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E. Lim
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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 - 12:00 | 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)
10:30 - 12:00 | 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)
10:30 - 12:00 | 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)
10:30 - 12:00 | 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)
10:30 - 12:00 | 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)
10:30 - 12:00 | 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)
10:30 - 12:00 | 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)
10:30 - 12:00 | 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)
10:30 - 12:00 | 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)
10:30 - 12:00 | 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)
10:30 - 12:00 | Author(s): M.M. Tin
- Abstract
- Presentation
Abstract not provided
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MS16 - ESTS/IASLC Thymic Session (ID 33)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Thymoma & Other Thoracic Malignancies
- Presentations: 5
- Moderators:P. Goldstraw, E. Lim
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Gallery A, Level 1
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MS16.1 - Pathological Classification of Thymic Tumours in the Molecular Age: Proposals for the Next WHO Classification (ID 530)
10:30 - 12:00 | Author(s): W.D. Travis
- Abstract
- Presentation
Abstract
Thymomas are epithelial neoplasms arising in the thymus with a spectrum of morphology, genetic characteristics and clinical behavior. Thymomas are composed of a mixture of neoplastic epithelial cells and non-neoplastic T lymphocytes, admixed in varying proportions. Much of the controversy about classification of thymic epithelial tumors can be attributed to confusion about differences in histologic classification versus grading. While genetic studies have provided some insights into the biology of these tumors and classification, a major hurdle is how to identify molecular abnormalities specific to the epithelial cells of B1 and B2 tumors because the genetic findings are dominated by the numerous lymphocytes in the tumor stroma. Thymic epithelial tumors are classified into thymomas and thymic carcinomas according to the 2004 World Health Organization (WHO). Thymomas are classified into Type A and Type B tumors with the latter being divided into B1, B2 and B3 with an increasing percentage and degree of atypia of epithelial cells and decreasing numbers of lymphocytes. THYMOMA Type A thymoma, is composed of bland spindle or oval shaped and few lymphocytes. Type AB thymoma, , is composed of two components, one resembling the type A thymoma and one with plump cells and predominant lymphocytic infiltrate. Type B1 thymoma, is composed of a prominent lymphocyte population with a minor component of epithelial tumor cells with vesicular nuclei and small nucleoli. Type B2 thymoma, is a thymoma with relatively even mixtures of lymphocytes and plump epithelial cells with vesicular nuclei. Type B3, is predominantly composed of polygonal or round epithelial cells with mild atypia. This category shows variable degree of cytologic atypia. THYMIC CARCINOMA Thymic carcinoma was previously classified as Type C thymoma, but in the 2004 classification this term was dropped. These tumors show much greater degree of cytologic atypia than thymoma. CLASSIFICATION ISSUES Histologic heterogeneity is common, with more than one histologic subtype frequently present in a given tumor, making histologic subclassification difficult. The clinical relevance of the WHO classification system has been validated by many studies. In general the classification from type A to AB, B1, B2 and B3, then thymic carcinoma represent an increasing histologic grade that corresponds to increasing aggressiveness of clinical behavior. Increasing molecular alterations are also found along this spectrum from A to B3 thymoma and thymic carcinoma. Thymic epithelial cells stain for epithelial markers such as keratin and squamous markers such as p63 or p40 while thymic lymphocytes stain for T-cell markers such as TdT and CD3. Type A thymomas tend to have fewer immature (CD1a+) lymphocytes and more mature (CD1a-) lymphocytes, while the type B thymomas have many CD1a+ lymphocytes. PAX8 has been reported to be positive in tumor cells of thymomas. Confusion between histologic classification and grading has led to proposals to collapse the classification into a smaller number of entities. One meta-analysis suggested that the current WHO classification scheme of thymomas could be simplified into three types with significant prognostic value: A/AB/B1, B2, and B3. However, what these authors propose is more of a grading system based on clinical behavior rather than histologic typing. The proposal suggests combining two tumors that are completely different morphologically and genetically (type A and B1) both of which are low grade tumors with indolent clinical behavior. Genetic studies have shown distinct gene expression profiles that support the WHO subclassification of thymomas, as far as the subdivision in type A and B thymomas is concerned. Type AB thymomas are genetically heterogeneous, being more closely related to type B thymomas. Expression of the autoimmune regulator AIRE is lost in approximately 95% of thymomas. Genetic alterations in thymomas are most frequent on chromosome 6p23.3 (major histocompatibility complex locus) and 6q25.2 to 25.3. Thymic carcinoma has a distinctive morphology and biology. It is composed of highly atypical cells with cytoarchitectural features of carcinoma similar to those seen in other organs. Although many lymphocytes can be seen in its stroma, they are of B cell type and mature T cell type. Thymic carcinoma lacks the immature T cell lymphocytes that are present in thymoma. Thymic carcinomas are cytologically malignant.{Travis, 2004 #21463} While a certain amount of necrosis, atypia, and mitoses can be encountered in occasional epithelial thymomas, these findings are common in thymic carcinomas. An infiltrative growth pattern associated with desmoplastic stroma is often seen, without evidence of immature T lymphocytes. Thymic carcinomas display a variety of histologic subtypes, emphasizing the ability of thymic epithelium to differentiate toward different cells: squamous cell carcinoma, basaloid carcinoma, mucoepidermoid carcinoma, lymphoepithelial-like carcinoma, sarcomatoid carcinoma, clear cell carcinoma, adenocarcinoma, and NUT carcinoma with t(15:19) translocation. Several immunohistochemical studies have been employed in an attempt to confirm the diagnosis of thymic carcinoma. Several studies have found that CD5 will stain the epithelial cells of some thymic carcinomas. C-kit (CD117) also frequently stains thymic carcinomas. However, neither of these markers are found in all thymic carcinomas and uncommonly they can be positive in B3 thymomas or carcinomas from other sites such as the lung. Comprehensive genomic analysis using comparative genomic hybridization has shown thymic carcinomas are molecularly distinct from thymomas and squamous cell carcinomas of the lung. While c-Kit expression is common in thymic carcinomas mutations are rare. Despite multiple trials of molecular targeted therapies for the EGFR pathway, angiogenesis inhibition, c-kit pathway, histone deacetylase inhibition, octreotide, an IGF-1 receptor pathway, there are no validated targeted therapies that can be recommended at this time. With some of these approaches in early therapeutic trials, and active molecular investigation of these rare tumors, hopefully, in the near future, new treatment options for patients with advanced disease will become available. So far, molecular studies have provided useful insights into the histologic subtypes of thymic epithelial tumors and provide genetic validation of the existing classification, but they have not demonstrated superiority over morphology in classifying these tumors. Hopefully molecular markers can be identified that will aid in refining the existing classification or in separating the existing subtypes.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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MS16.2 - Towards a TNM-Based Prognostic Classification for Thymic Tumours (ID 531)
10:30 - 12:00 | Author(s): F. Detterbeck
- Abstract
- Presentation
Abstract
There are many impediments to achieving scientific progress in thymic malignancies, starting with the fact that these are relatively rare tumors. Another problem is the fact that there is no official stage classification system. At least 15 different systems have been proposed, all of which have been based on a limited number of patients, and none of which has been universally adopted with clear definitions that are consistently interpreted. This lack of a common basic language is a crucial fundamental building block for scientific advancement. The International Thymic Malignancies Interest Group (ITMIG) is an academic organization devoted to promoting the scientific advancement in thymic and other mediastinal malignancies. ITMIG has partnered with IASLC to develop proposals to the AJCC/UICC for the 8[th] edition of the stage classification system. This process began in 2010 and is now in full swing. ITMIG has pulled together an international database of approximately 9,000 patients. This involves 77 centers and 16 countries, with a notable major contribution from the Japanese Association for Research in the Thymus (JART). This data, together with an additional approximately 1,800 patients provided by the ESTS have been made available to CRAB, the statistical center for IASLC stage classification analyses. The Thymic Domain of the Staging and Prognostic Factors Committee (SPFC) is currently analyzing this data. The committee is considering multiple factors, starting with an analysis of the prognostic value of the Masaoka and Masaoka-Koga stage classification systems. Subcommittees of the thymic domain are also looking specifically at T, N, M factors, the impact of tumor size, invasion into particular structures and clinical stage. Internal validation will be performed, considering treatment factors, clinical stage, histologic subtypes, geographic regions and taking into account both survival and recurrence. Potentially useful factors will be compared to assess the relative impact, and to select the best factors to propose for use in the 8[th] edition stage classification system.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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MS16.3 - Surgery for Thymic Tumours: Outcomes from the ESTS Data Base (ID 532)
10:30 - 12:00 | Author(s): E. Ruffini, D. Van Raemdonck, W. Weder, A. Brunelli, F. Detterbeck, P. Thomas
- Abstract
- Presentation
Abstract
Introduction: Thymic tumors are rare malignancies and most of the current literature is composed of single-institutional series collecting small number of patients spanned over short time periods. The European Society of Thoracic Surgeons (ESTS) thymic working group developed a retrospective database among its members collecting patients with thymic tumors submitted to surgical resection between 1990 and 2010. Methods: A total of 2151 patients were collected from 35 Institutions, including 1798 thymomas, 191 thymic carcinomas (TC), and 41 Neuroendocrine Thymic Tumors (NETT)). 1709 patients (89%) received a complete resection. Myasthenia Gravis (MG) was present in 629 patients (35%). Different clinical-pathologic characteristics were analyzed for their impact on survival and recurrence. Primary outcome was overall survival (OS); secondary outcomes were the proportion of incomplete resections, disease-free survival (DFS) and the cumulative incidence of recurrence (CIR). Results: Ten-year OS and DFS rates were 73% and 70%. The risk of mortality increased with age and with the stage. It also increased in the presence of TC, NETT and incomplete resection. Ten-year CIR was 12%. Predictors of incomplete resection included male gender, tumor size, the absence of MG, non-thymoma categories (TC and NETT) and high-risk thymomas (B2-B3). The risk of recurrence increased with tumor size, increased stage and NETT. Finally, our analysis indicates that the overall effect of adjuvant therapy after complete resection on OS was significantly beneficial (p=0.05) using a propensity score. Conclusions: Masaoka stages III-IV, incomplete resection and non-thymoma histology showed a significant impact in increasing recurrence and in worsening survival. The administration of adjuvant therapy after complete resection is associated with improved survival.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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MS16.4 - Chemotherapy for Thymic Tumours (ID 533)
10:30 - 12:00 | Author(s): N. Girard
- Abstract
- Presentation
Abstract
Thymic epithelial tumors represent a wide range of anatomical, clinical, histological, and molecular malignant entities, which may be aggressive and difficult to treat. The histopathological classification distinguishes thymomas from thymic carcinomas. Chemotherapy may be used in two clinical scenarios in thymic epithelial tumors: 1) chemotherapy may constitute primary part of the multimodal curative-intent treatment of locally-advanced tumors, and is subsequently combined with surgery or radiotherapy; the main objective is to achieve long-term survival with no evidence of tumor recurrence; 2) chemotherapy may be delivered as the sole treatment modality in unresectable, advanced, metastatic, or recurrent tumors; then a palliative-intent treatment, the aim is to improve tumor-related symptoms through achievement of tumor response, while no prolonged survival is expected. Several chemotherapy regimens have been used in the curative-intent setting, mostly consisting of adriamycin- and/or platin-based multi-agent combinations. Usually 2-4 cycles of chemotherapy are administered before imaging reassessment. Aiming at increasing the response rate to primary treatment, and thus complete resection rate, chemotherapy may be combined with radiotherapy; however, retrospective data available do not provide with interpretable figures to compare chemotherapy to chemo-radiotherapy in the pre-operative setting. Response rates to curative-intent chemotherapy ranged from 70% to 80% in the largest studies. Patients for whom R0 resection was thought to be feasible undergo surgery, and complete resection is achieved in about 50% of cases. Postoperative radiotherapy is then frequently delivered. When the patient is not deemed to be a surgical candidate - either because R0 resection is not thought to be achievable or because of poor performance status or co-existent medical condition, definite radiotherapy, as reported above, is delivered. If radiotherapy is not feasible, either because of a large tumor burden that precludes safe delivery of appropriate doses or because of co-morbidities increasing the risks of radiation-induced toxicity, treatment is chemotherapy alone, in a strategy that may ultimately be considered palliative. In the reported literature, 10-21% of patients with locally-advanced thymic tumors receiving upfront chemotherapy did not receive either surgery or radiation therapy or other local treatment. Survival of these patients is frequently limited. Overall, the major challenge in interpreting data about pre-operative chemotherapy in thymic malignancies is the wide variation in the number of patients subsequently treated with surgery, radiotherapy, or chemotherapy alone, which suggests significant heterogeneity in the inclusion criteria among series. Response has been evaluated based on elusive criteria in some studies published before CT scan was largely available. In most studies, thymomas and thymic carcinomas, as well as newly diagnosed and recurrent tumors, were not analyzed separately. Ultimately, the majority of studies are retrospective, with uncontrolled design. Finally, one should consider the potential effect of corticosteroids, that have been known for a long time to have a “lympholytic” effect. Palliative chemotherapy is given as the sole treatment modality for thymic tumors, usually in the setting of stage IV, unresectable, recurrent disease. Prolonged disease control is possible, but tumor eradication is not expected. Several studies - both prospective and retrospective - described several regimens for definite chemotherapy, but because there are no randomized studies, it is unclear which are best; multi-agent combination regimens and anthracycline-based regimens appear to have improved response rates compared to others, especially the etoposide, ifosfamide and cisplatin combination. In general, combination regimen is recommended, for at least 3 and no more than 6 cycles. Overall, response rates are 20-40%, lower than that observed in the preoperative setting. Progression-free and overall survival of patients ranges from 12 to 66 months, and 37 to 72 months, respectively; such variability may be related to the various settings in which chemotherapy was delivered in those studies. In the palliative-intent setting, several consecutive lines of chemotherapy may be administered when the patient presents with tumor progression. It is estimated that 50-70% of patients with thymoma recurrence are eligible to chemotherapy. Strategy may consist of the re-administration of a previously effective regimen, especially in case of previous response, late occurring recurrence, and for anthracyclins, a patient in a good medical condition and not having received cumulative doses precluding the safe delivery of at least 3 additional cycles. In case of recurrence, the strategy may actually primarily consist of a similar multimodal management to that conducted at time of first diagnosis, with surgery and radiotherapy in eligible cases. Complete re-resection remains a major prognostic factor in this setting. In patients not eligible to receive additional chemotherapy, octreotide may represent a valuable option; as a single agent, octreotide produced objective tumor responses rates, and of more relevance in this setting, disease control rates. Novel treatment strategies are needed, especially for refractory, recurrent tumors, and thymic carcinomas, which carry a poor prognosis despite multimodal treatment. Potentially druggable targets are emerging, laying the foundations to implement personalized medicine for patients. Given the currently available targeted agents outside of a clinical trial, the signaling pathways that are relevant in the clinical care of patients, are the KIT and the Vascular Endothelial Growth Factor (VEGF)-R (Receptor) pathways. Promising new targets in thymoma and thymic carcinoma include IGF-1R and histone-deacetylase. Cixutumumab, an IGF1-R directed monoclonal antibody was recently reported to produce a promising 90%-disease control rate in refractory thymomas. Belinostat, a histone deacetylase inhibitor was evaluated in thymic malignancies in a recently completed phase II trial enrolling 41 patients (25 thymomas and 16 thymic carcinomas). Response and 2-year survival rates were 8% and 77% in thymomas. mTOR inhibitors, in the setting of phase I trials, have been reported to produce significant control rates in thymoma and thymic carcinoma. Along with the large variety of questions relative to the treatment strategy, thymic epithelial tumors represent a model of therapeutic implementation and achievement in orphan thoracic oncology, showing how the advent of new results induces new questions, as well as diversifies further clinical research directions; in this setting, regional and international collaborative initiatives are mandatory to progress both in the understanding of the biological mechanisms underlying the development of thymic malignancies, and in the identification and validation of new targets with prognostic and predictive value.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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MS16.5 - Radiotherapy for Thymic Tumours: Induction, Adjuvant and Definitive (ID 534)
10:30 - 12:00 | Author(s): R. Komaki
- Abstract
- Presentation
Abstract
Although the predominant approach in the treatment of thymoma and thymic carcinoma is surgery, radiation therapy also has an important role, either as postoperative therapy to reduce the risk of mediastinal recurrence or as part of definitive treatment for patients that who cannot undergo surgery. We present here a review of radiation therapy for thymic malignancies and briefly discuss the potential benefits from novel technologies for such treatment. Thymic carcinoma is a rare but more aggressive tumor which has a tendency to fail locally and distantly. Thymic carcinoma has more frequent EGFR and/or HER2 abnormalities compared to thymoma., and the outcome of thymic carcinoma is usually worse than invasive thymoma. Postoperative Radiation Therapy: Indications R0 (Completely Resected) Thymic Malignancies In general, radiation should be considered more strongly as the risk of recurrence increases. Therefore, for patients with the lowest likelihood of recurrence (i.e. completely resected Masaoka stage I thymoma), radiation can be safely omitted. For those at intermediate risk of local recurrence after complete resection, i.e. those with aggressive tumor histologies (such as thymic carcinoma) or Masaoka stage II and stage III disease, retrospective evidence exists both to support and contradict claims of benefit from adjuvant radiotherapy after complete resection. In general, our institutional practice includes postoperative radiation for completely resected Masaoka-Koga stage III thymoma and stage II or III thymic carcinoma. Risk assessment and stratification is usually done in a multidisciplinary setting and drives the choice of adjuvant treatment. The International Thymic Malignancy Interest Group (ITMIG) published a set of definitions and reporting guidelines for the use of radiation therapy for thymic malignancies in 2011. Pertinent recommendations for postoperative therapy are as follows. First, the term “postoperative” should be used for situations in which the tumor is resected and no residual disease is evident on imaging. If gross disease is present on postoperative imaging, then the disease should be defined as “recurrent” and the intent as “radiation for postoperative disease.” Second, the minimum acceptable dose for postoperative R0 disease is 50 Gy in 5 weeks. Finally, radiation to elective nodal regions not recommended, and the extent of malignancy before surgery should be used as a guide for designing the treatment fields. Microscopic Positive Margins (R1) and Gross Disease (R2) Radiation for R1 or R2 thymic malignancies should be started within 3 months of surgical resection. Doses between 40 Gy and 64 Gy are most appropriate for microscopically positive margins, whereas doses of 54 Gy or higher should be used for gross disease; both given in standard fractions of 1.8- to 2.0-Gy. Patients with positive margins should be considered for concurrent chemotherapy and radiotherapy, especially among patients with thymic carcinoma. Definitive Radiation Therapy Definitive radiation therapy is generally used for patients who are not candidates for surgery because of either the extent of disease at diagnosis or medical comorbidities. Because chemotherapy is a known radiation sensitizer, the combination of chemotherapy and radiation is considered most likely to control disease in these circumstances. In this setting, which is analogous to recurrent disease after surgical resection, we recommend radiation doses of 60 Gy -66 Gy to encompass gross disease plus a margin for microscopic regions at risk. Thymic carcinoma behaves more like non-small cell lung cancer arising from the thymus. Therefore, unresectable thymic carcinoma needs to be treated based on the histology or molecular biomarkers of expression e.g. EGFR, HER2 c-KIT and BCL-2. Approximately 50% of thymic carcinoma has squamous histology which can be treated with cisplatin based chemotherapy and radiotherapy. If unresectable thymic carcinoma has atypical carcinoid histology, etoposide and cisplatin plus radiotherapy might be the best option. For recurrent thymic carcinoma, molecular targeted agents e.g EGFR-TKI, c-KIT inhibitors and VEGFR inhibitors can be delivered in the protocol setting with or without radiotherapy. Techniques Because of the central location of thymic malignancies and the relatively high doses used in radiation therapy, we strongly recommend the use of conformal techniques, such as three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or, if available, proton beam therapy owing to the physical properties of the particles (i.e., the Bragg peak) which produce lower doses both proximal and distal to the target volume. In addition, because tumors can show substantial changes in shape or size over the course of several weeks of radiation therapy, we recommend that when radiation is to be used as definitive therapy, adaptive planning should be considered. Long-Term Consequences of Radiation on the Heart and Vasculature An abundance of evidence exists to show that long-term survivors of mediastinal radiation therapy can develop both acute and chronic cardiac sequelae. With regard to acute effects, the dose and fractionation of the radiation and the volume of heart irradiated all affect the risk of pericarditis and pericardial effusion. Given the close physiologic association between perfusion and ventilation, one might expect that radiation to the heart could affect lung function and vice versa. In a clinical study, investigators found that several heart dose-volume variables predicted radiation pneumonitis and that the fit of a model predicting pneumonitis was improved by the incorporation of heart variables. In conclusion, considerable evidence has shown that irradiation of the heart and vasculature can lead to increased acute and long-term toxicity and that these side effects are related to the dose, volume, and exact location of the irradiated field. Short-term surrogates of long-term toxicity such as findings on cardiovascular imaging or biomarker correlates would be helpful for identifying which patients at greatest risk for cardiac events. In the meantime, we recommend the continued use of advanced radiation therapy technologies such as IMRT, proton beam therapy, 4D imaging and treatment planning, and adaptive planning whenever possible to minimize the dose to mediastinal structures for patients with thymic disease, many of whom will survive for several decades and thus will live to see the long-term consequences of irradiation of these vital organs.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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MO13 - SCLC I (ID 118)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:C.K. Liam, E.S. Santos
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside 201 - 203, Level 2
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MO13.07 - Survival of small cell lung cancer patients undergoing lung resection in England 1998-2009 (ID 1691)
10:30 - 12:00 | Author(s): E. Lim
- Abstract
- Presentation
Background
Chemotherapy or chemoradiotherapy is the recommended treatment for small cell lung cancer (SCLC) except in stage I disease where clinical guidelines state there may be a role for surgery based on favourable outcomes in case series. Evidence supporting adjuvant chemotherapy in resected small cell lung cancer is limited but this is widely offered.Methods
Data on 359,873 patients who were diagnosed with a first primary lung cancer in England between 1998 and 2009 were grouped according to histology (SCLC; non-SCLC [NSCLC]) and whether they underwent a surgical resection. We explored their survival using Kaplan-Meier analysis and Cox regression, adjusting for age, sex, comorbidity and socio-economic status.Results
The survival of 465 resected SCLC patients was lower than resected NSCLC patients (five-year survival 31% and 45%, respectively), but much higher than patients of either group who were not resected (3%). The difference between resected SCLC and NSCLC diminished with time after surgery. Survival was superior for the subgroup of 198 “elective” SCLC where the diagnosis was most likely known before resection than for the subgroup of 267 “incidental” cases, where the SCLC diagnosis was likely to have been made after resection.Conclusion
These data serve as a natural experiment testing the survival after surgical management of SCLC according to NSCLC principles. SCLC patients treated surgically for early stage disease may have survival outcomes that approach those of NSCLC, supporting the emerging clinical practice of offering surgical resection to selected SCLC 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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MO22 - Advanced Disease and Outcomes (ID 103)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Surgery
- Presentations: 1
- Moderators:T. Yano, J. Roth
- Coordinates: 10/30/2013, 10:30 - 12:00, Parkside 110 A+B, Level 1
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MO22.01 - High procedure volume is strongly associated with improved survival after lung cancer surgery (ID 1704)
10:30 - 12:00 | Author(s): E. Lim
- Abstract
- Presentation
Background
Surgical resection is the first line treatment offered to patients with early stage non-small cell lung cancer (NSCLC) who are considered medically fit. Many studies have shown that patients undergoing surgery for lung cancer benefit from receiving treatment in hospitals where high numbers of lung cancer resections are carried out. This study explores the association between hospital volume and survival among all NSCLC patients diagnosed in England who underwent surgical resection and takes into account the differences in case selection and propensity to resect.Methods
We analysed data on 134,293 patients with NSCLC diagnosed in England between 2004 and 2008 of whom 12,862 (9·6%) underwent surgical resection. Hospital volume was defined according to the number of patients with resected lung cancer in each hospital in each year of diagnosis. Cox proportional hazard regression analyses were used to assess the association between hospital volume and survival among resected patients. We calculated multivariable hazard ratios according to hospital volume, with adjustment for potential confounders (sex, age, socioeconomic deprivation, comorbidity and resection quintile). In addition, to account for the risk of death potentially varying between groups of patients treated within a given hospital, a shared frailty Cox model was used, with hospital as a random effect. The follow-up period was divided into three pre-defined periods: 0-30 days, 31-365 days and >365 days post-surgery.Results
There was increased survival in hospitals performing more than 150 surgical resections compared with those carrying out less than 70 [HR 0·78 (95% CI 0·67-0·90), p~trend~ <0·01]. The association between hospital volume and survival was present in all three periods of follow-up, but the magnitude of the association was greatest in the period 0-30 days (HR for the 150+ hospital volume group compared with less than 70: 0·58, 95% CI 0·38-0·89) and smallest in the period after 365 days (HR 0·84, 95% CI 0·71-0·99).Conclusion
High volume hospitals have higher resection rates, operate on patients who are older, have lower socioeconomic status, more comorbidities and despite that they achieve better survival, most notably in the early post-operative period.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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MS05 - Modern Management of Neuroendocrine Tumours (ID 22)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Surgery
- Presentations: 1
- Moderators:V. Rusch, Y. Wu
- Coordinates: 10/28/2013, 14:00 - 15:30, Bayside Gallery B, Level 1
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MS05.2 - Combined Modality for LCNEC and Atypical Carcinoids (ID 477)
14:00 - 15:30 | Author(s): E. Lim
- 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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P1.03 - Poster Session 1 - Technology and Novel Development (ID 150)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P1.03-006 - The efficiency of detection of <em>KRAS</em>, <em>EGFR </em>and <em>BRAF </em>mutations in primary lung cancer via peripheral blood circulating tumour cells (ID 2762)
09:30 - 16:30 | Author(s): E. Lim
- Abstract
Background
Circulating tumour cells (CTCs) are present in the blood of a proportion of patients with lung cancer. However, it is currently unclear how suitable CTCs are for use in the detection of predictive genetic mutations. We sought to determine the utility of DNA extracted from CTCs to screen for the underlying primary tumour mutation.Methods
Using ScreenCell™ MB devices, from 20/01/12 to 25/01/2013, CTCs were captured in peripheral blood of 100 patients who underwent surgery for lung cancer at The Royal Brompton Hospital. DNA was extracted using QIAamp DNA Micro kit (QIAGEN) followed by whole-genome amplification using GenomePlex® SingleCell WGA kit (Sigma). DNA from matched primary tumours was used as reference. Mutation detection in EGFR and KRAS genes was undertaken using cobas®4800 (Roche) and single-strand conformation analysis for BRAF gene. Sensitivity and specificity analyses were undertaken to measure predictive performance of mutation testing in CTCs.Results
The DNA extracted from CTCs, were of sufficient quality to allow mutation analyses to be successfully performed in 100%, 99%, and 98% of samples for EGFR, KRAS, and BRAF genes, respectively. In CTC DNA, the KRAS mutation rate (codons 12/13 and 61) was 9.1% and concordance with the primary tumour was 78.8%. Six mutations were detected in CTCs, but not in primary tumours, and 13 mutations in primary tumours were not detected in corresponding CTC samples. Three mutations were detected in matched CTC and primary tumour specimens. One mutation in EGFR was detected in CTC DNA and 3 mutations were detected in primary tumours. In all cases, the mutations were detected in discordant specimens. The concordance between mutations detection in CTCs and primary tumours was 95.8%. BRAF V600E mutation was not detected in any sample. In general, the results suggested low sensitivity but high specificity (Table). Due to low number of EGFR mutations detected, test performance results require further validation.The performance of mutation testing in circulating tumour cells
Statistic KRAS EGFR Sensitivity (95% CI), % 18.8 (4.05-45.6) 0.0 (0.0-70.8) Specificity (95% CI), % 91.8 (83.0-96.9) 98.9 (94.1-100) Positive predictive value (95% CI), % 33.3 (7.49-70.1) 0.0 (0.0-97.5) Negative predictive value (95% CI), % 83.8 (73.8-91.1) 96.8 (91.0-99.3) Conclusion
The result of our study indicates that the DNA extracted from CTCs can be used to screen for primary tumour mutations with reasonable concordance. Differences in the mutation results from the CTC and primary tumours needs to be explored in more detail and may be due to issues related to processing and / or tumour versus CTC heterogeneity.
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P1.07 - Poster Session 1 - Surgery (ID 184)
- Event: WCLC 2013
- Type: Poster Session
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P1.07-020 - Thoracoscore and European Society Objective Score Do Not Predict Mortality in The UK Population - Is It Time For a New Risk Model? (ID 1459)
09:30 - 16:30 | Author(s): E. Lim
- Abstract
Background
Thoracoscore and the European Society Objective Score (ESOS.01) are two risk scoring systems used to estimate risk of death as part of informed consent, and to allow risk adjusted outcomes to be evaluated. We aimed to evaluate if these are valid tools for use in the United Kingdom (UK) population.Methods
A multi-centre, prospective study was carried out on patients undergoing lung resection at 6 UK centres. Data were submitted electronically using our online data collection tool. Univariate and multivariate analyses were carried out to determine the factors affecting mortality. A Receiver Operating Characteristic (ROC) analysis was performed in order to determine the ability of the Thoracoscore and ESOS.01 to predict in-hospital mortality.Results
Data were submitted for 2570 patients. 345 patients were excluded due to incomplete data fields. Of the remaining 2245 patients, the observed in-hospital mortality was 31 patients (1.38%). Mean Thoracoscore was 2.66(SD±3.21). Logistic regression analysis identified gender (p=0.004, hazard ratio 4.786) and co-morbidity score (p=0.005, hazard ratio 3.289) as risk factors for mortality. A sub-analysis was performed using data from 1912 patients. In this group, mean Thoracoscore was 2.55(SD±2.94), mean ESOS.01 was 2.11(SD±1.41), and these were statistically significantly different (p<0.0001). The observed in-hospital mortality was 28 patients (1.46%). The c-index for Thoracoscore was 0.705, and for ESOS.01, 0.739. Furthermore, there was poor correlation between the two scoring systems (r=0.362).Conclusion
Both Thoracoscore and ESOS.01 overestimated mortality in the UK population. There is a continued need to develop an appropriate risk prediction system for the UK.
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P3.12 - Poster Session 3 - NSCLC Early Stage (ID 206)
- Event: WCLC 2013
- Type: Poster Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.12-016 - Frequency in EGFR, K-RAS, BRAF and ALK mutations in a cohort of cancers: ALK translocations are more frequently seen in advanced disease (ID 2696)
09:30 - 16:30 | Author(s): E. Lim
- Abstract
Background
Routine mutation testing for potential targeted therapy is a challenge in the management of lung cancer. As part of a feasibility study on the implementation of molecular testing in the United Kingdom, Cancer Research UK (CRUK) set up a stratified medicine program testing EGFR, K-RAS, BRAF mutations and ALK translocation on lung cancer samples. We present the result from the first ten months from two hospitals feeding into one diagnostic molecular laboratory.Methods
Mutations detection in EGFR and KRAS genes was undertaken using cobas®4800 (Roche) and single-strand conformation analysis for BRAF gene. ALK translocations were screened using Vysis ALK break apart rearrangement probe.Results
A total of 94 resections all (but one) in stages I - IIIA were analysed, with mutations found entirely within adenocarcinomas (n=64), with a frequency of mutations/translocation identification of 30% (K-RAS) , 12.5% (EGFR), 1.5% (ALK) and 1.5% (BRAF) (Figure 1). Over the same period, 360 biopsies from patients with non-resectable/advanced disease, were analysed, the majority being stage 4, with a frequency of 24% (K-RAS), 10%.6 (EGFR), 4.3% and 1.9% (Figure 2). Figure 1 Figure 2Conclusion
The data suggest that frequency of K-RAS, EGFR and BRAF mutations are similar in early and advanced non-small cell carcinoma, however ALK translocations were observed to be more frequent in patients with advanced disease. This may have implications when considering which patients should undergo FISH testing for ALK translocation and entry into clinical trials. This study was funded by Cancer Research UK, Astra Zenica and Pfizer.
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P3.20 - Poster Session 3 - Early Detection and Screening (ID 174)
- Event: WCLC 2013
- Type: Poster Session
- Track: Imaging, Staging & Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.20-009 - Diagnostic performance of a filter-based antibody-independent peripheral blood circulating tumour cell capture paired with cytomorphologic criteria for the diagnosis of lung cancer (ID 2782)
09:30 - 16:30 | Author(s): E. Lim
- Abstract
Background
The ability to capture and characterise peripheral blood circulating tumour cells (CTCs) has the potential for the development of a blood test for cancer. A number of technological platforms are available to obtain CTCs including filtration-based devices utilising advances of antibody independent capture of cells. This technique shows promising results in experimental conditions; however, its performance has not yet been well evaluated in a clinical setting. We have evaluated diagnostic performance of filtration-based technology using cytomorphologic criteria in patients undergoing surgery for lung cancer.Methods
From 06/03/2012 to 24/01/2013 we obtained and processed blood from 74 patients undergoing surgery for known or suspected lung cancer using ScreenCell[TM] Cyto devices. Captured cells were stained using H&E and independently assessed by two pathologists (AGN, AR) for the presence of atypical cells suspicious for cancer. Results were reported as confirmed cancer, suspicious or no evidence for cancer. Diagnostic performance was evaluated against the reference of cancer identified within surgically obtained specimens reported by a principal pathologist. Sensitivity and specificity analyses were undertaken. Inter-observer agreement was established by kappa-statistics.Results
According to histopathology assessment, 42 patients (56.7%) had primary lung cancer, 18 patients (24.3%) had metastatic cancer (predominantly of colorectal origin), and 14 patients (18.9%) had benign lung diseases. The proportion of patients in which cells suspicious for cancer were identified was 39 (52.7%) and 42 (56.7%) as reported by two pathologists. Among those cases, 6 (15.4%) and 14 (33.3%) were reported as confirmatory. The agreement between the pathologists was 77% corresponding to a kappa-statistics of 53.7% indicating moderate agreement. In metastatic cancer patients, suspicious cells were discovered in 10 (55.6%) and 9 (50%) cases by two pathologists. In non-cancer patients, suspicious cell were found in 6 (42.8%) and 5 (35.7%) cases by two pathologists, respectively. The test performance for the diagnosis of cancer using cytomorphological criteria yielded poor-to-moderate sensitivity and specificity values, high positive predictive values and low negative predictive values (Table).The performance of the diagnosis of cancer using filter-based antibody-independent technique of CTCs trapping
Statistic Pathologist 1 Pathologist 2 Sensitivity (95% CI), % 55.0 (41.6-67.9) 61.7 (48.2-73.9) Specificity (95% CI), % 57.1 (28.9-82.3) 64.3 (35.1-87.2) Positive Predictive Value (95% CI), % 84.6 (69.5-94.1) 88.1 (74.4-96.0) Negative Predictive Value (95% CI), % 22.9 (10.4-40.1) 28.1 (13.7-46.7) Conclusion
The results of our study highlight the potential of filter-based antibody-independent technology to develop an accurate blood test for the diagnosis of cancer in the peripheral blood. However, conventional cytomorphological criteria used for the diagnosis provide inadequate sensitivity and specificity. Improved performance with immunocytochemistry is still required prior to further clinical validation.
