- Email: [email protected]
ED13.04 Systemic Induction Therapy of Malignant Pleural Mesothelioma
S58
epithelioid, biphasic-epithelioid and biphasic-sarcomatoid) derived from RNA-seq analysis. MicroRNA expression has also been linked to outcome. Early studies revealed prognostic significance of miR-29c-3p, with higher levels corresponding to longer survival. More recently, microRNA expression profiles differing between long and short survivors yielded a 6-microRNA score that predicted outcome in two surgical series. Whether TCGA data confirm these observations remains to be determined. In addition to RNA and protein biomarkers, the cellular composition of tumors influences patient outcomes. It is likely that the mix of cell types within tumor samples also contributes to biomarker expression, especially for RNA extracted from whole tumors. For some proteins, differential expression in the stromal and tumor compartments is of prognostic value, for example in the case of SPARC expression. The importance of the immune cell infiltrate was recently investigated in a large number of epithelioid samples revealing that greater numbers of tumor-infiltrating CD4+ and CD8+ T lymphocytes (TILs), as well as fewer tumorassociated macrophages (TAMs) of the M2-type correlate with survival. In addition, the ratio of the TAMs/TILs was also shown to predict outcome in epithelioid MPM. Other cell populations associated with vascular and lymphatic invasion are also linked to survival. Prediction: Unlike lung cancer, few actionable mutations are present in MPM that predict sensitivity to targeted agents, and clinical trials with these drugs have yielded disappointing results. Markers for single agent chemotherapy and the standard cisplatin/pemetrexed doublet have also been investigated in retrospective studies attempting to link patient outcomes with gene (mRNA and protein) expression and polymorphisms. Multiple reports have linked levels of TS protein, but not mRNA, to outcomes with pemetrexed-based chemotherapy. As expected from a multi-targeted agent, other levels of other proteins such as folypoly-glutamate synthase (FGPS) and the reduced folate carrier (RFC) were also associated with tumor response and patient outcomes. However, a subsequent study with a similar number of patients suggested that both TS and FPGS lack predictive value. With respect to DNA repair genes involved in cisplatin activity, ERCC1 and others have been evaluated, but results are again inconclusive. The picture is complicated by assessment of target genes in patients treated with two interacting agents (with or without subsequent surgery), and the true value of these genes awaits carefully controlled prospective analyses. The recent breakthrough success of immune checkpoint inhibiting antibodies targeting CTLA4 and the PD-1/PD-L1 axis in melanoma and lung cancer has seen these agents applied to MPM patients. With response rates of around 25% for PD-1 targeting
Journal of Thoracic Oncology
Vol. 12 No. 1S
antibodies pembrolizumab and nivolumab in MPM, new predictive markers are needed to improve patient selection and for health economics reasons. Although the Keynote trial included patients based on positivity of PDL1 staining, PD-L1 status appears to have little value in predicting response rate. Ongoing research into immune cell involvement may shed more light on this. Future directions: Continuing research in this area should learn from limitations of the biomarker studies of the last decades to improve the search for useful molecular markers. Large prospective trials are needed to carefully evaluate predictive markers. Alternative approaches such as the analysis of live cell populations taken from fine-needle aspirates and investigation of circulating tumor cells and tumor-derived markers in the circulation (DNA, exosomes) may yield novel markers. Conclusions: Extensive research into tumor-based markers for MPM is gradually making progress. New markers to assist in diagnosis and prognosis have been identified, but the selection of accurate predictive markers has so far remained elusive. Next-generation sequencing has identified multiple new candidate markers requiring further investigation, and may provide breakthroughs in the future. Keywords: predictive markers, diagnosis, Prognosis
ED13.04 Systemic Induction Therapy of Malignant Pleural Mesothelioma Paul Baas Thoracic Oncology, Netherlands Cancer Institute, Amsterdam/Netherlands Over the last 3 decades clinical researchers have focused on the optimal treatment of patients with mesothelioma (MPM). In the 80’s surgery had become a standard approach in some centers but it became clear that a complete resection (R0) was not achievable. The anatomical location of the mesothelioma simply does not allow a resection with save margins of normal tissue. Therefore additional therapies were looked for and a different number of approaches have been taken. To answer the question if any systemic induction therapy is considered the best, this can be answered with a clear No. reasons for this is the lack of randomized studies in this patient population and the fact that patients with MPM are grouped together despite differences in pathology, surgical approach (EPP vs Pleurectomy decortication) and biological behavior. There has been a number of preferential approaches with chemotherapy in this disease ranging from Induction chemotherapy; Intracavitary therapy and Adjuvant chemotherapy. (Table) In the case
January 2017
Abstracts
of induction therapy it is clear that one aims at reducing the tumor bulk and to prevent metastases during surgery. The preferred treatment is cisplatin with pemetrexed since this is considered to be the standard of this disease.1 Other regimens have been tested in small extend but usually involved. The use of intra-cavitary treatment has attracted attention since MPM cells show the tendency to stay localized in the thoracic cavity for a relative long period. The administration of a local cytotoxic drug would allow an improvement in local control and limited systemic effects. Cisplatin has been used frequently during surgery and were combined with heating of the lavage fluid to 400 Celsius.2 Special precautions for this so-called Hyperthermic lavage approach have to be taken in the operating suite with protection of the staff to avoid exposure to the drugs. In general the lavage procedure adds another hour to the debulking surgery. Measurements of platin adducts in the blood during this procedure have shown that there is no important systemic levels measured. Unfortunately there has not been any comparison of these approaches. Most series only report the feasibility of the treatment with sometimes impressive survival figures. These are partly due to the strong selection of patients for the studies. A relative new approach is the use of a platin containing fibrin glue that can be applied to the thoracic wall after debulking using a spray system. The initial results indicate that the treatment is fast and serial biopsies show that the effect is sustained for many weeks.3 Finally, adjuvant therapies can be applied. In this field, there are no data to support any specific treatment and the choices are generally defined based on the study protocol. No prospective trials have been reported. Most of the studies are trimodality therapies where RT is an important part of the protocol. One typical example is the EORTC study where the feasibility of trimodality therapy in a phase II trial (EORTC 08031) with clearly defined timelines was tested.5 Patients with pathologically proven mesothelioma received induction chemotherapy (3 courses cisplatin and pemetrexed) followed by EPP within 21e56 days after the last dose of chemotherapy in the absence of progressive disease and unacceptable toxicity. A ‘‘success of treatment’’ was
S59
defined as a patient who had received the full protocol and was alive after 90 days without progressive disease and without grade 3 or 4 toxicity. Of the 57 patients included, 42 had EPP (73.7%) after induction therapy. The 90-day mortality was 6.5% with an overall survival time of 18.4 months and progression-free median survival time of 13.9 months. Only 24 (42.1%) patients met the definition of success, thereby failing the primary endpoint. This study shows how difficult it is to complete a trimodality study in this patient group and only when a standard is defined, proper comparative studies can be performed. Other important studies addressing the neoadjuvant approach are presented in the table. References: 1. Baas P, Fennel D, Kerr K, van Schil PE. Malignant Pleural Mesothelioma: Guidelines for Diagnosis, treatment and follow-up. Annals Oncology 2015. 2. Sugarbaker DJ, Gill RR, Yeap BY, Wolf AS, DaSilva MC, Baldini EH, Bueno R, Richards WG. Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among lowrisk patients with malignant pleural Mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg. 2013 Apr;145(4):955-63. 3. Opitz I. Use of fibrin glue in malignan pleural mesothelioma, presented at the xxth IMIG conference Birmingham UK. 4. Van Schil P, Baas P, Gafaar R, Maat AP, van der Pol M, Hassan B et al. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. 5. Weder W, Stahel RA, Bernhard J, Bodis S, Vogt P, Ballabeni P, et al. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 2007;18:1196-202. 6. Cao C, Tian D, Manganas C, Matthews P, Yan TD. Systematic review of trimodality therapy for patients with malignant pleural mesothelioma. Ann Cardiothor Surg 2012;1:428-37. Keywords: surgery; mesothelioma; chemotherapy
Table. Study
type
# pts drugs
Completed Completed Completed Chemotherapy Surgery Radiotherapy
SAKK 17/04 Lancet Onc 2015;16;1651 Frederico BMC Cancer 2013;13;22 Krug JCO 2009;27;3007 Weder JCO 2004;22;3451 Van Schil ERJ 2010;36;1362 Richards JCO 2006;24;1561 Tilleman JTCS 2009;138;405
Neo-adj Neo-adj Neo-adj Neo-adj Neo-adjuvant intracavitary intracavitary
151 54 77 20 59 61 121
145 96% 83% 90% 93% n.a. n.a
Cis/pem Cis/pem Cis/pem Cis/gem Cis/pem Cispl 50-225 Cispl 225
125 83% 74% 80% 79% 72% 79%
Outcome (mOS)
23/27 in 2nd stage 7.6-9.4 41% 15.5 52% 16.8 n.a. 23 65% 18.4 n.a. 9.0 n.a. 12.8
epithelioid, biphasic-epithelioid and biphasic-sarcomatoid) derived from RNA-seq analysis. MicroRNA expression has also been linked to outcome. Early studies revealed prognostic significance of miR-29c-3p, with higher levels corresponding to longer survival. More recently, microRNA expression profiles differing between long and short survivors yielded a 6-microRNA score that predicted outcome in two surgical series. Whether TCGA data confirm these observations remains to be determined. In addition to RNA and protein biomarkers, the cellular composition of tumors influences patient outcomes. It is likely that the mix of cell types within tumor samples also contributes to biomarker expression, especially for RNA extracted from whole tumors. For some proteins, differential expression in the stromal and tumor compartments is of prognostic value, for example in the case of SPARC expression. The importance of the immune cell infiltrate was recently investigated in a large number of epithelioid samples revealing that greater numbers of tumor-infiltrating CD4+ and CD8+ T lymphocytes (TILs), as well as fewer tumorassociated macrophages (TAMs) of the M2-type correlate with survival. In addition, the ratio of the TAMs/TILs was also shown to predict outcome in epithelioid MPM. Other cell populations associated with vascular and lymphatic invasion are also linked to survival. Prediction: Unlike lung cancer, few actionable mutations are present in MPM that predict sensitivity to targeted agents, and clinical trials with these drugs have yielded disappointing results. Markers for single agent chemotherapy and the standard cisplatin/pemetrexed doublet have also been investigated in retrospective studies attempting to link patient outcomes with gene (mRNA and protein) expression and polymorphisms. Multiple reports have linked levels of TS protein, but not mRNA, to outcomes with pemetrexed-based chemotherapy. As expected from a multi-targeted agent, other levels of other proteins such as folypoly-glutamate synthase (FGPS) and the reduced folate carrier (RFC) were also associated with tumor response and patient outcomes. However, a subsequent study with a similar number of patients suggested that both TS and FPGS lack predictive value. With respect to DNA repair genes involved in cisplatin activity, ERCC1 and others have been evaluated, but results are again inconclusive. The picture is complicated by assessment of target genes in patients treated with two interacting agents (with or without subsequent surgery), and the true value of these genes awaits carefully controlled prospective analyses. The recent breakthrough success of immune checkpoint inhibiting antibodies targeting CTLA4 and the PD-1/PD-L1 axis in melanoma and lung cancer has seen these agents applied to MPM patients. With response rates of around 25% for PD-1 targeting
Journal of Thoracic Oncology
Vol. 12 No. 1S
antibodies pembrolizumab and nivolumab in MPM, new predictive markers are needed to improve patient selection and for health economics reasons. Although the Keynote trial included patients based on positivity of PDL1 staining, PD-L1 status appears to have little value in predicting response rate. Ongoing research into immune cell involvement may shed more light on this. Future directions: Continuing research in this area should learn from limitations of the biomarker studies of the last decades to improve the search for useful molecular markers. Large prospective trials are needed to carefully evaluate predictive markers. Alternative approaches such as the analysis of live cell populations taken from fine-needle aspirates and investigation of circulating tumor cells and tumor-derived markers in the circulation (DNA, exosomes) may yield novel markers. Conclusions: Extensive research into tumor-based markers for MPM is gradually making progress. New markers to assist in diagnosis and prognosis have been identified, but the selection of accurate predictive markers has so far remained elusive. Next-generation sequencing has identified multiple new candidate markers requiring further investigation, and may provide breakthroughs in the future. Keywords: predictive markers, diagnosis, Prognosis
ED13.04 Systemic Induction Therapy of Malignant Pleural Mesothelioma Paul Baas Thoracic Oncology, Netherlands Cancer Institute, Amsterdam/Netherlands Over the last 3 decades clinical researchers have focused on the optimal treatment of patients with mesothelioma (MPM). In the 80’s surgery had become a standard approach in some centers but it became clear that a complete resection (R0) was not achievable. The anatomical location of the mesothelioma simply does not allow a resection with save margins of normal tissue. Therefore additional therapies were looked for and a different number of approaches have been taken. To answer the question if any systemic induction therapy is considered the best, this can be answered with a clear No. reasons for this is the lack of randomized studies in this patient population and the fact that patients with MPM are grouped together despite differences in pathology, surgical approach (EPP vs Pleurectomy decortication) and biological behavior. There has been a number of preferential approaches with chemotherapy in this disease ranging from Induction chemotherapy; Intracavitary therapy and Adjuvant chemotherapy. (Table) In the case
January 2017
Abstracts
of induction therapy it is clear that one aims at reducing the tumor bulk and to prevent metastases during surgery. The preferred treatment is cisplatin with pemetrexed since this is considered to be the standard of this disease.1 Other regimens have been tested in small extend but usually involved. The use of intra-cavitary treatment has attracted attention since MPM cells show the tendency to stay localized in the thoracic cavity for a relative long period. The administration of a local cytotoxic drug would allow an improvement in local control and limited systemic effects. Cisplatin has been used frequently during surgery and were combined with heating of the lavage fluid to 400 Celsius.2 Special precautions for this so-called Hyperthermic lavage approach have to be taken in the operating suite with protection of the staff to avoid exposure to the drugs. In general the lavage procedure adds another hour to the debulking surgery. Measurements of platin adducts in the blood during this procedure have shown that there is no important systemic levels measured. Unfortunately there has not been any comparison of these approaches. Most series only report the feasibility of the treatment with sometimes impressive survival figures. These are partly due to the strong selection of patients for the studies. A relative new approach is the use of a platin containing fibrin glue that can be applied to the thoracic wall after debulking using a spray system. The initial results indicate that the treatment is fast and serial biopsies show that the effect is sustained for many weeks.3 Finally, adjuvant therapies can be applied. In this field, there are no data to support any specific treatment and the choices are generally defined based on the study protocol. No prospective trials have been reported. Most of the studies are trimodality therapies where RT is an important part of the protocol. One typical example is the EORTC study where the feasibility of trimodality therapy in a phase II trial (EORTC 08031) with clearly defined timelines was tested.5 Patients with pathologically proven mesothelioma received induction chemotherapy (3 courses cisplatin and pemetrexed) followed by EPP within 21e56 days after the last dose of chemotherapy in the absence of progressive disease and unacceptable toxicity. A ‘‘success of treatment’’ was
S59
defined as a patient who had received the full protocol and was alive after 90 days without progressive disease and without grade 3 or 4 toxicity. Of the 57 patients included, 42 had EPP (73.7%) after induction therapy. The 90-day mortality was 6.5% with an overall survival time of 18.4 months and progression-free median survival time of 13.9 months. Only 24 (42.1%) patients met the definition of success, thereby failing the primary endpoint. This study shows how difficult it is to complete a trimodality study in this patient group and only when a standard is defined, proper comparative studies can be performed. Other important studies addressing the neoadjuvant approach are presented in the table. References: 1. Baas P, Fennel D, Kerr K, van Schil PE. Malignant Pleural Mesothelioma: Guidelines for Diagnosis, treatment and follow-up. Annals Oncology 2015. 2. Sugarbaker DJ, Gill RR, Yeap BY, Wolf AS, DaSilva MC, Baldini EH, Bueno R, Richards WG. Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among lowrisk patients with malignant pleural Mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg. 2013 Apr;145(4):955-63. 3. Opitz I. Use of fibrin glue in malignan pleural mesothelioma, presented at the xxth IMIG conference Birmingham UK. 4. Van Schil P, Baas P, Gafaar R, Maat AP, van der Pol M, Hassan B et al. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. 5. Weder W, Stahel RA, Bernhard J, Bodis S, Vogt P, Ballabeni P, et al. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 2007;18:1196-202. 6. Cao C, Tian D, Manganas C, Matthews P, Yan TD. Systematic review of trimodality therapy for patients with malignant pleural mesothelioma. Ann Cardiothor Surg 2012;1:428-37. Keywords: surgery; mesothelioma; chemotherapy
Table. Study
type
# pts drugs
Completed Completed Completed Chemotherapy Surgery Radiotherapy
SAKK 17/04 Lancet Onc 2015;16;1651 Frederico BMC Cancer 2013;13;22 Krug JCO 2009;27;3007 Weder JCO 2004;22;3451 Van Schil ERJ 2010;36;1362 Richards JCO 2006;24;1561 Tilleman JTCS 2009;138;405
Neo-adj Neo-adj Neo-adj Neo-adj Neo-adjuvant intracavitary intracavitary
151 54 77 20 59 61 121
145 96% 83% 90% 93% n.a. n.a
Cis/pem Cis/pem Cis/pem Cis/gem Cis/pem Cispl 50-225 Cispl 225
125 83% 74% 80% 79% 72% 79%
Outcome (mOS)
23/27 in 2nd stage 7.6-9.4 41% 15.5 52% 16.8 n.a. 23 65% 18.4 n.a. 9.0 n.a. 12.8