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David Waller



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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: 1
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      MS 06.04 - The Effect of the Timing of Chemotherapy: Induction vs Adjuvant after PD or EPP (ID 7666)

      15:45 - 17:30  |  Presenting Author(s): David Waller

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      Abstract:
      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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