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G.R. Simon
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MINI 37 - SCLC Therapy (ID 165)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 13
- Moderators:D. Ettinger, G.R. Simon
- Coordinates: 9/09/2015, 18:30 - 20:00, 605+607
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MINI37.01 - Chk1 Inhibition Enhances Cisplatin Cytotoxicity Regardless of p53 Status in Human Small Cell Lung Cancer Cells (ID 947)
18:30 - 20:00 | Author(s): W. Hsu, S. Hsu, G. Rao, I. Kim, A.T. Alberobello, Y. Wang, G. Giaccone
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) has a poor prognosis and harbors complex genetic alterations including frequent loss-of-function mutations of p53 and Rb, which impair the G1/S checkpoint control. Checkpoint Kinase 1 (Chk1) is a vital serine/threonine specific protein kinase responsible for halting the cell cycle in check after DNA damage. With abrogation of Chk1-mediated cell cycle checkpoint control, cancer cells may enter mitosis with extensive DNA damage leading to mitotic catastrophe and apoptotic cell death. Previous in vitro studies showed that p53 deficient cancer cells benefit from Chk1 inhibition. Here we demonstrate that a combination of Chk1 inhibition and cisplatin causes more growth inhibition and caspase activation in SCLC cell lines compared to cisplatin alone, regardless of p53 status.
Methods:
Chk1 inhibition was achieved by siRNA knockdown (Qiagen) and AZD7762 (Selleckchem) in p53 mutant SCLC cell lines (GLC4, NCI-H82) and p53 intact SCLC cell lines (NCI-H128, NCI-H209). Cell viability was measured by Cell-Titer Glo assay (Promega) after 72hrs of drug treatment. Synergism was defined by combination index (CI)>1 using the Chou-Talalay method. Cell cycle analysis was performed by PI staining and detected by FACS. Western blotting and immunofluorescent staining were used to evaluate caspase activation and other signaling proteins.
Results:
SCLC cell lines were treated with cisplatin 24hrs at each IC50 dosage after Chk1 siRNA transfection. In GLC4 after 2.5uM cisplatin treatment, cell viabilities of control siRNA-treated and Chk1 siRNA-treated cells were 28% and 10.6% (p=0.006, by paired t-test), respectively. Similar significant reduction of cell viability was observed in 1uM cisplatin-treated NCI-H82 cells (44.6% vs. 29.7%; p=0.0632) and in 3uM cisplatin-treated NCI-H128 cells (62.5% vs. 45.3%; p=0.0155), respectively. More cleaved caspase-2 and caspase-3 were noted in Chk1 knockdown plus cisplatin-treated GLC4 cells than in cisplatin alone. The IC50 (72hrs) of single agent AZD7762 (Chk1 inhibitor) treatment was 240nM, 211nM, 266nM and 215nM in GLC4, NCI-H82, NCI-H128 and NCI-H209 respectively. The combination indexes of AZD7762 and cisplatin (both given at around IC50s) calculated by Chou-Talalay method indicated synergism in all these 4 cell lines. Cell cycle analysis revealed that AZD7762 abrogated cisplatin-induced G2/M arrest in GLC4 and G1 arrest in NCI-H128. Inhibition Chk1 by AZD7762 was associated with reduction of CDC25C and CDC2 phosphorylation. Phospho-Histone H3 (mitotic marker) was increased in AZD7762 and cisplatin combined treatment compared to cisplatin alone in a p53 independent fashion. Intriguingly, inhibition of Chk1 by AZD7762 alone in GLC4 cells activated caspase-2.
Conclusion:
Chk1 inhibition both by siRNA knockdown and AZD7762 enhances cisplatin cytotoxicity. The synergism was primarily due to increased apoptosis and abolished cell cycle arrest. Although p53 is frequently mutated in SCLC, growth inhibition was seen in a p53 independent manner. In GLC4, single agent AZD7762 treatment can cause caspase-2 activation through an as yet unidentified mechanism. Our findings suggest that Chk1 is a potential therapeutic target in small cell lung cancer and is synergistic with chemotherapy. The effects of Chk1 inhibitor and its combination with chemotherapy agents in SCLC animal models are currently underway.
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MINI37.02 - The Novel HSP90 Inhibitor-SN-38 Conjugate (STA-12-8666), Is Highly Active in Preclinical Models of Small Cell Lung Cancer (SCLC) (ID 911)
18:30 - 20:00 | Author(s): Y. Boumber, A. Gaponova, A. Nikonova, A. Deneka, A. Kudinov, M. Kopp, B.L. Egleston, S. Litwin, J.S. Duncan, K. Duncan, H. Borghaei, R. Mehra, D. Proia, E. Golemis
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) is a highly aggressive disease representing 12-13% of all lung cancers, with 5 year survival rate of only 6%. While most patients respond initially to cytotoxic chemotherapies such as irinotecan, etoposide, or carboplatin, resistance rapidly emerges and response to second line agents such as topotecan is limited. In contrast to non-small cell lung cancer, few targetable oncogenes have been identified in SCLC. STA-12-8666 is a small molecule drug, which binds the tumor-concentrated active form of heat shock protein 90 (HSP90), with a cleavable linker attached to SN-38, the active metabolite of irinotecan. Cleavage of the linker within the tumor provides time-release of SN-38 at high local concentration, while significantly limiting drug exposure and toxicity in non-transformed tissue. The goal for this work was to evaluate STA-12-8666 for potential use as a new second line monotherapy, or as adjuvant in the frontline setting for SCLC.
Methods:
Three dose levels of STA-12-8666 were evaluated in comparison to irinotecan, ganetespib, carboplatin, etoposide, cisplatin and chemotherapy combinations in 4 independent SCLC xenograft models, including parental and cisplatin-resistant derivative cell lines (SCLC1, SR2), and a patient-derived xenograft (PDX). STA-12-8666 was also evaluated in drug combinations. Intratumoral responses were profiled using a mass spectrometry based approach to evaluate kinase pathway activation, and results confirmed by immunohistochemistry and western blot analysis. Pharmacokinetic analysis was performed to benchmark retention of STA-12-8666 to irinotecan in lung tumors.
Results:
In all four models, high dose (150 mg/kg) STA-12-8666 was tolerated without side effects. In most cases, three doses administered at weekly intervals caused complete regression of established tumors, with response durable for > 2 months. Those tumors that regrew were responsive to re-dosing with STA-12-8666, and were subsequently eliminated. Further, STA-12-8666 induced complete or partial regression of tumors that progressed following first or second line treatment with standard of care agents for SCLC. Low dose (50 mg/kg) STA-12-8666 inhibited tumor growth and enhanced the anti-tumor activity of 30 mg/kg carboplatin, resulting in complete tumor regression. Pharmacokinetic and proteomic analysis confirmed STA-12-8666 concentration in tumors, and identified a signature of DNA damage response biomarkers in STA-12-8666-treated tumors that is different from that induced by irinotecan.
Conclusion:
The findings that HSP90i-drug conjugate STA-12-8666 is highly active in preclinical models of SCLC (in both frontline and second line settings) support the evaluation of this novel compound in clinical trials.
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MINI37.03 - Survival after Surgery for pN1 and pN2 Small Cell Lung Cancer: A Comparison with Surgical Treatment of Non-Small Cell Lung Cancer (ID 3100)
18:30 - 20:00 | Author(s): C.J. Yang, D.Y. Chan, B.C. Gulack, P.J. Speicher, M.G. Hartwig, M.F. Berry, B.C. Tong, M.W. Onaitis, T.A. D'Amico, D. Harpole
- Abstract
- Presentation
Background:
With the advent of modern chemotherapy and radiotherapy, we hypothesize that patients who undergo surgery followed by adjuvant therapy for locally advanced small cell lung cancer (SCLC) may have significantly better long-term survival compared to historical data suggesting 2-year overall survival of 4-20% for patients undergoing surgery for SCLC.
Methods:
Prospectively-collected perioperative outcomes and survival data of patients with pathologic T1-3, N1 and (limited) N2 SCLC and non-small cell lung cancer (NSCLC) who underwent complete resection with adjuvant chemotherapy ± radiation and no induction therapy were reviewed from the US National Cancer Data Base from 2003-2011 using Kaplan-Meier method and propensity-score matching. Groups were matched for common prognostic co-variates including year of diagnosis, age, sex, race, education, insurance status, facility type, distance from facility, Charlson/Deyo co-morbidity score, T and N status, tumor size, and tumor location. These prospective data were acquired by certified tumor registrars and include over 70% of cancer diagnoses annually in the U.S.
Results:
During the study period, 369 and 12,152 patients underwent complete resection for pathologic T1-3 N1-2 M0 SCLC and pT1-3 N1-2 M0 NSCLC, respectively. Median follow-up time was 43 months. Five-year overall survival was 37% for SCLC pN1 patients and 26% for SCLC pN2 patients (Table). Matched patients with pN1/N2 NSCLC had better 5-year survival compared to patients with pN1/N2 SCLC (Table and Figure). Figure 1 Figure 2
Conclusion:
SCLC T1-3 N1-2 patients who undergo complete resection followed by adjuvant chemotherapy ± radiation have 5-year survival greater than 26%. Compared to NSCLC, SCLC patients with N1/N2 disease have worse survival; however, the differences in survival between NSCLC and SCLC patients with N1/N2 disease are much smaller than previously reported. These results support a re-evaluation of the role of surgery in multimodality therapy for locally advanced small cell lung cancer.
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MINI37.04 - Discussant for MINI37.01, MINI37.02, MINI37.03 (ID 3444)
18:30 - 20:00 | Author(s): M.C. Pietanza
- Abstract
- Presentation
Abstract not provided
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MINI37.05 - Carfilzomib, Carboplatin and Etoposide for Previously Untreated Extensive-Stage Small Cell Lung Cancer: Initial Results from a Phase 1b/2 Study (ID 3008)
18:30 - 20:00 | Author(s): F. Badin, E. Eskander, H. Harper, A. Chiang, D. Haggstrom, W. Harb, S. Aggarwal, E. Demirhan, W. Fisher
- Abstract
- Presentation
Background:
Proteasome inhibitors synergize with topoisomerase inhibitors (eg, etoposide), which are frequently used to treat extensive-stage small cell lung cancer (ES-SCLC; Takigawa et al. Anticancer Res 2006;26:1869–76). Results from study PX‑171-007 (NCT00531284) suggest that carfilzomib has activity in relapsed SCLC (Papadopoulos et al. Cancer Chemother Pharmacol 2013;72:861–8), and clinical experience in myeloma suggests that carfilzomib may be added to other agents with limited additive toxicity. Preliminary results are presented from the phase 1b portion of the CFZ004 trial (NCT01987232) intended to determine the maximum tolerated dose (MTD) and safety of carfilzomib with carboplatin and etoposide in patients with previously untreated ES-SCLC.
Methods:
Patients received carfilzomib (30-minute intravenous infusion) on days 2, 3, 9, and 10 (20 mg/m[2] [days 2 and 3 of cycle 1]; 20–56 mg/m[2] thereafter) and fixed doses of carboplatin (target area under the concentration-time curve: 5 mg/mL/min) on day 1 and etoposide (100 mg/m[2]) on days 1, 2, and 3 of a 21‑day cycle for up to 6 cycles. Assessment of dose‑limiting toxicities (DLTs) in cycle 1 was used to determine dose escalation up to the MTD or recommended phase 2 dose. Disease response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Patients achieving ≥stable disease (SD) after 6 cycles could receive single-agent carfilzomib until disease progression or unacceptable toxicity.
Results:
As of March 31, 2015, 17 patients (median age: 59.0 years) had been treated in the phase 1b portion in 5 dosing cohorts; enrollment in the 56-mg/m[2] cohort is ongoing. Patients initiated a median of 6 cycles of carfilzomib; the median treatment duration was 16.3 weeks. One patient (56-mg/m[2] cohort) experienced a DLT. There were no on-study deaths. Two patients discontinued carfilzomib due to an adverse event (AE; metastatic pain: n=1; decreased neutrophil count: n=1). All-grade AEs were generally consistent with the profiles of the agents under study. Thirteen patients (76.5%) had a grade ≥3 AE; the most common (≥3 patients) were anemia (n=4), neutropenia (n=4), decreased neutrophil count (n=4), and leukopenia (n=3). The preliminary overall response rate (≥partial response) in 14 response-evaluable patients was 57.1%, with 1 complete response (Table 1). All response-evaluable patients achieved ≥SD.
Conclusion:
The MTD of carfilzomib with carboplatin and etoposide has not been reached. Patients are showing encouraging responses to treatment, with AEs generally consistent with the profiles of the agents under study. Response data, currently immature, will be updated at the meeting. Table 1. Phase 1b Best Overall Responses per Investigators
[a]Per RECIST, v1.1.Cohort 1 2 3 4 5 Total CFZ, mg/m[2] 20/20 (n=5) 20/27 (n=3) 20/36 (n=3) 20/45 (n=3) 20/56 (n=3) (N=17) Best overall response, n (%)[a] CR 0 1 (33.3) 0 0 0 1 (5.9) PR 2 (40.0) 2 (66.7) 3 (100.0) 0 0 7 (41.2) SD 3 (60.0) 0 0 2 (66.7) 1 (33.3) 6 (35.3) Not evaluable 0 0 0 1 (33.3) 2 (66.7) 3 (17.6) Overall response rate (CR+PR), n (%) All patients 2 (40.0) 3 (100.0) 3 (100.0) 0 0 8 (47.1) Response-evaluable patients 2 (40.0) 3 (100.0) 3 (100.0) 0 0 8 (57.1)
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MINI37.06 - Randomized Phase II Trial of CODE or Amrubicin Plus Cisplatin Chemotherapy after Chemoradiotherapy for Limited-Disease Small Cell Lung Cancer (ID 1033)
18:30 - 20:00 | Author(s): I. Sekine, H. Harada, N. Yamamoto, T. Takahashi, K. Goto, N. Nogami, T. Seto, F. Oshita, H. Okamoto, H. Tanaka, M. Wakabayashi, Y. Ohe
- Abstract
- Presentation
Background:
Four cycles of etoposide plus cisplatin (EP) concurrently with accelerated hyperfractionation thoracic radiotherapy (AHTRT) is the standard treatment for limited-disease small cell lung cancer (LD-SCLC). The objectives of this study were to evaluate efficacy and toxicities of CODE or amrubicin plus cisplatin (AP) chemotherapy following one cycle of EP and AHTRT in patients with LD-SCLC, and to select the promising arm for subsequent phase III trials.
Methods:
Eligibility criteria included patients with previously untreated LD-SCLC with measurable lesion, ECOG PS of 0-1, and 20-70 years of age. Eligible patients received one cycle of EP (etoposide 100 mg/m[2] on days 1-3 and cisplatin 80mg/m[2] on day 1) plus AHTRT (45Gy/ 30 fractions in 3 weeks). Patients who achieved CR, PR or SD were secondarily registered and randomized to receive either 3 cycles of CODE (cisplatin 25 mg/m[2] on days 1 and 8, doxorubicin 40 mg/m[2] on day 1, etoposide 80 mg/m[2] on days 1-3, and vincristine 1 mg/m[2] on 8 every 2 weeks) or 3 cycles of AP (amrubicin 40 mg/m[2] on days 1-3 and cisplatin 60 mg/m[2] on day 1 every 3 weeks). G-CSF was administered on the days when chemotherapy was not administered in CODE, or on day 5 to the day when a neutrophil count exceeded 5,000/µL in AP. Patients with CR after CODE or AP received prophylactic cranial irradiation. The primary endpoint was the one-year progression-free survival (PFS) after the second registration. Tumor responses were assessed with RECIST version 1.1 by the central review committee. A better regimen for phase III trial is determined with a randomized phase II selection design. The sample size was 72 randomized patients to detect >= 10% difference in one-year PFS with a probability of 80%.
Results:
From May 2011 to Jan 2014, 85 patients from 28 institutions were registered. After the induction EP plus AHTRT, 75 patients were randomized to CODE (n=39) or AP (n=36). Patient demographics were well balanced between the arms. One patient did not receive CODE and 34 (89%) of the 38 patients received 3 cycles of CODE, whereas 33 (92%) of the 36 patients received 3 cycles of AP. Grade 4 neutropenia, anemia and thrombocytopenia were observed in 47%, 21% and 16% of patients in CODE, and in 78%, 6% and 17% of patients in AP, respectively. Grade 3 non-hematological toxicities with the incidence of 5% or higher included febrile neutropenia (16%), hyponatremia (8%), hypokalemia (5%), fatigue (5%), and anorexia (5%) in CODE, and febrile neutropenia (42%), nausea (11%), anorexia (11%), fatigue (8%), esophagitis (6%) in AP. CR and PR were noted in 13 and 25 patients in CODE, and in 10 and 24 patients in AP, respectively. The median overall survival in the 74 patients was 42.8 months. The one-year PFS (95% CI) was 41.0 (25.7 - 55.8) % in CODE and 54.3 (36.6 - 69.0) % in AP.
Conclusion:
The one-year PFS seemed better in AP than in CODE. AP arm is considered to be the test regimen for the subsequent phase III trial.
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MINI37.07 - PCI Survival Improvement for Extensive Stage SCLC Limited to Patients on Maintenance Systemic Therapy: A Secondary Analysis of CALGB 30504 (ID 861)
18:30 - 20:00 | Author(s): J.K. Salama, L. Gu, X. Wang, J. Bogart, J. Crawford, S. Schild, N. Ready, E. Vokes
- Abstract
- Presentation
Background:
PCI has become standard of care for extensive stage small cell lung cancer (ES-SCLC) patients. However, one recent randomized study establishing this standard did not require brain imaging prior to enrollment, and another, which did, failed to show a benefit for PCI. CALGB 30504 (Alliance) was a randomized phase II study of sunitinib vs placebo in ES-SCLC patients responding to at least 4 cycles of platinum based therapy requiring baseline brain imaging at enrollment. As this study spanned the introduction of PCI for ES-SCLC, PCI was left to the discretion of the treating team. Therefore, we performed a secondary analysis of CALGB 30504 to determine the impact of PCI on ES-SCLC patients.
Methods:
CALGB 30504 was a phase II randomized study in ES-SCLC comparing maintenance sunitinib versus placebo following SD or CR/PR to 4-6 cycles of etopside 100 mg/m[2] d1-3 and either carboplatin AUC=5 or cisplatin 80 mg/m[2] d1 q 21 days. Sunitinib was 150 mg PO d 1 then 37.5 mg PO qd until progression. The primary objective was to determine if maintenance sunitinib would improve PFS, as was recently reported. PCI was recommended at 25 Gy in 2.5 Gy fractions, within 4-6 weeks of chemotherapy, but not required. Sunitinib was to be held 2 days prior, during, and 2 days after the completion of PCI. All statistical analyses were performed by the statisticians at Alliance/CALGB Statistical and Data Center on the platform of SAS (version 9.3; SAS Institution Inc., Cary, North Carolina).
Results:
85 patients received maintenance therapy(41placebo, 44 sunitinib). 41 (48%) received PCI, 44 didn’t. All patients and tumor characteristics were balanced between PCI and no-PCI patients. PCI dose was 25 Gy for 31 patients (range: 25-37.5 Gy). Median time to PCI was 21 wks (range: 12-27 wks) from enrollment. For all patients, PCI was associated with an improvement in PFS (median 7.8 vs 6.5 mo HR=0.63 (95% CI: 0.41-0.98), p=0.037), but not OS (median 12.9 vs 13.2 mo, HR=1.01 (95% CI: 0.64-1.62), p=0.955). In placebo patients, there was no PFS or OS difference between patients receiving PCI or not. In patients randomized to sunitinib, PCI conferred a PFS benefit (9.7 vs 6.8 mo, HR=0.49 (95% CI: 0.26-0.92), p=0.024), but not an OS benefit (14.1 vs 13.5 mo, HR=0.85 (95% CI: 0.44-1.66), p=0.636). When restricted to patients who did not receive PCI, there was no difference in survival between sunitinib or placebo patients. In PCI patients, those receiving sunitinib had non-significant improvement in PFS (9.7 vs 6.7 months, HR=0.63 (95% CI: 0.34-1.20), p=0.158) and trended towards an improvement in OS (14.1 vs 10.6 months, HR=0.56 (95% CI: 0.29-1.10), p=0.087), which was magnified and approached significance when crossover patients were excluded (14.1 vs 10.0 mo, HR=0.49 (95% CI: 0.22-1.06), p=0.064).
Conclusion:
PFS, and trends for OS improvement were limited to patients receiving the combination of PCI and maintenance sunitinib. Placebo patients did not benefit from PCI. Improved outcomes for ES-SCLC patients with PCI are likely limited to patients who achieve both intracranial and extracranial disease control.
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MINI37.08 - Pazopanib as Second Line Treatment of Platinum Sensitive SCLC Patients: A Multicenter Phase II Trial of the Hellenic Oncology Research Group (ID 1683)
18:30 - 20:00 | Author(s): A. Kotsakis, V. Karavasilis, S. Agelaki, N. Kentepozidis, S. Peroukidis, E. Samantas, C. Christophyllakis, E.K. Dermitzaki, F. Koinis, G. Fountzilas, V. Georgoulias
- Abstract
- Presentation
Background:
Pazopanib is a small anti-angiogenic molecule inhibiting the tyrosine kinase of VEGFR‑1, VEGFR‑2, VEGFR‑3, PDGF, and c‑kit. An increased angiogenesis and VEGF expression has been reported in SCLC which is correlated with disease dissemination and poor prognosis. A multicenter phase II study of second line pazopanib in patients with SCLC was conducted.
Methods:
Patients with histologically confirmed SCLC who relapsed at least 3 months after the completion of front line VP-16/CDDP chemotherapy (platinum sensitive disease) were enrolled. Eligible patients should have measurable disease and ECOG performance status (PS) 0-2. Treatment consisted of daily p.o. pazopanib 800 mg in cycles of 28 days until disease progression. The primary endpoint was progression-free rate (PFR) at 8 weeks since anti-angiogenic factors are not associated with objective tumor shrinkage.
Results:
Thirty seven out of 39 enrolled patients (2 pts are still ongoing) were evaluable for response and toxicity. The median age was 65 years (range 39-82); male=33 pts; PS 0=22 pts; PS 1=15 pts. Eleven (28.2%) patients had only local relapse. The median interval from previous treatment was 5.4 months (3.0-38.2). One (3%) CR, 10 (26%) PR and 10 (26%) SD were documented, for an overall progression free rate (PFR) of 55% (95% CI: 39.4- 71.2%). The median PFS and OS was 3.7 and 10.6 mo, respectively, while the estimated 1-year survival was 58% (median follow up= 18.9 mo). Grade 4 adverse events (AEs) included neutropenia (n=2 pts) and diarrhea (n=2 pts) whereas grade 3 AEs were fatigue (n=4pts), nausea (n=1 pt), diarrhea (n=2 pts), hand-foot syndrome (n=1 pt) and transaminasaemia (n=1 pt). Epistaxis (gr 2) was reported in 3 pts, proteinuria (gr 2) and hypertension (gr 2) in 2 pts each. There were no treatment-related deaths.
Conclusion:
Second line treatment with pazopanib of patients with sensitive SCLC, was well-tolerated and resulted in a promising overall survival and disease control rate, including objective responses.
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MINI37.09 - Discussant for MINI37.05, MINI37.06, MINI37.07, MINI37.08 (ID 3445)
18:30 - 20:00 | Author(s): T.K. Owonikoko
- Abstract
- Presentation
Abstract not provided
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MINI37.10 - Factors Associated with Severe Pneumonitis for Limited Stage Small Cell Lung Cancer (ID 1714)
18:30 - 20:00 | Author(s): R.U. Komaki, X. Wei, P.K. Allen, E.B. Holliday, A. Farooqi, S.H. Lin, P. Balter, R. Mohan, Z. Liao, J.D. Cox
- Abstract
- Presentation
Background:
Pneumonitis is a major side effect for the treatment of limited stage small cell lung cancer with concurrent chemotherapy and radiotherapy (CChRT). Prevention is more important than treatment when patients develop grade 3-5 severe pneumonitis (SP). We investigated factors causing SP among patients with limited stage small cell lung cancer (SCLC) treated by CChRT.
Methods:
This is a retrospective analysis of 559 patients with limited-stage SCLC treated at a single institution from 1986-2009 with definitive CChRT to a total dose of 45-70 Gray (Gy). Candidate variables included tumor size, year of diagnosis & treatment period (1986-1999 vs. 2000-2009), gender, age, Karnofsky’s Performance Status (KPS), ethnicity, radiation dose, cycles of induction chemotherapy, use of intensity-modulated-radiation-therapy (IMRT) and fractionation. CTCAE v2 before 2003 and CTAE v3 in 2003-2009 were used to evaluate SP Grade 3-5 which were similar. Chi-square test was used for between group comparisons for categorical variables and the median test was used for between group comparisons for continuous variables. Kaplan-Meier estimates were constructed for overall survival (OS), disease-free survival (DFS), local-recurrence-free survival (LRFS), distant metastasis-free survival (DMFS). Analysis was performed using Logistic regression analysis with SP as the primary endpoint.
Results:
Of the 559 patients included in this analysis, tumor size was available for 520 patients. Median follow-up was 21.2 months (range 1.2-240.8). Thirty-five (6.2%) patients developed SP (26 Grade-3, 8 Grade-4 & 1 Grade-5). 2D or 3DCRT was used before 2000 and IMRT was usually used for small cell lung cancer in 2000-2009. Univariate analysis (UVA)showed that SP was associated with treatment given in 2000-2009 ( OR 3.93, P<001) ,age ≥ 60 (OR 7.72, P=0.001) ,KPS < 90 (OR 2.22, P=0.02), IMRT (OR 2.3, P= 0.026) and twice daily fractionation( OR 2.38, P=0.03).Induction Chemotherapy reduced SP (OR 0.39, P= 0.023) compared to immediate CChRT. Tumor size (at cut points 3 cm & 5 cm) did not make significant difference regarding SP. Multivariate analysis (MVA) has shown that significantly higher SP was associated with treatment given in 2000-2009 (OR 3.42, P=0.006), age ≥ 60 (OR 7.77, P= 0.001), male (OR 2.12, P=0.047)and twice daily RT (OR 2.45, P=0.026) . OS was significantly reduced among SP group vs. Pneumonitis ≤ Grade 2 (MST 17.9 vs.25 months, P= 0.038) (5-year OS 16 % vs. 27%), respectively. SP were not significantly correlated with DFS, LRFS and DMFS.
Conclusion:
Significantly higher SP was seen among patients with limited stage small treated in 2000-2009, age ≥ 60, male and twice daily RT. OS was significantly reduced SP. UVA showed IMRT causing significantly higher SP. MVA did not show IMRT was a significant factor for SP. Tumor size did not show significant difference regarding SP.
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MINI37.11 - Inter-Observer Variability in Hippocampus Delineation on MRI Scans for Hippocampal Avoidance Prophylactic Cranial Irradiation Trial (ID 2620)
18:30 - 20:00 | Author(s): C. Chen, M. De Ruiter, F. Bartel, F. Vandaele, S. Sunaert, K. De Jaeger, N. Dollekamp, M. Kwint, E. Dieleman, Y. Lievens, D. De Ruysscher, S. Schagen, J. Belderbos
- Abstract
- Presentation
Background:
Prophylactic cranial irradiation (PCI) is the standard treatment in patients with small-cell lung cancer (SCLC) without progression after chemo-radiotherapy in stage I-III disease and after having a remission after chemotherapy in stage IV. In an international phase III trial (NCT01780675), patients with SCLC are randomised to receive PCI with or without Hippocampal Avoidance (HA). Accurate delineation of the hippocampus is crucial for this trial. In this study we evaluate the hippocampus delineation variability among radiation oncologists in multi-institutions for SCLC patients.
Methods:
The left and right hippocampus from 5 randomly selected patients (10 structures) were delineated by 5 radiation oncologists and 2 neuroradiologist in 7 institutions according to the RTOG atlas (http://www.rtog.org/CoreLab/ContouringAtlases/HippocampalSparing.aspx), together with a questionnaire. For each patient, a high resolution 3D inversion recovery T1 weighted MRI-scan was first registered to the planning CT-scan (1mm slicing). The observer then delineated the hippocampus according to the atlas on axial slices of the MRI. The mapped delineations on the CT were then used in dose planning with a 5mm margin. The mean and standard deviation (SD) of 1) volume and 2) range in medio-lateral, superior-inferior and anterior-posterior directions were computed for each structure. The corresponding inter-observer reliability was estimated by the intra-class correlation coefficient (ICC absolute agreement) using a linear mixed model. A median surface was computed and the overall delineation variability per structure was calculated by the root-mean-square (rms) of the local SD per sampled points on the median surface, while the local SD corresponds to the perpendicular distance between each observer and a sampled point.
Results:
The standard deviation of the delineated volume per structure varied from 0.14 to 0.48cm3. The corresponding inter-observer reliability (ICC) was 0.19, implying a high variability among the observers. The overall delineation variability per structure varied from 0.6 to 1.0mm. Areas with good agreements were the superior and inferior part of the hippocampus. The difficult area (Fig.1) was in the anterior medial area, close to the amygdala and uncus. The ICC in medio-lateral, superior-inferior and anterior-posterior directions were 0.55, 0.64 and 0.80, respectively. A large spread of the SD of range in medio-lateral direction and the relative low ICC imply that a better instruction, or training is desirable to improve the delineations. Figure 1
Conclusion:
There was a substantial variability in hippocampus delineation among the observers. Stricter adherence to the RTOG guidelines and (web-based) training are needed. The implication of the variations on the dose distribution is currently verified.
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MINI37.12 - Survival Trends of Small Cell Lung Cancer (SCLC) in the United States: A SEER Database Analysis (ID 399)
18:30 - 20:00 | Author(s): K.M. Islam, L. Nawal, P.E. Deviany, T. Anggondowati, A.K. Ganti
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) has poor outcomes. The past thirty years have seen some advances in the management options for SCLC. However the impact of these advances on outcomes in the general population with SCLC is unclear.
Methods:
The Surveillance, Epidemiology, and End Result (SEER) registry 18 was used to identify SCLC cases from 1988 to 2011. Patients were classified either limited stage (LS) or extensive stage (ES) disease at diagnosis. Cox regression model was used to compare overall survival after adjustment for confounding covariates.
Results:
A cohort of 83,396 SCLC patients was analyzed. A higher proportion of males had ES-SCLC compared to females (72.7% vs. 67.4%; p<0.0001) Males had worse median overall survival (OS) compared to females (LS-SCLC: 10 vs. 12 months, HR: 1.11; 95% CI, 1.08-1.14; ES-SCLC: 6 vs. 7 months; HR: 1.16, 95% CI, 1.14-1.18). A higher proportion of younger patients (≤70 years) compared to older patients (>70 years) had ES-SCLC at diagnosis (70.76 vs. 68.02%; p<0.0001). However, median OS was worse in older patients for both stages (LS-SCLC: 10 vs. 13 months; HR 1.31, 95% CI 1.27-1.34; ES-SCLC: 6 vs. 8 months, HR: 1.19, 95% CI 1.16-1.21). A higher proportion of whites presented with ES-SCLC as compared to blacks or others (70.1% vs. 66.5% and 65.9%; p<0.0001). Blacks had worse median OS compared to whites (LS-SCLC: 10 vs. 11 months; HR: 1.07, 95% CI, 1.02-1.12; ES-SCLC: 6 vs. 7 months, HR: 1.07, 95% CI 1.02-1.12). Compared to the reference period 1993-1997, patients diagnosed with ES-SCLC during the latter time periods had worse OS: 1998-2002 (HR: 1.12; 95% CI, 1.08-1.15), 2003-2007 (HR: 1.23, 95% CI 1.20-1.27) and 2008+ (HR: 1.53, 95% CI, 1.49-1.58). A similar difference was not seen in patients with LS-SCLC, where only the most recent time period 2008+, had a worse survival compared to 1993-1997 period (HR: 1.37, 95% CI, 1.30-1.43).
Conclusion:
Females, whites, and younger patients with SCLC had better OS compared to males, blacks and older patients, respectively. Unfortunately, survival from SCLC has not improved significantly and may actually have worsened, during the past 20 years. The reason for this discord between clinical trial evidence and real-world evidence need to be investigated further. Newer treatment approaches are urgently needed for this disease.
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MINI37.13 - Discussant for MINI37.10, MINI37.11, MINI37.12 (ID 3446)
18:30 - 20:00 | Author(s): N. Murray
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 21 - Novel Targets (ID 133)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:B.P. Levy, D.S. Tan
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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MINI21.07 - Oncogenic EZH2 Is an Actionable Target in Patients with Adenocarcinoma of the Lung (LUAD) (ID 3169)
16:45 - 18:15 | Author(s): G.R. Simon
- Abstract
- Presentation
Background:
The methyltransferase enhancer of zeste homolog 2 (EZH2) belongs to the polycomb repressive 2 complex (PRC2). EZH2 is upregulated in several malignancies including prostate, breast and lung cancer. The EZH2 protein forms one of the critical protein complexes of PRC2 by partnering with EED (embryonic ectoderm development) protein. This EED/EZH2 complex has been shown to interact with histone deacytelase (HDAC). This interaction is highly specific and HDAC does not interact with any other PRC2 protein complexes. In the present study, we investigated the link between EZH2 and HDAC in lung cancer cell lines and in human tumor tissue microarrays (TMAs). We also further investigated EZH2 as a marker for response to HDAC inhibitors.
Methods:
We analyzed EZH2 and HDAC1 mRNA expression in two lung adenocarcinoma datasets (MDACC n=152, and TCGA n=308), and correlated the gene expression with tumors’ clinico-pathological characteristics and patients’ outcome. To study the association of EZH2 and HDAC1 expression with response to the HDAC1 inhibitor suberanilohydroxamic acid (SAHA), we examined mRNA and protein expression by RT-PCR and Western blot, respectively, in twelve lung adenocarcinoma (LUAD) cell lines at baseline and after overexpression or knock-down of EZH2 or HDAC1 gene expression using siRNA. Response to (SAHA) in cell lines was measured by MTT assay and correlated with protein and mRNA expression levels of EZH2 and HDAC1.
Results:
Direct and positive correlation was found between EZH2 and HDAC1 expression NSCLC cell lines (P <0.0001). This correlation was confirmed in NSCLC specimens from MDACC (Spearman’s correlation r=0.416; p < 0.0001) and TCGA datasets (r=0.221; p <0.0001).Patients with high EZH2 and high HDAC1 expression in stage I NSCLC specimens of MDACC and TCGA datasets had lowest survival compared to the patients who had either or both low expressions. Overall survival in the univariate analysis (MDACC dataset; Hazard Ratio (HR)=2.97; p=0.031 and TCGA dataset; HR=2.6 and p=0.041) and multivariate analysis (MDACC; HR=2.92 and p=0.034 and TCGA; HR=3.17 p=0.016). When EZH2 expression was knock down, there was a significant reduction in HDAC1 expression; conversely, when HDAC1 was knocked down EZH2 expression was also decreased. These concordant change in expression was seen both at the protein and mRNA level. Importantly, while all 8 cell lines with high EZH2 protein expression responded to SAHA treatment with average inhibition rate reaching 73.1%, three out of four cell lines with low EZH2 expression had a significantly lower response rate to SAHA inhibition with average inhibition rate 43.2% (P<0.0001). Additionally, altering the expression of EZH2 concordantly altered the sensitivity to SAHA i. e. forced increased expression of EZH2 increased the response to SAHA and vice versa.
Conclusion:
Our data suggest that EZH2 and HDAC expression are correlated in LUAD cell lines in human tissue microarrays and overexpression of both is a negative prognostic indicator. Additionally we show that increased EZH2 expression predicts for response to HDAC inhibitors and thus could serve as a biomarker for selecting LUAD patients with HDAC inhibitors.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-041 - MD Anderson Oncology Expert Advisor™ System (OEA™): A Cognitive Computing Recommendations Application (App) for Lung Cancer (ID 3106)
09:30 - 17:00 | Author(s): G.R. Simon
- Abstract
Background:
The OEA[TM] is a clinical support system with a continuous improvement capability. Its objectives are to enable/empower evidence-based decisions/care by disseminating knowledge and expertise to physicians/users tailored to meet the clinical needs of individual patients as if consulting with an expert. Cognitive computing platforms have the potential to disseminate expert knowledge and tertiary level care to patients. This objective is made possible by making available to physicians/providers cognitive computing generated expert recommendations in diagnosis, staging and treatment. The cognitive computing software was trained by MD Anderson experts using currently available consensus guidelines and an iterative feedback process. Here we test the capability of this cognitive computing software program developed at MD Anderson to generate expert recommendations when patients with advanced-stage NSCLC have a targetable molecular aberration.
Methods:
We developed a web based prototype of MD Anderson’s Oncology Expert Advisor (OEA[TM]), a cognitive clinical decision support tool powered by IBM Watson. The Watson technology is IBM’s third generation cognitive computing system based on its unique capabilities in natural language processing and deep QA (question-answer). We trained OEA[TM] by loading historical patient cases and assessed the accuracy of targeted treatment suggestions using MD Anderson’s physicians’ decisions as benchmark. A false positive result was defined as a treatment recommendation rendered with high confidence that was non-correct (less optimal), whereas false negative was defined as a correct or more optimal treatment suggestion listed as a low confidence recommendation.
Results:
In our preliminary analyses, OEA[TM] demonstrated four core capabilities: 1) Patient Evaluation through interpretation of structured and unstructured clinical data to create a dynamic case summary with longitudinal view of the pertinent events 2) Treatment and management suggestions based on patient profile weighed against consensus guidelines, relevant literature, and MD Anderson expertise, which included approved therapies, genomic based therapies as well as automated matching to appropriate clinical trials at MD Anderson, 3) Care pathway advisory that alerts the user for anticipated toxicities and its early identification and proactive management, and 4) Patient-oriented research functionalities for identification of patient cohorts and hypothesis generation for future potential clinical investigations. Detailed testing continues and the accuracy of standard-of-care (SOC) treatment recommendations of OEA[TM], as well as false positivity and negativity rates will be presented in detail at the meeting.
Conclusion:
OEA[TM] is able to generate dynamic patient case summary by interpreting structured and unstructured clinical data and suggest personalized treatment options. Live system evaluation of OEA[TM] is ongoing and the application of OEA[TM] in clinical practice is expected to be piloted at our institution.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-055 - Anti-Glut-1 Antibody as a Novel Therapeutic Modality against Breast and Lung Cancers (ID 3158)
09:30 - 17:00 | Author(s): G.R. Simon
- Abstract
Background:
The growth and survival of many tumors are dependent upon high glucose uptake to meets it energy needs. A family of glucose transporters proteins (GLUTs) facilitate glucose uptake by cancer cells. There are at least 12 known isoforms of glucose transporter proteins. These transporter proteins differ in their kinetics and its expression is tailored to the requirement of the individual cell type. Although more than one Glut transporter protein may be expressed by a particular tumor cell type, tumors frequently over express Glut-1 which is a high affinity glucose transporter protein allowing the tumor to internalized a relatively large amount of glucose. Indeed tumoral Glut-1 expression correlates with the intensity of glucose uptake seen in a PET scan. We have previously demonstrated that anti-Glut-1 monoclonal antibody inhibited proliferation and induced apoptosis in breast cancer and lung cancer cell lines in vitro. Here we report the results of our in vivo studies where we investigated the ability of anti-Glut-1 monoclonal antibody to retard tumor growth in orthotopically implanted MDAMB-231 cell line in female athymic nude mice. We also examined the ability of the Glut-1 antibody to augment the retardation of tumor growth induced by cisplatin, paclitaxel, tamoxifen, and trastuzumab in the study.
Methods:
MDA-MB-231 breast cancer cells were orthotopically implanted in female thymic nude mice. Cohorts of tumor bearing mice were treated with control solution (PBS) or different dose levels of anti-Glut 1 antibody through tail vein injections. The Glut-1 monoclonal antibody used in the studies detailed here was generated from the clone SPM498. Once an optimal dose of Glu-1 antibody was selected we tested its ability to augment the growth retardation induced by cisplatin, paclitaxel, tamoxifen and trastuzumab. Tumors were measured as treatments continued. At the sign of earliest distress the animals were sacrificed and the organs were harvested and examined for evidence of toxicity and metastases. The harvested tumors were then subjected to Western blot and immunohistochemical analysis to look for markers of apoptosis and proliferation. All the organs and peripheral blood were examined to look for evidence of organ toxicity as a consequence of treatment by the Glut-1 antibody.
Results:
Anti-Glut 1 antibody can be administered safely in high doses to mice. No consistent organ toxicities associated with Glut-1 treatment were observed. Specifically, there was no central nervous system side effects noted in the mice given that the brain accounts for approximately 30% of the total glucose consumption. Treatment with Anti-Glut-1 antibody did not demonstrate significant single agent activity; however an increase in survival was observed in mice treated with the combination of tamoxifen and the anti-Glut-1 antibody compared with tamoxifen alone. The results of the detailed analyses will be presented at the meeting.
Conclusion:
Our studies demonstrate that anti-Glut1 antibody can be safely administered to mice without major organ toxicity including CNS toxicity. It demonstrated limited anti-tumor efficacy as a single agent, but it shows an increased anti-tumor effect when combined with tamoxifen. Further studies evaluating the combination of anti-Glut-1 antibody with targeted and hormonal agents are warranted.
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P3.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 214)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.03-032 - MD Anderson Oncology Expert Advisor™: A Cognitive Clinical Decision Support Tool for Evidence-Based Multi-Disciplinary Lung Cancer Care (ID 3039)
09:30 - 17:00 | Author(s): G.R. Simon
- Abstract
Background:
The majority of patients diagnosed with non-small cell lung cancer (NSCLC) receive care in the community setting with limited access to multidisciplinary management common in tertiary care centers. The availability of genomics allows tailored treatments for patients; and with novel, rapidly emerging therapeutic options, it is challenging for busy clinicians to maintain familiarity with current therapy recommendations. Therefore, to empower practicing oncologists in community settings to offer the optimal management at the first intervention, we have developed the MD Anderson Oncology Expert Advisor™ (OEA) application for multi-disciplinary management of lung cancer patients. As the first multi-disciplinary solution for providing comprehensive management of lung cancer, the objective of OEA™ Lung is to leverage cognitive analytics on vast and ever evolving clinical care information and patient big data to disseminate knowledge and expertise, thus enabling physicians to provide evidence-based care and management tailored for the individual patient, similar to consulting an expert. Further, we aimed to create a system for sharing knowledge from more experienced experts to provide care pathways and management recommendations for physicians globally.
Methods:
Using cognitive computing, our cancer center partnered with IBM Watson to develop an expert system designed to provide physicians with the tools needed to process high-volume patient and medical information and to stay up-to-date with the latest treatment and management options, so that they can make the best evidence-based treatment decisions for their lung cancer patients. The OEA™ application for lung was built upon core capabilities of the OEA™ applications for leukemia and molecular/targeted therapies. Experts in multiple disciplines including thoracic surgery, medical oncology, and radiation oncology met regularly to design and provide specialized input to the IBM technical team in an agile development cycle. This system was powered to utilize both structured and unstructured data from validated sources; to thoroughly evaluate and stage patients; and to offer eligible clinical trials and personalized therapeutic options. In addition to delivering evidence-based, weighted therapy recommendations, OEA™ Lung provides care pathways for management of toxicities for each treatment modality (surgery, radiation, and medical oncology).
Results:
The OEA™ Lung application supports three core functions: 1) dynamic patient summary assimilating complete (structured and unstructured) data to show demographics, labs, genotype, treatment history, and previous treatment responses; 2) weighted evidence-based, multimodality treatment options, with recommendations based on literature support which is provided, along with screening for relevant trials; 3) care pathway advisories, to manage treatment related toxicities for each modality. Further, this product improves quality of care by optimizing outcomes with access to trials and care pathways.
Conclusion:
The OEA™ application for lung is a cognitive expert system designed to assimilate multidisciplinary recommendations for care and management of lung cancer patients based on current consensus guidelines and expert recommendations from a quaternary referral cancer center to the community practice setting. By democratizing knowledge from our specialty cancer center, we have taken steps toward achieving an important goal of ending cancer for all, by providing global access to optimal cancer care for patients with this disease. Further evaluation of outcomes following implementation are warranted.
