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O-27 Photodynamic therapy for pleural mesothelioma: 100 patients
Oral Sessions/Mesotheliomn. Systemic Therapy
s12
0 27 lY
Photodynamic patients
Therapy for Pleural Mesothelioma:
100
Malignant Mesothelioma is a miserable condition for which there is no reliably curative modality available to date. The condition is relentless and lethal with a median survival in most series of approximately 9 months. In 1989 we began a program of Photo Dynamic Therapy (PDT) in conjunction with pleurectomy and decortication in an attempt to improve disease control. Haematoporphyrin Derivative has been used as the photosensitizer and 630nm light from a laser source was used for illumination. We treated our 100th patient in June of 2002. Operative mortality has been acceptably low at 2%. Post operative morbidity has included persistent air leaks, pleural space infections and cutaneous “burns”. Median postoperative inpatient stay has been 9 days. Cutaneous photosensitivity is a limiting factor in the post operative recovery of our patients. Although recurrence has been almost inevitable, median survival is 440 days vs 250 days in our own non PDT group as well as historical controls and other reported series. We believe this is probably due to improved local disease control. PDT as an isolated therapy is not a curative modality but it is safe and does offer a degree of hope for these patients in an otherwise hopeless situation.
[Illei et al., Cancer (Cancer Cytopathol) 99:51-6, 20031. The aim of the present study was to evaluate MTAP deletion detection methods in a series of pleural M M with defined CDKNPA status. We used two separate FISH assays to examine interphase nuclei in imprints of frozen tissue from 58 cases of pleural M M for CDKN2A and MTAP loss, using Pl clones 1063 and 1069 as probes, respectively. Cases were considered homozygously deleted when both signals were lost in at least 20% of nuclei. IHC was performed using a new monoclonal antibody to MTAP. Homozygous deletion of CDKN2A was demonstrated by FISH in 39 cases (67%). MTAP was scored as co-deleted by FISH in 34 of these cases (87%). No case with MTAP deletion without CDKN2A deletion was identified by FISH. Comparison with loss of MTAP nuclear staining by IHC showed a very strong correlation of IHC and FISH data (PcO.OOOl), with only 9 discrepant cases, of these 9 cases, 5 were IHC-negative but FISH non-deleted, 3 of which had loss of both MTAP FISH signals in IO-19% of nuclei. Frequent MTAP codeletion in M M makes it an ideal candidate for targeted therapy using inhibitors of de novo AMP svnthesis (e.a. SDX-102/L-alanosine). The MTAP IHC assay correlates very weil with MTAP deletions confirmed by FISH. MTAP IHC can help to resolve cases with borderline MTAP deletion scores by FISH and can identify cases to be further examined for MTAP microdeletions (undetectable by FISH). This MTAP IHC assay is now being used to screen tumors for patient elrgrbrlrty as part of an ongoing Phase II trial of SDX-102/L-alanosine.
0 28 El
0 30 El.
Simon R. Kniqht, Peter Clarke, Fredy Daniel, Siven Seevanayagam. Repatriation Medical Cenfre, Melbourne, Australia
Austin &
The Use of Mitomycin C, Vinblastine, and Cisplatin (MVP) Chemotherapy in Patients with Malignant Mesothelioma Outcome and Predictive Factors
E. Andreopoulou, P.J. Ross, M.E.R. O’Brien, A. Norton, K. Priest, S. Ashley, H. Ford, I.E. Smith. Lung Unit, Royal Marsden Hospital Sutton, UK This study aimed to assess the palliative benefit of MVP chemotherapy in patients with mesothelioma and assess prognostic factors. Patients with histologically confirmed mesothelioma were treated with mitomycin-C 8 mg/ms IV on day 1 (given on courses 1,2,4 and 6) vinblastine 6 mg/m* (maximum IOmg) IV on day 1 and cisplatin 50 mg/m2 IV day 1 every 21 days for a maximum of 6 cycles. 150 patients were treated and analysed for objective and symptomatic tumour response, toxicity and survival. The overall response rate was 15.3% (95% confidence intervals [Cl] 9.3 - 21.4%) and 68.6% demonstrated no objective change. 147 patients reported symptoms at the start of chemotherapy including dyspnoea, cough, chest pain and malaise. 69% had a symptomatic response to MVP, including 2 patients with a complete resolution of all symptoms. There were no toxic deaths. The most frequent grade 3/4 non-haematological toxicities were infection (12%), nausea/vomiting (9%) and constipation (5%). Grade 3/4 haematological toxicities were neutropaenia (22%) anaemia (6%) and thrombocytopaenia (5%). Median survival was 7 months and at l-year 31.6% (95% Cl 24.0 - 39.5%) were alive. Univariate analyses demonstrated that ooor uerformance status (WHO 2/3) (u=O.O03). weiaht loss (p=O.O09), non-kpitheiioid histology (p=0.063), low haemoglobin (< 13 g/dl in males and <11,5g/dl in females) (p=O.OOB), low white cell count (c 11 x 109/l) (p=O.O08) and low absolute neutrophil count (< 5.0 x log/l) (p=O.O2) were all significant prognostic factors. Multivariate analysis demonstrated that weight loss (relative risk [RR] 3.34, p=O.OOl), non-epithelioid histology (RR 2.69, p=O.Oi), low haemoglobin (RR 2.41 p=O.Oi), low white cell count (RR 2.94, p=O.OOl) were all independent prognostic factors. We conclude that MVP is a palliative regimen which can be given safely to patients with poor performance status. In addition, we have confirmed that weight loss, non-epithelioid pathology, and anaemia are poor prognostic factors. For patients’ outcomes to be improved treatment strategies will need to address symptoms such as weight loss and anaemia. Dr E Andreopoulou was supported by an ESMO Fellowship
1
The methylthioadenosine phosphorylase (MTAP) gene is homozygously co-deleted with CDKNPA in most pleural mesotheliomas. Detection by fluorescent in situ hybridization (FISH) and by immunohistochemistry (IHC) using a novel MTAP monoclonal antibody
Peter B. Illei’, Lorenzo Leoni’, Weidong Huang3, Stephanie Astrows, Alan Cheeks3, Valerie Rusch’ , Marc Ladanvi’. ’ Memorial Sloan-Kettering Cancer Center, New York, lJSA;‘Sa/medix, Inc., San Diego, USA; 31MPATH Predictive Oncology Inc., Los Angeles, USA Loss of both copies (homozygous deletion) of the CDKN2A gene (encoding the pi6 protein) at chromosome region 9p21 has been described in malignant mesothelioma (MM). MTAP, a gene 100 kb from CDKN2A, encodes an enzyme essential in the salvage of cellular adenine and methionine, and is co-deleted with CDKN2A in other tumors. Because loss of MTAP renders cells dependent on de novo synthesis of purine derivatives, this is potentially of therapeutic interest. We have recently shown that homozygous deletion of CDKN2A +/- MTAP is seen in most pleural M M (Illei et al., Clin Cancer Res, in press) and that FISH detection of CDKN2A deletion can be used in the cytologic diagnosis of M M
Statrstical Validation of the EORTC Prognostic Model for Malrgnant Pleural Mesothelioma Based on Three Consecutive Phase II trials
Dean A. Fennell, Amit Parmar, Jonathan Shamash, Marie T. Evans, Richard J. Sylvester, Kevin Dhaliwal, Nicole H. Gower, Robin M. Rudd, Jeremy P.C. Steele. Sf Bartholomew’s Hospita/, London, United Kingdom
Introduction: Malignant pleural mesothelioma (MPM) carries a poor prognosis due to chemoresistance. The EORTC prognostic model was reported to predict for survival in MPM [I]. This retrospective analysis set out to (a) test the validity of the model as a prognostic tool in patients treated in three phase II trials at St Bartholomew’s Hospital between 1999 and 2003 (b) analyze characteristics of respective EORTC subgroups. Methods: A total of 145 patients were treated in the following phase II trials; vinorelbine (70 patients) [2], vinorelbine/oxaliplatin (VO, 26 patients), and irinotecan/cisplatin/mitomycin C (IPM, 49 patients). Two subgroups were defined according to prognostic score (EPS), determined by incorporation into the EORTC model of 4 clinicopathological variables based on age, sex, histology, and leucocyte count. An EPS score was calculated, and the cutoff cl.27 or > 1.27 was used to stratify Kaplan Meier survival curves [I]. Results: From the pooled dataset, 134 pts were evaluable for EPS; 63 patients had an unfavourable EPS > 1.27; 71 patients had an EPS < 1.27. Median overall survival (OS) was calculated using the product limit estimator. For EPS < 1.27, OS was 9.9 months (95% Cl = 8.8 - 11.1). For EPS > 1.27, OS was 14.6 months (95% Cl = 11.8-17.4). Logrank statistic for difference in survival was 15.3 (p = 0.0001). In subgroup analyses, the EPS stratified the vinorelbine cohort; OS = 9.9 months (95% Cl =8.5-i 1.3) and 19.2 months (95% Cl= 14.723.7) respectively: logrank statistic = 13.39 (p=O.O03). Trends to worse survival were associated with an EPS >I .27 for IPM and VO cohorts. Subgroup analysis of patient characteristics will be presented. Conclusion: This study validates the EORTC prognostic scoring system as a robust tool for stratifying small series into homogenous subgroups; its use should facilitate patient selection and analysis in randomized clinical trials. [1] Curran, D., et al., Prognostic factors in patients with pleural mesothelioma: the European Oraanization for Research and Treatment of Cancer experience. J Clin On&t, 1998. 16(l): p. 145-52. [2] Steele, J.P., et al., Phase II study of vinorelbine in patients with malignant pleural mesothelioma. J Clin Oncol, 2000. 18(23): p. 3912-7.
s12
0 27 lY
Photodynamic patients
Therapy for Pleural Mesothelioma:
100
Malignant Mesothelioma is a miserable condition for which there is no reliably curative modality available to date. The condition is relentless and lethal with a median survival in most series of approximately 9 months. In 1989 we began a program of Photo Dynamic Therapy (PDT) in conjunction with pleurectomy and decortication in an attempt to improve disease control. Haematoporphyrin Derivative has been used as the photosensitizer and 630nm light from a laser source was used for illumination. We treated our 100th patient in June of 2002. Operative mortality has been acceptably low at 2%. Post operative morbidity has included persistent air leaks, pleural space infections and cutaneous “burns”. Median postoperative inpatient stay has been 9 days. Cutaneous photosensitivity is a limiting factor in the post operative recovery of our patients. Although recurrence has been almost inevitable, median survival is 440 days vs 250 days in our own non PDT group as well as historical controls and other reported series. We believe this is probably due to improved local disease control. PDT as an isolated therapy is not a curative modality but it is safe and does offer a degree of hope for these patients in an otherwise hopeless situation.
[Illei et al., Cancer (Cancer Cytopathol) 99:51-6, 20031. The aim of the present study was to evaluate MTAP deletion detection methods in a series of pleural M M with defined CDKNPA status. We used two separate FISH assays to examine interphase nuclei in imprints of frozen tissue from 58 cases of pleural M M for CDKN2A and MTAP loss, using Pl clones 1063 and 1069 as probes, respectively. Cases were considered homozygously deleted when both signals were lost in at least 20% of nuclei. IHC was performed using a new monoclonal antibody to MTAP. Homozygous deletion of CDKN2A was demonstrated by FISH in 39 cases (67%). MTAP was scored as co-deleted by FISH in 34 of these cases (87%). No case with MTAP deletion without CDKN2A deletion was identified by FISH. Comparison with loss of MTAP nuclear staining by IHC showed a very strong correlation of IHC and FISH data (PcO.OOOl), with only 9 discrepant cases, of these 9 cases, 5 were IHC-negative but FISH non-deleted, 3 of which had loss of both MTAP FISH signals in IO-19% of nuclei. Frequent MTAP codeletion in M M makes it an ideal candidate for targeted therapy using inhibitors of de novo AMP svnthesis (e.a. SDX-102/L-alanosine). The MTAP IHC assay correlates very weil with MTAP deletions confirmed by FISH. MTAP IHC can help to resolve cases with borderline MTAP deletion scores by FISH and can identify cases to be further examined for MTAP microdeletions (undetectable by FISH). This MTAP IHC assay is now being used to screen tumors for patient elrgrbrlrty as part of an ongoing Phase II trial of SDX-102/L-alanosine.
0 28 El
0 30 El.
Simon R. Kniqht, Peter Clarke, Fredy Daniel, Siven Seevanayagam. Repatriation Medical Cenfre, Melbourne, Australia
Austin &
The Use of Mitomycin C, Vinblastine, and Cisplatin (MVP) Chemotherapy in Patients with Malignant Mesothelioma Outcome and Predictive Factors
E. Andreopoulou, P.J. Ross, M.E.R. O’Brien, A. Norton, K. Priest, S. Ashley, H. Ford, I.E. Smith. Lung Unit, Royal Marsden Hospital Sutton, UK This study aimed to assess the palliative benefit of MVP chemotherapy in patients with mesothelioma and assess prognostic factors. Patients with histologically confirmed mesothelioma were treated with mitomycin-C 8 mg/ms IV on day 1 (given on courses 1,2,4 and 6) vinblastine 6 mg/m* (maximum IOmg) IV on day 1 and cisplatin 50 mg/m2 IV day 1 every 21 days for a maximum of 6 cycles. 150 patients were treated and analysed for objective and symptomatic tumour response, toxicity and survival. The overall response rate was 15.3% (95% confidence intervals [Cl] 9.3 - 21.4%) and 68.6% demonstrated no objective change. 147 patients reported symptoms at the start of chemotherapy including dyspnoea, cough, chest pain and malaise. 69% had a symptomatic response to MVP, including 2 patients with a complete resolution of all symptoms. There were no toxic deaths. The most frequent grade 3/4 non-haematological toxicities were infection (12%), nausea/vomiting (9%) and constipation (5%). Grade 3/4 haematological toxicities were neutropaenia (22%) anaemia (6%) and thrombocytopaenia (5%). Median survival was 7 months and at l-year 31.6% (95% Cl 24.0 - 39.5%) were alive. Univariate analyses demonstrated that ooor uerformance status (WHO 2/3) (u=O.O03). weiaht loss (p=O.O09), non-kpitheiioid histology (p=0.063), low haemoglobin (< 13 g/dl in males and <11,5g/dl in females) (p=O.OOB), low white cell count (c 11 x 109/l) (p=O.O08) and low absolute neutrophil count (< 5.0 x log/l) (p=O.O2) were all significant prognostic factors. Multivariate analysis demonstrated that weight loss (relative risk [RR] 3.34, p=O.OOl), non-epithelioid histology (RR 2.69, p=O.Oi), low haemoglobin (RR 2.41 p=O.Oi), low white cell count (RR 2.94, p=O.OOl) were all independent prognostic factors. We conclude that MVP is a palliative regimen which can be given safely to patients with poor performance status. In addition, we have confirmed that weight loss, non-epithelioid pathology, and anaemia are poor prognostic factors. For patients’ outcomes to be improved treatment strategies will need to address symptoms such as weight loss and anaemia. Dr E Andreopoulou was supported by an ESMO Fellowship
1
The methylthioadenosine phosphorylase (MTAP) gene is homozygously co-deleted with CDKNPA in most pleural mesotheliomas. Detection by fluorescent in situ hybridization (FISH) and by immunohistochemistry (IHC) using a novel MTAP monoclonal antibody
Peter B. Illei’, Lorenzo Leoni’, Weidong Huang3, Stephanie Astrows, Alan Cheeks3, Valerie Rusch’ , Marc Ladanvi’. ’ Memorial Sloan-Kettering Cancer Center, New York, lJSA;‘Sa/medix, Inc., San Diego, USA; 31MPATH Predictive Oncology Inc., Los Angeles, USA Loss of both copies (homozygous deletion) of the CDKN2A gene (encoding the pi6 protein) at chromosome region 9p21 has been described in malignant mesothelioma (MM). MTAP, a gene 100 kb from CDKN2A, encodes an enzyme essential in the salvage of cellular adenine and methionine, and is co-deleted with CDKN2A in other tumors. Because loss of MTAP renders cells dependent on de novo synthesis of purine derivatives, this is potentially of therapeutic interest. We have recently shown that homozygous deletion of CDKN2A +/- MTAP is seen in most pleural M M (Illei et al., Clin Cancer Res, in press) and that FISH detection of CDKN2A deletion can be used in the cytologic diagnosis of M M
Statrstical Validation of the EORTC Prognostic Model for Malrgnant Pleural Mesothelioma Based on Three Consecutive Phase II trials
Dean A. Fennell, Amit Parmar, Jonathan Shamash, Marie T. Evans, Richard J. Sylvester, Kevin Dhaliwal, Nicole H. Gower, Robin M. Rudd, Jeremy P.C. Steele. Sf Bartholomew’s Hospita/, London, United Kingdom
Introduction: Malignant pleural mesothelioma (MPM) carries a poor prognosis due to chemoresistance. The EORTC prognostic model was reported to predict for survival in MPM [I]. This retrospective analysis set out to (a) test the validity of the model as a prognostic tool in patients treated in three phase II trials at St Bartholomew’s Hospital between 1999 and 2003 (b) analyze characteristics of respective EORTC subgroups. Methods: A total of 145 patients were treated in the following phase II trials; vinorelbine (70 patients) [2], vinorelbine/oxaliplatin (VO, 26 patients), and irinotecan/cisplatin/mitomycin C (IPM, 49 patients). Two subgroups were defined according to prognostic score (EPS), determined by incorporation into the EORTC model of 4 clinicopathological variables based on age, sex, histology, and leucocyte count. An EPS score was calculated, and the cutoff cl.27 or > 1.27 was used to stratify Kaplan Meier survival curves [I]. Results: From the pooled dataset, 134 pts were evaluable for EPS; 63 patients had an unfavourable EPS > 1.27; 71 patients had an EPS < 1.27. Median overall survival (OS) was calculated using the product limit estimator. For EPS < 1.27, OS was 9.9 months (95% Cl = 8.8 - 11.1). For EPS > 1.27, OS was 14.6 months (95% Cl = 11.8-17.4). Logrank statistic for difference in survival was 15.3 (p = 0.0001). In subgroup analyses, the EPS stratified the vinorelbine cohort; OS = 9.9 months (95% Cl =8.5-i 1.3) and 19.2 months (95% Cl= 14.723.7) respectively: logrank statistic = 13.39 (p=O.O03). Trends to worse survival were associated with an EPS >I .27 for IPM and VO cohorts. Subgroup analysis of patient characteristics will be presented. Conclusion: This study validates the EORTC prognostic scoring system as a robust tool for stratifying small series into homogenous subgroups; its use should facilitate patient selection and analysis in randomized clinical trials. [1] Curran, D., et al., Prognostic factors in patients with pleural mesothelioma: the European Oraanization for Research and Treatment of Cancer experience. J Clin On&t, 1998. 16(l): p. 145-52. [2] Steele, J.P., et al., Phase II study of vinorelbine in patients with malignant pleural mesothelioma. J Clin Oncol, 2000. 18(23): p. 3912-7.