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B. McCaughan
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MO14 - Mesothelioma II - Surgery and Multimodality (ID 121)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Mesothelioma
- Presentations: 12
- Moderators:E. Lim, B. McCaughan
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside Gallery B, Level 1
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MO14.01 - The impact of macroscopic complete resection radical pleurectomy for mesothelioma on pulmonary function (ID 1692)
10:30 - 10:35 | Author(s): J. Friedberg, M. Culligan, M. Putt, S.M. Hahn, C. Simone, E. Alley, K.A. Cengel, D. Sterman
- Abstract
- Presentation
Background
Radical pleurectomy is our standard approach for achieving a macroscopic complete resection in patients with malignant pleural mesothelioma undergoing surgery-based treatment. This procedure, not pneumonectomy, is performed even in the setting of advanced stage disease, bulky tumors and/or extensive involvement of the pulmonary fissures. Although the majority of patients subjectively rate their breathing as “good” after this operation we recently started measuring postoperative pulmonary function, reported herein.Methods
We examined pre and postoperative FEV~1~ levels among 27 patients undergoing radical pleurectomy: 2 stage I, 3 stage II, 17 stage III, 5 stage IV.Results
The figure shows pre/postoperative FEV-1. Median preoperative levels did not differ significantly between stages (P=0.25): 2.47 (Stage I/II) 2.19 (Stage III) and 1.68 (Stage IV) liters/second. Post-operative median values were 2.16 (Stage I/II), 1.97 (Stage III) and 1.05 (Stage IV) liters/second. The median (interquartile range) decrease in FEV-1 was 0.28 (0.12, 0.51) liters/second, which corresponds to a median (interquartile range) decrease in percent predicted FEV-1 of 7% (4.5%, 16.0%), neither change being statistically significant between stages. Figure 1Conclusion
These operations were conducted in an advanced stage cohort of patients, 81% stage III or IV. The nominal decrease in FEV1 corresponds with the subjective impression of the patients regarding their pulmonary function. While lung parenchyma is preserved with radical pleurectomy, we conjecture the decrease in FEV1 is likely related to compromise in breathing mechanics. Further studies are ongoing to better quantify and characterize the decrease in pulmonary function observed with this operation and to more rigorously integrate this information with formal quality of life assessments.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO14.02 - 16 Year Experience of Routine Laparoscopy and Selective Contralateral Thoracoscopic Staging for Malignant Pleural Mesothelioma (ID 1651)
10:35 - 10:40 | Author(s): J. Friedberg, M. Culligan, S.M. Hahn, C. Simone, J. Buyske, G. Korus, D. Sterman, K. Kuhns, E. Alley, K.A. Cengel
- Abstract
- Presentation
Background
Surgery for malignant pleural mesothelioma (MPM) is typically restricted to patients without intraperitoneal or contralateral pleural spread. Imaging studies are accompanied by both false positive and false negative errors for both types of spread. To avoid these errors our group has routinely performed laparoscopy and selective contralateral video-assisted thoracoscopy (VATS) since 1997.Methods
168 patients with MPM were evaluated for surgery as part of a multimodal treatment protocol. Radiographic staging studies included CT Chest with contrast for all 168 patients, PET Scan (112 patients) and MRI Abdomen (17 patients) for concerning findings on CT and/or PET. 150 patients underwent laparoscopy (two 5mm ports) with both peritoneal biopsy and lavage for cytology. 130/150 laparoscopies were performed in virgin abdomens with the remainder being reoperative procedures. 18 patients also underwent contralateral VATS, based upon any suspicious radiographic findings by either the interpreting radiologist or as reviewed by a multidisciplinary panel of treating physicians. All VATS were performed through a single 1 cm incision. Laparoscopies were performed as outpatient procedures. Patients undergoing combination VATS/laparoscopy were scheduled as same day admissions.Results
There were no operative complications for either procedure. 5/132 (4%) laparoscopy patients scheduled as outpatients required overnight hospitalization – the most common reason being urinary retention. Laparoscopy revealed inaccuracies in radiographic staging in 13/150 (9%) patients- 6 false positive studies (1 interpretation of diaphragm transgression that was not through the diaphragm and 5 metastases that were not present) and 7 false negative studies (3 detected by lavage and 4 by biopsy). All of the false positive and all of the false negative studies occurred in patients who had PET scans. 2/18 (11%) patients who underwent VATS were positive for mesothelioma in the contralateral pleura, only one of whom had a positive PET scan finding.Conclusion
Routine laparoscopy was performed safely and revealed inaccuracy in radiographic staging in 9% of the patients, all of whom had both CT and PET scans. Selective contralateral VATS was performed safely and revealed cancer in 11% of patients with suspicious findings, as determined by the interpreting radiologists and/or the treating clinicians and with PET only being accurate in one of the two positive findings. We conclude that prior to offering patients surgery-based treatment for MPM routine laparoscopy and VATS, based upon any suspicion, are indicated.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO14.03 - Meta-analysis of extrapleural pneumonectomy versus radical pleurectomy for patients with resectable malignant pleural mesothelioma (ID 3467)
10:40 - 10:45 | Author(s): D. Tian, K. Pataky, T.D. Yan, S. Peeceeyen, C. Cao
- Abstract
- Presentation
Background
Malignant pleural mesothelioma (MPM) is an aggressive disease of the pleural lining with a dismal prognosis of 6 – 12 months from the time of diagnosis. Surgical treatment of MPM includes extrapleural pneumonectomy and pleurectomy/decortication (P/D). Recently, IASLC has reclassified P/D according to therapeutic intent and surgical technique into partial P/D, P/D, and radical P/D. The present meta-analysis aimed to compare the perioperative and long-term outcomes of EPP and radical P/D for patients with resectable MPM.Methods
A systematic review of the literature was performed on five electronic databases to identify all relevant data on comparative outcomes of radical P/D and EPP. Endpoints included perioperative mortality and overall morbidity, as well as long-term overall survival.Results
Six relevant studies with comparative data of EPP (n= 601) versus radical P/D (n=493) were identified from the current literature. Comparison of these two groups demonstrated significantly lower perioperative mortality (3.0% vs 6.5%, p=0.04) and overall morbidity (30.4% vs 64.3%, p<0.0001) for patients who underwent radical P/D compared to EPP. Median overall survival ranged between 13 – 29 months for radical P/D and 12 – 22 months for EPP, with a strong trend favouring radical P/D. Figure 1Figure 2Conclusion
Although it must be emphasized that patient selection and treatment strategies differ between EPP and radical P/D, a number of comparative studies have recently been conducted to compare these two surgical techniques for patients with resectable MPM. The present study indicated that appropriately selected patients who underwent radical P/D had lower perioperative morbidity and mortality with similar, if not superior, long-term survival compared to EPP.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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- Abstract
Background
Pleurectomy/decortication (P/D) in the treatment of malignant pleural mesothelioma includes a number of procedures with different clinical indications and therapeutic intents. To unify the nomenclature, IMIG and IASLC recently defined P/D-related procedures according to surgical technique, including ‘extended P/D’, ‘P/D’ and ‘partial pleurectomy’. The present systematic review aimed to assess the safety and efficacy of these techniques.Methods
A systematic review of relevant studies was performed by electronic search of five online databases from 1985 to 2012 by two independent reviewers according to predefined selection criteria.Results
Thirty-four studies involving 1916 patients who underwent pleurectomy were included for quantitative analysis. These included 12 studies on ‘extended P/D’, 8 studies on ‘P/D’ and 14 studies on ‘partial P/D’. Perioperative mortality ranged from 0% - 11% and perioperative morbidity ranged from 13% - 43%. Median overall survival ranged from 7.1 – 31.7 months and disease-free survival ranged from 6 – 16 months. One study reported on quality-of-life outcomes using a standardized questionnaire suggesting superior outcomes for ‘extended P/D’ compared to extrapleural pneumonectomy. Figure 1Figure 2Conclusion
Results of the present systematic review suggested similar perioperative mortality outcomes between different P/D techniques but a trend towards higher morbidity and length of hospitalization for patients who underwent ‘extended P/D’. However, overall and disease-free survival appeared to favour ‘extended P/D’ compared to less aggressive techniques. Future studies on P/D should adhere to recent definitions to enable accurate analysis of similar procedures. Direct comparisons of pleurectomy to extrapleural pneumonectomy remain challenging, and should be restricted to ‘extended P/D’ procedures only. -
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MO14.05 - Intracavitary Cisplatin-Fibrin Chemotherapy after Resection for Malignant Pleural Mesothelioma Patients (INFLuenCe-Meso) - preliminary results (ID 2683)
10:50 - 10:55 | Author(s): I. Opitz, O. Lauk, M. Meerang, M. Friess, C. Bommeli, A. Jetter, D. Günther, R. Stahel, W. Weder
- Abstract
- Presentation
Background
Local mesothelioma recurrence remains a challenge even after multimodal therapy. Intracavitary chemotherapy is a promising approach to improve local tumor control. In preclinical studies we observed improved pharmacokinetic characteristics when cisplatin was loaded to a fibrin carrier and applied to the chest wall after surgery while effectiveness remained the same compared to cisplatin applied as a solution. We will present the first results of a phase I –dose-escalation-clinical study.Methods
Since 11/2012 3 patients were included in the study. Cisplatin-fibrin was applied after pleurectomy/decortication (P/D) to the chest wall in a concentration of 11 mg/m[2] BSA. Blood samples were taken at several time points after the application (2, 6, 10, 24, 48 and 120 hours) to assess serum cisplatin levels and to test toxicity in the early phase until 14 days postoperatively. The concentration of total platinum was quantified by means of inductively coupled plasma sector field mass spectrometric detection. Adverse events were graded according to the CTCAE.Results
Between November 2012 and March 2013 three patients (2x epithelioid, 1x biphasic) in stage II, III and stage IV were included and received P/D plus Cisplatin-Fibrin in a concentration of 11 mg/m[2]. The maximum concentration of cisplatin in the serum was below 0.3 µg/g at 2 h after application and continued to decrease over a period of 5 days (see image 1). No severe adverse events were observed. The adverse events documented were not related to cisplatin (table 1):
Figure 1Diagnosis / symptoms CTC AE grading Number of patients Related to Cisplatin Fatigue Grade II 2 possible Anemia Grade III 2 unlikely Nausea / vomiting Grade I 1 possible Increased kreatinin & urea levels Grade II 1 possible Increased CK levels Grade IV 1 unlikely Increased level of transaminases Grade III 1 unlikely Urinary retention Grade II 1 unlikely Hypotension Grade II 1 unlikely Pneumothorax Grade II 1 unlikely Conclusion
Our preliminary results show, that cisplatin-fibrin application to the chest wall and the lung surface after P/D is safe on a dose level of 11mg/m2 BSA. As no treatment related mortality and no drug related toxicity was observed we escalate the dosage to 22 mg/m2 BSA, further results including chest wall concentrations of cisplatin will be available in October.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO14.06 - DISCUSSANT (ID 3969)
10:55 - 11:10 | Author(s): B. McCaughan
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO14.07 - Elevated tumour expression of miR-210 is associated with short survival in malignant pleural mesothelioma patients undergoing extrapleural pneumonectomy (ID 1491)
11:10 - 11:15 | Author(s): M.B. Kirschner, Y.Y. Cheng, S. Kao, N. Van Zandwijk, B. McCaughan, G. Reid
- Abstract
- Presentation
Background
Malignant pleural mesothelioma (MPM) is an aggressive cancer with a median survival of around one year and a 5 year survival rate of less than 10%. A selected group of patients with a potentially resectable tumour mass and good performance status may be considered for extrapleural pneumonectomy (EPP). However the results of this form of treatment are variable. Several prognostic markers have been explored to assist with patient selection including histological subtype, neutrophil-to-lymphocyte ratio (NLR), calretinin and microRNA miR-29c* expression in tumour tissue. In the present study we used microarray profiling to identify other microRNAs which might have the potential to serve as a prognostic biomarker.Methods
The study used 60 formalin-fixed paraffin embedded (FFPE) tumour tissues from MPM patients who underwent EPP and had sufficient tumour for RNA extraction, a series which had been previously used to assess the prognostic value of the NLR. MicroRNA microarray profiling was performed on RNA from the 8 patients with longest (median: 53.7 months) and the 8 patients with shortest (median: 6.4 months) survival. Candidate microRNAs were selected on a basis of biological (>2-fold difference) and statistical (p<0.05) significance, and selected candidates were independently validated in the initial profiling samples using TaqMan assay-based microRNA-specific RT-qPCR. Levels of validated candidates were then assessed by RT-qPCR in 44 additional tumour samples. Overall survival (OS) was calculated from date of EPP and date of death or last follow-up, with patients still alive at last follow-up censored. The median relative expression level of each candidate was used as cut-off to determine high and low expression for examination using the Kaplan-Meier method. Individually significant (p<0.05) variables were entered into a multivariate model together with the established risk factors age, gender, histological subtype, NLR.Results
Microarray profiling identified 12 microRNAs with lower expression in long-term survivors and 4 microRNAs with higher expression in long-term survivors. None of the microRNAs with higher expression in long-term survivors could be validated using RT-qPCR. Of the microRNAs with lower expression in long-term survivors, miRs-30e, -93, -106b, -210, and -222 were validated by RT-qPCR in the same samples used for the profiling and found to be significantly different between long-term and short-term survivors. The expression levels of miR-30e and miR-210 showed a significant association with survival. MiR-30e: median OS of 24.2 months for low expression vs 13.3 months for high expression (p=0.03); miR-210: median OS of 24.2 months for low expression vs 13.7 months for high expression (p=0.008). In addition, both gender and histological subtype were significant prognostic factors using a univariate model. Multivariate analysis with age, gender, histological subtype, NLR and microRNA expression included as variables revealed that miR-210 was the only factor remaining significant (p= 0.006; hazard ratio: 0.41; 95% CI: 0.2-0.85).Conclusion
This study has identified expression of miR-210 as a potential new prognostic factor for patients undergoing EPP. Further validation is needed, but this marker has the potential to assist in better selection of patients considered for radical surgery of MPM.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO14.08 - Validation of a stage-independent pre-operative risk assessment algorithm for patients considering surgery for malignant pleural mesothelioma. (ID 2906)
11:15 - 11:20 | Author(s): W. Richards, R.R. Gill, B.Y. Yeap, R. Bueno, D.J. Sugarbaker
- Abstract
- Presentation
Background
We previously introduced a 3-level risk assessment algorithm based on tumor volume, gender and hemoglobin level (JTO 6:S486-7). Its applicability was limited to patients with epithelial disease undergoing surgery. We now report an expanded 4-level risk algorithm incorporating histologic subtype determined by pleural biopsy and interlobar septum thickness as additional predictors. We test its ability to stratify outcome among patients treated on a prospective phase I trial (protocol 07-091) of primary surgery and hyperthermic intraoperative intracavitary cisplatin plus dose-escalated gemcitabine.Methods
All patients who underwent primary extrapleural pneumonectomy (EPP) or pleurectomy (PDC) between 2001-2012 with preoperative CT scan available for retrospective review were included. Patients enrolled on 07-091 were reserved for validation; the remaining patients were used to train the model. Maximal thickness among measurable interlobar septae was measured on CT and binned into 2 categories (≤5mm, >5mm). Kaplan-Meier estimates of overall survival functions were used to define risk strata. Cox regression was used to assess algorithm stratification of overall survival and time to recurrence.Results
The model cohort comprised 308 patients (221 EPP, 87 PDC; 241 male; 244 epithelial histology on biopsy; median age 63). The validation cohort comprised 90 patients (53 EPP, 37 PDC; 70 male; 53 epithelial histology on biopsy; median age 66). Alignment of survival functions after stratification of 3-level risk by septum thickness and biopsy histology in the model cohort suggested 4 risk strata (A-D). The expanded algorithm stratified both model and validation cohorts into balanced groups with distinct overall survival and time to recurrence (Table).Overall Survival Time to recurrence N median HR 95% C.I. median HR 95% C.I. Model risk A 82 40 mo 1.0 23 mo 1.0 risk B 90 19 mo 2.1 (1.5-3.1) 9 mo 2.3 (1.6-3.2) risk C 87 12 mo 3.5 (2.4-5.1) 7 mo 3.3 (2.4-4.7) risk D 49 6 mo 8.7 (5.7-13.3) 3 mo 9.3 (6.1-14.1) Validation risk A 21 NR 1.0 21 mo 1.0 risk B 26 30 mo 2.3 (0.9-6.0) 13 mo 1.4 (0.7-2.9) risk C 29 15 mo 5.2 (2.1-12.8) 10 mo 4.0 (1.9-8.1) risk D 14 9 mo 19.6 (6.8-55.6) 4 mo 9.0 (3.9-20.8) Conclusion
This expanded risk stratification algorithm is based on information available preoperatively for the majority of patients with pleural mesothelioma being considered for surgical resection. It provides important prognostic information that is not reflected in conventional clinical stage regarding the risks and potential benefits of aggressive management for individual patients.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO14.09 - 5-year experience with accelerated induction hypofractionated hemithoracic intensity modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) (ID 2022)
11:20 - 11:25 | Author(s): M. De Perrot, O. Mercier, R. Feld, N. Leighl, T. Waddell, A. Hope, K. Yasufuku, S. Keshavjee, B.C.J. Cho
- Abstract
- Presentation
Background
Our experience in tri-modality therapy for MPM with induction chemotherapy followed by EPP and high dose hemithoracic radiation demonstrated that completion of EPP and radiation provided the best results. We therefore developed a new protocol of accelerated induction hypofractionated hemithoracic IMRT followed by EPP to deliver optimal radiation to the whole tumor bed in a short period of time. EPP is performed approximately one week after completion of radiation to limit the risk of pneumonitis. The results of Surgery for Mesothelioma After Radiation Therapy (SMART) was reviewed and compared to our previous cohort of patients undergoing induction chemotherapy followed by EPP and adjuvant hemithoracic radiation.Methods
All patients undergoing EPP in our institution between 01/2001 and 06/2013 were reviewed. The SMART protocol (25 Gy in 5 daily fractions over 1 week delivered to the entire ipsilateral hemithorax by IMRT with concomitant boost of 5 Gy to volumes at high risk based on CT and PET scan findings) was started in 2008. EPP was performed 6±2 days after radiation therapy. The results of the SMART protocol were compared to the group of patients undergoing induction chemotherapy followed by EPP as part of a trimodality approach.Results
A total of 111 patients underwent EPP between 01/2001 and 06/2013 with a hospital mortality of 4.5% (n=5). A total of 64 patients (81% men, 59±9 years old, 81% with epithelial histologic subtype) underwent induction chemotherapy, while 39 (82% men, 62±9 years old, 69% with epithelial histologic subtype) underwent SMART. Seven patients had no induction therapy and one had pre-operative chemo- and radiation therapy. Since 2008, the number of surgical patients undergoing SMART progressively increased from 14% in 2008 to 100% in 2013. None of the patients undergoing SMART died in hospital or within 30 days of surgery, while 4 of the 64 patients (6.4%) undergoing induction chemotherapy died in hospital after EPP (p=0.1). Patients undergoing SMART tended to have a greater proportion of ypN2 disease on final pathology than patients completing induction chemotherapy before EPP (58% vs 41%, respectively; p=0.09). After a median follow-up of 16 months after the start of therapy, the 3-year survival was significantly better in patients with epithelial disease undergoing SMART (n=27) compared to patients with epithelial disease undergoing induction chemotherapy and EPP (n=52) (79% 3-year survival vs 30% 3-year survival, respectively; p=0.04). In contrast, the 3-year survival of patients with biphasic disease was similar between patients undergoing SMART (n=12) or induction chemotherapy and EPP (n=12) (20% vs 8%, respectively; p=0.8). Multivariate survival analysis using Cox regression model demonstrated that epithelial histologic subtype (p=0.0003), the absence of ypN2 disease (p=0.007) and SMART (p=0.03) were predictors of better survival.Conclusion
Over the past 5 years, accelerated hemithoracic IMRT followed by EPP has become our preferred approach for surgically resectable MPM. Surgery for mesothelioma after radiation therapy was feasible with no operative mortality in 39 patients. Although comparison with our historical cohort of patients has limitations, our current protocol provides very encouraging results in patients with epithelial disease with a 3 year survival of 79%.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO14.11 - Safety of hemithoracic pleural intensity-modulated radiation therapy (IMRT) for malignant pleural mesothelioma (MPM) in the multimodality setting: interim analysis of a phase II study. (ID 2802)
11:25 - 11:30 | Author(s): A.J. Wu, M.G. Zauderer, D. Gomez, K.E. Rosenzweig, A. Foster, E. Yorke, D. Rice, A. Tsao, V.W. Rusch, L.M. Krug, A. Rimner
- Abstract
- Presentation
Background
Pleurectomy/decortication (P/D) is increasingly used for the surgical management of MPM. The presence of the remaining ipsilateral lung poses a challenge when delivering adjuvant radiation therapy, as the risk for radiation pneumonitis (RP) is high. We developed an IMRT technique targeting the entire pleura of the involved hemithorax, with promising early results. Here, we present the interim results of a prospective phase II study to determine the safety and toxicity profile of pleural IMRT following induction chemotherapy and P/D.Methods
Twenty-nine patients with locally advanced MPM have been enrolled to date. All patients received up to four cycles of pemetrexed/platinum chemotherapy. P/D was performed for all resectable patients. Sequential hemithoracic pleural IMRT was then administered with the intent of achieving a total planned dose of 50.4Gy in 28 fractions, as previously described (Rosenzweig et al., IJROBP 2012). All patients were simulated with a 4D-CT scan. A PET scan for image fusion and radiation planning was available for all patients. A Simon two-stage design was applied. A safety analysis after the first 9 patients led to the identification of only one case with ≥grade 3 RP in the first 3 months. The cohort was therefore expanded to 28 evaluable patients, defined as having initiated RT. The primary endpoint is the incidence of ≥grade 3 RP defined per Common Terminology Criteria for Adverse Events, v4.0. Steroids are typically initiated for ≥grade 2 RP.Results
To date, 21 out of 29 patients total are evaluable. The median follow-up is 10 months. The median age at diagnosis is 66 years (range 38-79). Median KPS was 90% (range 70-90%). Three patients had sarcomatoid, 3 had biphasic and 23 had epithelioid MPM. All patients received chemotherapy. Eight patients (28%) had a partial response, nine patients (38%) progressed, and all others had stable disease. Twenty-four patients (83%) underwent surgical exploration. Five patients underwent an extended P/D or P/D, 11 had a partial P/D, and 8 were found to be unresectable. Eight patients were removed from the study prior to receiving IMRT (7 due to disease progression and 1 due to grade 4 pulmonary embolism after one cycle of chemotherapy). To date, nineteen patients have completed IMRT [median dose 4680cGy (range 4500 to 5040cGy)]; one patient had distant disease progression after 16 fractions; one patient is currently on treatment. Five patients experienced grade 2 RP that was successfully controlled with steroids. One patient experienced grade 3 RP requiring supplemental oxygen, but quickly improved after steroid initiation. Other commonly observed ≥grade 2 radiation-related toxicities included fatigue (37%), dyspnea (47%), nausea (42%), esophagitis (26%), and cough (11%). No grade 4 or 5 radiation-related toxicities were observed.Conclusion
Hemithoracic pleural IMRT appears to have an acceptable toxicity profile in this ongoing phase II study. Early intervention with steroids is effective in controlling RP. This novel radiation technique has great promise as a component of lung-sparing multi-modality therapy in locally advanced MPM.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO14.12 - Neoadjuvant Hemithoracic Intensity Modulated Radiotherapy: The "SMART" Approach for Managing Malignant Pleural Mesothelioma (ID 2328)
11:30 - 11:35 | Author(s): J. Cho, A. Hope, A. Bezjak, A. Brade, M. Giuliani, A. Sun, E.P. Saibishkumar, M. De Perrot
- Abstract
- Presentation
Background
Management of malignant pleural mesothelioma (MPM) remains controversial. After extra-pleural pneumonectomy (EPP) and adjuvant radiotherapy, many fail distantly (peritoneal cavity, contralateral lung), possibly due to inadvertent tumour spillage at time of EPP. We hypothesize that neoadjuvant radiation followed by planned imminent EPP can limit the proliferation of clonogens spilt intraoperatively. The radiotherapy technique developed for the Surgery for Mesothelioma After Radiation Therapy (SMART) study is described.Methods
We conducted a phase II prospective REB approved single cohort clinical feasibility study on surgically resectable stage T1-3N0M0 MPM. The pre-operative clinical target volume (CTV) was defined as the ipsilateral hemithorax, , including biopsy and drainage tract sites. The gross tumour volume (GTV) was defined as any tumour seen on imaging. The dose prescription to the CTV was 25 Gy in 5 daily fractions over approximately 1 week with a concomitant boost of 5 Gy to the GTV and tract sites. All patients underwent EPP within 1 week of completing the neoadjuvant RT. If ypN2 found, patients were offered adjuvant chemotherapy. Treatment related toxicity was defined by the CTCAE v3.Results
The accrual goal of 25 patients was completed between Nov 2008 and Oct 2012. All completed their intended RT and EPP. IMRT was well tolerated with only grade 1-2 toxicities noted (fatigue, nausea, and esophagitis). EPP was performed 6±2 days after completion of IMRT. Dosimetric values are shown in the table below.Dosimetric Parameter dose max (cGy) 3290.5 CTV>2750 cGy (%) 95.5 CTV>2300 cGy (%) 97.8 PTV>2750 cGy (%) 93.3 PTV>2300 cGy (%) 91.7 LUNG>700 cGy 4.9 LUNG mean (cGy) 315.0 LIVER>1400 cGy (%) 45.3 LIVER mean (cGy) 1371.8 HEART>1400 cGy (%) 50.3 HEART mean (cGy) 1473.7 contra KIDNEY>750 cGy (%) 19.6 contra KIDNEY mean (cGy) 318.1 ipsi KIDNEY>750 cGy (%) 49.5 ipsi KIDNEY mean (cGy) 561.6 ESOPHAGUS 2880.1 CANAL max (cGy) 2026.1 prv3mmCANAL max (cGy) 2125.4 Conclusion
Short neoadjuvant hemithoracic radiotherapy (30 Gy in 5 daily fractions over 1 week) using the SMART protocol constraints are well tolerated. The SMART protocol is technically demanding, requiring very close and careful coordination and planning between the multiple disciplines.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO14.13 - DISCUSSANT (ID 3971)
11:35 - 11:50 | Author(s): M.M. Tin
- Abstract
- Presentation
Abstract not provided
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Author of
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MO14 - Mesothelioma II - Surgery and Multimodality (ID 121)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Mesothelioma
- Presentations: 2
- Moderators:E. Lim, B. McCaughan
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside Gallery B, Level 1
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MO14.06 - DISCUSSANT (ID 3969)
10:55 - 11:10 | Author(s): B. McCaughan
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO14.07 - Elevated tumour expression of miR-210 is associated with short survival in malignant pleural mesothelioma patients undergoing extrapleural pneumonectomy (ID 1491)
11:10 - 11:15 | Author(s): B. McCaughan
- Abstract
- Presentation
Background
Malignant pleural mesothelioma (MPM) is an aggressive cancer with a median survival of around one year and a 5 year survival rate of less than 10%. A selected group of patients with a potentially resectable tumour mass and good performance status may be considered for extrapleural pneumonectomy (EPP). However the results of this form of treatment are variable. Several prognostic markers have been explored to assist with patient selection including histological subtype, neutrophil-to-lymphocyte ratio (NLR), calretinin and microRNA miR-29c* expression in tumour tissue. In the present study we used microarray profiling to identify other microRNAs which might have the potential to serve as a prognostic biomarker.Methods
The study used 60 formalin-fixed paraffin embedded (FFPE) tumour tissues from MPM patients who underwent EPP and had sufficient tumour for RNA extraction, a series which had been previously used to assess the prognostic value of the NLR. MicroRNA microarray profiling was performed on RNA from the 8 patients with longest (median: 53.7 months) and the 8 patients with shortest (median: 6.4 months) survival. Candidate microRNAs were selected on a basis of biological (>2-fold difference) and statistical (p<0.05) significance, and selected candidates were independently validated in the initial profiling samples using TaqMan assay-based microRNA-specific RT-qPCR. Levels of validated candidates were then assessed by RT-qPCR in 44 additional tumour samples. Overall survival (OS) was calculated from date of EPP and date of death or last follow-up, with patients still alive at last follow-up censored. The median relative expression level of each candidate was used as cut-off to determine high and low expression for examination using the Kaplan-Meier method. Individually significant (p<0.05) variables were entered into a multivariate model together with the established risk factors age, gender, histological subtype, NLR.Results
Microarray profiling identified 12 microRNAs with lower expression in long-term survivors and 4 microRNAs with higher expression in long-term survivors. None of the microRNAs with higher expression in long-term survivors could be validated using RT-qPCR. Of the microRNAs with lower expression in long-term survivors, miRs-30e, -93, -106b, -210, and -222 were validated by RT-qPCR in the same samples used for the profiling and found to be significantly different between long-term and short-term survivors. The expression levels of miR-30e and miR-210 showed a significant association with survival. MiR-30e: median OS of 24.2 months for low expression vs 13.3 months for high expression (p=0.03); miR-210: median OS of 24.2 months for low expression vs 13.7 months for high expression (p=0.008). In addition, both gender and histological subtype were significant prognostic factors using a univariate model. Multivariate analysis with age, gender, histological subtype, NLR and microRNA expression included as variables revealed that miR-210 was the only factor remaining significant (p= 0.006; hazard ratio: 0.41; 95% CI: 0.2-0.85).Conclusion
This study has identified expression of miR-210 as a potential new prognostic factor for patients undergoing EPP. Further validation is needed, but this marker has the potential to assist in better selection of patients considered for radical surgery of MPM.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 2
- Moderators:
- Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P2.06-011 - Phosphorylated-Akt expression is a prognostic marker in early stage non-small cell lung cancer (NSCLC) (ID 1151)
09:30 - 09:30 | Author(s): B. McCaughan
- Abstract
Background
The 5-year survival for stage IB non-small cell lung cancer (NSCLC) is only 55%, but the benefit of adjuvant chemotherapy in this setting remains equivocal. Numerous prognostic markers have been examined, but none to date have moved into clinical practice. There is an urgent need to identify novel molecular markers that can select high risk patients, who may potentially benefit from adjuvant chemotherapy.Methods
We identified 471 consecutive patients with stage IB primary NSCLC according to the American Joint Commission on Cancer, (AJCC) 6[th] edition tumour-node-metastasis staging system, who underwent surgical resection between 1990 and 2008. Patients who received neoadjuvant or adjuvant treatments were excluded. Pathology reports were reviewed and pathologic characteristics were extracted. Expression of phosphorylated Akt (pAkt) in both cytoplasmic and nuclear locations was assessed by immunohistochemistry, and clinicopathologic factors were analyzed against 10-year overall survival using Kaplan-Meier and Cox proportional hazards model.Results
455 (96.6%) cancers were adequate for pAkt immunohistochemical analysis. The prevalence of pAkt expression in the cytoplasm and nucleus of the cancers was 60.7% and 43.7% respectively. Patients, whose cancers expressed higher levels of pAkt in the cytoplasm, had a trend towards longer overall survival than those with lower levels of cytoplasmic pAkt (p=0.06). Conversely, patients whose cancers expressed higher levels of pAkt in the nucleus had a poorer prognosis than those with lower levels of nuclear pAkt expression (p=0.02). Combined low cytoplasmic/high nuclear expression of pAkt was an independent predictor of overall survival [HR=2.86 (95% CI:1.35-6.04); p=0.006] when modeled with age [HR= 1.05 (95% CI: 1.03-1.07); p<0.001], extent of operation [HR= 2.11 (95% CI: 1.48-3.01); p<0.001], visceral pleural invasion [HR=1.63 (95% CI: 1.24-2.15); p<0.001], gender, tumour size, histopathologic type and grade (p>0.05).Conclusion
Levels of expression of pAkt in the cytoplasm and nucleus and visceral pleural invasion are independent prognostic factors that can help to select patients with high risk disease, who may potentially benefit from adjuvant chemotherapy. -
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P2.06-017 - Long non coding RNAs (lncRNAs) are dysregulated in malignant pleural mesothelioma (MPM) (ID 1524)
09:30 - 09:30 | Author(s): B. McCaughan
- Abstract
Background
Malignant Pleural Mesothelioma (MPM) is an aggressive disease, often diagnosed at an advanced stage. It is characterized by a long latency period and prior asbestos exposure. Currently accurate diagnosis of MPM is difficult due to the lack of sensitive biomarkers, and despite minor improvements in treatment, median survival rates rarely exceed 12 months. Accumulating evidence suggests that aberrant expression of long non-coding RNAs (lncRNAs) plays an important functional role in cancer biology. LncRNAs are a class of recently discovered non-protein coding RNAs >200 nucleotides in length with a role in regulating transcription. The aims of this study were to characterize the expression and function of these lncRNAs in MPM.Methods
To identify novel lncRNAs involved in MPM, microarray profiling was performed on five cell lines - the immortalized normal mesothelial cell line (MeT-5A) and four MPM lines (two epithelioid H28 and H226 and two biphasic MM05 and MSTO) using Invitrogen’s NCode lncRNA microarrays. These allow simultaneous assessment of mRNA and lncRNA content. High priority candidate lncRNAs were selected on the basis of statistical (P<0.05) and biological (>3-fold difference) significance. Expression of high priority candidates were technically validated using RT-qPCR, and biologically validated in three independent test sets. Pathway analyses were performed to interrogate the relationship between lncRNA and mRNA expression. Cell proliferation and colony formation assays were used to investigate lncRNA function.Results
Microarray profiling and real-time qPCR validation identified 9 lncRNA candidates with significant differential expression in MPM compared with normal mesothelial cells Validation in three independent test sets by RT-qPCR analysis demonstrated consistent up-regulation of four of these lncRNAs. Receiver Operating Curve analysis showed that two of these candidates were able to separate benign pleura and MPM with high sensitivity and specificity. In addition, high expression of AK054908 was associated with nodal metastases with lower levels of AK130275 and AF268386 observed in patients receiving induction chemotherapy. Cases with higher EF177379 levels also demonstrated a trend to improved survival. The majority of mRNAs co-expressed with candidate lncRNAs were associated with cellular and metabolic processes including cell cycle, cell death and apoptosis. In functional studies, siRNA knockdown of AK130275 showed suppression of cell growth and colony formation in MPM cells with moderate changes observed following knockdown of EF177379.Conclusion
To our knowledge this is the first systematic study of lncRNA expression profiles in MPM. We have found that lncRNA expression profiles can distinguish malignant mesothelium from normal pleural tissue, and that some lncRNAs are associated with nodal metastasis and long term survival. We also demonstrate that lncRNAs have potential prognostic and diagnostic utility with functional roles in regulating cell growth. Further work is required to evaluate whether these lncRNAs are capable of differentiating mesothelioma from lung cancer and benign asbestos-related diseases, and to reveal their specific functions in MPM pathogenesis.
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P3.01 - Poster Session 3 - Cancer Biology (ID 147)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.01-008 - The importance of the Secreted Frizzled-Related Protein (SFRP) tumour suppressor gene family and the effect of long-term asbestos exposure on SFRP expression in malignant pleural mesothelioma (MPM) (ID 3495)
09:30 - 09:30 | Author(s): B. McCaughan
- Abstract
Background
The etiology of malignant pleural mesothelioma (MPM) is closely linked with asbestos exposure. Asbestos is capable of inducing chronic inflammation which potentiates tumour suppressor gene silencing. Epigenetic silencing of the Wnt pathway, well characterized in the progression of colon cancer, is associated with chronic inflammation. As antagonists of Wnt pathways, the SFRPs are functional tumour suppressors of colon, gastric, breast, ovarian and lung cancers, with some members methylated in mesothelioma. In this study, we aimed to investigate the functional significance of the SFRP2 and 5 in MPM, and the effect of long-term asbestos exposure on epigenetic alteration in the immortalised mesothelial cell MeT-5A.Methods
Gene expression and promoter DNA methylation of the SFRP family were analysed in MPM lines and MeT-5A with and without 5’Azacitidine treatment using RT-qPCR, MSP and COBRA. The effect of SFRP2 and SFRP5 re-expression on MPM cells was determined by cell growth and clonogenic assays in 2D and 3D culture. The expression and promoter DNA methylation of SFRP genes was also assessed in MPM patient samples using RT-qPCR and MSP. MeT-5A cells were cultured long-term (12 months) in the presence of asbestos, and SFRP mRNA expression and promoter DNA methylation was analysed.Results
SFRP2 and SFRP5 were either absent or down-regulated MPM lines, and restored after 5’Azacitidine treatment. SFRP1 was highly expressed and unmethylated in MeT-5A line. Expression of the SFRP family was down-regulated in MPM patient samples and this correlated with methylation of promoter CpG islands. Ectopic expression of SFRP2 or SFRP5 inhibited MPM cell growth and colony formation in both 2D and 3D culture. SFRP1 was down-regulated and methylated following prolonged asbestos exposure in MeT-5A cells.Conclusion
Our results indicate that both SFRP2 and SFRP5 function as tumour suppressor genes in MPM and long-term asbestos exposure induce gene silencing via DNA hypermethylation.
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P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.06-017 - Distinctive Insulin-Like Growth Factor 1 gene copy number and protein expression in non-small cell lung cancer (ID 1753)
09:30 - 09:30 | Author(s): B. McCaughan
- Abstract
Background
The insulin-like growth factor (IGF) pathway is involved in the development and progression of many tumours and there is growing preclinical evidence that blockade of this pathway has anti-tumour effects in NSCLC. IGF receptors (IGFR) are another potential target for targeted treatment of NSCLC and a number of agents are already undergoing clinical trial. Biomarkers are needed to select patients most likely to derive clinical benefit from these agents. The downstream pathway components of IGF1R and MET activation include PI3K and AKT, which are other potential biomarkers currently being investigated in this patient cohort. IGF1R has also been implicated in acquired resistance to EGFR-TKI treatments. Only a few small retrospective studies have investigated the prognostic role of IGF1R in NSCLC and the relationship with EGFR mutations is not known.Methods
IGF1R status was evaluated by chromogenic silver in situ hybridization (ISH) and immunohistochemistry (IHC) in tissue microarray sections from a retrospective cohort of 264 surgically resected NSCLCs and results were compared to clinicopathological features and patient survival. Patients were classified as IGF1R gene amplification (either presence of tight gene clusters, IGF1R to CEN15 ratio ≥ 2, or ≥ 15 copies of IGF1R per cell in ≥ 10% of analysed cells); high polysomy (≥ 4 copies of IGF1R in ≥ 40% of tumour cells); low copy number (< 4 copies of IGF1R in < 40% of cells). Patients were also grouped as IGF1R-positve (amplification or high polysomy) or IGF1R-negative (low copy number).Results
High IGF1R gene copy number was identified in 77 cases (29.2%) in which there were 32 amplified IGF1R cases (12.1%) and 45 high-polysomy IGF1R cases (17%). Increased copy number of IGF1R was more common in squamous cell carcinomas (SCC) compared to large cell carcinomas (LCC) or adenocarcinomas (ADC) (p<0.05). There was no correlation between IGF1R gene copy number status and other clinicopathological features including patient age, gender, smoking status, tumour size, vessel, perineural or lymphatic invasion, grade or stage. IGF1R copy number alteration in primary tumours was highly correlated with IGF1R copy number status in metastatic tumours (p<0.01). High IGF1R protein expression was observed in 61/259 (23.6%) primary tumours and 14/215 (6.5%) normal adjacent bronchial mucosae. High expression of IGF1R protein was significantly associated with SCC in comparison with non-SCC primary tumours, as well as with lymphatic and vessel invasion. There was a moderate correlation between IGF1R copy number status (positive versus negative) and IGF1R protein expression (high versus low) (Cramer’s V=0.3, p-value <0.001). Both IGF1R copy number status and protein expression were not associated with patient overall survival in univariate analyses (p>0.05).Conclusion
High IGF1R gene copy number and its protein expression are frequent in NSCLC, particularly in SCC. However, alterations of IGF1R are not associated with patient prognosis. IGF1R gene copy number can readily be assessed in formalin fixed paraffin embedded tissue and warrants further investigation as a potential biomarker of targeted therapy in NSCLC.
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P3.14 - Poster Session 3 - Mesothelioma (ID 197)
- Event: WCLC 2013
- Type: Poster Session
- Track: Mesothelioma
- Presentations: 2
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.14-004 - Adjuvant Hemithoracic Radiotherapy After Extrapleural Pneumonectomy For Malignant Pleural Mesothelioma: Experience At The Sydney Cancer Centre (ID 1249)
09:30 - 09:30 | Author(s): B. McCaughan
- Abstract
Background
Radiotherapy reduces local recurrence following extrapleural pneumonectomy (EPP), and forms part of a potentially curative, multimodality treatment of malignant pleural mesothelioma. Hemithoracic radiotherapy poses a significant dosimetric challenge. Conventional techniques have suffered with marked dose uncertainty, while modern IMRT techniques have been associated with increased pulmonary toxicity. We conducted a retrospective review of all patients referred to our institution for hemithoracic radiotherapy following EPP, with the aim of assessing treatment toxicity and outcomes. The present study is, to our knowledge, the largest Australian series of adjuvant radiotherapy for this disease.Methods
53 patients were referred following EPP for malignant pleural mesothelioma, with or without neoadjuvant chemotherapy, between 2004 and 2012. 4 patients were excluded or did not commence radiotherapy due to poor performance (n = 3) or disease progression (n = 1). Radiotherapy involved a 3D conformal, mixed photon and electron technique, delivering 45-55 Gy in 25-28 fractions (2004-2009, n=31), and a 9-field IMRT technique, delivering 50.4-60 Gy in 28-30 fractions (2009-2012, n=18). We assessed toxicity, disease progression and survival in all patients who commenced radiotherapy (n = 49). Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0 and survival was calculated from the date of EPP using the Kaplan-Meier method.Results
31 patients (59%) received neoadjuvant chemotherapy, with a combination of platinum agent and pemetrexed. 41 patients (84%) completed treatment as prescribed. 6 patients stopped prematurely due to toxicity, and 2 due to disease progression. Most patients discontinuing due to toxicity (n = 5) received over 90% of the prescribed dose. Low grade nausea, anorexia and fatigue were near universal, however severe (grade 3) skin toxicity, nausea and oesophagitis were 8%, 6% and 2%, respectively. One patient developed a grade 4 Pneumocystis carinii infection, however there were no cases of radiation pneumonitis. Late toxicities were rare, with the exception of a persistent elevation in the liver enzymes alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT). Of the patients treated with right-sided disease (n = 26), 9 (35%) developed grade 2-3 elevations in ALP or GGT. Grade 2-3 liver toxicity was more common in patients treated with a conventional technique (53%) than with IMRT (11%). No patients developed clinical hepatitis. With a median follow up of 19 months (range 2-102 months), median progression-free survival and overall survival were 22 and 30 months, respectively. 2-year overall survival was 53.8%. 7 patients (14%) were alive beyond 5 years.Conclusion
Hemithoracic radiotherapy can be safely delivered in selected patients following EPP. Although associated with significant early toxicity, most patients complete treatment and late toxicity is uncommon. Our outcomes compare favourably with recently-published international series. -
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P3.14-013 - Longitudinal Observation of Health Related Quality of Life following Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma (ID 3159)
09:30 - 09:30 | Author(s): B. McCaughan
- Abstract
Background
The aim of this study was to describe the longitudinal picture of Health Related Quality of Life (HQOL) in people with Malignant Pleural Mesothelioma (MPM) post Extrapleural Pneumonectomy (EPP).Methods
Participants receiving EPP from 2011- 2013 were assessed pre-operatively, pre and post adjuvant radiotherapy (Rt), and at 8, 12 and 24 months following surgery. Here we report Global HQOL and HQOL Domain Scores of the EORTC QLQ-C30, and Fatigue Scores from FACT-F. Least squares means were obtained from a mixed models analysis with time as a fixed effect, the pre-op assessment as a covariate and a random subject effect.Results
Twelve men with a mean age of 65 years (range 48-78) completed pre-op and at least one post op assessment. Table 1 and Figure 1 report the mean HQOL domain scores, global HQOL and fatigue at baseline as well as the least squares mean and 95% confidence intervals at each follow up assessment. Table 1. Health related quality of life over time Figure 1 Figure 2 Figure 1: Health related quality of life over time These results suggest that people who elect to have EPP have baseline levels of HQOL comparable to the general population. As expected, HQOL declines after surgery and during adjuvant radiotherapy. Emotional functioning changes least, while physical and social functioning closely mirror each other. Role functioning is the domain most affected and remains low out to 24 months. Global HQOL is relatively stable over time, with an apparent increase at 24 months. Fatigue is worst at the conclusion of radiotherapy and gradually improves.Conclusion
People electing to have EPP report a sudden decline in HQOL, with the nadir around the end of adjuvant radiotherapy. This gradually improves over time, returning to slightly below baseline in many domains.
