urbanization: from 61.8 per 100.000 in rural areas to 73.9 per 100.000 in urban areas. A majority of patients was diagnosed at a metastatic stage (52.7%) and regional disparities were important ranging from 45.0% to 58.1%. This rate also appeared higher in patients diagnosed in public hospitals compared to private ones (56.1% vs 42.9%, p<0.0001) and in local hospitals compared to university ones (60.2% vs 49.6%, p<0.0001). Adjusted comparisons showed significantly higher incidences of stage IV patients at the time of diagnosis in five regions for men and two regions for women. A majority of patients (N=23,842; 57.2%) died in the hospital during the 2-year follow-up, including 15,642 patients (71.2%) having metastasis at the time diagnosis.
Conclusion:
We have demonstrated that a comprehensive population-based cohort using medico-administrative data is a suitable approach to illustrate disparities in lung cancer incidence, management care and outcomes in France. Data from this study should help local clinical teams and health stakeholders to better understand inequality issues in their areas.
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P2.07 - Poster Session/ Small Cell Lung Cancer (ID 222)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.07-005 - AVE plus Valproate for Refractory/Relapsing SCLC: A Phase II Study by the ELCWP (ID 142)
09:30 - 09:30 | Author(s): A. Scherpereel
- Abstract
Background:
Salvage chemotherapy (CT) for relapsing or refractory small cell lung cancer (SCLC) to platinum-etoposide remains disappointing. In vitro experiments are suggesting that valproic acid, by inhibiting histone deacetylases (HDAC), could increase apoptosis of SCLC cell lines exposed to doxorubicin, vindesine and bis(2-chloroethyl)amine. The primary objective of this phase II study is to determine if epigenetic modulation with valproic acid in addition to a doxorubicin, vindesine, cyclophosphamide (AVE) regimen may allow adequate improved 6-months progression-free survival (PFS) in refractory/relapsing SCLC.
Methods:
Patients (pts) with previously pathologically proven SCLC, either primary or secondary refractory to prior chemotherapy regimen including platinum derivatives and etoposide, Karnofsky performance status ≥ 60, adequate haematological, hepatic, renal, lung and cardiac functions were eligible. After central registration, pts received AVE (doxorubicin 45 mg/m², vindesine 3 mg/m², cyclophosphamide 1 g/m² every 3 weeks) plus daily oral valproic acid to obtain serum concentration in the range of the recommended values for the treatment of epilepsy (50-100 μg/ml). Response was assessed after 3 courses and responders continued treatment until best response, unacceptable toxicity or cumulative dose of doxorubicin > 500 mg/m². The trial was designed to show that 6-months PFS was > 18%, powering the trial to detect an increase to at least 39%. With this assumption, at least 43 pts assessable for PFS had to be registered (a 10%, b 10%).
Results:
From 11/2008 to 12/2013, 64 pts were registered of whom 6 were ineligible. The main characteristics of the 58 eligible pts were: male/female 38/20 pts, PS 60-70/80-100 17/41 pts, median age 60 years, 19 pts received two or more previous lines of CT. Seven pts did not receive any CT leaving 51 pts assessable for the primary endpoint. Objective response rate was 19.6% (95% CI 8.7%-30.5%). Median PFS was 2.75 months (95% CI, 2.46 to 3.61) and 6-months PFS was 6%. Median survival time was 5.9 months (95% CI, 4.7 to 7.5) with 6 and 12-months survival rates of 50% and 6%. As expected, toxicity was mainly haematological with 88% and 26% grade 3-4 neutropenia and thrombopenia, respectively.
Conclusion:
Despite an interesting response rate, the addition of valproic acid to AVE did not translate into adequate PFS in relapsing/refractory SCLC to platinum/etoposide. This regimen cannot be recommended for further investigation.
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PRC 02 - Press Conference 2 (ID 197)
- Event: WCLC 2015
- Type: Press Conference
- Track: Other
- Presentations: 1
- Moderators:J.R. Jett
- Coordinates: 9/07/2015, 09:45 - 10:45, 108+110+112
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PRC02.05 - Abstract – Bevacizumab 15mg/kg Plus Cisplatin-Pemetrexed (CP) vs CP in Malignant Pleural Mesothelioma (MPM): IFCT-GFPC-0701 MAPS Randomized Phase 3 Trial - Dr. Arnaud Scherpereel, Head of the Pulmonary and Thoracic Oncology Department and Professor at the University Hospital (CHU) of Lille, France (ID 3623)
10:25 - 10:35 | Author(s): A. Scherpereel
- Abstract
Abstract not provided
