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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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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
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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
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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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MTE 13 - Malignant Pleural Mesothelioma: State of the Art (Sign Up Required) (ID 562)
- Event: WCLC 2017
- Type: Meet the Expert
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 07:00 - 08:00, Room 501
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MTE 13.01 - Surgery for Malignant Pleural Mesothelioma (ID 7792)
07:00 - 07:30 | Presenting Author(s): Scott Swanson
- Abstract
- Presentation
Abstract:
Surgical treatment for malignant pleural mesothelioma (MPM) has an interesting history and currently remains the foundation of the best treatment for select cases of MPM. At its outset a radical pleural pneumonectomy was fraught with very high surgical mortality which overshadowed any possible benefit. As surgical technique, anesthesia and post-operative care improved the mortality plummeted to low single digits thus allowing the benefit of surgery to emerge. Currently the median survival for patients with MPM is 21, 19, 14 and 10 months for stage I, II, III and IV disease per IASLC data (1) Certain well selected subgroups of patients treated surgically in a multimodal fashion have a median survival up to 4 years or more (2). The optimal surgical procedure and multimodal protocol is currently in flux but the principles that are important include a complete macroscopic resection either by extended pleurectomy and decortication that generally includes resection of the diaphragm and pericardium or by an extrapleural pneumonectomy that includes the entire pleural envelope, lung and en-bloc pericardium and diaphragm. A complete node dissection is vital as nodal involvement is a negative prognostic factor in most series. Reconstruction of the diaphragm and pericardium is an important feature of the operation and when done well will limit the post-operative morbidity significantly. Intra-operative adjuncts such as photodynamic therapy, heated intrapleural chemotherapy or heated povodone-iodine have been shown in select series to likely improve local control and perhaps survival. Systemic chemotherapy and radiation therapy also are important to the outcome but the exact type and sequence is controversial. (3-5). The correct surgical technique and sequence is critical to a good outcome. Similarly, choosing the best patient for surgery is complex and of vital importance. Generally patients should have reasonable cardiopulmonary reserve and limited co-morbidities. Age is not a sole determinant and probably less important than the functional status of the patient but patients over age 80 should be approached with caution. An extensive cardiopulmonary workup and staging evaluation is mandatory. Assessment of pulmonary function including split function with a quantitative ventilation and perfusion scan, cardiac reserve with an echocardiogram (look at pulmonary artery pressures) and stress test and general assessment of functional status are basic points of information that are needed to move forward with surgery. Evaluation of tumor burden with a magnetic resonance chest scan, PET scan and mediastinal node evaluation with either endobronchial ultrasound or cervical mediastinoscopy are important to avoid operating on patients with disease outside the chest or disease involving N2 nodes. Induction therapy on a protocol is reasonable particularly if patients have mediastinal nodal disease or non-epithelial histology. Also assessment of either tumor thickness or tumor volume helps prognosticate and determine likelihood of nodal involvement. Other factors such as severe pain or a high platelet count portend a poor outcome. Right sided resections particularly pneumonectomy have a higher risk and if at all possible a pleurectomy/decortication procedure is preferred . However if the lung is contracted or so involved by tumor that the only way for complete resection is to remove the lung then it should be done particularly if the functional contribution is 20% or less. A generous posterolateral thoracotomy through the bed of the resected 6[th] rib is carried out. The extrapleural plane is entered and fully mobilized so that it is clear the tumor is resectable. Posteriorly, the aorta and esophagus must be free, apically the tumor should come off the subclavian artery, anteriorly the tumor should be able to be freed from the pericardium. The pericardium is often resected en-bloc with the tumor. It should be opened early to be sure there is no invasion of the heart. Inferiorly the diaphragm is resected bluntly at its origin from the chest wall and care is taken to be sure the pleural recesses are respected such that all of the pleura is taken with the specimen. The peritoneum is left intact from the overlying diaphragm. Care is taken to avoid injury to the inferior vena cava near its entrance into the right atrium. At this point the pleural envelope should be opened and the lung assessed. If the tumor can be completely resected by taking the visceral pleura then this is preferred and the lung is spared. If the lung is so involved that gross tumor will be left behind if significant lung is not removed then a pneumonectomy is carried out. A full mediastinal node dissection is performed and hemostasis is obtained. If an intra-operative adjunct is to be used it is given at this point. Following that, the stump is covered with local tissue, likely a strip of pericardium and in some cases omentum. The pericardium and diaphragm are reconstructed, each with a goretex patch, which has been described in referenced publications. For the left side the operation is very similar other than the inferior vena cava is not an issue and if a pneumonectomy is required is generally well tolerated (6). Newer molecular techniques are proving very useful in aiding the surgeon in making decisions about how aggressive a strategy to use (7). References 1. Rusch VW, Chansky K, Kindler HL et al. The IASLC mesothelioma staging project: proposals for the M descriptors and for revisions of the TNM stage groupings. J. Thorac Oncol. 2016;11:2112-9. 2. Sugarbaker DJ, Gill RR, Yeap BY 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. 2013;145:955-63. 3. Friedberg JS, Simone CB 2[nd], Culligan MJ, et al. Extended pleurectomy-decortication-based treatment for advanced stage epithelial mesothelioma yielding a of nearly 3 years. Ann Thorac Surg. 2017;103:912-919 4. 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;149:558-65. 5. Sugarbaker DJ, Richards WG, Bueno R. Extrapleural pneumonectomy in the treatment of epithlioid malignant pleural mesothelioma: novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients. Ann Surg. 2014;260:577-80. 6. Sugarbaker DJ, Norberto JJ, Swanson SJ. Extrapleural pneumonectomy in the setting of multimodal therapy for diffuse malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg. 1997 Oct;9(4):373-382 7. De Rienzo A, Cook RW, Wilkinson J et al. Validation of a gene expression test for mesothelioma prognosis in formalin-fixed paraffin-embedded tissues. J. Mol. Diagn. 2017,19:65-71.
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