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63 Chemotherapy for malignant mesothelioma and response assessment by modified RECIST criteria, the St James's Hospital, Dublin experience
Posters, 10th Annual British Thoracic Oncology Group Conference, 2012: Mesothelioma
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62 Audit of patients receiving cisplatin/pemetrexed chemotherapy for malignant mesothelioma in NHS Tayside 2005 2010 A. Cockburn1 *, H. Lord2 , E.M. Rankin2 , E. Brown2 . 1 University of Dundee Medical School, Dundee, UK, 2 NHS Tayside, Dundee, UK
sarcomatoid histology and a high baseline WCC were confirmed as indicators of poor prognosis.
Introduction: Malignant pleural mesothelioma is an aggressive malignancy with a poor prognosis. The primary treatment of choice is chemotherapy, using pemetrexed (500 mg/m2 ) and cisplatin (75 mg/m2 ) iv d1 q 21 days for 4 6 cycles. This audit aims to assess the level of toxicities and clinical benefit for patients receiving this regime in NHS Tayside between 2005 and 2010, and to compare results to the original trial led by Vogelzang. Method: Patients were identified from the departmental database. Patients’ age, gender, performance status (PS), histological diagnosis, date of first chemotherapy, toxicities, response, additional treatment and date of death were recorded. Results: Sixteen patients were identified, all male. Median age was 63 years (51 75 years). 81% were PS 0 1. 75% had epitheliod histology. Median number of cycles received 4, and 44% of patients received additional treatment. 12.5% had a partial response, 50% had stable disease and 37.5% progression of disease. Three patients had grade 3 toxicities: hearing change, constipation and fatigue; 1 patient had grade 4 vomiting and neutropenic sepsis. Median survival was 11.3 months (95% CI 6 to 16.6) with a censorship rate of 31%. One year survival was 37.5% (6 of 16). Conclusions: This is a well tolerated regime with limited toxicities. Response is satisfactory, and median overall survival at 11.3 months, compares well with 12.1 months in original Vogelzang study.
A.-M. Baird1,2 *, D. Easty2 , A. Soltermann4 , D. Nonaka5 , D. Fennell6 , L. Mutti7 , H. Pass5 , I. Schmitt-Opitz4 , D. O’Donnell3 , K. O’Byrne2,3 , S. Gray2,3 . 1 Dept. of Clinical Medicine, Trinity College Dublin, Dublin, Ireland, 2 Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James’s Hospital, Dublin, Ireland, 3 HOPE Directorate, St. James’s Hospital, Dublin, Ireland, 4 Zurich University, Zurich, Switzerland, 5 NYU School of Medicine, New York, USA, 6 Queen’s University, Belfast, UK, 7 Laboratory of Clinical Oncology, Hospital of Vercelli, Vercelli, Italy
63 Chemotherapy for malignant mesothelioma and response assessment by modified RECIST criteria, the St James’s Hospital, Dublin experience J. O’Flaherty *, M. Knox, S. Cuffe, K. O’Byrne. St. James’s Hospital, Dublin, Ireland Introduction: Malignant pleural mesothelioma (MPM) is a rare malignancy primarily related to inhalational asbestos exposure. Chemotherapy including platinum and pemetrexed has become the standard of care. However, response assessment in MPM remains difficult due to the circumferential growth of the tumour in the thorax, which means that standard RECIST criteria are difficult to apply in this disease. Recently, Modified RECIST criteria have been published which may be a superior method for assessing response in MPM. Method: Patients with MPM attending our institution and treated with platinum/pemetrexed chemotherapy between 2004 and 2010 were analysed. Baseline age, gender, histological subtype, white cell count, haemoglobin, platelet count and LDH were recorded for all patients. CT scans were performed at the start of chemotherapy, once during chemotherapy and again at the end of treatment. All CT scans were assessed using the Modified RECIST criteria. Overall survival was compared to response as determined by CT assessment. In addition survival was also compared to the aforementioned clinical and demographic criteria. Results: 31 patients were subject to analysis. Median survival for the cohort as a whole was 12.4 months. CT response was found to correlate significantly with survival. Patients with partial response (PR), stable disease (SD) and progressive disease (PD) had median survivals of 25.73 months, 12.4 months and 6.23 months respectively (p = 0.0006) In addition histological subtype and baseline WCC were also found to significantly correlate with survival, with sarcomatoid histology and a high baseline WCC indicative of a poorer prognosis. Conclusions: The survival for patients with MPM treated with chemotherapy in our institution compare favourably with those of recently published trials in MPM. CT response accurately predicted survival, which provides a useful validation of the Modified RECIST criteria for response assessment in this disease. In addition
64 Macrophage stimulating protein (MSP) up-regulates the Src kinases in malignant pleural mesothelioma
Introduction: Macrophage stimulating protein (MSP) is an 80 kDa serum protein heterodimer composed of an alpha and beta chain. It is the only ligand recognised to bind to the RON receptor (MST1R). The MSP-RON signalling pathway has been implicated in a variety of cellular functions such as macrophage activity and wound healing. We have previously identified MST1R/RON as being an independent predictor of favourable prognosis. We therefore hypothesized that MSP, may also play a role in MPM. Method: A panel of mesothelioma cell lines were screened for the expression of MSP and MST1R at the mRNA (RT-PCR) and protein (Western blot) level. IHC expression of MSP was also determined. The response of MPM cells to MSP treatment was examined (proliferation/migration). A phospho-kinase proteome profiler array was utilised to detect the downstream signalling pathways activated upon MSP stimulation. Results: MSP and MST1R expression varied between the mesothelioma cell line panel at both the mRNA and protein level. Multivariate analysis demonstrates that MSP (but not RON) is an independent prognosticator for survival. Treatment with MSP reduces proliferation of Met5A cells (non-malignant), but not in malignant Ju77 or H2052 cell lines. MSP stimulation affects the migration of MPM cell lines, and results in phosphorylation of various kinase protein targets. Analysis is currently ongoing for macrophage (CD 68) staining and we are presently testing samples for the presence/absence of mutations within MST1R. The MSPMST1R pathway is currently being knocked down via shRNA in the Ju77 cell line. Conclusions: Co-expression of MSP and RON in MPM cells may indicate an autocrine signalling pathway and paracrine activation of macrophages. In multivariate analysis, MSP was identified as an independent prognosticator for survival in MPM. The MSP-RON axis may be a novel therapeutic target in mesothelioma. 65 Steroid receptor coactivators in malignant pleural mesothelioma: expression and prognostic value C.J. Jennings1 *, A. O’Grady1 , R. Cummins1 , B. Murer2 , E.W. Kay1 , B.J. Harvey1 , W. Thomas1 . 1 Royal College of Surgeons Ireland, Dublin, Ireland, 2 Dell’Angelo Hospital, Mestre, Italy Introduction: Malignant pleural mesothelioma (MPM), which is associated with asbestos exposure, is an aggressive disease arising from the pleural mesothelium. The incidence of MPM is higher in men than women which is probably linked to occupational exposure, however women experience longer post diagnosis survival. Recent studies indicate that this gender difference in survival may be due to hormonal status since expression of oestrogen receptor (ER)b is associated with better prognosis. Oestrogen signalling is amplified via the recruitment of steroid receptor coactivators (SRCs) to the DNA bound steroid receptor. This study investigated the association between clinical outcome and the expression of ERb and the p160 group of SRCs. Method: The expression of ERb, SRC-1, SRC-2/TIF-2 and AIB-1/SRC-3 was analysed by immunohistochemistry (IHC) in tumour biopsies
S21
62 Audit of patients receiving cisplatin/pemetrexed chemotherapy for malignant mesothelioma in NHS Tayside 2005 2010 A. Cockburn1 *, H. Lord2 , E.M. Rankin2 , E. Brown2 . 1 University of Dundee Medical School, Dundee, UK, 2 NHS Tayside, Dundee, UK
sarcomatoid histology and a high baseline WCC were confirmed as indicators of poor prognosis.
Introduction: Malignant pleural mesothelioma is an aggressive malignancy with a poor prognosis. The primary treatment of choice is chemotherapy, using pemetrexed (500 mg/m2 ) and cisplatin (75 mg/m2 ) iv d1 q 21 days for 4 6 cycles. This audit aims to assess the level of toxicities and clinical benefit for patients receiving this regime in NHS Tayside between 2005 and 2010, and to compare results to the original trial led by Vogelzang. Method: Patients were identified from the departmental database. Patients’ age, gender, performance status (PS), histological diagnosis, date of first chemotherapy, toxicities, response, additional treatment and date of death were recorded. Results: Sixteen patients were identified, all male. Median age was 63 years (51 75 years). 81% were PS 0 1. 75% had epitheliod histology. Median number of cycles received 4, and 44% of patients received additional treatment. 12.5% had a partial response, 50% had stable disease and 37.5% progression of disease. Three patients had grade 3 toxicities: hearing change, constipation and fatigue; 1 patient had grade 4 vomiting and neutropenic sepsis. Median survival was 11.3 months (95% CI 6 to 16.6) with a censorship rate of 31%. One year survival was 37.5% (6 of 16). Conclusions: This is a well tolerated regime with limited toxicities. Response is satisfactory, and median overall survival at 11.3 months, compares well with 12.1 months in original Vogelzang study.
A.-M. Baird1,2 *, D. Easty2 , A. Soltermann4 , D. Nonaka5 , D. Fennell6 , L. Mutti7 , H. Pass5 , I. Schmitt-Opitz4 , D. O’Donnell3 , K. O’Byrne2,3 , S. Gray2,3 . 1 Dept. of Clinical Medicine, Trinity College Dublin, Dublin, Ireland, 2 Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James’s Hospital, Dublin, Ireland, 3 HOPE Directorate, St. James’s Hospital, Dublin, Ireland, 4 Zurich University, Zurich, Switzerland, 5 NYU School of Medicine, New York, USA, 6 Queen’s University, Belfast, UK, 7 Laboratory of Clinical Oncology, Hospital of Vercelli, Vercelli, Italy
63 Chemotherapy for malignant mesothelioma and response assessment by modified RECIST criteria, the St James’s Hospital, Dublin experience J. O’Flaherty *, M. Knox, S. Cuffe, K. O’Byrne. St. James’s Hospital, Dublin, Ireland Introduction: Malignant pleural mesothelioma (MPM) is a rare malignancy primarily related to inhalational asbestos exposure. Chemotherapy including platinum and pemetrexed has become the standard of care. However, response assessment in MPM remains difficult due to the circumferential growth of the tumour in the thorax, which means that standard RECIST criteria are difficult to apply in this disease. Recently, Modified RECIST criteria have been published which may be a superior method for assessing response in MPM. Method: Patients with MPM attending our institution and treated with platinum/pemetrexed chemotherapy between 2004 and 2010 were analysed. Baseline age, gender, histological subtype, white cell count, haemoglobin, platelet count and LDH were recorded for all patients. CT scans were performed at the start of chemotherapy, once during chemotherapy and again at the end of treatment. All CT scans were assessed using the Modified RECIST criteria. Overall survival was compared to response as determined by CT assessment. In addition survival was also compared to the aforementioned clinical and demographic criteria. Results: 31 patients were subject to analysis. Median survival for the cohort as a whole was 12.4 months. CT response was found to correlate significantly with survival. Patients with partial response (PR), stable disease (SD) and progressive disease (PD) had median survivals of 25.73 months, 12.4 months and 6.23 months respectively (p = 0.0006) In addition histological subtype and baseline WCC were also found to significantly correlate with survival, with sarcomatoid histology and a high baseline WCC indicative of a poorer prognosis. Conclusions: The survival for patients with MPM treated with chemotherapy in our institution compare favourably with those of recently published trials in MPM. CT response accurately predicted survival, which provides a useful validation of the Modified RECIST criteria for response assessment in this disease. In addition
64 Macrophage stimulating protein (MSP) up-regulates the Src kinases in malignant pleural mesothelioma
Introduction: Macrophage stimulating protein (MSP) is an 80 kDa serum protein heterodimer composed of an alpha and beta chain. It is the only ligand recognised to bind to the RON receptor (MST1R). The MSP-RON signalling pathway has been implicated in a variety of cellular functions such as macrophage activity and wound healing. We have previously identified MST1R/RON as being an independent predictor of favourable prognosis. We therefore hypothesized that MSP, may also play a role in MPM. Method: A panel of mesothelioma cell lines were screened for the expression of MSP and MST1R at the mRNA (RT-PCR) and protein (Western blot) level. IHC expression of MSP was also determined. The response of MPM cells to MSP treatment was examined (proliferation/migration). A phospho-kinase proteome profiler array was utilised to detect the downstream signalling pathways activated upon MSP stimulation. Results: MSP and MST1R expression varied between the mesothelioma cell line panel at both the mRNA and protein level. Multivariate analysis demonstrates that MSP (but not RON) is an independent prognosticator for survival. Treatment with MSP reduces proliferation of Met5A cells (non-malignant), but not in malignant Ju77 or H2052 cell lines. MSP stimulation affects the migration of MPM cell lines, and results in phosphorylation of various kinase protein targets. Analysis is currently ongoing for macrophage (CD 68) staining and we are presently testing samples for the presence/absence of mutations within MST1R. The MSPMST1R pathway is currently being knocked down via shRNA in the Ju77 cell line. Conclusions: Co-expression of MSP and RON in MPM cells may indicate an autocrine signalling pathway and paracrine activation of macrophages. In multivariate analysis, MSP was identified as an independent prognosticator for survival in MPM. The MSP-RON axis may be a novel therapeutic target in mesothelioma. 65 Steroid receptor coactivators in malignant pleural mesothelioma: expression and prognostic value C.J. Jennings1 *, A. O’Grady1 , R. Cummins1 , B. Murer2 , E.W. Kay1 , B.J. Harvey1 , W. Thomas1 . 1 Royal College of Surgeons Ireland, Dublin, Ireland, 2 Dell’Angelo Hospital, Mestre, Italy Introduction: Malignant pleural mesothelioma (MPM), which is associated with asbestos exposure, is an aggressive disease arising from the pleural mesothelium. The incidence of MPM is higher in men than women which is probably linked to occupational exposure, however women experience longer post diagnosis survival. Recent studies indicate that this gender difference in survival may be due to hormonal status since expression of oestrogen receptor (ER)b is associated with better prognosis. Oestrogen signalling is amplified via the recruitment of steroid receptor coactivators (SRCs) to the DNA bound steroid receptor. This study investigated the association between clinical outcome and the expression of ERb and the p160 group of SRCs. Method: The expression of ERb, SRC-1, SRC-2/TIF-2 and AIB-1/SRC-3 was analysed by immunohistochemistry (IHC) in tumour biopsies