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K. Suzuki
Moderator of
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MO09 - Mesothelioma I (ID 120)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track:
- Presentations: 14
- Moderators:K. Suzuki, S.G. Armato III
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 204 A+B, Level 2
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MO09.01 - Evaluation of tolerability and anti-tumor activity of GDC-0980, an oral PI3K/mTOR inhibitor, administered to patients with advanced malignant pleural mesothelioma (MPM) (ID 1712)
16:15 - 16:20 | Author(s): S.O. Dolly, L.M. Krug, A.J. Wagner, L.H. Schwartz, J.C. Bendell, J.O. Lauchle, T.Y. Seiwert, K. Rihawi, N. Tunariu, M.G. Zauderer, L. Delasos, D. Kwiatkowski, J.P. Marcoux, M.S. Rabin, D. Apt, J. Fredrickson, M. Lackner, H. Koeppen, J.A. Ware, H.A. Burris, J.S. De Bono, H. Kindler
- Abstract
- Presentation
Background
The PI3K-AKT-mTOR signaling pathway is dysregulated in a wide variety of cancers. Pathway activation in mesothelioma may occur through diverse cellular mechanisms, including activation of receptor tyrosine kinases that signal through Ras and PI3K/Akt/mTOR, and loss of PTEN expression. GDC-0980 is a potent and selective oral dual inhibitor of class I PI3K and mTOR kinases that has demonstrated broad activity in various xenograft cancer models.Methods
A phase I dose-escalation study was conducted in 2 Stages: Stage 1 evaluated oral, daily (QD) doses of 2-70 mg GDC-0980 given 21/28 or 28/28 days in a 3+3 dose escalation design. Stage 2 evaluated disease specific cohorts at the recommended phase 2 dose (RP2D), including a MPM cohort at 30 mg GDC-0980 QD 28/28 days. Safety and tolerability of GDC-0980 was assessed as well as pharmacokinetics (PK) and pharmacodynamics (PD) assessment of PI3K pathway inhibition by FDG-PET. Anti-tumor activity was assessed by modified RECIST; CT scans were centrally reviewed retrospectively by a radiologist with MPM expertise. Archival tumor tissue was evaluated for PIK3CA mutation by allele specific PCR or Sanger sequencing and PTEN expression was assessed by immunohistochemistry.Results
33 MPM patients were enrolled: 6 in Stage 1 at 8-70 mg and 27 in Stage 2 at 30mg GDC-0980. Safety and tolerability of GDC-0980 in Stage 1 was similar in MPM compared to other solid tumor patients, with the exception of a Grade 5 pneumonitis that occurred in a MPM patient at 40 mg GDC-0980 QD. Based on Stage 1 tolerability data, a RP2D of 30 mg QD was evaluated in Stage 2 for MPM patients. The most frequent Grade ≥3 drug-related adverse events (AEs) at 30 mg GDC-0980 were rash (19%), with one patient (4%) having to discontinue GDC-0980. Other AEs were fatigue (15%), and hyperglycemia, diarrhea, and colitis (7% each). Reversible Grade 2 pneumonitis was reported for 2 patients (7%). Population PK analysis was used to assess the behavior of GDC‑0980 in MPM patients. Additionally, PK/PD relationships will be discussed for efficacy and safety, including exposure‑response, where appropriate. Archival tissue was analyzed for 29 MPM patients. Two samples had PIK3CA mutations (R88Q and E545G) and one sample showed loss of PTEN expression. PI3K pathway inhibition by FDG-PET responses was observed in 8 of 24 MPM patients with available scans. Anti-tumor activity was observed in both stages. Two patients achieved a partial response (PR) in Stage 1, one patient at 50 mg and one patient with the PIK3CA mutation R88Q at 8 mg GDC-0980. Two PRs were observed at the RP2D of 30 mg in Stage 2. Eleven (41%) MPM patients at the RP2D remained on study for >6 months, and 2 (7%) patients remained on study >12 months.Conclusion
GDC-0980 was generally well tolerated in MPM patients at the RP2D. Anti-tumor activity, evidenced by tumor regression and prolonged disease control, has been observed. PIK3CA mutations and PTEN loss were uncommon.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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MO09.02 - A Randomised Phase II trial of Pegylated Arginine Deiminase in patients with Malignant Pleural Mesothelioma (ID 1355)
16:20 - 16:25 | Author(s): P.W. Szlosarek, J. Steele, M. Sheaff, T. Szyszko, S. Ellis, L. Nolan, P. Taylor, D. Gilligan, J. Spicer, M. Lind, P. Luong, L. Butcher, S. Beck, N. Avril, J. Bomalaski, N. Lemoine, R. Rudd, D. Fennell, A. Hackshaw
- Abstract
- Presentation
Background
Preclinically, arginine deprivation has shown activity as a novel antimetabolite strategy for MPM patients who are deficient for the rate-limiting enzyme in arginine biosynthesis argininosuccinate synthetase (ASS1). Here, we examine the efficacy and safety of the arginine-lowering agent ADI-PEG20 (Polaris Group, San Diego, US) among patients with MPM.Methods
We performed a multicentre randomised phase II clinical trial, based on patients with good performance status (0 or 1), non-resectable disease, ASS1-deficient MPM, and measurable disease. Patients were randomized 1:2 to receive best supportive care (BSC) or BSC+ADI-PEG20, stratified by: gender, histology (sarcomatoid versus non-sarcomatoid), prior treatment (chemonaive or previous platinum combination therapy), and centre. The primary endpoint, progression-free survival (PFS), is assessed by modified RECIST, and secondary endpoints include overall survival, tumor response rate, and toxicity. Translational endpoints included measurement of plasma arginine, citrulline and ADI-PEG20 antibody levels, assessment of metabolic response by [18F]Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and ASS1 methylation status using Illumina’s 450K DNA methylation array. The target sample size was estimated to detect a PFS hazard ratio of 0.60. [Trial funded by Cancer Research UK].Results
ASS1 deficiency was detected in 98 of 214 patients (46%) of which 68 were randomized on the trial (44 ADI-PEG20+BSC and 24 BSC alone). 66 patients have progressed so far (42 ADI-PEG20+BSC vs. 24 BSC alone), and 32 patients were alive (23 ADI-PEG20+BSC vs. 9 BSC alone). The hazard ratio for PFS was 0.53 (95%, CI 0.31 to 0.90, p=0.02) with a median PFS of 98 days for patients randomized to ADI-PEG20+BSC compared with 59 days for patients receiving BSC alone. ADI-PEG20 toxicity in patients with MPM has been consistent with previous trials of ADI-PEG20 in melanoma and liver cancer: commonly skin injection site reactions (grade 1-2), infrequent episodes of neutropenia (range: grade 1-4), anaphylactoid reactions (2 patients with grade 3 episodes) and serum sickness (1 patient). The best response by modified RECIST was stable disease. Metabolic responses (in 39 evaluable ADI-treated patients) were as follows: 46% with partial response (18/39), 31% with stable disease (12/39), 15% progressive metabolic disease (6/39) and 8% mixed metabolic response (3/39) by FDG-PET assessment. There was a significant difference between IHC assessed ASS1-negative and ASS1-positive patients and the methylation status of the ASS1 gene (p=0.025).Conclusion
ADI-PEG20 is generally well tolerated and shows evidence of clinically significant activity in patients selected for arginine-dependent MPM demonstrating differential methylation of ASS1. Arginine deprivation may have a role in the future management of MPM either alone or in combination with selected therapies.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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MO09.03 - A pilot and feasibility trial evaluating two different chemotherapy regimens in combination with intrapleural adenoviral-mediated interferon-alpha (SCH 721015, Ad.hIFN-alpha2b) gene transfer for malignant pleural mesothelioma (ID 3374)
16:25 - 16:30 | Author(s): D. Sterman, E. Alley, A. Recio, J.P. Stevenson, S. Metzger, E.K. Moon, A.R. Haas, A. Vachani, S. Katz, G. Cheng, J. Sun, N. Chertack, N. Saballos, D. Heitjan, L. Litzky, K.A. Cengel, C. Simone, J. Friedberg, M. Culligan, K. Mudrick, S.M. Albelda
- Abstract
- Presentation
Background
Malignant pleural mesothelioma is an incurable thoracic neoplasm for which combination chemotherapy offers limited improvement in survival. Novel agents that offer synergy with standard systemic cytotoxic therapy are under investigation. Among these agents are a variety of immunotherapeutics which can be administered either locally or in a systemic fashion.Methods
We conducted a Phase I/II “in situ vaccination” clinical trial commencing in March2011 involving repeated intrapleural administration of a replication-defective recombinant adenoviral vector containing the human interferon-alpha (hIFN-α2b) gene at a dose of 3x10[11 ]viral particles concomitant with a 14-day course of high-dose cyclo-oxygenase-2 (COX-2) inhibitor (Celecoxib). This was followed by standard first-line or second-line chemotherapy agents. Primary outcome measures were safety, overall best response rate, and survival.Results
We completed accrual (n=25) in the first-line chemotherapy arm, in which all patients received pemetrexed-based chemotherapy regimens. This group included patients who previously received pemetrexed chemotherapy but did not subsequently receive this agent for >6 months. In the second-line chemotherapy arm, 13of a planned 15 subjects have enrolled (with 12 evaluable), all of whom received gemcitabine-based chemotherapy (Table 1). In both arms, the combination of intrapleural Ad.IFN-α2b vector, high-dose celecoxib, and systemic chemotherapy proved safe. Adverse events during the chemotherapy portion of the study were comparable to historical controls.Most patients experienced expected mild toxicities from vector (cytokine release syndrome, interferon production), including nausea, fatigue, anemia, lymphopenia (grade 3-4) and hypoalbuminemia. Serious adverse events included: pleural catheter infection (n=2); hypoxia (n=2); supraventricular tachycardia (n=1); and esophagitis (n=1), none directly attributable to the vector or vector administration. Serial chest CT and PET/CT scans demonstrated an overall response rate of 31% by Modified RECIST criteria and disease control rate (DCR) of 78% (partial and complete responses plus stable disease) at initial follow-up scan after the first two cycles of chemotherapy. Partial responses were seen in 9/25 evaluable patients with pemetrexed-based chemotherapy and 1/12 with gemcitabine. Patients who received first-line pemetrexed-based chemotherapy (n=14) had a median survival of 10.5 months, 95% ci=(5.5,inf), whereas second-line patients (n=21; 12 gemcitabine)had a median survival of 15.0 months, 95% ci=(9.0,inf).
TABLE 1Pem/Platin (N=25) Gemcitabine (N=13) Male % 64% (16/25) 84.6% (11/13) Median Age 67 (51-86) 65 (43-81) Histologic Subtype % Epithelioid - 17 (68%) Biphasic - 4 (17%) Sarcomatoid - 4 (17%) Epithelioid - 11 (84.6%) Biphasic - 2 (15.4%) Sarcomatoid - 0 Stage I - 2 (8%) II - 6 (24%) III - 13 (52%) IV - 4 (16%) III - 4 (30%) IV - 9 (70%) Prior Treatment Chemotherapy - 4 (16%) RP/PDT - 4 (16%) XRT - 5 (20%) Chemotherapy - 13 (100%) RP/PDT - 7 (53%) XRT - 2 (15%) Platin Agent Cisplatin - 12 Carboplatin - 10 Cis-Carbo - 1 None - 2 Cisplatin - 0 Carboplatin - 2 None - 8 Median Cycles of Chemo 6 (1-6) 3 (0-6) Conclusion
The combination of intrapleural Ad.IFN-α2b vector, Celecoxib, and systemic chemotherapy proved safe. Disease control rates observed in this study compare favorably with historical data andthe especially encouraging OS in the second-line chemotherapy group argue strongly for proceeding with a multi-center randomized clinical trial of chemo-immunogene therapy versus chemotherapy alone.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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MO09.04 - Defining BAP1 Syndrome: Preliminary results from an epidemiologic ascertainment study (ID 3437)
16:30 - 16:35 | Author(s): M.G. Zauderer, R. McMillan, C.S. Sima, M. Robson, V.W. Rusch, L.M. Krug, M. Ladanyi
- Abstract
- Presentation
Background
Identifying tumorigenic mutations in malignant pleural mesothelioma (MPM) is essential to advance therapy. Somatic mutations in the BRCA-1 associated protein-1 (BAP1) gene occur in about 20% of MPM tumors (Bott et al., Nature Genetics, 2011). In a retrospective analysis evaluating demographics, exposures, and survival, a history of smoking was the only clinical feature associated with the presence of BAP1 mutations (Zauderer et al., in press, J Thorac Oncol, 2013). Germline BAP1 mutations have also been identified in families predisposed to MPM (Testa et al., Nature Genetics, 2011). BAP1 germline mutations have also been associated with other tumors including atypical Spitz nevi, uveal melanoma, and renal cell carcinoma. These discoveries suggest that BAP1 mutations in mesothelioma represent part of a new hereditary cancer syndrome but the exact clinical phenotype remains unclear. To establish the frequency of germline BAP1 mutations in MPM patients and to accurately assess exposure history and family histories in these patients, we have undertaken a clinical trial to prospectively collect this information from patients with MPM.Methods
All consenting patients provide a saliva or blood specimen from which germline DNA is extracted. Existing tumor samples are collected and analyzed for BAP1 mutation. Everyone completes a questionnaire regarding asbestos exposure, personal cancer history, and family history of malignancy. First, we will perform a de-identified assessment of the prevalence of germline BAP1 mutation. Patients whose tumors harbor BAP1 mutation and/or meet prespecified high risk criteria will be approached for identified germline testing after appropriate pre-test counseling. Mutations identified through research testing with be confirmed with clinical testing and additional genetic counseling will be undertaken. Testing will be offered to family members of patients with identified BAP1 germline mutations. Please see Figure 1 for study flow. Figure 1Results
During the first 3 months that this protocol was open, we accrued 26 patients with mesothelioma, 15 of whom qualify for identified research testing. We will present results from ongoing testing at the meeting.Conclusion
Recruiting patients to perform both de-identified and identified germline testing is feasible. Given the paucity of information regarding penetrance and appropriate screening interventions, BAP1 germline testing should continue only in the context of research programs. Additional preclinical work is ongoing to exploit this potential therapeutic target. Supported, in part, by a grant from the Mesothelioma Applied Research Foundation.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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MO09.05 - DISCUSSANT (ID 3966)
16:35 - 16:45 | Author(s): A.K. Nowak
- Abstract
- Presentation
Abstract not provided
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MO09.06 - Malignant Pleural Mesothelioma in the UK National Lung Cancer Audit: An analysis of 8503 cases (ID 916)
16:45 - 16:50 | Author(s): M.D. Peake, P. Beckett, I. Woolhouse, R. Stanley, D. Fennell, J. Edwards, R. Hubbard
- Abstract
- Presentation
Background
The National Lung Cancer Audit is run jointly by the Royal College of Physicians and The Information Centre for health and social care with the aim of recording outcomes in lung cancer (and mesothelioma) on a population scale, explaining the wide variations seen within the UK and between the UK and other countries and ultimately improving outcomes. This abstract presents results for England only, focusing on mesothelioma.Methods
All patients with mesothelioma seen in in secondary care 2006-2011 were analysed. A hierarchy of diagnosis from surgical histology to non-surgical histology to clinical diagnosis was used to exclude patients with potentially conflicting diagnoses. These records were further analysed to extract data on age/sex distribution, referral source, histological subtype, treatment regime and survival rates.Results
There were 8,503 patients with mean age 72yrs (83% male), representing around 65% of expected incident cases (a substantial number diagnosed at autopsy and not included in the audit). 45% have right-sided disease, 28% were left-sided, and 1% were bilateral (data missing in 26%). The majority of patients (47%) were referred by their primary care physician, but at least 20% present to secondary care as emergencies. Overall, 89% of cases were histo-cytologically confirmed with that figure appearing to rise slowly over the audit period from 81% (2006) to 92% (2011). Survival data is shown below.
37% of patients received no anti-cancer treatment, but 28%, 26% and 30% of patients received “surgery”, chemotherapy or radiotherapy at any time. Most surgical operations (60%) were pleurodesis. Median survival varied by first treatment modality: surgery 378 days, chemotherapy 399 days, radiotherapy 308 days, no anti-treatment 140 days. Survival was highest in patients having “surgery” and chemotherapy (491 days). Use of chemotherapy varied across 28 regional cancer networks from 14% to 41% of patients, but overall increased over the audit period from 13% to 34%.n (%) Median survival (days) 1 year survival (%) All patients 8,503 (100%) 278 41 Survival was slightly better in females (median 304 days vs 274 days HR 0.91, p=0.002) Subtype n (%) Median survival (days) 1 year survival (%) Unspecified 3,798 276 39.5 Epithelioid 2,300 388 53.2 Sarcomatoid 439 123 16.4 Biphasic 268 274 36.0 Conclusion
Mesothelioma is predominantly a cancer of elderly males, with a striking tendency for right-sided disease. Only 11% have no histological confirmation, but where this is obtained, the epithelioid subtype has best prognosis. Low rates of anti-cancer treatment may reflect therapeutic nihilism as well as patient fitness, but there is an encouraging trend towards wider use of chemotherapy which was associated with a greater than doubling in survival compared with no treatment.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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MO09.07 - Disease and Patient Characteristics related to Survival in a large population-based cohort of patients with Malignant Pleural Mesothelioma (MPM) (ID 3184)
16:50 - 16:55 | Author(s): A. Linton, N. Pavlakis, S. Kao, S. Clarke, J. Vardy, N. Van Zandwijk
- Abstract
- Presentation
Background
Despite advances in therapy, the prognosis of MPM remains poor (median overall survival (OS) of 9-12 months). Nevertheless, as described in surgical series, a small proportion of patients survive far longer. Previously identified prognostic factors in patients undergoing extra-pleural pneumonectomy (EPP) include histological subtype, gender and neutrophil-lymphocyte ratio (NLR). Similar factors including stage and performance status have also been shown to be prognostic in chemotherapy studies. We aim to assess in the general MPM patient population, what factors predict for better prognosis independent of the treatment path chosen.Methods
We reviewed records of patients registered (2002 -2009) with the NSW Dust Diseases Board; a government compensation body for NSW workers with occupational asbestos exposure. We evaluated a priori prognostic factors including age, gender, histological subtype, staging on CT imaging and NLR using Kaplan Meier and Cox regression analysis, and by treatment interventions, smoking and asbestos exposure history. Exploratory subgroup analyses compared these factors in long-term (>20 months) survivors versus the remainder of the study population.Results
We identified 913 patients: 90% male; median age 71.9 years; histological subtype (epithelioid 54%; biphasic 11%; sarcomatoid 16.3%; unknown 19%); stage on CT imaging (Tx-I-II 49%; III-IV 51%). 51% of patients received chemotherapy and 6% underwent EPP (of which 67% received chemotherapy. Median age of first occupational asbestos exposure was 18 years, cumulative duration of exposure, 24 years and latency from exposure to diagnosis, 50 years. Median OS was 10.0 months, 15.0 months (range(1-120) in patients receiving chemotherapy and/or EPP and 5.8 months (range 0-125) in patients receiving neither. On univariate analysis, younger age (<70 vs. >70yrs at diagnosis; 13.1 vs. 8.5 months; p<0.001); female gender (12.0 vs. 9.8months; p<0.001); epithelioid subtype (11.8 vs. 7.2 months ;p>0.001); and NLR <5 (12.9 vs. 7.5months; p<0.001) were associated with prolonged OS. Patients who underwent chemotherapy (13.6 vs. 7.2 months; p<0.001) and EPP (17.9 vs. 9.6 months; p<0.001) also had an improved survival. Smoking history (current/ex vs. never) and cumulative asbestos exposure did not affect survival. A trend to improved survival was noted with early stage disease (11.2 vs. 9.1 months; p=0.284) and younger age at first exposure (<18 vs. >18 years of age; 10.9 vs. 9.4 months; p=0.091). On multivariate analysis, age, gender, histological subtype, NLR, EPP and chemotherapy administration remained significant. 24% of patients demonstrated survival over 20 months. Of those, 14% underwent EPP, and 63% received chemotherapy. On multivariate analysis, epithelioid histology (p<0.001), chemotherapy use(p=0.002), undergoing EPP(p=0.01) and NLR<5(p=0.007) were independently associated with survival over 20 months.Conclusion
In this large, population based cohort of MPM patients, we have validated age, gender, histological subtype and NLR as significant prognostic factors. Patients undergoing interventions such as EPP or chemotherapy demonstrated more favourable survival, however it is important to note that 86% of long survivors did not receive radical surgery, and 37% did not receive chemotherapy. As such, we hypothesise that apart from active treatment and inherent selection criteria, there are additional factors, such as favourable tumour biology, that seem to positively influence survival of MPM 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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MO09.08 - NF-kB in cisplatin resistance and as a prognostic marker in Malignant pleural mesothelioma (ID 3338)
16:55 - 17:00 | Author(s): K. Gately, E. Jennions, P. Godwin, M. Barr, S. Heavey, K. Umezawa, J. Edwards, S. Gray, K. O'Byrne
- Abstract
- Presentation
Background
Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Currently rates of MPM are rising and estimates indicate that the incidence of MPM will peak in western world within the next 10-15 years. Untreated, MPM has a median survival time of 6 months, with poor survival rates for most patients after 24 months of diagnosis. Nuclear Factor kappa B (NF-kB) is a pro-inflammatory transcription factor which is activated in many cancer types, including MPM. The NF-kB pathway regulates important cellular processes including survival and proliferation signals, which are often found to be dysregulated in cancer. Furthermore, we and others have shown that increased NF-kB activation is linked to development of cisplatin resistance. We aim to outline the potential role of NF-kB as a mediator of cisplatin resistance in MPM and determine its value as a potential candidate for therapeutic intervention.Methods
NF-kB expression was examined in a cohort of MPM patients (n=200) by IHC, and correlated with clinicopathological variables and survival. NF-kB expression was examined in both a panel of MPM cell lines and isogenic parent/cisplatin resistant cell lines by Western blot analysis. The effect of NF-kB inhibition on cellular proliferation was measured by BrdU assay, in a panel of MPM and isogenic parent/cisplatin resistant cell lines, using the novel NF-kB inhibitor Dehydroxymethylepoxyquinomicin (DHMEQ). In addition, the effect of DHMEQ on nuclear translocation of NF-kB was examined by high content screening (HCS).Results
Cytoplasmic or membranous immunostaining was seen in the majority of tumour samples (96.5%), but nuclear localisation of NF-kB was seen in only 11% cases. Kaplan-Meier survival analysis showed that nuclear NF-kB expression correlated with reduced survival (p=0.05). There was no significant correlation between the level of expression of NF-kB and standard clinicopathological parameters. NF-kB was expressed in all MPM cell lines tested to a varying extent (n=20), with no associations to histology. NF-kB levels were shown to be elevated in cisplatin resistant cell lines when compared to the isogenic parent from which they were derived. DHMEQ was shown to reduce nuclear translocation of NF-kB, inhibiting cell proliferation in all cell lines but to a lesser extent in NCI 2596 cells which have low NFkB expression.Conclusion
Nuclear NFkB expression is a poor prognostic factor in MPM. DHMEQ, which inhibits nuclear translocation of NF-kB, inhibits cell proliferation in MPM cell lines. Furthermore, increased NF-kB expression in resistant cells suggests this pathway may play a role in development of cisplatin resistance in MPM. Inhibition of NF-kB may therefore prove to be of potential therapeutic benefit in MPM treatment and re-sensitisation of resistant MPM to cisplatin.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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MO09.09 - DISCUSSANT (ID 3967)
17:00 - 17:10 | Author(s): H.L. Kindler
- Abstract
- Presentation
Abstract not provided
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MO09.10 - Volumetric Response Classification Criteria in Mesothelioma (ID 3302)
17:10 - 17:15 | Author(s): S.G. Armato III, A.H. Belcher, Z.E. Labby, A.K. Nowak, H. Kindler
- Abstract
- Presentation
Background
Tumor response criteria provide a framework for therapeutic decisions and clinical trials management in oncology. The standard response classification categories (partial response (PR), stable disease (SD), and progressive disease (PD)) were defined by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines based on relative changes in linear measurements of tumor diameter on computed tomography (CT) scans. An increase in linear dimension of at least 20% is categorized as PD, a decrease in linear dimension of at least 30% is categorized as PR, and a change in linear dimension not great enough to exceed either of these thresholds is categorized as SD. With improvements in imaging technology and enhancements in computer algorithms, the extraction of tumor volume from CT scans has become more practical. The possibility that tumor volume may eventually become the preferred tumor measurement metric rather than linear dimension necessitates the development of volumetric response criteria. Although extrapolation of the RECIST response criteria to volume is straightforward for spherical nodules, tumors as non-spherical as mesothelioma likely will require unique volumetric response criteria.Methods
A semi-automated computerized method was used to determine the mesothelioma tumor volume from CT scans (baseline and all available follow-up scans) retrospectively collected from 70 patients undergoing standard-of-care chemotherapy. Relative changes in tumor volume from baseline were categorized as PR, SD, or PD based on different combinations of percent change thresholds. Overall patient survival was correlated with best response using Harrell’s C statistic. The response criteria for PD and PR were each varied in 1% increments to obtain optimized classification criteria.Results
The process that systematically evaluated various combinations of response criteria identified an increase in tumor volume of at least 58% and a decrease in tumor volume of at least 17% for PD and PR, respectively, as the criteria that were best correlated with patient survival. These criteria yielded a C statistic of 0.76, where a C statistic value of 1.0 would indicate perfect separation of response groups with respect to subsequent survival times. This result may be compared with the C statistic value of 0.61 obtained when volumetric response criteria extrapolated directly from the RECIST criteria (+73% for PD and -66% for PR) were applied to this cohort.Conclusion
The evolution toward volumetric assessment of tumor burden and response to therapy necessitates the derivation and validation of volume-specific tumor response criteria to distinguish among PR, SD, and PD. The present study motivates such response criteria for mesothelioma and indicates that mesothelioma volumetric response criteria differ substantively from a simplistic extension of the RECIST criteria to three dimensions. Future prospective studies will be required to validate these criteria.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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MO09.11 - Quantitative Clinical T Classification Criteria for Malignant Pleural Mesothelioma. (ID 2947)
17:15 - 17:20 | Author(s): R.R. Gill, W. Richards, B.Y. Yeap, R. Bueno, D.J. Sugarbaker
- Abstract
- Presentation
Background
Clinical T classification of Malignant Pleural Mesothelioma involves qualitative estimation of tumor involvement of the thorax and does not accurately predict prognosis (JTO 7(11):1631-9, 2012). We explored whether novel quantitative assessment of standard CT images might improve the prognostic accuracy of clinical T classification.Methods
All patients who underwent primary extrapleural pneumonectomy (EPP) or pleurectomy (PDC) between 2001-2012 with available preoperative CT for retrospective review were included. Tumor volume was derived using Vitrea software (Vital) and binned into 3 categories (≤75cc, >75≤500cc, >500cc). Maximal thickness among measurable interlobar septae was measured on CT and binned into 2 categories (≤5mm, >5mm). Kaplan-Meier estimates of overall survival were computed for each combination of volume and septum thickness categories. Combinations with similar estimated survival functions were combined to create criteria for T classification levels. Cox regression was used to evaluate the relative hazard for death and disease recurrence associated with classification levels.Results
406 patients met inclusion criteria (278 EPP, 128 PDC; 317 male; 297 epithelial histology on biopsy; median age 64). Alignment of survival functions yielded combinations of volume and septum thickness categories defining T1 through T4. These classifications were associated with progressively increasing hazard for death and recurrence (Table).Overall Survival Time to Recurrence T status N Median(mths) HR 95% C.I. Median(mths) HR 95% C.I. T1 85 37 1.0 - 16 1.0 -- T2 118 21 1.5 1.0 - 2.1 11 1.6 1.1-2.1 T3 105 14 2.5 1.7 - 3.5 8 2.3 1.7 -3.2 T4 98 10 4.2 3.0 - 6.1 5 4.1 3.0 - 5.8 Conclusion
Tumor volume and septum thickness are readily measured on standard CT imaging and provide robust prognostic information not accounted for by current clinical T classification criteria. As quantitative measurements, they should be minimally affected by inter-observer variability. The feasibility and value of these simple and cost effective adaptations to clinical staging should be evaluated as the TNM staging system is revised.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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MO09.12 - Posterior intercostal lymph nodes - First report of a new independent prognostic factor for malignant pleural mesothelioma (ID 1684)
17:20 - 17:25 | Author(s): J. Friedberg, M. Culligan, M. Putt, S.M. Hahn, E. Alley, C. Simone, D. Sterman, K.A. Cengel
- Abstract
- Presentation
Background
Little is known about the significance of metastases to the posterior intercostal lymph nodes, located within the intercostal spaces at the level of the rib heads, in patients with malignant pleural mesothelioma. These nodes are not part of any staging system. This report is an initial attempt to determine the significance of these lymph nodes.Methods
We sampled posterior intercostal lymph nodes from 48 patients undergoing radical pleurectomy for malignant pleural mesothelioma. Statistical analyses were then performed correlating metastases to these lymph nodes with progression free and overall survival.Results
26/48 (54%) patients had positive posterior intercostal lymph nodes. Standard staging revealed: 6/48 (13%) N0, 3/48 (6%) N1, 39/48 (81%) N2, 9/49 (19%) stage III and 39/48 (81%) stage IV. Presence of positive posterior intercostal lymph nodes was not associated with stage (Fisher exact P=0.48), but was associated with N status. N1 and N2 were associated with higher rates of positive posterior intercostal lymph nodes (Fisher exact P=0.011). At a median follow-up of 9.6 months, progression-free survival was 0.83 years, 95% CI: (0.74, 1.30) years; median overall survival was 1.89 years, 95% CI: (1.29, ND) years. Patients with negative posterior intercostal lymph nodes had a median progression-free survival of 1.25 years, 95% CI: (0.95, 1.95) years, while that for patients with positive posterior intercostal lymph nodes was 0.73 years, 95% CI: (0.61, 1.40) years (p=.017 by log-rank test). Patients with negative posterior intercostal lymph nodes had a median overall survival of 3.43 years, 95% CI: (1.89, ND) years, while that for patients with positive ICLNs was 1.01 years, 95% CI: (0.61, 1.40) years (p=.007 by log-rank). In a Cox regression model that adjusted for stage, positive posterior intercostal lymph nodes were associated with an increased risk of failure (HR=2.71, 95% CI=1.15.6.39, P=.048) and death, (HR=3.3, 95% CI: 1.3, 8.1, P=0.0098. Figure 1Conclusion
Bearing in mind the limitations of this retrospective study with short-term follow-up, these results suggest that the posterior intercostal lymph nodes may have independent prognostic significance. This data has served as a trigger for us to now routinely include the posterior intercostal lymph nodes in our thoracic lymphadenectomies in patients undergoing surgery for malignant pleural mesothelioma. Further investigation of this nodal station is indicated and it is likely that these nodes should be included in any future staging system for malignant pleural mesothelioma.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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MO09.13 - Comparison of Three Radiographic Tumor Volume Estimation Techniques for Malignant Pleural Mesothelioma: Their Correlation with Each Other, Actual Measured Intraoperative Tumor Volumes, and Survival (ID 1689)
17:25 - 17:30 | Author(s): J. Friedberg, M. Culligan, S. Katz, D.A. Torigian, J. Udupa, M. Galperin-Aizenberg, M. Putt, J. Li, M. Shin, K. McKay, E. Glatstein, S.M. Hahn, K.A. Cengel, C.B. Simone
- Abstract
- Presentation
Background
Studies have assessed correlation between radiographically estimated tumor volume (TV) and outcomes for malignant pleural mesothelioma, no standard radiographic model exists for estimating TV. Although radical pleurectomy yields a surgical specimen essentially all cancer, thereby allowing accurate determination of TV, empirically-derived intraoperative TVs have never been reported. We compare multiple radiographic estimates of TV with TVs determined at resection to determine which radiographic approach most accurately predicts intraoperative TV, and we correlate TV with survival.Methods
Actual TVs were measured for 41 consecutive radical pleurectomy specimens by volume displacement. Radiographic TV estimates were performed by radiologists/radiation oncologists blinded to intraoperative TVs. Radiographic estimates were obtained with: Live Wire algorithm (automated tumor delineation after manual algorithm training), radiology TeraRecon (tumor automatically circumscribed with subsequent manual tracing corrections), and radiation oncology Eclipse (non-automated tumor delineation).Results
Median age was 63yrs, with 80% male and 83% having epithelial histology. Stage distribution was: 3-Stage I (7%), 4-Stage II (10%), 29-Stage III (71%), and 5-Stage IV (12%). Median (interquartile range) intraoperative TV was 600(400,800)cm[3]. Median TV of 800(575,1100)cm[3] among nonepithelial compared to 500(350,838)cm[3] for epithelial was not significantly difference (p=0.099). TVs were largest for stage III (p=0.01). Median TVs for Live Wire, TerraRecon, and Eclipse were 260(147-452), 293(161-465), and 447(247-559)cm[3], respectively. Pearson correlation coefficients were 0.60, 0.75, and 0.78, with all models underestimating intraoperative TVs (Figure 1A). Among 34 epithelial patients (mean/median follow-up 9.8/8.0mo), median survival was not reached (only 9 recurrences). Epithelial patients with large (>500cm[3]) intraoperative TVs had numerically worse progression-free (p=0.148) and overall (p=0.161) survival than patients with TVs ≤500cm[3](Figure 1B), but limited events precluded statistical significance. Larger radiologic TVs similarly correlated with shorter survivals. Figure 1Conclusion
This is the first study to compare radiographic estimates of TV to actual TV determined by volume displacement of radical pleurectomy specimens, arguably the TV measurement gold standard. This study is also the first to compare estimated TVs using multiple established and previously reported radiographic techniques. Our results demonstrate a clear trend toward greater overall and progression-free survival for actual TVs <500cm[3]. All radiographic techniques underestimated actual TV, with estimates progressively closer to the actual volume with each technique as they became less automated and more manual. Further analysis is ongoing to determine if any radiographic method can serve as an accurate surrogate for actual TV and if models correlate as closely with outcomes as actual TVs.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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MO09.14 - DISCUSSANT (ID 3968)
17:30 - 17:40 | Author(s): A. Tsao
- Abstract
- Presentation
Abstract not provided
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Author of
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MTE25 - Less than Pneumonectomy after XRT (High Dose Radiotherapy) (ID 69)
- Event: WCLC 2013
- Type: Meet the Expert (ticketed session)
- Track: Surgery
- Presentations: 1
- Moderators:N. n/a
- Coordinates: 10/30/2013, 07:00 - 08:00, Bayside Gallery B, Level 1
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MTE25.1 - Less than Pneumonectomy after XRT (High Dose Radiotherapy) (ID 623)
07:00 - 08:00 | Author(s): K. Suzuki
- Abstract
- Presentation
Abstract
Background Standard treatment for stage IIIA or IIIB non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT). In patients with infiltrative stage III (N2) NSCLC and PS 0-1 being considered for curative-intent treatment, platinum-based chemotherapy and radiotherapy (60-66 Gy) are recommended based on the revised American College of Chest Physicians (ACCP) guidelines for lung cancer. This guideline adopted new criteria for clinical N2 status, discrete and infiltrative N2 status. Infiltrative N2 means no radiolucency between nodes and surrounding organs, and usually considered to be unresectable unless combined resection not performed. Discrete N2 was defined as nodes having surrounding radiolucency on computerized axial tomogram (CAT). Surgery alone is not recommended for both clinical N2 diseases, based on several retrospective studies reported in 1990’s. Some cases would be candidates for upfront surgery followed by adjuvant chemotherapy, but approximately 40% of patients with resected lung cancer cannot tolerate postoperative adjuvant chemotherapy. ACCP guideline does not recommend surgery followed by chemotherapy, if N2 was verified preoperatively, which is reasonable for considering Thus preoperative treatment should be suitable for most clinical N2 NSCLC, if trimodal treatment is taken into consideration. As to a suitable preoperative treatment, induction chemotherapy is generally preferred to CRT, for pulmonary resection following CRT is believed to be more difficult and higher complication rate. However one of the major disadvantages for induction chemotherapy should be incomplete resection, which means losing local control for patients with N2 disease. In this respect induction treatment should include radiotherapy for infiltrative or discrete N2 NSCLC. The significance of surgery in N2 NSCLC is controversial. Randomized controlled trial definitive CRT vs induction CRT followed by surgery, i.e. “Intergroup 0139 trial”, resulted in negative. Overall survival was not improved for surgery group. While in subset analysis lobectomy appeared to improve survival, pneumonectomy did not. This is partly due to a high mortality rate in pneumonectomy group, which is a matter of debate. Some authors insisted that pneumonectomy is feasible following CRT with a low surgical mortality rate. Lessons from “Intergroup 0139 trial) were described in the recent ACCP guidelines as follows; 1) patients preferences and characteristics should be considered; 2) highlight the importance of minimizing harms, and surgery should be undertaken in a center with experience; 3) if there are reasons to be concerned about the ability of radiotherapy to achieve local control, surgery may have a benefit provided R0 resection is likely to be achieved; 4) lobectomy is preferred to pneumonectomy following induction CRT. Dose of irradiation in surgery group is 45Gy, and in the other side of definitive CRT group 61Gy. Considering tumor biology under radiotherapy, the difference of the doses cannot be negligible. Cancer cells tend to response in the late phase of radiation rather than early phase. Thus ideal radiation dose would be 60 to 66Gy, and lobectomy rather than pneumonectomy should be performed in trimodal treatment for stage IIIA N2 NSCLC. In this setting surgery is performed following definitive CRT, and called as “salvage surgery.” There are few reports on the significance and feasibility of salvage surgery for lung cancer, and the indications should be limited. On the other hand, definitive CRT can control local disease at most 40% resulting in approximately 20% of long-term survival. Not a few patients die due to local disease without distant metastasis. Recent randomized study on the feasibility of very high dose radiotherapy, RTOG 0617, showed inferiority of 74Gy to 66Gy, and better local control should be obtained only with additional surgical resection, i.e. salvage surgery. Methods Comprehensive review of the literature will be presented. Experience of salvage surgery at Juntendo Hospital was investigated and presented. Between February of 2008 and July of 2013, 1240 patients with lung cancer underwent surgical resection, which includes 20 salvage surgeries. Salvage surgery was performed in 10 patients following chemotherapy, and 10 CRT. Majority of the mode of surgery was 6 pulmonary lobectomies, including 3 sleeve resection, and 3 pneumonectomies, including 1 sleeve pneumonectomy. The dose of radiation was 60Gy in 8 patients, 45Gy in 1 patient, and 140Gy in 1 patient who underwent proton and heavy particle radiotherapy. All cases underwent irradiation to the primary tumor and hilar and mediastinal region. Surgical outcome was investigated. Results There were no surgical mortality. There were 3 postoperative morbidity including empyema, pneumonia and bronchopleural fistula (BPF). BPF developed following right side pneumonectomy following proton and heavy particle radiation for the primary and hilar region. This patient underwent open window and remain alive without evidence of disease for 19 months. Sleeve bilobectomy of right middle and lower lobectomy following 45Gy radiation was performed in 1 patient, sleeve right upper lobectomy combined resection of the superior vena cava following concurrent CRT with 60Gy was performed in 2 patients. Postoperative course for those patients were no problems at all. Postoperative bronchial healing was excellent. Conclusion Salvage lobectomy following high dose radiation could be feasible even performing radical resection of the superior vena cava or pulmonary artery.Age/Gender Regimen Rt (Gy) Stage & Hist-ology Discrete? Timing Operation Compli-cations 73 M CBDCA+PAC×3 CBDCA+GEM ×5 60 IIIB Sq infiltrative 12 months Rt. Sleeve pneumonectomy No 68 M CBDCA+PAC×3 DOC×4 PEM×13 60 IIIA Ad infiltrative 11 months WWR No 74 M CDDP+VNR×2 60 IIIA NSCLC discrete 7 months RUL & S6 segmentectomy Pneumonia 63 M CBDCA+PAC×5 60 IIIB Sq Infiltrative 9 months RULobectomy Non 56 M CDDP+PEM×3 PEM×2 60 IIIA Ad Discrete 12 months Rt pneumonectomy Non 40 M CDDP+PEM×5 CDDP+DOC×2 VNR+Bev×2 140 IV Ad Infiltrative 4 months Rt pneumonectomy BPF 72 F CDDP+VNR×2 60 IIIA Ad Discrete 84 months RULobectomy Empyema 61 M CDDP+VNR×3 60 IIIA Ad Infiltrative 15 months Sleeve RUL SVC replacement None 61 M CDDP+VNR 60 IIIA NSCLC Discrete 2 months Sleeve RUL SVC PA plasty None 60 F CDDP+DTx 45 IIIA Ad Discrete 3 months Sleeve Middle and lower lobectomy None Only Members that have purchased this event or have registered via an access code will be able to view this content. 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