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GR 03 - Extensive Small Cell with Excellent Response to 1st Line Rx (PCI, Chest and/or Oligomet RT) and Second Line and Treatment of Thymic Malignancies (ID 16)
- Event: WCLC 2015
- Type: Grand Rounds
- Track: Small Cell Lung Cancer
- Presentations: 6
- Moderators:B.E. Johnson, B. Kavanagh, P. Kosmidis, E. Ruffini
- Coordinates: 9/09/2015, 14:15 - 15:45, 102+104+106
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GR03.01a - SCLC Therapy (ID 1838)
14:20 - 14:40 | Author(s): R.U. Komaki
- Abstract
- Presentation
Abstract:
The incidence of lung cancer has been declining since the advent of tobacco cessation efforts, and screening has improved 5-year overall survival rates among smokers to some extent. Nevertheless, about 13% of lung cancers are of the small cell subtype (SCLC), and many such cases present as extensive disease. Outcomes for patients with extensive SCLC remain poor, with median times to progression of 4–6 months, median survival times of 7–11 months, and 2-year survival rates of <5%.[1] Chemotherapy has been the cornerstone of treatment, with the current standard being 4–6 cycles of platinum-based chemotherapy. Other approaches involving other chemotherapeutic agents, molecular targeted drugs, or maintenance chemotherapy have not led to improvement. A notable exception, however, is prophylactic cranial irradiation (PCI) for patients who experience a complete response after induction chemotherapy. PCI has been shown to eliminate the progressive increase in the risk of brain metastasis that accompanies extended survival in patients with SCLC, and in that context is important for maximizing the probability for cure for such patients.[2] Indeed, PCI has led to extended survival among patients with limited-stage SCLC and some patients with extensive SCLC. A randomized phase III trial of patients with extensive SCLC reported by Slotman et al.[3] showed that PCI reduced the incidence of symptomatic brain metastases (15% versus 40% in a no-PCI control group) and increased the 1-year overall survival (OS) rate from 13% to 27%. However, a benefit of PCI for patients with extensive SCLC has not been noted consistently. A multicenter trial from Japan (UMIN000001755, reported in abstract form at ASCO 2014)[ 4] was terminated early because the futility boundary was crossed for OS. That study indicated that receipt of PCI after response to chemotherapy for extensive SCLC reduced the risk of developing brain metastases but had a negative effect on OS (median OS time 10.1 months for PCI vs. 15.1 months for observation, HR=1.38, 95% CI 0.95-2.01, stratified log-rank test P=0.091). Differences between that study and the phase III trial reported by Slotman included the use of magnetic resonance imaging to rule out brain involvement at enrollment, use of only platinum-based doublet chemotherapy, and use of a single PCI schedule (25 Gy in 10 fractions). Another multicenter study involving PCI, RTOG 0937, was also closed early for crossing a survival futility boundary. Further, although the Japanese study showed no difference between the PCI vs. observation groups in terms of incidence of grade >2 adverse events, a disproportionate distribution of grade 4 and 5 events in RTOG 0937 between groups (PCI with or without consolidative extracranial irradiation) also contributed to the early closure of that trial. In addition to PCI, thoracic radiation therapy can improve local control and extend survival for patients with limited-stage disease and possibly for some patients with extensive disease. Controlling intrathoracic tumors remains problematic in SCLC, as such disease remains after induction chemotherapy in most patients and progresses in nearly all patients within the first year after diagnosis. Evidence of benefit for patients with extensive disease includes a single-institution trial of patients with a complete response to induction chemotherapy at distant disease sites, and a complete or partial local response, who received additional low-dose chemotherapy with or without thoracic radiotherapy; that study showed significant improvements in local control and survival after thoracic radiotherapy.[5] Other evidence of benefit comes from two retrospective analyses,[6,7] one non-randomised phase II trial,[8] and a recent phase III multicenter trial of thoracic radiotherapy with PCI for patients with extensive SCLC that had responded to chemotherapy.[9] The latter study involved 247 patients who received thoracic radiation and PCI and 248 who received PCI only after responding to chemotherapy. Although OS at 1 year was no different between groups (33% [95% confidence interval {CI} 27–39] thoracic vs. 28% [95% CI 22–34] control), a secondary analysis showed that the 2-year OS rate was better (13% [95% CI 9–19] vs. 3% [95% CI 2–8], P=0.004) and progression was less likely in the group that received thoracic radiotherapy (hazard ratio 0.73, 95% CI 0.61–0.87, P=0.001). These findings, in combination with low rates of severe toxic effects (no grade 5; grade 3-4 in 26 thoracic and 18 control patients), led the authors to recommend that thoracic radiotherapy be considered, in addition to PCI, for all patients with extensive SCLC who respond to chemotherapy. References 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the Surveillance, Epidemiology, and End Results database. J Clin Oncol 2006;24:4539–44. 2. Komaki R, Cox JD, Whitson W. Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat Rep 1981;65(9-10):811-814. 3. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:664–672. 4. Seto T, Takahashi T, Yamanaka T, et al. Prophylactic cranial irradiation has a detrimental effect on the overall survival of patients with extensive disease small cell lung cancer: results of a Japanese randomized phase III trial (abstract). J Clin Oncol 2014;32:5s (suppl; abstr 7503). 5. Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol 1999;17:2092–2099. 6. Giuliani ME, Atallah S, Sun A, et al. Clinical outcomes of extensive stage small cell lung carcinoma patients treated with consolidative thoracic radiotherapy. Clin Lung Cancer 2011; 12: 375–379. 7. Zhu H, Zhou Z, Wang Y, et al. Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer with distant metastasis. Cancer 2011; 117: 5423–5431. 8. Yee D, Butts C, Reiman A, et al. Clinical trial of post-chemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234–238. 9. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015;385:36–42.
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GR03.01b - Systemic Therapy of Extensive Stage Small Cell Lung Cancer (SCLC): Contrasting Therapeutic Principles for SCLC and Non-small Cell Lung Cancer (NSCLC) in 2015 (ID 1839)
14:40 - 15:00 | Author(s): N. Murray
- Abstract
- Presentation
Abstract:
Since the 1960’s, SCLC has been recognized as a distinct lung cancer subtype with unique sensitivity to chemotherapy and radiotherapy. Indeed SCLC and NSCLC are generally discussed as separate topics. After 50 years of investigation, it may be useful to recognize similarities as well as differences in therapeutic principles for systemic therapy. For metastatic disease, palliative first-line systemic therapy for SCLC and NSCLC patients without a drugable driver mutation is a platinum-based two drug chemotherapy combination. For SCLC, platinum and etoposide has generally prevailed as standard although platinum plus irinotecan is widely used in Asia. The platinum doublet used for first-line chemotherapy for NSCLC has had a more complex evolution with many variations, however, the evidence for improved survival with modern platinum doublets can be questioned, even for non-squamous cancers.(1) In both pathologic types, single agents or dose attenuation with first-line therapy result in inferior outcomes. Three and four drug chemotherapy regimens are not better than two drug regimens. Dose-dense and high dose cytotoxic regimens do not generate superior survival results. Non-platinum regimens are not superior to platinum-based two drug combinations. Four to six cycles of first-line therapy is sufficient for most patients. Maintenance chemotherapy is not recommended for SCLC whereas it is an option for NSCLC that confers a survival advantage if patients fail to receive second-line therapy. Second-line treatment for both types of lung cancer is single agent chemotherapy and the survival benefit is worthwhile but modest. Topoisomerase-1 inhibitors have been extensively investigated and used in SCLC. Docetaxel is standard second-line therapy for squamous cancers whereas docetaxel and pemetrexed have equal efficacy in second-line chemotherapy of non-squamous cancers. For both types of lung cancer, second-line chemotherapy is usually unrewarding for cases progressing on first-line chemotherapy or relapsing within less than three months as these tumors have demonstrated chemotherapy resistant biology with response rates of about 10%. Tumors that are sensitive to first-line chemotherapy with a long time to progression are somewhat more tractable with second-line therapy. Third line chemotherapy is not evidenced-based for either SCLC or NSCLC, but may be a reasonable option in selected patients that have responded to second-line treatment. The survival outcome for metastatic SCLC and metastatic NSCLC (without EGFR or ALK mutations) is similar with a median survival of 11-12 months and a two-year survival of 5-10%. Although the initial response rate of SCLC of 60-70% is about double that of NSCLC, the median time for chemotherapy resistant clones to cause a fatal outcome is about the same for both diseases. Without doubt, the natural history of metastatic lung cancer unrestrained by any chemotherapy is worse for SCLC than NSCLC. With respect to trials of SCLC with new chemotherapy agents, it is important to recognize themes of investigation that have been unrewarding. Generally speaking, analogues of active drugs have failed to show evidence of improved survival compared to the parent compounds. This has been shown for alkylating agents, platinum compounds, vinca alkaloids, epipodophylotoxins, and anthracyclines. Moreover, randomized trials have demonstrated statistically significantly inferior survival outcomes for two novel analogues when compared to regimens considered to be standard-of-care. The folate antagonist pemetrexed was studied in a phase III trial of first-line chemotherapy. The GALES (Global Analysis of Pemetrexed in SCLC Extensive Stage) randomized pemetrexed/ cisplatin versus etoposide/ cisplatin.(2) Accrual was terminated early by the data safety and monitoring committee. Survival was inferior in the pemetrexed-platinum arm (median survival 8.1 months) compared to 10.6 months for etoposide-cisplatin (p <0.01). Time to progression (TTP) and response rates (RR) were worse as well. The inferior result was not explained by thymidylate synthase expression or other folate pathway biomarkers.(3) Pemetrexed is simply a bad drug for treatment of SCLC. Similarly, the taxane analogue cabizitaxel was tested in the second-line setting against topotecan.(4) Cabizitaxel was signifantly inferior to topotecan for RR, TTP and survival. This result stands as another example of analogue investigation failure and makes one wonder about the use of any taxane in SCLC. The discovery of treatable molecular targets in adenocarcinomas with approved drugs is a conspicuous difference in systemic therapy of NSCLC compared to SCLC. No molecular targets that can be treated with drugs with proven efficacy have as yet been approved for SCLC.(5) This is not due to a lack of trying. A large number of molecular targeted agents have already been studied in SCLC without a signal of sufficient activity to continue development.(6) The roster includes pathways suggested by analysis of the SCLC genome but numerous other molecular targeted drugs of interest in other cancers were also tested. Drugs with better efficacy may be identified by more extensive SCLC genome analysis,(5) but there is no escaping the fact that results reported to date have been disappointing. Data from genome analysis have shown a bewildering array of abnormalities in this tobacco hyper-mutated tumor. Like squamous carcinomas, the SCLC molecular battlefield is bleak and complex with little opportunity for even temporary respite by identification of mutually exclusive oncogenic drivers. An intriguing possibility is that the numerous mutations in SCLC may be an asset for immunotherapy studies. Checkpoint inhibition has already been demonstrated superior to standard of care in second-line therapy of both squamous (8) and non-squamous NSCLC.(9) At ASCO 2015, two phase II studies of immunotherapy in previously treated SCLC were presented and the results are provocative. Nivolumab produced a RR of 18% and nivolumab plus ipilumimab had a RR of 17% in a population unselected for PD-L1 positivity.(10) In patients selected for PD-L1 positivity, pembrolizumab produced responses in 35%.(11) Although data is preliminary, some responses in these immunotherapy studies may be long-lasting. . The therapeutic principles of systemic therapy of SCLC and NSCLC may be converging again with immunotherapy becoming the most exciting advance in both histologic types. References (1) Murray N. Reality check for pemetrexed and maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 2014 Feb 10;32(5):482-483. (2) Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, et al. Phase III Study of Pemetrexed Plus Carboplatin Compared With Etoposide Plus Carboplatin in Chemotherapy-Naive Patients With Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol 2009 October 1;27(28):4787-4792. (3) Smit EF, Socinski MA, Mullaney BP, Myrand SP, Scagliotti GV, Lorigan P, et al. Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer. Ann Oncol 2012 Jul;23(7):1723-1729. (4) Evans TL, Kim J, Shepherd FA, Syrigos KN, Udud K, Chubenko V, et al. Cabazitaxel (Cbz) versus topotecan in patients (pts) with small cell lung cancer (SCLC) that has progressed during or after first-line treatment with platinum-based chemotherapy: A randomized phase II study. ASCO Meeting Abstracts 2013 June 17;31(15_suppl):TPS7609. (5) Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012 Oct;44(10):1111-1116. (6) Murray N, Noonan K. Can we expect progress of targeted therapy of small cell lung cancer? In: Dingemans A, Reck M, Westeel V, editors. Lung cancer Sheffield: European Respiratory Society; 2015. p. 234. (7) Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015 May 31. (8) Paz-Ares L, Horn L, Borghaei H, Spigel DR, Steins M, Ready N, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 2015 June 22;33(18_suppl):LBA109. (9) Antonia SJ, Bendell JC, Taylor MH, Calvo E, Jaeger D, De Braud FG, et al. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. ASCO Meeting Abstracts 2015 May 18;33(15_suppl):7503. (10) Ott PA, Fernandez MEE, Hiret S, Kim D, Moss RA, Winser T, et al. Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028. ASCO Meeting Abstracts 2015 May 18;33(15_suppl):7502.
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GR03.02 - Treatment of Thymic Malignancies - Surgery (ID 1840)
15:00 - 15:10 | Author(s): F. Detterbeck
- Abstract
- Presentation
Abstract not provided
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GR03.03 - Treatment of Thymic Malignancies - Radiotherapy (ID 1841)
15:10 - 15:20 | Author(s): D. Gomez
- Abstract
- Presentation
Abstract:
Indications and techniques for radiation therapy for thymic malignancies have evolved over the past decade. The primary indication for radiation has historically been mediastinal radiation in the adjuvant setting (postoperative radiation therapy, PORT). The recommendations for PORT vary by stage. As increased evidence suggests high local control rates with surgery alone in Masaoka-Koga stage I-II disease, there is a general consensus that in early stages PORT can be omitted. Several studies have demonstrated that local control rates after surgery alone in stage I disease are excellent, and thus there is no indication for PORT in this setting[1-3]. In contrast, for stage III disease, many studies have shown increased rates of local failure after surgery alone, and with an improvement in outcomes with PORT[3-5]. Indeed, common approaches in stage III disease include neoadjuvant chemotherapy, followed by surgery, and then PORT, based on institutional results that demonstrate high levels of disease control with this approach[6-8], and neoadjuvant chemoradiation followed by surgery[9]. Similar to other thoracic malignancies, the advent of advanced radiation techniques has allowed for increased sparing of mediastinal structures such as the heart, great vessels, and lung. This reduction in dose may ultimately lead to lower side effects, thus enhancing the quality of life for survivors of this malignancy. It is recommended that all patients undergo computed tomography-based simulation and radiation treatment with conformal techniques, to minimize dose to the surrounding structures such as the lungs, heart, and underlying vasculature. If possible, motion management should be performed during treatment planning to encompass the extent of respiratory motion. The radiation treatment field should encompass the preoperative extent of disease, including regions of surgical clips. Radiation oncologists should consult the surgeon in the design of their field to ensure that high-risk operative regions are included. Elective nodal radiation is not indicated, based on studies showing that there are minimal to no recurrences in elective nodes after mediastinal radiation. In addition to PORT to the mediastinal bed, as patterns of failure analyses have demonstrated a propensity for pleural failure, there has been interest in utilizing more extensive radiation fields (e.g. hemithoracic radiation therapy), either as prophylaxis or when pleural recurrence occurs[10]. Given the lack of strong evidence supporting this approach, it is recommended that this treatment primarily be performed in the context of a clinical trial. At this time, there is not an established role for radiation in stage IV disease, and studies assessing this technique using modern radiation modalities are ongoing. References 1. Park HS, Shin DM, Lee JS, et al. Thymoma. A retrospective study of 87 cases. Cancer. 1994;73: 2491-2498. 2. Forquer JA, Rong N, Fakiris AJ, Loehrer PJ, Sr., Johnstone PA. Postoperative radiotherapy after surgical resection of thymoma: differing roles in localized and regional disease. Int J Radiat Oncol Biol Phys. 2010;76: 440-445. 3. Fernandes AT, Shinohara ET, Guo M, et al. The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Oncol. 2010;5: 1454-1460. 4. Weksler B, Shende M, Nason KS, Gallagher A, Ferson PF, Pennathur A. The role of adjuvant radiation therapy for resected stage III thymoma: a population-based study. Ann Thorac Surg. 2012;93: 1822-1828; discussion 1828-1829. 5. Gao L, Wang C, Fang W, Zhang J, Lv C, Fu S. Outcome of multimodality treatment for 188 cases of type B3 thymoma. J Thorac Oncol. 2013;8: 1329-1334. 6. Kim ES, Putnam JB, Komaki R, et al. Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer. 2004;44: 369-379. 7. Huang J, Riely GJ, Rosenzweig KE, Rusch VW. Multimodality therapy for locally advanced thymomas: state of the art or investigational therapy? Ann Thorac Surg. 2008;85: 365-367. 8. Modh A, Rimner A, Allen PK, et al. Treatment Modalities and Outcomes in Patients With Advanced Invasive Thymoma or Thymic Carcinoma: A Retrospective Multicenter Study. Am J Clin Oncol. 2014. 9. Korst RJ, Bezjak A, Blackmon S, et al. Neoadjuvant chemoradiotherapy for locally advanced thymic tumors: a phase II, multi-institutional clinical trial. J Thorac Cardiovasc Surg. 2014;147: 36-44, 46 e31. 10. Sugie C, Shibamoto Y, Ikeya-Hashizume C, et al. Invasive thymoma: postoperative mediastinal irradiation, and low-dose entire hemithorax irradiation in patients with pleural dissemination. J Thorac Oncol. 2008;3: 75-81.
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GR03.04 - Treatment of Thymic Malignancies - Biology and Standard Treatment (ID 1842)
15:20 - 15:30 | Author(s): G. Giaccone
- Abstract
- Presentation
Abstract:
Thymic epithelial tumors (TETs) are rare malignanices of the thymic epitehlial cells. Recent research has identified recurrent mutations in these tumors, using NextGen sequencing (Petrini et al. Nature Gen 2014; Wang et al Sci. Rep. 2015). GTF2i, a general transcription factor has been found to have a high frequency of a unique muation in over 70% of type A and AB, whereas this mutation decreases in frequency in thymic carcinomas. Mutation in GTF2i may represent an oncogenic event in TETs. Common recurrent mutations in known cancer genes have been found more frequenty in thymic carcinomas, where the number of mutations is higher than in more indolent forms of TETs. In particular genes involved in epigenetic regulation have been found recurrently mutated. Presence of P53 mutations was also found to be related to poorer survival, as well as the number of recurrent mutations. The implications of molecular characterization of TETs on treatment are still relatively small, but they represent a first step toeards more targeted treatments. Chemotherapy remains the standard treatment for first line therapy of patients with un-resectable disease, or as neoadjuvant therapy in large tumors before surgery or radiation. The more commonly employed regimes still are represented by the PAC regimen, PE regimen and more recently carbo-taxol. Targeted therapies have been studied in unselected patients and of all of those tested in properly conducted phase II studies, sunitinib appears to be the most effective in thymic carcinoma (25% response rate; Thomas et al. Lancet Oncol 2015). A phase II of pembrolizumab is actively accruing in patients with thymic carcinomas, where PDL-1 expression is relatively high.
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GR03.05 - Thymic Epithelial Tumors: New Hope on the Horizon with Novel Therapeutic Strategies (ID 1843)
15:30 - 15:40 | Author(s): J. Remon-Masip, B. Besse
- Abstract
- Presentation
Abstract:
Thymic Epithelial Tumors (TET) comprised of thymoma (T) and thymic carcinoma (TC) are rare cancers with an incidence of 1.7 and 1.3 per million per year in Europe[i] and the US[ii], respectively. Five-year overall survival (OS) varies significantly sitting at > 80% for T compared with ~40% for TC[iii],[iv]. Surgery remains the treatment of choice for operable TET, whereas chemotherapy is standard of care for metastatic or inoperable / recurrent disease. The response rate (RR) of TET to current chemotherapy agents differs by histological features: T responds better to first-line platinum based chemotherapy than TC (69% vs. 41%)[v]. No standard treatments are available for advanced TET after failure of first-line platinum-based chemotherapy, although single agents are generally used with modest benefit. For example pemetrexed, has been associated with a 17% partial response (PR) rate in T and 10% of PR in TC, with a median progression free survival (PFS) of 13.8 months and 6.5 months, respectively[vi]. Other drugs have recently been tested in second-line with promising results. In a phase II trial which recruited 14 T and 19 TC patients, amrubicin (a topoisomerase II inhibitor) was administered at 35 mg/m[2] IV days 1-3 on a 21-day cycle, producing an 18% RR (n=6, all PR: 29% in T and 11% in TC) without unexpected toxicity or cardiotoxicity[vii]. Another phase II trial investigated the combination of capecitabine plus gemcitabine in 30 pretreated TET patients (22 T and 8 TC). Overall RR was 40% (3 CR and 8 PR, with 3 PR in TC 3), PFS for T and TC was 11 months and 6 months, respectively and median OS was 16 months[viii]. In octreoscan positive patients with TET, somatostatin analogs with or without prednisone have also been shown to be effective as maintenance or as second-line treatment[ix][,[x]]. Given the poor survival of advanced TET, especially TC, there is a clear need for new treatment options. However, the molecular pathogenesis of TET is poorly understood at present. Profiled somatic genetic variations in 78 advanced-TET[xi] cases showed higher a incidence of somatic non-synonymous mutations in TC compared to T (62% vs. 13%; p<0.0001). TP53 was the most frequently mutated gene (overall in TET was 17% and especially in TC, 26%) and was associated with poorer OS (p<0.0001). Moreover, genes invovlved with histone modification (e.g. BAP1), chromatin remodelling, DNA methylation genes and c-KIT were also frequently mutated in advanced TCs. Although the presence of activating mutations is low in TET, the SPECTA-lung trial (NCT02214134) will allow analysis of more than 360 genes in patients with thoracic tumors, including T and TC. In this EORTC/ETOP umbrella study, eighteen European centres will allocate patients to different treatment arms based on the molecular characteristics of their disease, suggesting that basket trials allow the study of the genetics of less common malignancies[xii]. Despite data demonstrating EGFR and KIT overexpression in TET, EGFR and c-KIT mutations are rare, reported at 2%-10% and 9%, respectively[xiii]. This low percentage could explain the lack of RR observed in phase II studies evaluating Gefitinib, Erlotinib plus bevacizumab, and Glivec. In a recent retrospective analysis of 48 TC and thymic neuroendocrine tumors, the probability to finding c-KIT mutations was higher in CD117-positive thymic squamous cell carcinoma with poorly-differentiation and co-expression of CD5 and p63 in the absence of neuroendocrine markers (6 out of 23, 26%)[xiv], suggesting that a subgroup of TC might respond to c-KIT inhibitors. Recently SRC inhibitors (AZD0530) reported no RR in a phase II trial[xv]. Angiogenesis is another relevant pathway in TET. VEGF-A, -C, -D and VEGFR-1,-2,-3- are all overexpressed in high risk T and TC[xvi]. Sunitinib is an oral tyrosine kinase inhibitor (TKI) of VEGFR, KIT, and PDGFR. In a single arm phase 2 trial of sunitinib (50 mg/day for 4 weeks on, 2 weeks off) after at least one previous line of chemotherapy, a PR was reported in 26% of TC and 6% in T, with a mPFS of 7.2 months and 8.5 months, respectively. Main adverse events (AE) reported were lymphocytopenia, fatigue, and oral mucositis[xvii]. Although response was mainly limited to TC, sunitinib demonstrated an unprecedented activity for a targeted agent so far. Other antiangiogenic compounds that could be of value include Lucitanib, a selective TKI of FGFR1-3, VEGFR1-3, and PDGFR α/β. Efficacy data in 15 patients will be reported for this drug at the WCLC 2015. Insulin-like growth factor-1 receptor (IGF-1R) over-expression has been reported in 86% of TC and 43% of T[xviii], and carries poor prognosis. In a recent phase II trial of 49 patients with recurrent TET (37 T and 12 TC), single agent cixutumumab (a fully human IgG1 monoclonal antibody anti-IGF-1R, 20 mg/kg every 3 weeks), reported clinical activity only in T (14% PR, 28% SD, TTP 9 months and OS 27.5 months). No activity was recorded in the TC cohort (42% SD, TTP 1.7 months and OS 8.4 months). The most common toxicity in both groups was hypoglycemia (10%). Of note, 9 patients with T experienced autoimmune disorders[xix]. A phase II trial, Belinostat (PXD101, a pan-histone deacetylase inhibitor, 1g/m2 on days 1 through 5 in a 3-week schedule) among 41 patients (25 T and 16 TC) has reported only modest activity, with an 8% RR in T and no responses observed in TC. However, based on the duration of response and disease stabilization (median TTP and OS were 5.8 and 19.1 months, respectively), additional testing of belinostat in this disease may be warranted[xx]. Milciclib (PHA-848125AC) is an inhibitor of cyclin-dependent kinase2/cyclin A and SRC family members. Milciclib (150 mg/d 7 days on / 7 days off, 2-week cycles) has been evaluated in a phase II trial with 43 patients (26 TC and 9 B3-T). Out of 30 patients, 14 cases (46.7%) reached the primary end point and were PFS at 3 months, including PR. Five cases of SD lived longer than 1 year. The median PFS was 8.2 months and median OS has not been yet reached. The toxicity profile appeared favourable with nausea, asthenia and neutropenia (8.3%) reported as the most common severe AEs[xxi]. The mTOR inhibitor everolimus (10 mg/d) has been tested in a phase II trial in 50 patients with advanced or recurrent T (n=30) or TC (n=19) previously treated with cisplatin-containing chemotherapy. Preliminary data among the 43 evaluable patients showed a disease control rate (DCR) of 86% (1 CR, 10 PR, 32 SD) that was beyond the pre-specified endpoint of 40% DCR. The median PFS was 11.3 months (T not reached vs. 5.5 months in TC), and median OS was 18.6 months for TC and not reached for T. Few severe AEs were reported (asthenia, dyspnoea, neutropenia and hyperglycemia)[xxii]. Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has clinical activity in many tumors types. In a cohort of 139 TET, retrospective PDL-1 expression by IHC with the E1L3N antibody has been reported in 70% of TC and 23% of T, respectively. PDL-1 expression was not a significant prognostic factor in multivariable analysis[xxiii], although in other reported cohorts overexpression of PD-L1 was associated with worse prognosis [xxv, xxiv]. These results generally support immunotherapeutic strategies in TET (NCT02364076). At present, antiangiogenics, mTOR and CDK inhibitors, are the most promising drugs in TET treatment. Consensus on meaningful end-points, and knowledge of predictive biomarkers are challenges in this disease. [i] Siesling S, van der Zwan JM, Izarzugaza I et al. Rare thoracic cancers, including peritoneum mesothelioma. Eur J Cancer 2012; 48: 949-60. [ii] Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010; 5 (10 Suppl 4): S260–S265. [iii] Mariano C, Ionescu DN, Cheung WY et al. Thymoma. A population-based study of the management and outcomes for the province of British Columbia. J Thorac Oncol 2013; 8: 109–117. [iv] de Jong WK, Blaauwgeers JLG, Schaapveld M et al. Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer 2008; 44(1): 123–130. [v] Okuma Y, Saito M, Hosomi Y et al. Key components of chemotherapy for thymic malignancies: a systemic review and pooled analysis for anthracyclines-, carboplatin- or cisplatin-based chemotherapy. J Cancer Res Clin Oncol 2015; 141: 323-31 [vi] Liang Y, Padda SK, Riess JW et al. Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung Cancer 2015, 87: 34-8 [vii] Wakelee HA, Padda SK, Burns M et al. Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies. J Clin Oncol 2015; 33 (suppls; abstr 7580) [viii] Palmieri G, Buonerba C, Ottaviano M, et al. Capecitabine plus gemcitabine in thymic epithelial tumors: Final analysisof a phase II trial. Future oncology 2014; 10: 2141-7 [ix] Palmieri G, Ottaviano M, Nappi L et al. Somatostatin analogs as maintenance therapy in heavily pretreated thymic epithelial tumors. J Clin Oncol 2015; 33 (suppl; abstract 7581) [x] Ottaviano M, Damiano V, Nappi L et al. Effectiveness of somatotstain analogs plus prednisone in aggressive histotype and advanced stage of thymic epithelial tumors. J Clin Oncol 2015; 33 (suppl; abstract 7582) [xi] Wang Y, Thomas A, Lau Ch et al. Mutations of epigenetic regulatory genes are common in thymic carcinomas. Scientific Reports 2014; 4: 7336 [xii] Lopez-Chavez A, Thomas A, Rajan A et al. Molecular profiling and targeted therapy for advanced thoracic malignancies: A biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol 2015; 33: 1000-7 [xiii] Yoh K, Nishiwaki Y, Ishii G et al. Mutational status of EGFR and KIT in thymoma and thymic carcinoma. Lung Cancer 2008; 62: 31-20 [xiv] Schirosi L, Nannini N, nociloi D et al. Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors. Ann Oncol 2012; 23: 2409-14 [xv] Gubens MA, Burns M, Perkins SM et al. A phase II study of saracatinib (AZD0530), a SRC inhibitor, administered orally daily to patients with advanced thymic malignancies. Lung Cancer 2015; 89: 57-60 [xvi] Lattanzio R, La Sorda R, Facciolo F et al. Thymic epithelial tumors express vascular endothelial growth factors and their receptors as potential targets of antiangiogenic therapy: A tissue micro array-based multicenter study. Lung Cancer 2014; 85: 191-6 [xvii] Thomas A, Rajan A, Berman A et al. Sunitinib in patients with chemotherapy-refrtactory thymoma and thymic carcinoma: an open-label phase 2 trial Lancet Oncol 2015; 16: 177-86 [xviii] Girard N, Teruya-Feldstein J, Payabyab EC et al. Insulin-like growth factor-1 rceptor expression in thymic malignancies. J Thorac Oncol 2010; 5: 1439-46 [xix] Rajan A, Carter CA, Berman A et al. Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial. Lancet Oncol 2014; 15:191–200. [xx] Giaccone G, Rajan A, Berman A et al. Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol 2011; 29: 2052-9 [xxi] Besse B, Garassino MA, Rajan A et al. A phase II study of milciclib (PHA-848125AC) in patients with thymic carcinoma. J Clin Oncol 2014; 32 (suppl; abstract 7526) [xxii] Zucali PA, Martino de Pas T, Palmieri G et al. Phase II study of everolimus in patients with thymoma and thymic carcinoma previously treated with cisplatin-based chemotherapy. J Clin Oncol 2014; 32 (suppl; abstract 7527) [xxiii] Katsuya Y, Fujita Y, Horinouchi H et al. Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer 2015; 88: 154-9 [xxiv] Programmed cell death 1 (PD-1) and its ligand (PD-L1) expression in thymic epithelial tumors (TETs): Impact on the treatment efficacy and alteration in expression after chemotherapy (C) J Clin Oncol 2015; 33 (suppl; abstr 7515) [xxv] Padda SK, Riess JW, Schwartz EJ et al. Diffuse high intensity PDL-1 staining in thymic epithelial tumors. J Thorac Oncol 2015; 10: 500-8
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MINI 07 - ChemoRT and Translational Science (ID 110)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 15
- Moderators:D. Raben, B. Kavanagh
- Coordinates: 9/07/2015, 16:45 - 18:15, 201+203
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MINI07.01 - A Randomized Phase II Study of S-1 and Cisplatin vs Vinorelbine and Cisplatin with Concurrent Radiotherapy for Locally Advanced NSCLC: WJOG5008L (ID 544)
16:45 - 16:50 | Author(s): J. Shimizu, T. Kodaira, T. Seto, T. Sasaki, T. Yamanaka, N. Kunitake, F. Ohyanagi, T. Kozuka, M. Takeda, K. Nakamatsu, T. Takahashi, H. Harada, N. Yoshimura, S. Tsutsumi, H. Kitajima, M. Kataoka, K. Nakagawa, Y. Nishimura, Y. Nakanishi
- Abstract
- Presentation
Background:
Cisplatin-based chemotherapy and concurrent radiotherapy is the standard treatments for locally advanced non-small cell lung cancer ( LA-NSCLC). This trial evaluated two experimental regimens of chemotherapy with concurrent radiotherapy.
Methods:
Eligible patients (pts) with unresectable stage III NSCLC, 20 to 74 years of age, and ECOG PS of 0–1 were randomized to either Arm SP, S-1 (40 mg/m[2]/dose per oral, b.i.d, on days 1-14) and cisplatin (60 mg/m[2] on day 1) repeated every 4 weeks or Arm VP, vinorelbine ( 20mg/m[2] on day 1, 8) and cisplatin (80 mg/m[2] on day) repeated every 4 weeks with early concurrent thoracic radiotherapy of 60Gy at 2 Gy per daily fraction. The primary endpoint was overall survival rate at 2-year (2yr-OS). A pick-the-winner design was used to identify the treatment regimen most likely to be superior. The planned sample size was 55 patients per arm, assuming in each arm that the null hypothesis for 2yr- OS was 50% versus an alternative hypothesis for 65% with one-sided alpha of 0.10 and power of 80%. All the radiation treatment plans were reviewed at quality assurance committee meetings. (Study ID: UMIN000002420)
Results:
One hundred eleven patients were registered between Sep 2009 and Sep 2012. Of 108 patients for efficacy analysis, the 2yr-OS was 76% (95% CI, 62-85%) for SP and 69% (95% CI, 54-79%) for VP. The hazard ratio (HR) of death between the two arms was 0.85 (0.48-1.49). The median progression-free survival (PFS) was 14.8 months for SP and 12.3 months for VP with a HR of 0.92 (0.58-1.44). 80% and 48% of pts completed the protocol treatment in SP and VP, respectively. Common grade 3-4 toxicities of both SP and VP were neutropenia 33%, 75%, platelets 9%, 4%, hemoglobin 26%, 28%, febrile neutropenia 9%, 17%, diarrhea 6%, 0% respectively. There were 4 and 5 treatment-related deaths in Arms SP and VP, respectively. The quality assurance committee judged that 74% of radiation treatment plans had no deviation and 24% had a minor deviation.
Conclusion:
Both arms rejected the null hypothesis for 2yr-OS. In this study Arm SP was declared the winner in terms of 2yr-OS, PFS, treatment completion, and toxicity.
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MINI07.02 - Chemoradiotherapy versus Radiotherapy Alone in Elderly Patients with Stage III Non-Small Cell Lung Cancer: A Systematic Review (ID 3163)
16:50 - 16:55 | Author(s): D.E. Dawe, D. Christiansen, R. Zarychanski, A. Abou-Setta, P.M. Ellis, A. Swaminath, J. Rothney, R. Rabbani, S. Mahmud
- Abstract
- Presentation
Background:
Approximately 30% of non-small cell lung cancer (NSCLC) patients present with locally advanced (stage III) disease, and half are elderly (age ≥70). Young, fit patients with stage III NSCLC have improved survival with the use of combined chemotherapy and radiation therapy (CRT) over radiation therapy (RT) alone – HR 0.74 in a 2010 Cochrane systematic review. Elderly patients have more comorbid illnesses and suffer greater treatment toxicity, thus it is unclear whether they benefit more from CRT over RT. The objective of this systematic review is to explore the evidence base for using CRT in elderly patients with stage III NSCLC.
Methods:
We performed a systematic review including trials identified in MEDLINE, EMBASE and CENTRAL databases from inception to March 8, 2015, plus relevant conference proceedings since 2000. We included randomized controlled trials (RCTs) of elderly patients (≥70 years old) with stage III NSCLC or elderly subgroups from individual patient meta-analyses comparing CRT versus RT alone. We excluded studies that treated patients with palliative intent, included surgical patients, or in which both arms received chemotherapy. We did not restrict language. Two reviewers independently extracted summary outcome data. Risk of bias was assessed using the Cochrane Risk of Bias tool. We used a random effects model and inverse variance method to pool time-to-event outcomes. We calculated Peto Odds Ratios (POR) using RevMan 5.3 to pool dichotomous outcomes with a zero cell and otherwise calculated Risk Ratios (RR).
Results:
We screened 2951 citations identifying 68 articles for full text evaluation, 16 of which have not been accessible yet. Four reports of three studies met inclusion criteria (n = 407 elderly patients). All trials were evaluated as having a high risk of bias due primarily to lack of blinding. Overall survival in elderly patients was superior in those treated with CRT compared to RT (HR 0.66, 95%CI 0.53 to 0.82, I[2] 0%, p 0.0009). Progression-free survival was also improved with CRT (HR 0.67, 95%CI 0.53 to 0.85, I[2] 0%, p 0.001). Toxicity assessments were available in two studies with 119 patients receiving CRT and 121 RT. Treatment-related death occurred in 6 (5%) with CRT and 5 (4%) with RT (RR 1.22, 95%CI 0.38 to 3.88) and grade ≥3 pneumonitis was seen in 6 patients in each group, (RR 1.01, 95%CI 0.34 to 3.06) – neither was significantly different between treatments. Neutropenia – 57% v 2% (POR 14.38, 95%CI 8.26 to 25.04) and thrombocytopenia – 30% v 3% (RR 7.62, 95%CI 2.09 to 27.79) were more common with CRT. Febrile neutropenia occurred in 3 (2.5%) patients with CRT and zero patients with RT, but this did not meet significance (POR 7.54, 95%CI 0.78 to 72.82). No studies included patient-reported quality of life.
Conclusion:
CRT in elderly patients with stage III NSCLC results in improved survival as compared to RT alone, at the expense of increased treatment-related hematologic toxicity. Quality of life assessment should be included in any future trial design. CRT can be considered for fit patients ≥70 years of age with stage III NSCLC.
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MINI07.03 - The NARLAL2 Phase III Trial: Heterogeneous FDG-Guided Dose Escalation of Advanced NSCLC. A Clinical Trial by the Danish Lung Cancer Group (ID 2248)
16:55 - 17:00 | Author(s): D.S. Møller, J.L. Andersen, A.L. Appelt, C. Brink, O. Hansen, L. Hoffmann, N.K.G. Jensen, M. Josipovic, A.A. Khalil, M.M. Knap, M.D. Lund, C.M. Lutz, M.S. Nielsen, S.K. Nielsen, T.B. Nielsen, C.H. Nyhus, W. Ottosson, G.F. Persson, P. Sibolt, K. Wedervang, T. Schytte
- Abstract
- Presentation
Background:
Locally advanced lung cancer lacks effective treatment options and requires aggressive radiotherapy (RT) with higher doses. In the light of RTOG 0617, multi-center dose escalation trials should avoid increasing organ at risk (OAR) toxicity and require strict quality assurance (QA). Exploiting the predictive value of FDG-PET, sub-volumes can be dose escalated, and by implementing image-guided adaptive RT, the total treatment volume (PTV) can be reduced. Incorporating these elements, the randomized multicenter trial NARLAL2 aims at increasing loco-regional control at 30 months without increasing major toxicity.
Methods:
Figure 1 In the standard arm, the PTV is treated with a homogenous dose of 66 Gy/33 fractions. In the experimental arm, the dose is heterogeneously escalated to the FDG-PET avid volumes, with mean doses up to 95 Gy/33 fractions and 74 Gy/33 fractions to the escalated volumes in the tumor and malignant lymph nodes, respectively. The escalation dose will be limited in favor of OAR constraints. A standard and an experimental treatment plan with similar mean lung doses of maximum 20 Gy are made for each patient prior to randomization. Quality Assurance: FDG-PET scans of a standard phantom (NEMA) and PET signal processing software from all centers were compared and acceptable agreement achieved. Multicenter delineation of OARs was performed and consensus achieved. Treatment planning and adaptive strategy consensus were based on a study including five patients with repeated CT-scans, requiring several steps before the achievable level of dose escalation and the number of patients needed in the trial could be defined. Daily online tumor set-up and adaptive strategies were mandatory. A QA committee for evaluation of RT plans and treatments and a central committee for evaluation of all non-biopsy-verified recurrences were established.
Results:
A mean dose of 91,9 Gy to the FDG-PET avid part of the tumor and 80 Gy to the clinical target volume was achieved in the planning study, corresponding to 16% estimated increase in locoregional control at 30 months. Assuming a loco-regional control of 56% at 30 months in the standard arm, a total of 330 patients were needed in order to resolve this effect with a power of 80% (95% significance level). Recalculation of escalated plans on CT-scans acquired at fraction 20 revealed an increase in OAR doses of 4-7Gy for two of five patients, endorsing the need for adaptive strategies.
Conclusion:
A dose escalation trial with strict QA has been set up. Patient enrollment started January 2015.
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MINI07.04 - Dynamic Changes in Cell-Free Circulating Tumor DNA to Track Tumor Response and Risk of Recurrence in Stage III Non-Small Cell Lung Cancer (ID 2499)
17:00 - 17:05 | Author(s): S.H. Lin, T. Xu, J. He, K. Banks, R.B. Lanman, D. Sebisanovic, A.A. Talasaz, C. Lu, T. Buchholz, S. Hahn, R.U. Komaki, Z. Liao
- Abstract
- Presentation
Background:
While the curative management of unresectable stage III non-small cell lung cancer (NSCLC) is definitive chemoradiotherapy, clinical outcomes remain poor. Cellular heterogeneity in tumors is correlated with therapeutic resistance and poor prognosis. We hypothesize that tumor-specific mutant allelic frequency in cell-free DNA from plasma quantifies tumor heterogeneity and that tracking allelic evolution via blood from patients during and after treatment can serve as a non-invasive means to monitor treatment response and recurrence.
Methods:
Between 2009-2013, 156 patients with unresectable NSCLC who received definitive radiotherapy or chemoradiotherapy were consented to have blood drawn at baseline before starting radiotherapy, once or twice during treatment, and once or twice during follow up visits. Cell-free plasma DNA was sequenced using a cell-free circulating tumor DNA (ctDNA) next generation sequencing (NGS) assay (Guardant360) that uses digital sequencing to report single nucleotide variants (SNVs) in 68 genes and amplifications in 16 genes. This ctDNA assay has high sensitivity (detects 85%+ of the SNVs detected in tissue in advanced cancer patients) and analytic specificity (>99.9999%). Over 670 serial samples were collected from these patients. Here we report the initial analysis of the first 26 patients of this ongoing study.
Results:
Among this initial cohort, 23 (88%) had a recurrence (PFS ranged from 1.2 – 27.9 months) and three (12%) had no evidence of recurrence as of last contact (32.8 – 42.8 months post-radiotherapy completion). Twenty-one patients (81%) had ctDNA alterations present pre-radiotherapy, of which six had a classic driver mutation: KRAS G12F x2; KRAS G12S; PIK3CA E545K x2; PIK3CA H1047R. These six patients had significantly shorter PFS compared to patients without a driver mutation present pre-radiotherapy: average PFS of 4.2 months (1.2 - 8.3) vs. 18.6 months (4.4 - 42.8) respectively (p=0.002). All six had the driver mutation disappear during radiotherapy, four had new alterations appear during and/or post-treatment. One patient had the driver mutation reappear in ctDNA post-radiotherapy and had the shortest PFS (1.2 months) of all patients. Ten patients (38%) had no ctDNA alterations present in the post-radiotherapy blood sample and a trend was observed of improved PFS among patients without ctDNA alterations post-treatment (average PFS 52.3 vs. 75.5 months respectively) however this was not statistically significant (p=0.1). Of note, the three patients without evidence of recurrence as of last contact had no ctDNA alterations identified in the post-treatment sample. This trend is anticipated to become significant with larger sample size.
Conclusion:
In this interim analysis, we found that the dynamic alterations of specific mutant alleles strongly correlated with clinical response and that persistence of ctDNA mutant allele concentrations post-definitive treatment is likely a marker of early metastatic recurrence. Undetectable ctDNA in post-treatment sample was seen in the three patients with approximately three years of PFS. These initial results suggest that serial ctDNA analysis may be useful to monitor treatment response and identify patients at high risk for early recurrence who may benefit from additional systemic therapy.
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MINI07.05 - Discussant for MINI07.01, MINI07.02, MINI07.03, MINI07.04 (ID 3311)
17:05 - 17:15 | Author(s): J. Schiller
- Abstract
- Presentation
Abstract not provided
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MINI07.06 - Pattern of Loco-Regional Failure after Definitive Chemo Radiotherapy for NSCLC. Results from NARLAL, a Phase II Randomized Trial (ID 1042)
17:15 - 17:20 | Author(s): T. Schytte, T.B. Nielsen, M. Knap, A. Khalil, C. Nyhus, T. McCulloch, B. Holm, C. Brink, O. Hansen
- Abstract
- Presentation
Background:
Concurrent chemo-radiotherapy (CRT) is the treatment of choice in loco-regional advanced non-small cell lung cancer (LA-NSCLC). Even though the patients are treated with curative intend the loco-regional control at 2 year is only about 30% in clinical trials. The aim of this study is to compare the loco-regional failure in patients treated with 66 Gy vs 60 Gy in the randomized phase II trial, NARLAL. Furthermore to analyze the localization of relapse compared to the original treatment plan.
Methods:
From 2009-2013 117 patients with LA-NSCLC were randomized in a national multicentre protocol between 60 Gy/ 30 F (arm A) and 66 Gy/ 33 F (Arm B), 5 FW. Navelbine[®] 50 mg 3 days a week was given as concomitant regimen. Patients were followed with CT scans every 3[rd] month in 2 years and hereafter every 6[th] month for another 3 years. As part of the protocol a PET-CT scan was performed 9 months after randomization. In case recurrent disease was suspected a biopsy was done from the lesion if possible. The recurrence gross tumor volume will be delineated and registered with the original radiation treatment plan to identify the site of failure.
Results:
Fifty-nine patients were treated in arm A and 58 patients in arm B. The median local recurrence free interval was 10 months in arm A and 10.9 months in arm B (p=0.57). At the end of this analysis 22 patients were alive with no evidence of loco-regional disease, 16 patients had died with no evidence of loco-regional failure. Loco-regional failure in high-dose area was diagnosed in 60 (51%) patients (33 patients in arm A and 27 patients in arm B). Loco-regional failure outside high-dose area was diagnosed in 19 patients. Fig 1. Treatment plan 60 Gy/ 30 F and PET-CT with relapse (verified by biopsy) Figure 1
Conclusion:
Although this treatment was with curative intend, the loco-regional control was disappointingly poor in both treatment arms. This is in line with other newly published clinical dose-escalations trials for NSCLC. In order to improve loco-regional control and hopefully survival homogeneous dose-escalation is not the choice. Inhomogenous dose-escalation may be an alternative. A phase III trial on this subject has just started enrolment in Denmark (NARLAL II, www.clinicaltrials.gov). Acknowledgements Supported by CIRRO- The Lundbeck Foundation Center for Interventional Research in Radiation Oncology.
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- Abstract
- Presentation
Background:
Surgical resection after neoadjuvant chemoradiation therapy for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) carries high postoperative complications. Careful selection of candidate for surgery should be based on analysis of proven risk factors.
Methods:
We retrospectively reviewed all consecutive patients with clinical stage IIIA-N2 non-small cell lung cancer who underwent surgical resection after neoadjuvant chemoradiation therapy from 1997 to 2013. Preoperative, perioperative, and outcome variables which related to the morbidity and mortality were assessed. Univariate and multivariate analysis was done to identify predictors of postoperative morbidity and mortality.
Results:
During the study period, 574 patients underwent major pulmonary resection after induction therapy. The median time interval between the end of induction therapy and surgery was 33 days (range, 5-79 days). Thirty-day and ninety-day postoperative mortality were 1.4% (8 patients), and 7.1% (41 patients), respectively. The most common cause of In-hospital mortality was acute respiratory distress syndrome (n=6, 4.5%). Morbidity rate was 34.7 % (199 patients). Median hospital stay was 8 days (interquartile range, 7-11 days). Significant predictors of morbidity by multivariable analysis included patient age more than 70 years (odds ratio- 1.82;p=0.040), low body mass index <18.5 (odds ratio - 2.62;p=0.022), and pneumonectomy (odds ratio – 1.8;p=0.026). Significant predictors of mortality by multivariable analysis included patient age more than 70 years (odds ratio – 1.82; p=0.022), and pneumonectomy (odds ratio – 3.256; p=0.003). Ninety-day mortality was 15.8 % (9/57) in patient age more than 70 years, and 17.8 % (13/73) in patients who underwent pneumonectomy.
Conclusion:
Surgical outcomes after neoadjuvant CCRT for patients who are older than 70 year or undergo pneumonectomy are relatively poor. For those patients, there should be extra concern about the respiratory complications. And for the elderly patients with limited pulmonary reserves, other possible alternative treatment options, such as definitive CCRT rather than surgery should be considered.
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MINI07.08 - Mutation Profile Prognostic Value in Stage III Non Small Cell Lung Cancer (NSCLC) Patients Treated with Chemo-Radiotherapy (CRT) (ID 2262)
17:25 - 17:30 | Author(s): A. Boros, L. Lacroix, B. Lancas, J. Adam, J. Pignon, C. Caramella, D. Planchard, A. Levy, V. De Montpreville, E. Deutsch, B. Besse, C. Le Pechoux
- Abstract
- Presentation
Background:
Molecular profiling is a standard procedure in advanced non squamous NSCLC. Gene alteration in EGFR, BRAF or ALK gene can lead to prescription of targeted therapies and prolongs survival. The influence of molecular abnormalities on the survival of stage III NSCLC patients definitely treated by CRT is unknown.
Methods:
We reviewed all consecutive patients that received CRT or RT with a curative intent for stage III NSCLC in a single institution. Paraffin embedded tissue block were collected. DNA was extracted for gene mutation analysis by next generation sequencing and ALK, ROS1 and RET rearrangements were detected by FISH analysis. Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method.
Results:
Between January2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Platinum-based chemotherapy was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Seventy-eight patients were evaluable for mutation profile, 20 (26%) were female, 47 (60%) were current smoker, 40 (51%) had adenocarcinoma and there were 47/31 stage IIIA/IIIB. Mutations were positive as follow: EGFR 12% (9/78), KRAS 15% (12/78), BRAF 5% (3/66), PI3KCA 2% (1/58), HER2 0% (0/65), NRAS 3% (1/32), CTNNB1 3% (1/32). FISH was positive for ALK in 5% (3/56) of the NSCLC. In 32 NSCLC for which the test was performed, there was no alteration in ROS1, RET, HRAS and AKT1. Median Follow-up was 3.1 years (minimum 0.9 year). EGFR mutated or ALK+ (EGFR/ALK) group (n=11) and other mutation group (n=17) had a poorer progression free survival (median 0.8[95%CI: 0.6 ; 0.9] year and 0.5 [0.4 ; 0.8] year ; multivariate hazard ratio (HR)= 1.8 [0.8 ; 3.8] and 2.8 [1.5 ; 5.1] respectively, p=0.004) compared to the wild group (n=50) (median 1 year [0.9;1.3]). There was no significant difference (p=0.23, multivariate Cox) in overall survival: median 2.4 years [1.3 ; NR] for EGFR/ALK group, 1.1 [0.6 ; 2.5] for other mutation group and 1.9 [1.5 ; 2.5] for wild type. In multivariate analysis, only the dose of radiotherapy was significantly associated with overall survival (HR=0.5 [0.3 ; 1.0], p=0.04 in contrast with performance status or stage.
Conclusion:
This study suggests that selected gene alterations could be associated with a poorer survival in stage III NSCLC patients treated by combined modality treatment or radiotherapy alone. Their prognostic and/or predictive value should be further evaluated in a larger population.
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- Abstract
- Presentation
Background:
Combined chemoradiotherapy (CCRT) improves long-term outcome of patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC). However, most pts die from distant failure due to preexisting occult metastases. Based on the premise that EGFR-TKI would improve the outcome of pts with stage III NSCLC that harbors sensitive EGFR mutations, as for the pts with stage IV NSCLC, we initiated a randomized phase II pilot trial that incorporated erlotinib (E) into CCRT treatment paradigms.
Methods:
Eligible pts over 18 years old with unresectable stage IIIA or IIIB NSCLC, ECOG PS 0–1, and adequate organ function were screened for EGFR mutation in axons 18–21 in the tumor sample. Those with EGFR mutation (+) tumors were randomized upfront to receive 3 cycles of 3-weekly E 150 mg/day treatment, and then either E x2 cycles concurrently with CCRT and x6 more cycles after CCRT (Arm A) or CCRT with 2 cycles of irinotecan-cisplatin (IP) but no additional therapy after CCRT (Arm B). When disease progression (PD) is documented during follow-up, E was re-instituted. Pts with EGFR mutation (-) or unknown tumors were randomized to receive either 3 cycles of IP induction followed by CCRT concurrently with 2 cycles of IP (Arm C) or CCRT with IP x2 first then consolidation with IP x3 (Arm D). IP chemo dose-schedule was irinotecan 60 mg/m[2] and cisplatin 30mg/m[2] iv on days 1 and 8 when given concurrently with RT (2.4 Gy/fx, total 60 Gy); irinotecan 65 mg/m[2] and cisplatin 30 mg/m[2] iv on days 1 and 8 when given every 3 weeks as induction or consolidation. The primary endpoint was overall response rate (ORR), toxicity, and overall survival (OS).
Results:
From 02/2008 to 03/2015, 59 pts (44 men and 8 women) with median age of 62 years (range: 37-78) were enrolled. There were 13 never smokers, 28 had adenocarcinoma, and 44 had IIIB tumors. EGFR mutation was (+) in 12, (-) in 28, and unknown in 19. There was apparent imbalance in histology and smoking status between the pts assigned to Arms A&B and C&D. ORR after induction E therapy was 75.0% for the 12 pts with EGFR mutation(+) tumors (Arm A, n=7; B, n=5). ORR after IP induction therapy was 63.6% for pts with EGFR mutation(-) or unknown tumors in Arm C (n=22). After completion of upfront CCRT therapy with IP in Arm D (n=25), ORR was 68.0%. There were no noticeable unusual side-effects. Median PFS for Arm A, B, C, and D, was 11.84, 8.09, 8.36, and 11.81 months respectively, with a trend toward better OS for pts with EGFR mutation(+) tumors (Arm A: not reached, B: 31.18 mos) than those EGFR mutation(-) or unknown tumors (Arm C: 17.93 mos, Arm D: 25.33 mos).
Conclusion:
The combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC patients. Although the number is rather small, pts with EGFR mutation (+) tumors seem to be a distinct subset with better overall survival than the others, which warrants careful consideration in chemoradiation therapy trial design and outcome evaluation.
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MINI07.10 - Discussant for MINI07.06, MINI07.07, MINI07.08, MINI07.09 (ID 3312)
17:35 - 17:45 | Author(s): B. Loo
- Abstract
- Presentation
Abstract not provided
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MINI07.11 - Isotoxic Dose Escalation and Acceleration in Lung Cancer Chemoradiotherapy (ID 1522)
17:45 - 17:50 | Author(s): D. Landau, I. Khan, A. Baker, A.T. Bates, M.C. Bayne, N. Counsell, A. Garcia-Alonso, S.V. Harden, J. Hicks, L. Hughes, M.C. Illsley, S.R. Hughes, V. Laurence, Z. Malik, H. Mayles, P.W.M. Mayles, E. Miles, N. Mohammed, Y. Ngai, E. Parsons, J. Spicer, P. Wells, D. Wilkinson, J.D. Fenwick
- Abstract
Background:
RTOG 0617 investigated standard dose radiotherapy (RT) versus higher dose in the context of concurrent chemoRT with no advantage to higher dose treatment. IDEAL CRT investigated an alternative RT dose-escalation strategy with concurrent chemoRT in locally advanced NSCLC. Dose-per-fraction-escalation was used to achieve intensification without treatment prolongation. The trial would determine the maximum tolerable dose (MTD) deliverable to esophagus, and assess toxicity and early clinical outcomes for the schedule.
Methods:
Patients were enrolled to 2 groups, depending on maximum esophageal dose. Tumor doses were determined by esophageal constraints in Group 1 and other normal tissue constraints in Group 2. Patients received 63-73Gy in 30 once-daily fractions / 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. Group 1 esophageal dose-escalation followed a 6+6 design, increasing maximum dose to 1cc esophagus from 65Gy, 68Gy then 71Gy in successive cohorts, defining MTD by early and late toxicity. Efficacy endpoints were overall survival (OS), progression-free survival (PFS) and tumor response.
Results:
8 centres recruited 84 patients, treating 13, 12 and 10 in 65Gy, 68Gy and 71Gy group 1 cohorts. Prescribed RT doses are shown in figure 1. Median follow-up 24 months. 57 patients (68%) were stage IIIa and 21 (25%) IIIb. 5 grade 3 esophagitis events observed across both groups and 3 grade 3 pneumonitis. Following 1 fatal esophageal perforation in the 71Gy cohort, 68Gy was declared as esophageal MTD. Overall Survival (OS) and Progression Free Survival (PFS) were 87.8% and 72.0% at 1 year, and 67.1% and 50.4% at 2 years, median OS 39.3 months. OS is shown in figure 2. Figure 1 Figure 2
Conclusion:
Acceptable toxicity rates and promising survival were achieved. The isotoxic design proved practical, allowing significant treatment intensification and definition of MTD with relatively few patients. Results from longer follow-up are required and will be presented at the meeting.
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MINI07.12 - Stage III NSCLC in the Elderly: Patient Characteristics Predictive for Tolerance and Survival of Chemoradiation in Daily Clinical Practice (ID 1512)
17:50 - 17:55 | Author(s): E. Driessen, G. Bootsma, L. Hendriks, F. Van Den Berkmortel, B. Bogaarts, J. Van Loon, A. Dingemans, M. Janssen-Heijnen
- Abstract
- Presentation
Background:
Although the mean age at diagnosis of stage III non-small cell lung cancer (NSCLC) is 70 years, trials mainly include younger patients. Therefore, a lack of knowledge remains regarding tolerance and survival of standard treatment (concurrent chemoradiation (cCHRT)) and other treatment options for the elderly. The aim of this study was to evaluate administered treatment, assess motivations to omit cCHRT, and determine predictors for treatment tolerance and survival among unselected elderly with stage III NSCLC.
Methods:
In this multicenter retrospective study, all stage III NSCLC patients aged ≥70 and diagnosed in 2009-2013 in three Dutch teaching hospitals were included. Data on patient and tumor characteristics were derived from the Netherlands Cancer Registry and medical records regarding treatment details, geriatric patient characteristics, tolerance (completing treatment and/or no unplanned hospitalizations) and survival. Treatment and motives for omitting cCHRT were described. Univariate and multivariable analyses were performed to gain insight into predictive factors.
Results:
In the 219 included patients, mean age was 76 years, 78% was male and 51% had squamous cell carcinoma. Sixty-eight percent had a WHO Performance Status (PS) of 0-1, 22% PS 2, and 11% PS 3. Serious co-morbidity (severe organ decompensation or ≥2 moderate decompensations) was present in 59%, average co-morbidity (moderate organ compensation or ≥2 mild decompensations) in 16%, mild co-morbidity (mild organ decompensation) in 11% and 15% had no co-morbidities. Chemoradiation (CHRT) was administered in 55% of patients (33% cCHRT and 22% sequential CHRT (sCHRT)), 16% received only radical radiotherapy (RT) and 29% Best Supportive Care (BSC). CHRT was less often administered to patients aged ≥75 and those with a PS 2-3 (p<0.001). Also, patients with serious co-morbidity were less likely to receive CHRT, although not significant (p=0.10). The most common motives for omitting cCHRT were co-morbidity and/or poor PS (57%) and patient refusal (15%). Multivariable analyses showed that treatment and co-morbidity were predictive for tolerance. In comparison to cCHRT, tolerance was significantly better for RT (Odds Ratio (OR) = 5.1(95% Confidence Interval (95%CI) 2.1-13)) and non-significantly better for sCHRT (OR=2.2 (0.97-4.9)). Patients with serious co-morbidity had significantly worse tolerance compared to no co-morbidity (OR=0.28 (0.11-0.68). Even when corrected for patient characteristics, survival was not significantly better after cCHRT compared to sCHRT (Hazard Ratio (HR) = 1.1 (95%CI 0.76-1.7)) or compared to RT (HR=1.3 (0.81-2.0)). The 1-and 3-year Overall Survival (OS) rates for cCHRT were respectively 56% and 17%, for sCHRT 54% and 16%, and for RT 48 % and 9%.
Conclusion:
Co-morbidity, poor PS and patient refusal were the most common motives for omitting cCHRT. Although relatively fit and younger elderly were assigned to cCHRT, treatment tolerance was worse. OS was not significantly different between cCHRT, sCHRT and even RT. Since limited information on geriatric characteristics was available in this retrospective study, prospective studies including geriatric assessments are urgently needed to gather evidence on treatment options, resulting in the most optimal balance between quality of life and survival.
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MINI07.13 - Clinical Impact of Frequent Surveillance Imaging in the First Year following Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer (ID 2538)
17:55 - 18:00 | Author(s): N.K. Harandi, M.E. Daly
- Abstract
- Presentation
Background:
Uncertainty exists regarding the optimal surveillance strategy following definitive chemoradiation (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC) with regards to both frequency and modality. We sought to determine the efficacy of frequent (q2-4 month) post-treatment imaging in detecting asymptomatic recurrent disease and document the clinical impact of frequent surveillance imaging.
Methods:
The records of all patients treated with CRT for stage IIIA/IIIB NSCLC between August 1999 and April 2014 at our institution were reviewed. Patients were included if they underwent frequent (Q2-4 month) chest computed tomography (CT) or positron emission tomography (PET/CT) for routine surveillance following CRT for at least one year following CRT or until disease progression or death. Radiographic findings and clinical interventions from the first year following CRT were identified.
Results:
We identified 145 patients with LA-NSCLC treated with CRT, 65 of whom underwent Q2-4 month surveillance imaging for at least one year or until progression or death. Median age was 63.6 years (range, 41.0-86.9 years). Forty-nine (75.4%) also underwent an initial baseline CT within the first 6 weeks following CRT. An asymptomatic recurrence was detected by surveillance imaging within the first year in 40 (61.5%) patients, 31 (77.5%) by CT and 9 (22.5%) by PET/CT. Among these patients, 21 (52.5%) initiated palliative systemic therapy. Three (7.5%) underwent attempted definitive therapy for isolated disease, including one patient treated with definitive lobectomy for what was found to be a histologically distinct new primary early stage NSCLC, and two patients treated with stereotactic ablative radiotherapy for isolated recurrences, both of whom subsequently developed metastatic disease. Urgent palliative local therapies (radiotherapy and bronchoscopy) were performed in 2 patients for impending neurologic and airway compromise, respectively. Ten patients (25%) with recurrences detected on surveillance imaging were not candidates for or declined additional cancer-directed therapy. Seven patients (10.8%) developed a symptomatic recurrence detected between planned scans. Five patients (7.7%) underwent additional diagnostic procedures for false-positive surveillance imaging findings.
Conclusion:
Frequent surveillance imaging within the first year following CRT for LA-NSCLC detected asymptomatic recurrences in a high proportion of patients in our population. However, definitive interventions were attempted in less than 5%, and were successful in only one patient. The predominant potential benefit of frequent radiographic surveillance appears to be the expedient initiation of palliative systemic therapy. Evidence-based algorithms for follow-up imaging among this population are needed, and should account for patient-specific factors including expected tolerance of, benefit from, and willingness to undergo systemic therapies.
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- Abstract
- Presentation
Background:
Endostatin inhibits the pro-angiogenic action of basic fibroblast growth factor and vascular endothelial growth factor in different human cancers. This study assessed the efficacy of endostatin combined with concurrent chemoradiotherapy of non-small cell lung cancer (NSCLC).
Methods:
Nineteen patients with unresectable stage III NSCLC, ECOG performance status 0-l, and adequate organ function were treated with 60–66 Gy thoracic radiation therapy over 30–33 fractions concurrent with weekly 7.5 mg/m[2] endostatin for 14 days, 50 mg/m[2] paclitaxel, and 2 mg/mL/min carboplatin over 30 min. Patients were then treated with 7.5 mg/m[2] endostatin for 14 days, 150 mg/m[2] paclitaxel, and 5 mg/mL/min carboplatin every 3 weeks for 2 cycles as the consolidation treatment (Fig.1). The objective response rate was recorded according to the RECIST criteria, and the toxicity was evaluated using the NCI Common Toxicity Criteria. Figure 1
Results:
Six patients were unable to complete the consolidation treatment (4 pulmonary toxicity, 1 tracheoesophageal fistulae, and 1 progressive disease). Seventeen patients were included for data analysis. Specifically, one (5.9%) patient had a complete response and 13 (70.6%) had a partial response, whereas two patients had stable disease and the other two had disease progression. The overall response rate was 76% [95% CI, 51%–97%]. The median progression-free survival was 10 months (95% CI, 7.6–12.3 months), and the median overall survival was 14 months (95% CI, 10.7–17.2 months) (Tab.1). The toxicity analysis of 10 patients who completed the treatment regimen showed that four patients experienced grade III pulmonary toxicity. Figure 1
Conclusion:
The results demonstrated no evidence of the efficacy of endostatin concurrent with chemoradiotherapy of locally advanced unresectable NSCLC. The real impact of endostatin as the first-line treatment combined with chemoradiotherapy on the survival of NSCLC patients remains to be determined.
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MINI07.15 - Discussant for MINI07.11, MINI07.12, MINI07.13, MINI07.14 (ID 3325)
18:05 - 18:15 | Author(s): C.J. Langer
- Abstract
- Presentation
Abstract not provided
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ORAL 36 - Translational Science/Radiation (ID 151)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 8
- Moderators:E. Vokes, B. Kavanagh
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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- Abstract
Background:
Patient prognosis after complete resection for pathologic stage IIIA(N2) non-small cell lung cancer (NSCLC) remains a significant concern. Accumulating evidence suggests that the host immune response might determine tumor behavior and influence the survival prognosis; however, the clinical relevance of the host immune response to NSCLC has yet to be established. We aimed to investigate the prognostic value of tumor-infiltrating lymphocytes (TILs) in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC.
Methods:
From January 2005 to June 2012, all consecutive patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection in our hospital were retrospectively reviewed. Inclusion criteria for this study were as follows: complete resection through a surgical procedure of either lobectomy or pneumonectomy with microscopically tumor-free resection margins; systematic nodal dissection with a minimum of three N2 stations dissected; and histologically proven NSCLC of stage pT1-3N2M0 (according to the 7th UICC TNM classification). Patients who received neoadjuvant chemotherapy and/or radiotherapy were excluded. Full-face hematoxylin- and eosin-stained sections from surgical specimens from each case were evaluated for the density of TILs by two qualified specialized pathologists. A published recommended TILs scoring scale was followed. The degree of lymphocyte infiltration into the tumor was scored as none (score 0), low (score 1), moderate (score 2), or high (score 3). Patients were stratified into TIL-negative (none to low infiltration) or TIL-positive (moderate to high infiltration) group based on pathologic evaluation.
Results:
Of the eligible 320 patients included in the analysis, 135 (42%) patients were categorized as TIL-positive; and the 185 (58%) patients were defined as TIL-negative. The median follow-up duration was 30.8 months (range, 12-101.4 months) for the living patients. In the entire cohort, the median survival time (MST) was 42.5 months, and the 1-, 3-, and 5-year overall survival (OS) rates were 90.9%, 54.3%, and 35%, respectively. For the patients in the TIL-negative and TIL-positive groups, the MST was 35.7 and 45.5 months, respectively. The 1-, 3-, and 5-year OS rates were 88.6%, 49.5%, and 34%, respectively, in the TIL-negative group and 94.1%, 61.2%, and 35.6%, respectively, in the TIL-positive group. A higher density of TILs (TIL-positive) was associated with improved OS and the differences trended toward significance (P=0.06). Multivariate analyses confirmed that TIL-positive was an independent prognostic factor for improved OS (HR=0.70, 95%CI 0.50-0.99, P=0.05). Subgroup analyses indicated that this positive effect was the greatest for patients with squamous cell carcinoma (SCC; HR=0.44, 95%CI 0.21-0.94, P=0.03). Of the 93 patients with SCC, TIL-positive was significantly associated with improved distant metastasis-free survival (DMFS; P=0.02) and OS (P=0.03). The TIL-positive was a strong prognostic factor in the multivariate model, both for prolonged DMFS (HR=0.39, 95%CI 0.17-0.87, P=0.02) and OS (HR=0.47, 95%CI 0.22-1.00, P=0.05).
Conclusion:
Our data suggested a potential role of TILs in predicting the survival prognosis of patients with completely resected stage IIIA(N2) NSCLC. The beneficial effects of TILs were more pronounced for the prediction of DMFS and OS in patients with SCC. Studies assessing outcomes and therapeutic efficacies in prospective clinical trials should consider stratification for this immunological parameter.
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ORAL36.02 - Efficacy of Chemo-Radiotherapy (CRT) in Stage III Non-Small Cell Lung Cancer (NSCLC) and PD-L1 Expression (ID 2432)
16:56 - 17:07 | Author(s): J. Adam, A. Boros, B. Lacas, L. Lacroix, J. Pignon, C. Caramella, D. Planchard, A. Levy, B. Besse, C. Le Pechoux
- Abstract
- Presentation
Background:
Inhibition of the PD1/PD-L1 axis has been successfully developed in advanced NSCLC, and its role in locally advanced NSCLC is under investigation. The prognostic and predictive values of PD-L1 expression is still debated in advanced NSCLC and unknown in stage III NSCLC patients definitely treated by CRT
Methods:
We reviewed all consecutive patients that received CRT or RT with a curative intentfor stage III NSCLC in a single institution. Paraffin embedded tissue block were collected, immunohistochemistry was performed on a Ventana Benchmarck Ultra platform using the E1L3N clone (Cell Signaling Technologies). All tumors were centrally reviewed and tumor cells were scored accordingly (Herbst et al., Nature 2014).Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method
Results:
Between January 2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Chemotherapy, mostly based on doublets with platin salt was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Fifty NSCLC were evaluable for PD-L1 expression, 22 (44%) being positive. Fourteen (28%) were female, 24 (48%) were current-smoker, 17 (34%) had adenocarcinoma and there were 23/27 stage IIIA/IIIB. Evaluable and unevaluable populations for PD-L1 were not different. There were no clinical or pathological factors related to PD-L1 positivity. Median follow-up was 7.6 years (minimum: 0.7 year). Median OS was 1.1year(95% confidence interval (CI) 0.6-1.5) in PD-L1 positive (pos) and 2.0 years (95% CI 1.5-3.8) in PD-L1 negative (neg) (p=0.01), HR=2.3 (95% CI 1.2-4.5, p=0.01). Median PFS was 0.7 year (95% CI 0.6-0.8) in PD-L1pos and 1.0 year (95% CI 0.8-1.5) in PD-L1neg (p=0.04), HR=2.1 (95% CI1.1-4.0, p=0.03). There was no difference in terms of acute toxicity according to PD-L1 status (positive or negative):25 had oesophagitis (grade≥2) and 16 had pneumonitis (p=0.57 and p=0.23 respectively).
Conclusion:
PD-L1 positivity was associated to a poorer survival in stage III NSCLC patients treated by definitive chemo-radiotherapy. Its prognostic and/or predictive value should be further evaluated in this population.
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ORAL36.03 - Discussant for ORAL36.01, ORAL36.02 (ID 3566)
17:07 - 17:17 | Author(s): E.E. Vokes
- Abstract
- Presentation
Abstract not provided
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ORAL36.04 - Nintedanib Safely Reduces Late Radiation-Induced Lung Damage: A Preclinical Study with a High Precision Image-Guided Small Animal Irradiator (ID 1456)
17:17 - 17:28 | Author(s): D. De Ruysscher, P.V. Granton, N.G. Lieuwes, S. Van Hoof, L. Wollin, F. Verhaegen, L. Dubois
- Abstract
- Presentation
Background:
The indolinone small-molecule derivative nintedanib has been originally designed as an anti-angiogenic drug targeting the receptor tyrosine kinases VEGFR, FGFR and PDGFR for the treatment of cancer. Additionally, preclinically nintedanib has demonstrated potent anti-fibrotic and anti-inflammatory activity. Nintedanib was recently approved in the US and EU for the treatment of idiopathic pulmonary fibrosis (IPF). The aim of this study was to assess the efficacy and safety of nintedanib in a mouse model of partial lung irradiation.
Methods:
266 C57BL/6 adult male mice were irradiated with a single fraction radiation dose of 0, 4, 8, 12, 16 or 20 Gy using 5-mm circular parallel-opposed fields targeting the upper right lung with a precision image-guided small animal irradiator (PXRAD225Cx, PXI Inc, USA) sparing heart and spine based on micro-CT images acquired at 200 µm resolution. One week post irradiation, mice were randomized across nintedanib daily oral gavage treatment with 0, 30 or 60 mg/kg respectively for a total of 39 weeks. Micro-CT imaging was repeated on a monthly basis. At the end of the experiment, lungs were removed and processed for H&E, Van Gieson’s and Masson’s trichrome staining to evaluate the fibrotic phenotype.
Results:
Increased lung density could be visually observed by CT in the late stage imaging time points of irradiated mice after 20 Gy and was spatially limited to the irradiated portion of the lung. This increased density was consistent with the development of fibrosis, confirmed by an increased fibrotic phenotype scored by an increase in alveolar wall thickness, interstitial edema, interstitial and perivascular fibrosis and inflammation, interstitial and alveolar macrophages, atelectasis and vasculitis. Although no macroscopic decrease in CT density could be observed, nintedanib was able to reduce the microscopic fibrotic phenotype, in particular interstitial edema, interstitial and perivascular fibrosis and inflammation and vasculitis, without adverse effects.
Conclusion:
Nintedanib efficiently and safely reduces radiation-induced lung fibrosis after partial lung irradiation. Since, as expected, nintedanib did not affect alveolar wall thickness and macrophage involvement, no significant changes in lung density could be observed by CT imaging. Based on its protective effect, nintedanib might be safely introduced in clinical trials for patients treated with irradiation to the lungs.
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ORAL36.05 - Results of a National Database Review of Video-Assisted Thoracoscopic versus Open Lobectomy after Induction Therapy (ID 1533)
17:28 - 17:39 | Author(s): J.L. Wilson, T. Curran, S.P. Gangadharan, R.I. Whyte, M.S. Kent
- Abstract
- Presentation
Background:
Minimally invasive lobectomy has become the standard of care approach for early stage non-small cell lung cancer (NSCLC); however video assisted thoracoscopic (VATS) lobectomy after induction therapy remains controversial. We sought to evaluate perioperative outcomes of VATS and open lobectomy after induction therapy using a national database.
Methods:
A cohort study of patients that underwent VATS and open lobectomy after induction chemotherapy and/or radiotherapy was conducted using the National Surgical Quality Improvement Program (NSQIP) database from 2005 through 2012. Perioperative complications and mortality were compared between groups. Comparisons were made using two-sided student’s t-test or chi square test as appropriate.
Results:
A total of 6730 patients underwent lobectomy during the study period and 166 patients had prior induction therapy (open = 132, VATS = 34). There were no statistically significant differences in age, comorbidities or ASA class between groups. There were no significant differences in the surgeon specialty between groups (cardiac, thoracic, general, and vascular). Operative time was similar (VATS: 228 minutes, Open: 190 minutes; p = 0.07). Perioperative complications, return to OR, respiratory complication, mortality, and hospital length of stay were similar between groups. Table 1. Patient Demographics
VATS = video assisted thoracoscopic, COPD = chronic obstructive pulmonary disease, ASA= American Society of Anesthesia class Table 2. Post-Operative OutcomesN (%) All (N = 166) Open (N = 132) VATS (N = 34) P-value Age, yrs; Mean (SD) 62.9 (10.2) 62.4 (10.7) 65.2 (7.6) 0.077 Female 88 (53) 72 (55) 16 (49) 0.563 Diabetes 16 (10) 11 (8) 5 (15) 0.325 COPD 35 (21) 26 (20) 9 (27) 0.479 Creatinine > 1.2 17 (10) 13 (10) 4 (12) 0.757 ASA Class ≥4 18 (11) 14 (11) 4 (12)
VATS= video assisted thoracoscopic, LOS = length of stay, OR= operating roomN (%) All (N = 166) Open (N = 132) VATS (N = 34) P-value LOS, days; mean (SD) 7.3 (6.1) 7.4 (6.1) 6.6 (6.3) 0.471 Wound complication 5 (3) 5 (4) 0 0.584 Pneumonia 16 (10) 15 (11) 1 (3) 0.197 Reintubation 18 (11) 15 (11) 3 (9) 1.000 Respiratory complication 25 (15) 22 (17) 3 (9) 0.419 Return to OR 15 (9) 14 (11) 1 (3) 0.311 In hospital mortality 9 (5) 8 (6) 1 (3) 0.687 30 day mortality 13 (8) 12 (9) 1 (3) 0.471
Conclusion:
This is the first review of a prospective national database comparing outcomes for VATS and open lobectomy after induction therapy for NSCLC. VATS lobectomy appears to be safe with no increased morbidity or mortality compared to open in patients that had prior induction therapy. A larger series of matched VATS and open approaches after induction therapy is needed.
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ORAL36.06 - 4D-VQ-PET/CT Imaging Allows Strong Correlation Between Radiotherapy Dose and Change in Lung Ventilation, Perfusion and Density (ID 211)
17:39 - 17:50 | Author(s): S. Siva, N. Hardcastle, T. Kron, M. Bressel, J. Callahan, M. Macmanus, M. Shaw, N. Plumridge, R. Hicks, D.P. Steinfort, M. Hofman, D. Ball
- Abstract
- Presentation
Background:
[68]Ga-V/Q PET/CT is a novel imaging modality for assessment of perfusion(Q), ventilation(V) and lung density changes in the context of radiotherapy (RT) for non-small cell lung cancer.
Methods:
In a prospective clinical trial, 20 patients underwent 4D-V/Q PET/CT before treatment, 4 weeks into treatment and 3 months after definitive lung RT. Eligible patients were prescribed 60 Gy in 30 fractions with or without concurrent chemotherapy. Functional images were registered to the RT planning 4D-CT and isodose volumes averaged into 10 Gy bins. Within each dose bin, relative loss in SUV was recorded for ventilation and perfusion, and loss in air-filled fraction was recorded to assess RT-induced lung fibrosis. A dose-effect relationship was described using both linear and 2-parameter logistic fit models and goodness of fit assessed using Akaike Information Criterion (AIC).
Results:
A total of 179 imaging datasets were available for analysis (1 scan unrecoverable). An almost perfectly linear dose-response relationship was observed for perfusion and air-filled fraction (r[2] = 0.99, p < 0.01), with ventilation also strongly linear (r[2] = 0.95, p < 0.01) [Figure]. Logistic models did not provide a better fit as evaluated by AIC [Table]. Perfusion, ventilation and the air-filled fraction changed by -7.5% ± 0.3%, -7.1% ± 0.6% and 4.9% ± 0.02% per 10 Gy, respectively. Within high-dose regions, higher baseline SUV was associated with greater rate of loss. At 50Gy and 60Gy the rate of loss was 1.35% (p = 0.07) and 1.73% (p = 0.05) per SUV, respectively. Of 8/20 patients with peri-tumoral reperfusion / re-ventilation during treatment, 7/8 did not sustain this effect post-treatment. Figure 1 Figure 2
Conclusion:
RT induced regional lung functional deficits occur in a dose dependent manner and can be estimated using simple linear models with 4D-V/Q PET/CT imaging. These findings may inform functional lung sparing by planning RT using this novel imaging technology.
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ORAL36.07 - Results of a National Test Run of Treatment Plans for the Standard Arm of a Dose Escalation Trial for Locally Advanced NSCLC (ID 1766)
17:50 - 18:01 | Author(s): T.B. Nielsen, C. Brink, D.S. Møller, L. Hoffmann, C.M. Lutz, A.L. Appelt, M.D. Lund, M.S. Nielsen, P. Sibolt, C. Larsen, W. Ottoson, T. Schytte
- Abstract
- Presentation
Background:
A national quality assurance program was conducted in order to compare standard radiation treatment plans for locally advanced non-small cell lung cancer (NSCLC) patients in Denmark.
Methods:
The five participating centres represented 71% of all radiotherapy centres in Denmark. They were provided with the CT images and delineations of GTV, CTV, PTV and organs at risks for five different NSCLC patients. Each centre created treatment plans based on the following optimization objectives: required dose distribution for target coverage 95%-107% of the prescribed dose of 66Gy/33fr to at least 95% of the PTV volume (90% for volume located in lung tissue); constraints for organs at risks D(max) < 50Gy to the spinal cord, D(max) < 70Gy to the oesophagus, V50 < 20% to the heart, V20 < 35% and D(mean) < 20Gy for the total lung volume (excluding the GTV). The treatment planning was done in accordance with the local centre practice; i.e. choice of IMRT versus VMAT, coplanar vs. non-coplanar technique, feasible functionalities for treatment planning optimisation (mean value versus different points at the DVH curve), and any additional local dose constraints (e.g. D(max) < 45Gy to spinal cord and/or V5 < 60% to the total lung volume). Finally, all treatment plans were collected and analysed cooperatively.
Results:
All objectives for target coverage and organs at risk were met. There was a wide variability in the dose volume histograms (DVHs) for some of the organs at risk, especially the lungs. This is illustrated in the figure, where the lung DVH from seven different treatment plans, created for the same patient by the five participating centres, is shown. The lung DVHs are overlapping around 20Gy, as all centres had a dose constraint on V20. Some centres had an additional local dose constraint on V5, which resulted in decreased doses to the lungs and increased doses to the mediastinal structures compared with centres that had no dose constraints on V5 for the lungs. Figure 1
Conclusion:
Differences in the dose distribution to the organs at risk can have an impact on treatment morbidity (e.g. pneumonitis, oesophagitis). These differences were seen for standard treatment plans, which are often used in multicentre clinical trials as the baseline compared to an experimental arm, where such differences can be even more pronounced. It is highly recommended to perform test runs across centres prior to entering clinical trials in order to uncover differences as the ones presented.
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ORAL36.08 - Discussant for ORAL36.04, ORAL36.05, ORAL36.06, ORAL36.07 (ID 3567)
18:01 - 18:11 | Author(s): P. Van Houtte
- Abstract
- Presentation
Abstract not provided
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Author of
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ORAL 19 - Radiation for Localized Lung Cancer (ID 126)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:D. De Ruysscher, M. Hiraoka
- Coordinates: 9/08/2015, 10:45 - 12:15, 102+104+106
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ORAL19.08 - Discussant for ORAL19.05, ORAL19.06, ORAL19.07 (ID 3561)
12:01 - 12:11 | Author(s): B. Kavanagh
- Abstract
- Presentation
Abstract not provided
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P3.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 211)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.02-036 - Predictors of Lung Fibrosis after Stereotactic Body Radiation Therapy (SBRT) for Stage I-II Non-Small Cell Lung Cancer (NSCLC) (ID 3197)
09:30 - 09:30 | Author(s): B. Kavanagh
- Abstract
Background:
Radiographic lung injury, fibrosis, occurs in over 50% of patients after SBRT. The purpose of this study was to evaluate clinical and dosimetric predictors of lung fibrosis after SBRT for stage I-II NSCLC
Methods:
A retrospective single institution database was examined for patients with Stage I-II NSCLC, T1-2N0, and lesions less than 5 cm treated with SBRT to 45-54 Gy in 3-5 fractions from 2010 to 2013. 4D CT imaging was used to assist with target localization and CT scans with at least 9 months of followup were rigidly registered to the planning CT scan based on common anatomical landmarks. Fibrosis volume was manually contoured. Simple and multiple linear regression were used to assess clinical and dosimetric variables under univariate and multivariate analyses.
Results:
We identified 26 patients and 27 lesions that met inclusion criteria. On UVA, increasing PTV volume, V20, and intermediate dose spillage (maximum total dose to any point 2 cm from PTV divided by dose prescribed) were significantly associated with increasing fibrosis (p<0.05). Non-significant predictors of fibrosis included patient age, pack years of smoking, COPD GOLD stage, use of ACE-I, and radiation dose to the PTV. On MVA accounting for factors significant for fibrosis (PTV volume, V20, intermediate dose spillage), only PTV volume remained significantly correlated with fibrosis volume (0.43 cm[3] increase in fibrosis for every 1 cm[3] increase in PTV, 95% CI, 0.08-0.77, p=0.02).
Conclusion:
In this analysis of predictors of fibrosis after SBRT, only increasing PTV volume was associated with increased fibrosis. We plan to utilize these results for future studies using pharmacologic strategies to decrease lung fibrosis.
