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C. Thomas
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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 - 12:15 | 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)
10:45 - 12:15 | 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)
10:45 - 12:15 | 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)
10:45 - 12:15 | 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)
10:45 - 12:15 | 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)
10:45 - 12:15 | 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)
10:45 - 12:15 | 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)
10:45 - 12:15 | Author(s): A. Rimner
- Abstract
- Presentation
Abstract not provided
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