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MS 06 - Combined Modality Treatment for Thymic and Pleural Malignancy (ID 528)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 6
- Moderators:Oscar Arrieta, Scott Swanson
- Coordinates: 10/16/2017, 15:45 - 17:30, F201 + F202 (Annex Hall)
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MS 06.01 - Proposal of Change for Future Staging System for Thymic Tumor (ID 7663)
15:45 - 16:00 | Presenting Author(s): Meinoshin Okumura
- Abstract
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Abstract:
Although Masaoka clinic-pathological staging system has been accepted as the global standard staging system for thymic epithelial tumors, several problems of this staging system have been pointed out because clinical practices in diagnosis, medical treatment and surgical procedure has enormously advanced during more than 30 years. Furthermore, there has not been a TNM classification system approved by UICC to describe a tumor’s clinical status adequately. To overcome these situations, International Thymic Malignancy Interest Group (ITMIG) established global database and proposed a novel staging system based on TNM definition in collaboration with IASLC staging committee in 2016. This is a great progress in clinical medicine in the field of thymic epithelial tumor, but as a matter of fact, stage grouping according to this novel TNM classification is mostly defined by tumor invasion to adjacent organs similarly to Masaoka staging system. Japanese Association for Research of the Thymus (JART) established by Akira Masaoka and colleagues contributed to the ITMIG project of global database, and several studies using JART database were performed and reported from Japanese researchers. Novel findings in the JART database study are reviewed and new insights in further modification in TNM staging system are addressed in the present article. The significance of involved organs as a prognostic factor has been a great interest, because some structures are easily resected while others are difficult to be completely resected. Actually, some previous studies showed prognostic significance of involvement of the great vessels. Based on the ITMIG database, involvement of the pericardium alone is defined as T2 in the UICC TNM classification while involvement of SVC and brachiocephalic vein is defined as T3 and involvement of the aorta, aortic branches and intrapericardial vessels is defined as T4. One of the JART database study focusing on the involved organs in Masaoka stage III tumors showed that invasion to the chest wall is an independent prognostic factor by multivariate analysis while involvement of the great vessels is not. The hazard ratio of involvement of the chest wall is 4.07. Invasion to the chest wall is defined as T3, but when invasion to the sternum is extended, resection of the chest wall including sternum is sometimes a difficult procedure, and complete resection is hard to be achieved. Lymphatic channels are distributed in the chest wall, of which involvement by the tumor can result in nodal metastasis. Thus, invasion to the chest wall might be considered as an important factor to determine the tumor spread, and therefore, as one factor in T definition. Involvement of SVC and brachiocephalic vein is defined as T3, but is heterogenous variable because some tumors invade to the outer surface of the vessel but others enter the lumen of the vessel, which can result in pulmonary metastasis. The extent in involvement of the great vessels could be a significant factor in T definition. Tumor size could reflect the time from initiation of the tumor and the larger tumor is more likely to be in an advanced status. Actually, tumor size is a critical factor in T definition in lung cancers. In thymic epithelial tumors, however, T definition does not reflect the tumor size. Using JART database, oncological significance of the tumor size was examined in thymoma and thymic carcinoma, separately. In thymoma, the rate of R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 94.4%, 91.3%, and 84.0%, respectively. Recurrence rate after R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 3.0%, 8.9% and 27.2%, respectively. In thymic carcinoma, the rate of R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 80.2%, 63.2%, and 62.5%, respectively. Recurrence rate after R0 resection in the tumors less than 5.0 cm, 5.1 to 10 cm, and more than 10.1 cm was 28.2%, 53.7% and 62.5%, respectively. Thus, there was apparent difference in oncological behavior between tumors less than 5.0 cm and those more than 5.1 cm both in thymoma and thymic carcinoma. These observations suggest that tumors size also should be included in T definition in thymic epithelial tumors. Finally, the category of Masaoka stage IVA disease includes pleural dissemination, but the situation of pleural dissemination varies greatly from a single lesion to numerous lesions. Furthermore, some disseminations are resectable while others are not. JART study revealed that the number of disseminated lesions on the pleura In conclusion, T definition remains to be further evaluated in reference to tumor size, chest wall invasion and extent of involvement of the great vessels. M definition also remains to be further discussed in terms of extent of the pleural dissemination.
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MS 06.02 - Is There a Role for Minimally Invasive Surgery in Locally Advanced Thymic Tumors? (ID 7664)
16:00 - 16:15 | Presenting Author(s): Wentao Fang | Author(s): Z. Gu
- Abstract
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Abstract:
Background: Thymectomy via median sternotomy has been the standard surgical approach for patients with thymic malignancies. However, the last decade has seen an increasing interest in minimally invasive thymectomy for early stage tumors. By avoiding sternal split, video-assisted thoracoscopic surgery (VATS) has been reported to be associated with similar operating time but less blood loss during operation, shorter length of intensive care unit and hospital stays, diminished postoperative pain, and improved postoperative pulmonary function. A recent propensity-score matched study by the Chinese Alliance of Research for Thymomas (ChART) reported 100% complete resection rate in both VATS and open thymectomies for UICC stage I (T1N0M0). Both overall and disease-free survivals, as well as cumulative incidence of recurrence were similar between the matched groups. The role of minimally invasive surgery has thus been well established in early stage thymic tumors. Using the International Thymic Malignancy Interest Group (ITMIG) global database, a recent propensity-score matched study found that complete resection rate was comparable between minimally invasive and open approaches (96% vs. 96%, P=0.7), including 33 and 10 patients with Masaoka stage III and IV diseases. And surgical approach was not a predictor of R0 resection in that study. The results suggested that minimally invasive surgery may also have a role in some patients with locally invasive tumors. To prove this, it is necessary to show that VATS is associated with improved peri-operative results, while maintaining similar resection rate and oncologic outcomes as open surgery. We therefore carried out a propensity-score matched study comparing the results of VATS and median sternotmy in UICC T2-3 thymic tumors to see whether minimally invasive surgery might be an acceptable approach. Patients and Methods: Surgical patients with UICC stage pT2-3 thymic tumors were retrospectively retrieved from a prospectively maintained database at the Shanghai Chest Hospital. Those who undergone VATS resection were compared with patients receiving median sternotomy (Open). A propensity-score matched study was then carried out to compare resection rate, peri-operative outcomes, and follow-up results between the two matched groups. Results: During 2007-2017, 115 patients who undergone surgical resection of thymic malignancies turned out to have UICC pT2-3 tumors upon histological examination. In 29 patients, video-assisted thoracoscopic surgery (VATS) was attempted and completed in 26 cases. In 89 patients (including the 3 conversion cases due to extensive tumor invasion) the lesion was resected via Open median sternotomy. Comparing with the VATS group, the Open group has larger tumor size, higher T stage, and received more induction therapies. A propensity-score match was carried out according to concomitant autoimmune disease, co-morbidity, induction therapy, tumor size, and UICC pTNM stage in 1:2 ratio. This leaves 26 patients in the VATS group and 52 patients in the Open group (Table 1). Induction therapies were given in 7.7% and 9.6% patients in the two groups (p=0.779). The two groups were comparable in patients’ age, gender, tumor histology, as well as all the matching factors. Complete resection (R0) rate was comparable (76.9% in both groups), with higher primary tumor resection rate in the VATS group (96.2% vs. 86.7%, p=0.151). Because of local tumor invasion, pericardium, lung (wedge resection), phrenic nerve, and left innominate vein were resected together with the tumor in 21, 17, 3, and 3 patients, respectively. Postoperative morbidity rate was also similar between the two groups (15.4% vs. 17.3%, p=0.830). Comparing to the Open group, VATS patients had less intraopertaive blood loss (127 ml vs. 219 ml, p=0.005), shorter duration of chest drainage (3±1.2 day vs. 5±4.7 day, p=o.oo5) and length of hospital stay (5.9±3.1 vs. 9.6±5.1, p<0.001). During a median follow-up of 35 months, overall survival was 100% in the VATS group and 95.2% in the Open group (Figure 1, p=0.664), and 3-year recurrence rates were 0.052 and 0.167, respectively (Figure 2, p=0.554). Conclusions: In addition to UICC stage I thymic malignancy, VATS may also be an acceptable approach for locally advanced thymic tumors. Complete resection rate and follow-up results are comparable to open surgery in well selected cases. And better peri-operative results can be expected via VATS approach as compared to median sternotomy. Based on these results, VATS should be attempted in those patients with potentially resectable thymic tumors. And long-term follow-up is still necessary to confirm its oncological effectiveness. Table 1. Comparison of patient demographics, tumor characteristics, and peri-operative results between the VATS and Open groups.
Figure 1. Overall survivals between the VATS and the Open groups after propensity-score matching. Figure 1 Figure 2. Cumulative incidences of recurrence after propensity-score matching in completely resected patients in the VATS and the Open groups. Figure 2VATS N=26 Open N=52 P Value Gender male 17 (65.4) 34 (65.4) 1.0 Age year 58.5±13.0 57.7±10.1 0.781 Autoimmune diseases yes 5 (19.2) 8 (15.4) 0.667 Co-morbidity yes 8 (30.8) 14 (26.9) 0.722 Tumor size cm 5.7±2.0 6.4±1.7 0.161 Histology Thymoma 15 (57.7) 29 (55.8) 0.889 Thymic Carcinoma 11 (42.3) 23 (44.2) pT T2 8 (30.8) 14 (26.9) 0.722 T3 18 (69.2) 38 (73.1) pN N0 25 (96.2) 51 (98.1) 1.0 N1 1 (3.8) 1 (1.9) pM M0 21 (80.8) 45 (86.5) 0.506 M1a 5 (19.2) 7 (13.5) Operation time min 136±50 134±47 0.85 Blood lose ml 127±90 219±150 0.005 Chest tube drainage day 3±1.2 5±4.7 0.005 Length of hospital stay day 5.9±3.1 9.6±5.1 0.000 Morbidity yes 4 (15.4) 9 (17.3) 0.830
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MS 06.03 - PD vs. EPP in the Treatment of MPM (ID 7665)
16:15 - 16:30 | Presenting Author(s): David Rice
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The argument for cytoreduction The argument in favor of cytoreduction is supported by several observations: First, several randomized trials support this procedure for other disease sites including advanced ovarian, colorectal and renal cell cancer. Second, most long-term survivors of MPM have had surgery as a component of their therapy, whereas there are very few long-term survivors who have been treated with non-operative strategies. Analyses of both the Surveillance Epidemiology and End Results (SEER) and the National Cancer Database have show longer survival of patients who have had ‘cancer-directed’ surgery compared to those whose treatment did not include surgery. Third, the median survival of patients in most recent phase III trials of chemotherapy is between 10 to 13 months, whereas in three multicenter trimodality phase II surgical studies median survival is significantly longer ranging 17 to 20 months. Nevertheless, the quality of evidence supporting a role for cytoreductive surgery for mesothelioma is low, and the only randomized study to performed date, the small, underpowered and highly controversial MARS 1 trial, failed to show benefit of extrapleural pneumonectomy compared to chemotherapy and supportive care. Cytoreductive surgical options There are two approaches to cytoreductive surgery for pleural mesothelioma: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (PD). The pendulum has swung back and forth over the last 40 years regarding the best operative approach and decisions are influenced by factors including tumor biology, patient physiology, surgical philosophy and availability of adjuvant therapies. A goal common to both EPP and extended PD/PD is macroscopic complete resection (MCR) of tumor, which is generally interpreted as <1cm residual tumor remaining after resection. The argument for EPP Extrapleural pneumonectomy (EPP) involves the en-bloc resection of the parietal and visceral pleura, lung, ipsilateral pericardium and diaphragm. The latter structures are usually reconstructed with prosthetic mesh, often polytetrafluoroethylene (Goretex), though use of polyglycolic acid (Vicryl), polypropylene and various biologic meshes has also been described. The procedure is associated with an operative mortality of 2 to 8% in experienced centers, however, a recent review of the Society of Thoracic Surgeon’s database reported a 30-day mortality rate of nearly 11%. 90-day mortality as high as 17% has been reported. Postoperative morbidity ranges from 30% to 80%, and major complications include bronchopleural fistula, empyema, hemorrhage, pulmonary embolus and ARDS/pneumonia. The potential value of EPP over PD is that it may offer a more complete cytoreduction in that tumor cells involving the lung and visceral pleura are completely removed. Indeed, most retrospective series show much lower rates of local failure after EPP (13%-35%) than PD (36%-100%). However, distant recurrence (most commonly in the contralateral chest or abdomen) are frequent (~50%). Median survival reported in 3 phase II trials that included EPP in the setting of neoadjuvant chemotherapy ranged between 17 to 20 months from initiation of treatment. Use of intrapleural adjuncts including photodynamic therapy (PDT), heated chemotherapy and other cytotoxic agents is controversial and has yielded varying results. Adjuvant radiation therapy is relatively easy to administer as there is no risk of ipsilateral lung toxicity (lung is removed) and though excellent local control has been reported in several phase II single arm studies, a recent randomized phase III trial showed no benefit to either disease free or overall survival. The argument for PD Pleurectomy decortication involves the resection of parietal and visceral pleura, and localized resection of any tumor involving the lung, diaphragm or pericardium. If the latter two structures are resected the term ‘extended’ PD (EPD) is applied. Several retrospective series have shown improved DFS and OS in patients undergoing either PD or EPD compared to partial pleurectomy (PP) although selection bias is likely to have influenced outcomes to some extent. Perioperative mortality rates following PD averages 3% and major morbidity ranges between 13% to 60%. A common complication after the procedure is prolonged air leak (14% - 58%). Rates of local recurrence after PD are higher than EPP most likely related to the larger surface area at risk for harboring residual microscopic tumor, however this does not appear to influence overall survival. Analysis of retrospective series reveals a median survival of approximately 20 months, similar to EPP, thought there have been notable recent reports of median survival as high as 36 months in patients who have received EPD with intrapleural therapies. Compared to EPP, adjuvant radiation therapy is more difficult to safely administer after PD, and though technically feasible, the benefit in terms of effect on local control (48% - 64%) is questionable. Comparisons of EPP and PD PD/EPD is associated with lower mortality and fewer and less severe postoperative complications than EPP. Additionally, retrospective comparisons of quality of life metrics tend to favor PD/EPD regarding global health, physical and social function and dyspnea[9]. Analysis of 9 retrospective series that have compared cancer related outcomes of EPP and PD/EPD reveals similar or improved survival in most cases with PD/EPD (Table). Differences in patient selection and prognostic factors such as tumor stage, volume and epithelioid histology make direct comparisons difficult, however. Nonetheless, there does not appear to be a survival benefit to performing EPP, and since the procedure is associated with greater risk of operative mortality, morbidity and functional deficit, it seems justified to recommend PD/EPD as the cytoreductive procedure of choice, where technically feasible[10]. The ongoing prospective, randomized MARS-2 trial currently accruing in the United Kingdom will better define the true role of cytoreductive surgery (PD) in the treatment of malignant pleural mesothelioma.
Table: Comparative studies of EPP and PD References 1. Nelson DB, Rice DC, Niu J, et al. Long-Term Survival Outcomes of Cancer-Directed Surgery for Malignant Pleural Mesothelioma: Propensity Score Matching Analysis. J Clin Oncol. 2017:JCO2017738401. 2. Flores RM, Riedel E, Donington JS, et al. Frequency of use and predictors of cancer-directed surgery in the management of malignant pleural mesothelioma in a community-based (Surveillance, Epidemiology, and End Results [SEER]) population. J Thorac Oncol. 2010;5(10):1649-1654. 3. Burt BM, Cameron RB, Mollberg NM, et al. Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality. J Thorac Cardiovasc Surg. 2014;148(1):30-35. 4. Stahel RA, Riesterer O, Xyrafas A, et al. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol. 2015;16(16):1651-1658. 5. Lang-Lazdunski L, Bille A, Papa S, et al. Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. J Thorac Cardiovasc Surg. 2015;149(2):558-565; discussion 565-556. 6. Marulli G, Breda C, Fontana P, et al. Pleurectomy-decortication in malignant pleural mesothelioma: are different surgical techniques associated with different outcomes? Results from a multicentre studydagger. Eur J Cardiothorac Surg. 2017. 7. Friedberg JS, Simone CB, 2nd, Culligan MJ, et al. Extended Pleurectomy-Decortication-Based Treatment for Advanced Stage Epithelial Mesothelioma Yielding a Median Survival of Nearly Three Years. Ann Thorac Surg. 2017;103(3):912-919. 8. Rimner A, Zauderer MG, Gomez DR, et al. Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma. J Clin Oncol. 2016;34(23):2761-2768. 9. Rena O, Casadio C. Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure. Lung Cancer. 2012;77(1):151-155. 10. Waller DA, Tenconi S. Surgery as part of radical treatment for malignant pleural mesothelioma. Curr Opin Pulm Med. 2017;23(4):334-338.Author Group n Epithelioid (%) Node +ve (%) T3 or T4 (%) Stage III or IV (%) Median survival (mo) Median follow-up (mo) Local failure (%) Distant failure (%) Flores, 2008 EPP 385 70% nr 75% 75% 12 17 (all) 19% 38% PD 278 64% nr 65% 65% 16* 31% 17% Lang-Lazdunski, 2012 EPP 22 64% 46% nr 87% 13 13 52% 56% PD 61 67% 30% nr 63% 23* 16 nr nr Rena,2012 EPP 40 86% 0% 0% 0% 20 nr 47% 53% PD 37 84% 0% 0% 0% 25 nr 100% 44% Nakas, 2012 EPP 98 78% (all) nr 100% 100% 15 21 60% 40% PD 67 nr 100% 100% 13 16 56% 18% Batirel, 2016 EPP 42 75% (all) 49% (all) 52% (all) nr 18 23 68% (all) 21% (all) PD 66 nr 15 16 Infante, 2016 EPP 91 89% 44% nr 80% 19 17 45% 50% PD 47 98% 30% nr 62% 30 11 26% 24% Sharkey, 2016 EPP 229 72% 53% 76% 86% 13 nr 43% 57% PD 133 76% 56%* 69% 80%* 12 nr 53% 41% Korston, 2017 EPP 52 94% nr nr 65% 23 nr nr nr PD 26 94% nr nr 65% 32* nr nr nr Verma, 2017 EPP 271 34% 27% 43% 51% 19 15 (all) nr nr PD 1036 26% 20% 37% 47% 16 nr nr
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MS 06.04 - The Effect of the Timing of Chemotherapy: Induction vs Adjuvant after PD or EPP (ID 7666)
16:30 - 16:45 | Presenting Author(s): David Waller
- Abstract
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Multimodality therapy for malignant pleural mesothelioma (MPM) including radical surgery has been associated with prolonged survival and in selected patients, but the evidence for a long term survival benefit is inconsistent [1,2]. There is little evidence regarding the optimal timing of additional chemotherapy, with some advocating induction treatment or in the immediate post operative setting, and others choosing to delay until progression. We have analysed our experience of the effect of the timing of chemotherapy on the outcome of extrapleural pneumonectomy (EPP) or pleurectomy/decortication (PD) [3] . Induction chemotherapy The use of a standardized neo-adjuvant chemotherapy regimen has been reported to be feasible in patients treated by EPP and adjuvant hemithoracic radiotherapy [4] . This regime requires high levels of patient fitness and is associated with a median survival of 16.8-25.5 months. However, this decreases dramatically if patients are unable to complete the entire trimodality therapy protocol (9-14 months) [5]. This may select those who will not have a prolonged survival, thus avoiding futile but morbid therapy. There is also the potential for tolerance of an increased number of cycles prior to surgery than in the adjuvant setting. The drawbacks include the risk of progression during chemotherapy, or severe toxicity, leaving the patient unsuitable for radical surgery. It is possible that neoadjuvant chemotherapy may select out chemoresistant cells, and lead to more aggressive disease progression following the inevitable R1 resection. There is currently no evidence to show that there is any long-term benefit to a response to chemotherapy prior to radical surgery. In fact, a true, significant, pathological response to chemotherapy is very rare [5]. Adjuvant chemotherapy The apparent benefit with adjuvant chemotherapy may be due to selection bias; only the fittest can receive the full regime, and will therefore have a survival benefit independent of therapy. Nevertheless, the IASLC staging committee found that the provision of adjuvant therapy was an independent prognostic factor for survival in patients with MPM [6]. Adjuvant chemotherapy may be contraindicated due to low compliance as a consequence of the morbidity of surgery In the case of EPP, many patients are not able to tolerate adjuvant chemotherapy, however in the case of EPD, most patients recover from surgery and are able to commence therapy within 8 weeks [7]. There has been a change in practice over time with regards the number of cycles given in the adjuvant setting, from 4 to 6. Delayed (expectant) chemotherapy Oncologists may wish to reserve an active agent, pemetrexed, until assessable disease or symptom-related progression. It may be beneficial as treatment of low volume residual disease following R1 resection may select out clones with resistance to platinum therapy thus reducing the efficacy at re-challenge during relapse. We found no difference in overall survival when chemotherapy was given in the immediate adjuvant setting or only at progression. However, subgroup analysis revealed that in non-epithelioid MPM delayed therapy was an independent predictive factor for poor survival/progression free survival. This could be explained in part by the continued presence of a subpopulation of aggressive and chemo-resistant stem cells in the sarcomatoid element of biphasic disease following an R1 resection. These more aggressive cells are then able to proliferate, as compared with a more indolent group of stem cells in epithelioid disease, leading to a shorter time to relapse and a more aggressive tumour type if no chemotherapy is given in the adjuvant setting. This is often seen after chemotherapy treatment alone, where these aggressive resistant cells are selected for, giving rise to rapid progression, even after an initial response [8]. Similarly, in those with nodal disease delaying chemotherapy was also found to be detrimental. In these patients tumour cells have already developed the ability to metastasise and it is likely that systemic micrometastases are present following local resection. Intra operative chemotherapy Intraoperative instillation of platinum based chemotherapy into the pleural cavity after resection has been shown to be safe in selected experienced institutions, where favourable median overall and progression free survival outcomes have been reported [9]. We did not include this modality in our protocol but one such study showed an increase in time to progression from 12.8 to 27.1 months, and overall survival from 22.8 to 35.5 months in clinically matched patients [10]. Conclusion Our retrospective study [3] showed no significant overall survival benefit from any particular timing of chemotherapy with either neo-adjuvant, adjuvant, or expectant management. Interestingly, we found no benefit in giving neo-adjuvant chemotherapy, despite the intrinsic bias within this group of patients, as only those who did not progress proceeded to surgery. We suggest that it may be important to tailor chemotherapy in 4 clinical sub-groups. In the poorer prognosis groups, non-epithelioid cell type and/or with pathological lymph node disease, giving chemotherapy in the immediate adjuvant setting (within 3 months of surgery) rather than delaying it until progression gave a survival advantage. Conversely, there was no benefit found in giving therapy in the immediate adjuvant setting in better prognosis patients with epithelioid cell type and with no evidence of lymph node metastases at operation. It may therefore be preferable to reserve first line chemotherapy until there is radiological evidence of disease progression in these patients. Future results from the EORTC NCT02436733 trial : a randomized phase II study of pleurectomy/ decortication (P/D) preceded or followed by chemotherapy in patients with early stage malignant pleural mesothelioma [11] will inform this debate. We suggest that the randomization in the trial is stratified in to epithelioid versus non-epithelioid and clinical node positive versus negative. References 1.C. Cao, D. Tian, C. Manganas, P. Matthews, T.D. Yan, Systematic review of trimodality therapy for patients with malignant pleural mesothelioma., Ann Cardiothorac Surg. 2012; 1: 428–37. 2.Nakas A, Waller D. Predictors of long-term survival following radical surgery for malignant pleural mesothelioma .Eur J Cardiothorac Surg. 2014;46:380-5. 3.Sharkey AJ, O'Byrne KJ, Nakas A, Tenconi S, Fennell DA, Waller DA. How does the timing of chemotherapy affect outcome following radical surgery for malignant pleural mesothelioma? Lung Cancer. 2016 Oct;100:5-13 4.Stahel RA, Riesterer O, Xyrafas A, et al. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol 2015;16:1651-8. 5. L. Donahoe, J. Cho, M. De Perrot, Novel Induction Therapies for Pleural Mesothelioma, Semin Thorac Cardiovasc. Surg. 2014;26:192–200. 6.Pass HI, Giroux D, Kennedy C, Ruffini E, Cangir AK, Rice D, Asamura H, Waller D, Edwards J, Weder W, Hoffmann H, van Meerbeeck JP, Rusch VW; IASLC Staging Committee and Participating Institutions. Supplementary prognostic variables for pleural mesothelioma: a report from the IASLC staging committee. J Thorac Oncol. 2014 Jun;9(6):856-64 7.S. Bölükbas, C. Manegold, M. Eberlein, T. Bergmann, A. Fisseler-Eckhoff, J.Schirren, Survival after trimodality therapy for malignant pleural mesothelioma:Radical Pleurectomy, chemotherapy with Cisplatin/Pemetrexed and radiotherapy, Lung Cancer. 71 (2011) 75–81 8.L. Cortes-Dericks, G.L. Carboni, R.A. Schmid, G. Karoubi, Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed, Int. J. Oncol. 37 (2010) 437–444. 9.M. Ried, T. Potzger, N. Braune, R. Neu, Y. Zausig, B. Schalke, et al., Cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion for malignant pleural tumours: Perioperative management and clinical experience, Eur. J.Cardio-Thoracic Surg. 43 (2013) 801–807. 10.D.J. Sugarbaker, R.R. Gill, B.Y. Yeap, A.S. Wolf, M.C. Dasilva, E.H. Baldini, et al.,Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection, J. Thorac.Cardiovasc. Surg. 145 (2013) 955–963. 11. EORTC NCT02436733 trial : a randomized phase II study of pleurectomy/ decortication (P/D) preceded or followed by chemotherapy in patients with early stage malignant pleural mesothelioma. https://clinicaltrials.gov/ct/show/NCT02436733
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MS 06.05 - The Use of Adjuvant IMRT after Pleurectomy/Decortication (ID 7667)
16:45 - 17:00 | Presenting Author(s): Andreas Rimner
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Intensity-modulated radiation therapy (IMRT) is a highly conformal radiation technique that allows more effective sparing of normal tissues, providing an opportunity for safer, less toxic treatments and increased efficacy by enabling higher radiation doses to the tumor target. It comes with a much higher level of dosimetric control and certainty leading to better target coverage than conventional OR 3D conformal radiation techniques.[1] The higher precision of IMRT delivery when used in the adjuvant setting requires detailed knowledge of the intrathoracic anatomy, incorporation of all diagnostic imaging tools available, incorporation of the pathologic findings at the time of surgery, assessment of the respiratory tumor motion using a 4D scan, and image-guided treatment delivery. IMRT with integration of a boost to areas of gross disease is technically feasible but has not yet been tested in a larger series. The use of 18-fluorodeoxyglucose positron emission tomography (PET) for RT planning purposes may reduce the likelihood of geographic misses and detect radiographically occult lymph node involvement. Small series have suggested that PET may guide the delineation of an integrated boost volume or improve local control.[2] The recent decline in extrapleural pneumonectomies (EPP) in the surgical management of malignant pleural mesothelioma (MPM) due to reports suggesting a lack of survival benefit compared with lung-sparing pleurectomy/decortication (P/D) has posed a particular challenge for adjuvant radiation treatments: how to safely treat the pleural space for microscopic residual disease without exceeding the radiation tolerance of the underlying sensitive normal lung tissue. Older radiation techniques result in unacceptable toxicity and insufficient local control.[3] Thus, an IMRT technique targeting the hemithoracic pleural space including the diaphragm that simultaneously spared the ipsilateral lung, heart, liver, kidneys and abdominal contents was developed (Figure 1).[4] Typically these patients are treated with six to nine coplanar 6 MV beams equispaced over 200-240 degrees around the ipsilateral hemithorax were used. More recently, rotational techniques such as volumetric arc therapy or tomotherapy have been shown to allow for even more effective sparing of organs at risk.[5,6] The first report in 36 MPM patients with 2 intact lungs showed that hemithoracic adjuvant pleural IMRT (50.4 Gy in 28 fractions) could be delivered with a 20% (n=7) ≥ grade 3 pneumonitis risk; 1 patient had grade 5 pneumonitis.[4] The median survival in resectable patients was 26 months. A tomotherapy technique was published with similar toxicity outcomes (20% ≥ grade 2 pneumonitis, one fatal case of pneumonitis).[6] The radiation dose delivered was slightly higher with 50 Gy delivered in 25 fractions including a simultaneous boost to 60 Gy for areas of concern for residual disease based on FDG-PET. A matched analysis of P/D, chemotherapy, and IMRT vs. EPP, chemotherapy and IMRT found favorable median overall (28.4 vs. 14.2 months) and progression-free survival (16.4 vs. 8.2 months) with trimodality therapy involving P/D compared with EPP.[7] Local failure rates vary significantly among studies, ranging from 40 to 68% at 2 years. A systematic review of 67 patients still found a significant risk of local failures in the radiation field, mostly in unresectable patients and sites of gross residual disease, emphasizing the importance of a macroscopic complete resection, need for optimization of radiation targeting and experience with this complex radiation technique.[8] Increasing experience over time led to fewer marginal failures and decreased toxicity, suggesting the improvement in target delineation and RT planning. Most recently an association of radiation dose to the heart and overall survival was reported,[9] similar to observations in locally-advanced non-small cell lung cancer. These encouraging results have led to a 2-institution phase II trial of trimodality therapy using induction chemotherapy with cisplatin and pemetrexed, P/D, and adjuvant hemithoracic intensity-modulated pleural radiation therapy (IMPRINT).[10] Twenty-seven patients were treated and 29.6% developed radiation pneumonitis (6 grade 2; 2 grade 3). Median progression-free and overall survival was 12.4 and 23.7 months, respectively. In resectable MPM patients who received chemotherapy and IMPRINT, 2-year OS was 59%. Based on these findings a multi-institutional phase II study was initiated to demonstrate the safety and exportability of this complex IMPRINT technique in a multicenter setting involving institutions without prior experience of IMPRINT (clinicaltrials.gov: NCT00715611). All patients’ treatment contours and plans are centrally reviewed and revised for uniformity. The goal is to accrue 36 patients from 5 institutions. Given the promising outcomes this study may be succeeded by a randomized trial testing the effect of adjuvant IMPRINT vs no additional treatment after lung-sparing P/D and chemotherapy. Figure 1: Figure 1 1. Krayenbuehl J, Dimmerling P, Ciernik IF, et al: Clinical outcome of postoperative highly conformal versus 3D conformal radiotherapy in patients with malignant pleural mesothelioma. Radiat Oncol 9:32, 2014 2. Fodor A, Fiorino C, Dell'Oca I, et al: PET-guided dose escalation tomotherapy in malignant pleural mesothelioma. Strahlentherapie und Onkologie 187:736-743, 2011 3. Gupta V, Mychalczak B, Krug L, et al: Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. International Journal of Radiation Oncology Biology Physics 63:1045-1052, 2005 4. Rosenzweig KE, Zauderer MG, Laser B, et al: Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma. International Journal of Radiation Oncology Biology Physics 83:1278-1283, 2012 5. Dumane V, Rimner A, Yorke ED, et al: Volumetric-modulated arc therapy for malignant pleural mesothelioma after pleurectomy/decortication. Applied Radiation Oncology 5:24-33, 2016 6. Minatel E, Trovo M, Bearz A, et al: Radical Radiation Therapy After Lung-Sparing Surgery for Malignant Pleural Mesothelioma: Survival, Pattern of Failure, and Prognostic Factors. Int J Radiat Oncol Biol Phys 93:606-13, 2015 7. Chance WW, Rice DC, Allen PK, et al: Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma: toxicity, patterns of failure, and a matched survival analysis. Int J Radiat Oncol Biol Phys 91:149-56, 2015 8. Rimner A, Spratt DE, Zauderer MG, et al: Failure patterns after hemithoracic pleural intensity modulated radiation therapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 90:394-401, 2014 9. Yorke ED, Jackson A, Kuo LC, et al: Heart Dosimetry is Correlated with Risk of Radiation Pneumonitis after Lung-Sparing Hemithoracic Pleural IMRT for Malignant Pleural Mesothelioma. Int J Radiat Oncol Biol Phys, 2017 10. Rimner A, Zauderer MG, Gomez DR, et al: Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma. J Clin Oncol 34:2761-8, 2016
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MS 06.06 - Chemotherapy for Thymic and Mesothelial Tumors (ID 7668)
17:00 - 17:15 | Presenting Author(s): Miyako Satouchi
- Abstract
- Presentation
Abstract:
Thymic and Mesothelial Tumors are relatively rare. There are few therapies that have been established in prospective studies, so the conditions have poor prognoses. Cisplatin+pemetrexed is the gold standard for unresectable malignant pleural mesothelioma in that it has shown a significantly longer survival than cisplatin in a controlled Phase III clinical study. Moreover, adding on bevacizumab to this combination therapy can extend survival, and these two therapies are recommended as 1L by the NCCN guideline. There have recently been promising results reported with anti-PD-1 antibody and anti-PD-L1 antibody single agent therapies as well as combination therapies with anti-CTLA-4 antibody, and there are many ongoing prospective clinical studies on these now. There are not very many therapies for Thymic malignancies that have already been examined in prospective studies. Carboplatin + paclitaxel, ADOC (cisplatin + doxorubicine + vibncristine + cyclophasphamide) therapy, CAP(Cisplatin + doxorubicine + cyclophosphamide) therapy, and the like are currently used as a result of outcomes in Phase II studies and retrospective studies. Furthermore, there have been reports of responses with molecular targeting therapies such as Sunitinib that target Kit. It has been reported that Thymic tumors express PD-L1, and there are currently several ongoing studies examining the relatively frequency and effect of anti-PD-1 antibody on such. My presentation will provide an overview of the current gold standards, recent clinical study outcomes, and promising pipeline therapies for Thymic and Mesothelial Tumors.
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MA 01 - SCLC: Research Perspectives (ID 650)
- Event: WCLC 2017
- Type: Mini Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:John V Heymach, Eun Kyung Cho
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 503
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MA 01.02 - Multigene Mutation Profiling and Clinical Characteristics of Small-Cell Lung Cancer in Never-Smokers Versus Heavy Smokers (ID 10335)
11:05 - 11:10 | Author(s): Oscar Arrieta
- Abstract
- Presentation
Background:
Small-cell lung cancer (SCLC) has been occasionally detected in never-smokers as smoking rates decrease worldwide. We investigated the clinical and genetic characteristics of SCLC in never-smokers (Geno1.3-CLICaP)
Method:
A cohort of patients diagnosed with SCLC were grouped into smokers (n=10) and ever/never-smokers (n=10). For both groups, somatic mutation profiling was carried out using a comprehensive NGS assay (TruSight Tumor 170) targeting the full coding regions of 170 cancer-related genes. Epidermal growth factor receptor (EGFR) mutation was confirmed by RT-PCR (Cobas[TM]). The clinical outcomes of the two groups were compared using Kaplan-Meier and Cox proportional models.
Result:
Median age was 58 years (r, 46-81), 55% (n = 11) were men, most patients had extended disease (85%) and the dominant tumor involvement site was pleura and lungs (65%). No significant differences were found in age, disease distribution, baseline performance status and cerebral metastases in relation to tobacco exposure. The ORR to first-line therapy were 50% and 90% between smokers and ever/never-smokers, respectively (p=0.032). The median overall survival (OS) was 29.1 months in ever/never-smokers (95%CI 23.5-34.6) versus 17.3 months in smokers (95%CI 4.8-29.7; p=0.0054). Never-smoking history (HR 0.543, 95%CI 0.41-0.80), limited stage disease (HR 0.56, 95%CI 0.40-0.91) and response to first line platinum based chemotherapy (HR 0.63, 95%CI 0.60-0.92) were independently related with good prognosis. Among ever/never smokers main genetic mutations were TP53 (80%), RB1 (40%), CYLD (30%), EGFR (30%), MET (20%), SMAD4 (20%) and BRIP1 (20%). None of the smokers had mutations in EGFR, MET or SMAD4, but there was a greater involvement in RB1 (80%, p=0.04), CDKN2A (30%, p=0.05), CEBPA (30%, p=0.05), FANCG (20%), GATA2 (20%), and PTEN (20%).
Conclusion:
Never-smokers with SCLC are increasingly prevalent and have a better prognosis than their smoker counterpart. EGFR, MET and SMAD4 are frequent mutations among SCLCs of ever/never smokers, and RB1, CDKN2A and CEBPA among smokers. Figure 1
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MA 08 - Supportive Care and Communication (ID 669)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Nursing/Palliative Care/Ethics
- Presentations: 1
- Moderators:E. Esposito-Nguyen, John McPhelim
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 511 + 512
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MA 08.10 - Favorable Clinical Status Predicts Benefit From Early-Palliative Cares & OS Improvement in NSCLC: A Randomized Clinical Study (ID 10348)
12:05 - 12:10 | Presenting Author(s): Oscar Arrieta
- Abstract
- Presentation
Background:
Early-palliative care (EPC) after lung cancer diagnosis is essential for a better quality-of-life (QoL), and even offers a substantial improvement in survival outcomes. We prospectively assessed the effect of EPC in overall survival (OS) and patient-reported outcomes in non-small cell lung cancer (NSCLC) patients.
Method:
Newly-diagnosed and treatment-naïve NSCLC patients were included and randomly assigned (1:1) to receive either EPC with oncologic, nutritional, and psychological care, or standard oncologic care alone. Assessments were performed at baseline, second, fourth and sixth cycle of chemotherapy, with evaluations including: QoL, evaluated by The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, depression and anxiety which were evaluated using the Hospital Anxiety and Depression Scale, and oncologic symptomatology, which was evaluated with the Edmonton System Assessment Scale. NCT01631565 [013/020ICI(CV773/13)].
Result:
Ninety-six NSCLC patients were enrolled; 42 patients were allocated to EPC while 54 patients were allocated to standard-care. Overall, patients receiving EPC have lower self-reported symptoms, depression and anxiety. Median OS of patients with EPC was 11.1 months (95% CI: 8.4–13.9), while in patients with standard-care was 5.9 months (95% CI: 4.8 – 7.1); p=0.049. In the multivariate analysis, factors associated with worse OS were: patients in standard-care arm (HR, 95% CI 1.6 (0.9 – 2.7); p=0.05), male patients (HR, 95% CI 1.8 (1.1 – 3.0); p=0.028) and worse ECOG performance status (≥2) (HR, 95% CI 1.9 (1.0 – 3.5); p=0.039).In a subgroup analysis, patients who reaped the most benefit from EPC included those with better ECOG performance status (<2) (8.9 vs. 5.7 months; p=0.05); those without depression at baseline (14.8 vs. 6.5 months; p=0.05) and those Corroborar que si sea mayor ansiedad basal-mayor beneficio Figure 1
Conclusion:
EPC might provide benefit in the clinical symptomatic burden and OS of NSCLC patients. Benefits from EPC in OS might be associated to favorable global clinical status.
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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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MA 12.10 - Clinical Utility of Plasma EGFR T790M Mutation Detection in Advanced Non-Small Cell Lung Cancer Patients According to RECIST Criteria (ID 9620)
12:05 - 12:10 | Author(s): Oscar Arrieta
- Abstract
- Presentation
Background:
Circulating tumor DNA (ctDNA) has emerged as a specific and sensitive blood based biomarker for detection of several mutations in non–small cell lung cancer (NSCLC). Other clinical applications for ctDNA include molecular assessment of patients at diagnosis and serial (real-time) monitoring of biomarker status or the development of resistance mutations.
Method:
Eighty patients with advanced NSCLC who either (Group 1) had a new diagnosis or (Group 2) had developed acquired resistance to an EGFR kinase inhibitor were analyzed with highly sensitive Biocept, Inc. TargetSelector[TM] Real Time PCR based plasma assays genotyping for the detection of EGFR mutations L858R, Del19 and T790M. In addition, group 1 was analyzed for KRAS, BRAF, ROS1 and ALK and circulating tumor cells (CTCs) before and after TKI treatment.
Result:
Our results showed concordance rates of EGFR, KRAS and ALK mutations for up to 90% between the tissue and blood samples in newly diagnosed patients (Group 1). Paired analysis of mutations status monitoring in this group (P= 0.016) showed that the pattern of mutant ctDNA and CTCs changed in response to systemic therapy in 83% of the cases (Partial response or disease progression; R2=0.808). Plasma ctDNA analysis of multiple mutations showed that 40% of patients had at least one more mutation besides the one detected in tissue biopsy; 28% of EGFR tissue positive patients also had a KRAS mutation. In addition, 75% of KRAS positive patients had a BRAF mutation. These results demonstrate that plasma ctDNA analysis may even detect mutations missed by standard tissue genotyping due to tissue heterogeneity. Plasma EGFR T790M mutation was analyzed in patients with clinical progression to TKI inhibitors. Considering the RECIST criteria, 58% of progressive disease, 10% of stable disease and 16% of partial response patients were positive for T790M. According to metastatic disease type (locoregional, oligometastatic, polimetastatic), the T790M mutation was found on 64.3% of polimetastatic patients, 30.8% of oligometastatic patients and 17.6% of loco-regional patients.
Conclusion:
TargetSelector[TM] ctDNA assay is capable of rapidly detecting EGFR, KRAS and ALK mutations and is highly concordant with mutations present in tumor tissue with the robustness needed for real world testing to identify patients who progress on first line TKI therapy as well as for real-time monitoring of patients’ clinical status. Our findings highlight the importance of the RECIST criteria to define the progressive disease and determine the right moment to test for T790M mutation regardless the metastatic disease type.
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MA 16 - Mediastinal, Tracheal and Esophageal Tumor: Multimodality Approaches (ID 675)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:K. Shibuya, Francoise Mornex
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 313 + 314
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MA 16.12 - Prolonged Survival after Pulmonary Metastasectomy for Testicular Germ-cell Tumors in a Single Institution (ID 10183)
17:00 - 17:05 | Author(s): Oscar Arrieta
- Abstract
- Presentation
Background:
Testicular Germ-cell tumors are a common cancer in adults younger than 30 years-old. Extensive dissemination and high senitivity to chemotherapy are their principal characteristics. Chemotherapy is the standard of care, with an 80% probability of complete biochemical response with first line chemotherapy. Surgical resection of residual lesions after chemotherapy is indicated in some cases to rule out the presence of mature teratoma or viable tumor.
Method:
Retrospective chart review of patients with metastastic testicular Germ-cell tumors treated with chemotherapy and pulmonary metastasectomy from January 2006 to December 2014.
Result:
We found 56 cases with complete data for revision. Mean age was 25 years (16-48) Patients with lung metastases at diagnosis were 83.9%. All patients were treated with chemotherapy after initial orchiectomy. Preoperative serum tumor markers were negative in 44 patients (78%) Thoracotomy was performed in 48 cases (85.7%) and minimally invasive surgery in 8 cases (14.3%) Pulmonary wedge resection was performed in 52 patients (92.8%) and a lobectomy was required in 4 patients (7.2%) A R0 resection was achieved in 98.3%. Necrosis was reported in 25 cases (44.6%), mature teratoma in 17 (30.4%), viable germ-cell tumor in 13 patients (23.2%) and 1 case with seminoma (1.8%) All patients with viable tumor were offered postoperative chemotherapy. Median follow-up was 53.2 months (6-110). Median Overall Survival has not reached. Factors associated with improved survival were negative preoperative serum tumor markers and abscense of viable germ-cell tumor on resected specimens. Figure 1
Conclusion:
Removal of residual lesions after chemotherapy serves a double purpose, as an adjuvant treatment to chemotherapy allowing for “local” control of metastases and it also provides information about response to chemotherapy, with implications on prognosis and guiding postoperative treatment. In our cohort we demonstrate that despite a high proportion of viable tumors on surgical specimen, multi-modality treatment including lung metastasectomy is associated with prolonged survival
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MA 20 - Recent Advances in Pulmonology/Endoscopy (ID 685)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Pulmonology/Endoscopy
- Presentations: 1
- Moderators:C. Lee, S. Sasada
- Coordinates: 10/18/2017, 14:30 - 16:15, F205 + F206 (Annex Hall)
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MA 20.12 - Longitudinal Evaluation of Pulmonary Function in Patients with Advanced NSCLC Treated with Concurrent Chemo-Radiotherapy (ID 10197)
15:45 - 15:50 | Author(s): Oscar Arrieta
- Abstract
- Presentation
Background:
Patients with locally advanced Non-small cell lung cancer (aNSCLC) receive standard treatment with concurrent chemo-radiotherapy (CCRT). Different studies have tried to identify the changes in lung function after radiation exposition due to the high risk of pulmonary toxicity. The aim of this work is to evaluate lung function with a broad spectrum of respiratory tests as an objective way of assessing lung injury in patients with locally aNSCLC treated with CCRT.
Method:
A prospective study was conducted from June 2013 to July 2015. Fifty-two patients with locally advanced and oligometastatic NSCLC were included. The candidates received treatment with CCRT at the Instituto Nacional de Cancerología (Mexico). Participants were evaluated at baseline, end of RT, week 6, 12, 24 and 48 post-RT through forced spirometry with bronchodilator, body plethysmography, carbon monoxide diffusing capacity (DLCO), arterial blood gases, impulse oscillometry, 6-minute walk test and exhaled fraction of NO (FeNO). The study was registered in clinicaltrials.gov (NCT01580579).
Result:
Before treatment, 34.7% patients presented airflow obstruction (post-BD FEV~1~/FVC < 70%) which remained constant after RT (33.3%). For baseline results, the median of the % of the predictive value in FEV~1 ~post-BD was 97% (79-108), FVC 105% (90-116), TLC 101% (91-111) and DLCO 77% (55-103). At the end of CCRT, FEV~1 ~and FVC showed a significant reduction of 10% within week 12-48 (p=0.0004, p= 0.0005). TLC declined after week 6 post-RT, with a maximum drop of 15% at week 48 (p=0.0015). DLCO changes occurred from RT start to week 48, decreasing up to 20% at week 12 (p=0.0001). FeNO increased, exceeding 20% of its initial/baseline value with a peak at week 6 post-RT. Eighteen patients (34.7%) were hypoxemic (SO2 <90%) at the beginning of the trial, oxygen saturation had a statistically significant reduction at week 6 and week 48 (p<0.03, p<0.01). No significant differences were found in impulse oscillometry and 6-minute walk test. The results of the respiratory tests that decreased with the CCRT did not return to baseline at the end of follow-up.
Conclusion:
Regardless of pre-existing lung damage, the reduction in FEV~1~, FVC, DLCO, TLC and SO2 may represent increased inflammation, tissue remodeling and modification in gas exchange, however further studies are required. The nadir of the lung function occurred at 12 weeks from CCRT initiation. Increased FeNO values may represent a non-invasive marker of airway inflammation that correlates with RT lung injury mechanisms.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-019 - ALK+ Non-Small Cell Lung Cancer Treated with First Line Crizotinib: Patient Characteristics, Treatment Patterns, and Survival (ID 10137)
09:30 - 09:30 | Author(s): Oscar Arrieta
- Abstract
Background:
This study describes the characteristics, treatment sequencing, and outcomes among locally advanced/metastatic crizotinib-treated ALK+ Non-small cell lung cancer (NSCLC) Hispanic patients.
Method:
From June 2014 to June 2017, a retrospective patient review was conducted among several centers from México (n=10), Costa Rica (n=4), Panamá (n=13), Colombia (n=16), Venezuela (n=10), and Argentina (n=20). Participating clinicians identified their ALK+ NSCLC patients who received crizotinib and reported their clinical characteristics, treatments, and survival using a pre-defined case report form. Kaplan-Meier analyses were used to describe overall survival (OS) and progression-free survival (PFS).
Result:
73 ALK+ NSCLC patients treated with crizotinib as a first line were included. Median age at diagnosis was 62 years (range, 34-77), 60.3% were female and histological distribution was adenocarcinoma in 93.2%, squamous cell carcinomas in 2.7%, NOS in 2.7% and adenosquamous in 1.4%. Sixty-five patients (89%) were never or former smokers, 52 (71.1%) had ≥2 sites of metastasis and 15 (20.5%) had brain metastasis at diagnosis. Median PFS to treatment with first line crizotinib was 12.3 months (95%CI 9.4-15.3) and overall response rate (ORR) was 52% (CR 6.8% and PR 45.2%). Of those who discontinued crizotinib, 26.1% had brain progression, 35.6% switched to chemotherapy, 14% switched to a different ALK inhibitor and 59% received no further therapy. After starting crizotinib, median OS was 32.5 months (95%CI 25.6-39.4), 42.6 months (95%CI 31.8-53.5) for those who received ceritinib or/and alectinib, and 23.8 months (95%CI 19.0-28.6) among those treated with second line platinum based chemotherapy (p=0.003).
Conclusion:
The ORR and PFS observed in Hispanic patients with ALK+ NSCLC treated with first-line crizotinib was similar to that previously described. Limited access to new-generation ALK inhibitors affects OS. Those patients exposed to ceritinib or alectinib demonstrated a significant improvement in OS versus those treated with second-line platinum-based chemotherapy.
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P1.01-022 - Prediction of Central Nervous System Progression During Crizotinib Treatment in ALK+ NSCLC Among Hispanics (ID 10479)
09:30 - 09:30 | Author(s): Oscar Arrieta
- Abstract
Background:
Crizotinib has offered patients with non-small cell lung cancer (NSCLC) positive to ALK rearrangements a powerful therapeutical option. Despite the benefit of crizotinib, most patients develop resistance and progression with special emphasis on the central nervous system. Early identification of patients that will present brain metastases could potentially lead to additional interventions preventing relapse. The objective of this study was to identify patients who would present with future CNS relapse after initiation of crizotinib.
Method:
A random forest tree model was constructed. Data from Hispanic patients with NSCLC harboring ALK rearrangements treated with crizotinib were collected from the CLICaP database. Clinical variables including age at diagnosis, sex, smoking status, number of metastasis and location and objective response were included. Based on these parameters, progression to central nervous system was predicted.
Result:
66 patients were included in the analysis. Median age for the cohort was 55 years old (r, 33-85), 33 (59%) were women, 38 (58%) were never smokers and 29 (44%) presented disease progression during crizotinib treatment while 17 had central nervous system involvement. Median overall survival (OS) was 13.9 months (95%CI 11.6-19.3) in contrast to 8.3 months (95%CI 4.47-13.13) in terms of progression free survival (PFS) after crizotinib initiation. The best predictors for central nervous system progression were age, sex, number of metastasis, objective response to crizotinib and previous CNS involvement. With an AUC of 0.99, a sensitivity of 100% and a specificity of 88%, the model reached an overall accuracy of 97%.
Conclusion:
Central nervous system progression after crizotinib treatment can be accurately predicted. Validation for this model in larger cohorts is warranted.
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-055 - Genotyping Squamous Cell Lung Carcinoma Among Hispanics (Geno1.1-CLICaP) (ID 10166)
09:30 - 09:30 | Author(s): Oscar Arrieta
- Abstract
Background:
Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer subgroup, largely because of a lack understanding of the molecular pathogenesis of the disease. To characterize SCC genomic profile among Hispanics we tested diverse alterations using a validated next generation sequencing (NGS) platform.
Method:
We performed sequencing using a comprehensive NGS assay (TruSight Tumor 170) targeting the full coding regions of 170 cancer-related genes on 26 squamous cell lung cancer samples from Hispanic patients. PD-L1 expression in tumor cells (TCs) was assessed using clone 22C3 (Dako) and main clinical outcomes like progression free survival (PFS), overall response rate (ORR), and overall survival (OS) were recorded.
Result:
Median age was 67 years (range, 33-83), 53.8% were men and all patients had previous exposure to tobacco (former 69.2%/current 30.8%) with a mean consumption rate of 34-year package. Almost all patients (80.8%) received cisplatin or carboplatin plus gemcitabine as first line with an ORR of 61.5%, a median PFS of 12.0 months (95% CI 10.9-13.2) and OS of 24.8 months (95% CI 20.8-28.7). We found a relatively high prevalence of inactivating mutations in TP53 (61.5%), PIK3CA (34.6%), MLL2 (34.6%), KEAP1 (30.8%) and NOTCH1 (26.9%). In addition, genetic alterations in the NF1 (19.2%), RB1 (15.4%), STK11 (15.4%), SOX2 (11.5%), PTEN (7.7%), KRAS (3.8%) and HRAS (3.8%). Distribution of PD-L1 expression were: negative, 1%, 2-49% and ≥50% in 23.1%, 38.5%, 26.9% and 11.5%, respectively. None of the genetic alterations affected PFS, OS or ORR and PDL1 expression was lower among those who had mutations in TP53 (p=0.037) and PIK3CA (p=0.05).
Conclusion:
We identified previously described mutations among Hispanic patients with SCC. Lower PDL1 expression was also found among those who had alterations in TP53 and PIK3CA.Figure 1
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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-050 - Clinical Consequences, Quality of Life, and Management of Neutropenic NSCLC Patients in the REVEL Trial (ID 8279)
09:30 - 09:30 | Author(s): Oscar Arrieta
- Abstract
Background:
Ramucirumab is a human IgG1 monoclonal antibody antagonist of VEGFR-2 approved as a post-platinum progression therapy in non-small cell lung cancer (NSCLC). Chemotherapy-induced neutropenia is a major risk during cancer treatment and can be potentially dose-limiting, as well as play a significant role in infection-related morbidity and mortality. In the REVEL phase 3 global, placebo-controlled study of Stage IV NSCLC patients (NCT01168973), ramucirumab plus docetaxel treatment improved patient survival versus docetaxel monotherapy independent of histology; however, all grade and high-grade (Grade ≥3) neutropenia was numerically increased with ramucirumab versus placebo (Table 1). A post-hoc analysis was performed on the REVEL data to characterize neutropenia: clinical consequences, quality of life (QoL), and clinical management.
Method:
The duration of neutropenia, as well as the course and incidence of complications and their severity and related consequences associated with neutropenia were summarized. Time to deterioration in ECOG performance status (PS) was analyzed using Kaplan-Meier method, and stratified hazard ratios and 95% confidence intervals (CI, Wald) were estimated for average symptom burden index and lung cancer symptom scale items using Cox model. Clinical management summary data will be presented at the meeting.
Result:
Neutropenia events from the REVEL trial are summarized in terms of duration, course, incidence of complications, severity and resolution status in Table 1. All-grade neutropenia risk ratio is 1.197 (95% CI 1.072, 1.338) and Grade ≥3 is 1.226 (95% CI 1.081, 1.390). Figure 1
Conclusion:
Despite numerically increased rates of neutropenia observed in the ramucirumab plus docetaxel arm of the REVEL trial, the clinical consequences (resolution) of neutropenia, rate of hospitalization, and duration/incidence of Grade ≥3 infection were similar to placebo. In addition, the quality of life results do not indicate any significant differences between placebo and ramucirumab. Therefore, neutropenia in the NSCLC population is considered to be manageable during ramucirumab treatment.
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-040 - Prognosis-Relevant Subgroups in NSCLC According to Granulocytic Myeloid-Derived Suppressor Cell Frequency and Cytokine Levels (ID 9397)
09:30 - 09:30 | Presenting Author(s): Oscar Arrieta
- Abstract
Background:
The percentage of Polymorphonuclear-MDSCs (PMN-MDSCs) has emerged as an independent prognostic factor for survival in Non-small cell lung cancer (NSCLC) patients. Similarly, cytokine profiles have been used to identify subgroups of NSCLC patients with different clinical outcomes. This prospective study investigated whether the percentage of circulating PMN-MDSC, in conjunction with the levels of plasma cytokines, was more informative of disease progression than the analysis of either factor alone.
Method:
We analyzed the phenotypic and functional profile of peripheral blood T-cell subsets (CD3[+], CD3[+]CD4[+] and CD3[+]CD8[+]), neutrophils (CD66b[+]) and polymorphonuclear-MDSCs (PMN-MDSCs; CD66b[+]CD11b[+]CD15[+]CD14-) as well as the concentration of 14 plasma cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 p70, IL-17A, IL-27, IL-29, IL-31, and IL-33, TNF-α, IFN-γ) in 90 treatment-naïve NSCLC patients and 25 healthy subjects (HS).
Result:
In contrast to HS, NSCLC patients had a higher percentage of PMN-MDSCs and neutrophils (P<0.0001) but a lower percentage of CD3[+], CD3[+]CD4[+] and CD3[+]CD8[+] cells. PMN-MDSCs% negatively correlated with the levels of IL1-β, IL-2, IL-27 and IL-29. Two groups of patients were identified according to the percentage of circulating PMN-MDSCs. Patients with low PMN-MDSCs (≤8 %) had a better OS (22.045 months [95% CI: 4.335-739.735]) than patients with high PMN-MDSCs (9.265 months [95% CI: 0-18.810]). OS was significantly different among groups of patients stratified by both PMN-MDSC% and cytokine levels. Figure 1
Conclusion:
Our findings provide evidence suggesting that PMN-MDSC% in conjunction with the levels IL-1β, IL-27, and IL-29 could be a useful strategy to identify groups of patients with potentially unfavorable prognoses.
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P1.07-041 - CD47 Expression and Prognosis in a Cohort of Patients with Lung Adenocarcinoma (NSCLC) (ID 10301)
09:30 - 09:30 | Presenting Author(s): Oscar Arrieta
- Abstract
Background:
CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha, inhibiting phagocytosis. Data on the clinical significance of CD47 expression in patients with different NSCLC subtypes remains limited.
Method:
173 treatment-naïve patients with NSCLC diagnosis were evaluated. Tumor samples obtained by biopsy or surgical resection were collected for CD47 evaluation by immunohistochemistry. Tumor samples were scored according to the fraction of stained cells at each intensity. Staining intensity of cell membrane was visually scored on a scale from 0-3, (0 indicating absent staining and 3 representing maximal staining). In order to assess the prognostic and predictive value of CD47 as a biomarker, patients were stratified according to a cutoff point. This cutoff was optimized as a function of overall survival (OS) using the X-tile and Cutoff Finder software. CD47 mRNA was measured by RT-PCR.
Result:
CD47 ≥ 150 was associated with EGFR mutations in 73% of the positive cases (n=35, p=0.002). Longer overall survival was associated with ECOG 0-1 (p=0.006), adenocarcinoma histology (p=0.009) EGFR mutation status (p=0.001) and the H-score for CD47 (p=0.021). Multivariate analysis supports CD47 as an independent factor for survival (HR 1.8 IC95%: 1.1-2.8; p=0.007) Table 1. Patients with high levels of CD47 mRNA expression correlated with the score of CD47 ≥ 150 (p=0.066).
Conclusion:
The immune checkpoint molecule CD47 expressed on the surface of tumor cells allows them to escape immunosurveillance and therefore higher CD47 expression confers worse prognosis. Figure 1
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P1.09 - Mesothelioma (ID 695)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.09-013 - Profiling Response to Chemotherapy in Malignant Pleural Mesothelioma Among Hispanics (MeSO-CLICaP) (ID 10430)
09:30 - 09:30 | Author(s): Oscar Arrieta
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a rare malignant disease, and the understanding of molecular pathogenesis has lagged behind other malignancies.
Method:
A series of 53 formalin-fixed, paraffin-embedded tissue samples with clinical annotations were retrospectively tested for BAP1 and PI3K mutations and for mRNA expression of TS and EGFR. Immunohistochemistry staining for CD26 (dipeptidyl-peptidase IV, DPP-IV) and Fibulin3 (Fib3) proteins were also performed. Outcomes like progression free survival (PFS), overall survival (OS) and response rate (ORR) were recorded and evaluated according to biomarkers. Cox model was applied to determine variables associated with survival.
Result:
Median age was 58 years (range 36-76), 27 (51%) were men, 89% were current or former smokers, and six patients had previous contact with asbestos. 77% had a baseline ECOG 0-1 and almost all patients (n=52/98%) received cisplatin or carboplatin plus pemetrexed (Pem) as first line; 58% of them were treated with Pem as maintenance for a mean of 4.7 +/-2.8 cycles. 53.5% and 41.5% of patients were positive for CD26 and fibulin-3, while 49% and 43.4% had low levels of EGFR and TS mRNA, respectively. The majority of epithelioid and biphasic types expressed CD26 (p=0.008), Fibulin3 (0.013) and had lower levels of TS mRNA (p=0.008). Mutations in PI3K (c.1173A> G, c.32G> C and c.32G> T) were found in 5 patients and only one patient had a mutation in BAP1 (c.241T> G). First line PFS were significantly longer in CD26+ (p=0.0001), in those with low EGFR mRNA expression (p=0.001), in patients with positive Fib3 (p=0.006) and lower TS mRNA expression (p=0.0001). OS were significantly higher in patients with CD26+ (p=0.0001), EGFR- (p=0.001), Fib3 + (p=0.0002) and low TS mRNA expression level (p=0.0001). Multivariate analysis found that CD26+ (p=0.012), Fib3 (p=0.020) and TS mRNA levels (p=0.05) were independent prognostic factors.
Conclusion:
CD26, Fib3 and TS were prognostic factors significantly associated with improved survival in patients with advanced MPM.
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P1.17 - Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies (ID 703)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.17-008 - Clinical and Oncological Outcomes on Resected Thymomas over a Decade at the National Cancer Institute at Mexico City (ID 9293)
09:30 - 09:30 | Author(s): Oscar Arrieta
- Abstract
Background:
Despite the fact that Thymic tumors are considered as an orphan disease, they represent the most common adult tumor in the anterior mediastinum. Most of evidence in this neoplasm comes from small, single institution reports. Moreover, the low incidence and a wide spectrum of clinical and morphological characteristics are well-known factors that difficult treatment decisions.
Method:
Single Institution, retrospective chart review of patients with resected thymoma, from January 2005 to December 2016.
Result:
We found 25 patients, with complete clinical data available for review, who underwent thymectomy for epithelial thymic neoplasm. There were 14 females (56%) and 11 males (44%), mean age 56.6 years (27 to 82 years). A total of 22 patients underwent up-front surgery and only 3 patients required neo-adjuvant treatment due to advanced disease. Trans-esternal thymectomy was the most common approach with 18 cases (72%), lateral thoracotomy in 4 cases (16%) and VATS in 3 cases (12%). A complete resection was achieved in 92% of patients. Most of cases, 15 (60%) required an extended thymectomy due to their extension, in 7 (28%) a standard thymectomy was performed,1 case (4%) required a maximal thymectomy and in 2 cases (8%) only a biopsy was performed. R0 resection was achieved in 88% (22 cases) and one patient (4%) was reported as R1 and 2 cases were R2 resections (8%). Distribution according to WHO classification was: A 12%, AB 36%, B1 8%, B2 28%, B3 8% and C 8%. Staging according to Masaoka-Koga Classification was: I 28%, IIA 16%, IIB 24%, III 8%, IVA 12% and IVB 8% Median size of thymomas was 82mm (47-140mm). Mean operative time was 194 minutes (88 – 480), mean blood loss was 362 ml (15 – 2000). Chest tube mean duration was 5.4 days, with a mean hospital stay of 6.2 days (3-18) Morbidity was 24%, but none of patients required re-intervention. Only 2 patients die in the 90 days after surgery for an 8% mortality. In 12 patients (48%) adjuvant treatment was required. Median follow-up was 11.03 months (1.8-108.5) and Median OS was 12.4 months. To date, 21 patients (84%) still alive and only 2 relapses were documented.
Conclusion:
Surgical resection stills the mainstay of treatment for thymomas. Our series comprises mostly large size thymomas requiring extended thymectomy for complete resection. Despite this fact, our perioperative and oncological results and are encouraging
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-049 - Long Progression Free Survival and Overall Survival in Advanced NSCLC Patients with EGFR Mutation and Complete Response with TKI Treatment (ID 10265)
09:00 - 09:00 | Author(s): Oscar Arrieta
- Abstract
Background:
Lung cancer is the first cause of death by cancer worldwide. Around 70% of patients are diagnosed in advances stages. The EGFR mutations (EGFRmut) are present in 15-20% of cases of lung adenocarcinoma. Most frequent mutations are exon 19 deletions and L858R (90%); in those patients, the TKI treatment have higher response rates (RR) and longer progression free survival (PFS) compared versus chemotherapy. However, the long time OS is low and the complete responses (CR) are achieved in 1-3% only. Nevertheless, contributing factors to long term survival are still unclear. Our objective was to describe long PFS and OS associated factors in patients with TKI treatment.
Method:
We analyzed patients with EGFRmut NSCLC, who received TKI between 2011 and 2017 in the Thoracic Tumors Clinic at Instituto Nacional de Cancerologia, Mexico. EGFR mutational test was performed by RT-PCR (SCORPION/ARMS therascreen). We search factors associated with CR and Major responses (MR; defined as tumor size reduction > 80%) and correlated with PFS and OS.
Result:
One-hundred sixty patients were analyzed. Median age was 62y (SD ±12.8), female 66%, never smoking 82%, adenocarcinoma 98%, exon 19 deletions 60.6% and L858R 34.4%, uncommon mutations 5%. The RR were 56.3%; 12/160 (7.5%) patients had CR (Group1), 16/160 (10%) patients had MR and received local control with Radiotherapy (Group2) and 132/160 (82.5%) had non-CR without radiotherapy (Group3). In the total population PFS and OS was 15months (CI95% 8.2-21.9mo) and 27.9mo (21.8-32.2mo) respectively; in group3 PFS/OS was 8.77 (CI95% 7.66-9.88mo)/24.7mo (CI95% 20.8-28.8mo); in Group1 PFS/OS was 38.7mo (CI 95% 35.7-41.6)/47.8mo (CI95% 40.1-55.5mo) and Group2 PFS/OS 28.1mo (0.43-56.4mo)/OS 36.1mo (CI95% 11.6-60.7mo). We found significant differences in PFS and OS compared group1 vs Group3 (p=0.003 and p=0.0001, respectively) and Group2 vs group3 (p=0.009 and 0.007, respectively). Was not significant differences in PFS/OS between Group1 vs Group2 (p=0.09/0.9, respectively). All patients with CR are alive, except one patient who died due to pneumoniae. In the multivariate analysis were not found association with CR and TKI or mutation subtype (Exon 19 vs L858R).
Conclusion:
Patients treated with TKI who reach CR or MR followed by local control with radiotherapy have longer PFS and OS. These findings support the importance to optimize TKI treatment, in order to achieve CR as well as the importance of local control in residual lesions to improve survival outcomes.
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P2.01-070 - FAACT- Anorexia Cachexia Scale: Cut-Off Value for the Anorexia Diagnosis in NSCLC Patients (ID 9504)
09:00 - 09:00 | Author(s): Oscar Arrieta
- Abstract
Background:
Lung cancer has the highest death rate among cancer types and anorexia is reported by a high percentage of patients, but the prevalence values may vary according to form of diagnosis. Anorexia is associated with reduced food intake, weight loss and a negative affect in quality of life and worse outcome. There is no gold standard for anorexia diagnosis. The anorexia cachexia scale (AC/S) from FAACT instrument has been proposed as a tool for diagnoses anorexia but a validated cut-off value for NSCLC patients is required. This study validates a cut-off value of AC/S for anorexia diagnosis in NSCLC patients.
Method:
The AC/S were evaluated in Non-Small Cell Lung Cancer (NSCLC) patients to establish a cut-off value by ROC curve analysis and CutOff Finder program with the anorexia score from QLQ-C30 questionary as a standard reference and by X-tile based on survival. The cut-off value was associated with clinical parameters
Result:
Three hundred and twelve ambulatory NSCLC patients were evaluated, 67% with adenocarcinoma, 65% stage IV and 98% with ECOG ≤2. The mean of AC/S was 31 ± 9 and the identified cut-off value was 32.5, sensitivity 80.3% (85.7-73.3) and specificity 85% (90%-78.2). The proportion of anorexia based on cut-off value of 24 was 26% and with cut-off value of 32 was 50%. AC/S cut-off value 32 was associated significantly with clinical parameters, nutritional consumption and quality of life. Overall survival was determined in all patients, stage III/IV and stage IV. The overall survival was independently associated with the cut-off value of 32. Figure 1
Conclusion:
Lung cancer patients with the score of ≤32 in AC/S for anorexia diagnosis is proposed, clinically useful and this cut-off can improve the identification of patients with a risk of complications of cancer related malnutrition. Future treatments and follow ups of cancer-related anorexia should be focus in this patients.
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P2.01-075 - Genomic Changes and Clinical Characteristics Associated with Wood-Smoke Exposure in Patients with Non-Small Cell Lung Cancer (ID 10324)
09:00 - 09:00 | Author(s): Oscar Arrieta
- Abstract
Background:
Chronic wood smoke exposure (WSE) is related to obstructive pulmonary disease and represents an increased risk of lung cancer. WSE is asociated with EGFR-mutations and low frequency of KRAS mutations. WSE signaling networks show better response to EGFR-TKIs, improving response rate and overall survival in NSCLC patients. Next-generation sequencing (NGS) has facilitated parallel analysis of multiple genes for treatment selection and monitoring response to treatment. We evaluated genomic alterations in patients with WSE based on tumor profiling by massive parallel sequencing.
Method:
52 patients with advanced lung cancer were evaluated. Fresh-frozen samples were used for DNA extraction with the Wizard Genomic DNA Purification Kit (Promega) including some formalin-fixed paraffin-embedded tissues (FFPE). The TruSeQ Cancer Panel (Illumina) was used for library construction in targeted sequencing of 48 genes spanning 212 amplicons in mutation hotspots.
Result:
WSE was more frequent in women (59% vs 41% p=0.038). We found diferent mutations in ATM (A1309H, G1679V, N1793I and T2749P), EGFR exon 7 (G288V), KDR (H267, Q1146S) and SMARCB1 (T72Q, G157A). WSE correlated with mutations in the genes KDR 89% vs. 11% (p=0.024), ATM 72% vs. 27% (p=0.040), SMARCB1 74% vs. 26% (p=0.020) and in exon 7 of EGFR 75% vs. 25% (p=0.034). Additionally, ATM mutations correlated with metastasis in CNS and bones 77% vs. 23% (p=0.006), also, patients with EGFR exon 7 presented major metastases in CNS and bones 67 vs. 33 % (p=0.084). SMARCB1 mutations were associated with worse overal survival (48 vs 5.6 months p=0.066). WSE patients carrying EGFR exon 7 mutations had better response showing either partial response or stable disease.
Conclusion:
Latin American patients of lung cancer and WSE present a distinctive mutation profile compared to non-WSE patients showing a positive correlation with KDR, ATM, EGFR exon 7, and SMARCB1 mutations. Figure 1
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-063 - EGFR Exon 20 Insertions in Lung Adenocarcinomas: Molecular and Clinicopathologic Characteristics Among Hispanics (Geno1.2-CLICaP) (ID 10406)
09:30 - 09:30 | Presenting Author(s): Oscar Arrieta
- Abstract
Background:
In contrast to other primary EGFR mutations in lung adenocarcinomas, insertions in exon 20 of EGFR have been generally associated with resistance to EGFR tyrosine kinase inhibitors. Their molecular spectrum, clinicopathologic characteristics and prevalence are not well established among Hispanics.
Method:
Tumors harboring EGFR exon 20 insertions were identified through a comprehensive screening of 4.500 lung adenocarcinomas from diverse Latin American Countries. Cases were tested for common and uncommon EGFR mutations and KRAS. Almost all cases (n=52) underwent extended genotyping for other driver mutations in BRAF, NRAS, PIK3CA, Her2 and MEK1 by NGS (TruSight tumor[TM]), EGFR amplification, ALK and PDL1 protein expression (D5F3CDx Assay and 22C3 Clone). Clinical outcomes were evaluated using Kaplan-Meier and Cox proportional models.
Result:
60 patients were included; median age was 66-yo (r, 24-79), 63.3% were females, most patients had a micropapillary (38.3%) or lepidic (20.0%) adenocarcinomas, 61.7% were never smokers and 36.7% had brain metastasis at diagnosis. 14 patients (23.4%) had common EGFR mutations (del19/L858R) in addition to the exon 20 insertion, 5 (10.0%) had non-common EGFR mutations (G719X /L861Q/S768I) plus the exon 20 insertion, and two cases had additional mutations in PIK3CA and MEK1. Insertion sequences were highly variable, with the most common variant (V769_D770insASV) making up only 21.7% of cases. 30% of patients had amplification of the EGFR and 75% had a PDL1 expression level of less than 50%. Overall response rate (ORR) to the first line was 30%, progression free survival (PFS) was 8.3 months (95%CI 6.9-9.6) and OS was 17.4 months (95%CI 16.4-19.5). Prognosis was positively influenced by concomitant presence of common EGFR mutations (p=0.016) and by response to first line therapy (p=0.06).
Conclusion:
Patients with EGFR exon 20 insertions have similar clinical characteristics to those with common EGFR mutations but a poorer prognosis. The mean PDL1 expression in this population appears to be higher than in patients with common EGFR mutations, finding that promote the potential use of immunotherapy alone or in combination for this population.
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P3.08 - Locally Advanced Nsclc (ID 724)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.08-005 - Hereditary Familial Overlap Syndrome with Multiple Synchronous Lung Tumors (ID 10257)
09:30 - 09:30 | Author(s): Oscar Arrieta
- Abstract
Background:
Here we report the case of a young, never-smoker Hispanic woman with a hereditary familial overlap syndrome (Li-Fraumeni plus CDHI) who develop synchronous multiple primary lung adenocarcinomas related to Intra-alveolar Tumor Spread (STAS) several years after the diagnosis of a locally advanced lower limb osteosarcoma.
Method:
Comprehensive genomic profiling by next generation sequencing (NGS) was performed on 90 cancer-related genes over each lung lesion (including two nodules of acinar adenocarcina, one lepidic spread tumor and in STAS area). In the same way, the broad genomic analysis was performed in archival tissue from the previous bone tumor.
Result:
Lung tumors were found to harbor PI3KCA (invasive lesions) and a rare in-frame insertion of 6 amino acids in exon 19 of EGFR (lepidic tumor), STAS area showed KRAS and BRAF mutations in two different segments, and osteosarcoma tested positive for well known PIK3CA, KRAS and CDH1 alterations.
Conclusion:
This unique case raises practical questions as to the challenges of molecular testing and highlights the potential association of germline p53 and CDH1 mutations with concurrent somatic alterations that elucidate the basis of tumor heterogeneity. Figure 1
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P3.09 - Mesothelioma (ID 725)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.09-010b - Predicting Response to First Line Chemotherapy in Pleural Mesothelioma: A Random Forest Tree Model (Meso-CLICaP) (ID 10389)
09:30 - 09:30 | Presenting Author(s): Oscar Arrieta
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy. Multidisciplinary treatment including surgery, radiation therapy and adjuvant chemotherapy has been established as the cornerstone of management prolonging progression free survival (PFS). Although beneficial, this treatment strategy has morbidity and mortality. Therefore, selection of patients who benefit from this treatment strategy is crucial for maximizing clinical benefit.
Method:
A random forest tree model was build for the prediction of response to first line chemotherapy among Hispanic patients with MPM. Variables evaluated included sex, age, ECOG performance status, smoking history, exposure to asbestos and histology. Based on these characteristics, patients were classified by responders (partial or complete response) and non-responders (stable disease or disease progression). In order to validate the results, a random subset of 70% of the sample was used to construct the model and the remaining 30% was utilized as an independent validation cohort. Predictions were compared to each patient’s treatment response and operational characteristics for the validation cohort model and receiver operational curves were computed.
Result:
A total of 153 patients were included. Median age was 59 years old (r, 33-84), 60 (39%) were females, 127 (83%) had an ECOG performance score of 0-1 and 127 (83%) had an epithelioid histological subtype. In terms of expositional hazards, 107 (70%) were smokers (24% current/46% former), whereas 61 (40%) presented active exposure to asbestos. In terms of survival, median overall survival (OS) was 25 months (95%CI 23.4-29.4) and median PFS after first line chemotherapy was 6.97 months (95%CI 5.83-8.57). An objective response was observed in 74 patients (48%; complete response in 7/5%). In terms of operational characteristics, the validated model obtained a 0.992 AUC, a sensitivity of 100% and a specificity of 95% for detecting responders and non-responders to first line chemotherapy.
Conclusion:
Selection of responders to first line treatment based on clinical variables can accurately be achieved. These results could lead to better selection of Hispanic patients for aggressive and morbid treatments.
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P3.14 - Radiotherapy (ID 730)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.14-012 - Risk of Developing Pneumonitis Increases in Patients Receiving Immunotherapy with a History of Lung Irradiation (ID 10344)
09:30 - 09:30 | Author(s): Oscar Arrieta
- Abstract
Background:
A large proportion of patients with locally advanced/metastatic Non-Small Cell Lung Cancer (NSCLC) present disease progression despite aggressive treatments and will further receive immunotherapy. Pneumonitis is an uncommon but potentially fatal toxicity related to immunotherapy treatment. The association with the history of radiotherapy and the risk of developing pneumonitis have not been well described. We associated the history of radiotherapy with the development of pneumonitis in patients receiving immunotherapy.
Method:
Clinical information was retrospectively obtained from histologically confirmed advanced NSCLC patients treated from February 2013 to February 2017. Clinical and radiologic features of pneumonitis were collected from patients receiving immunotherapy. We sought associations between pneumonitis incidence and clinical characteristics.
Result:
Of 59 patients who received immunotherapy 61.7% were treated with nivolumab, 29.9% with pembrolizumab and 6.7% with the combination durvalumab plus tremelimumab. Immunotherapy treatment was administered in first line in 26.6% of patients, 28.3% received in second line and 36.7% in third or more line of treatment. Twenty-five of the 59 patients (41.7%) received previous radiotherapy, 16 of them (26.7%) to the lung and 9 (15%) to the thoracic spine. Fifteen (15/59) patients (25%) developed pneumonitis; this occurred irrespective of line of therapy in which immunotherapy was received (first line: 38.5%; second line: 33.5%; third line or more: 26.7%). No association was found between line of treatment and pneumonitis development. Median time from therapy initiation to pneumonitis was 4.5 months (range 18 days - 13.1 months). For any grade of pneumonitis, the percentage was of 25% (15 patients) of which 48% (12/25) had received radiotherapy, Grade >2 pneumonitis was seen in 10 patients (17%) and 32% (8/25) had history of radiation therapy. All Grade 3 pneumonitis events (n=4) presented in patients with previous lung radiotherapy. The incidence and severity of pneumonitis was higher in patients who had received radiotherapy (OR, 95% CI: 6.8 (1.6 – 28.5); p=0.009).
Conclusion:
The incidence of pneumonitis related to immunotherapy treatment could be underestimated. We observed an increase in the risk and severity of pneumonitis in patients with previous radiation therapy and subsequent treatment with immunotherapy, regardless of used drug or line of therapy. In these patients, we recommend close clinical and radiologic follow-up.
