Mesothelioma: Manegold C

Anonymous00082, Manegold C. · No affiliation provided · Ann Oncol. · Pubmed #17491037 links to  free full text

This publication has no abstract.

Tomek S, Manegold C. · Clinical Division of Oncology, Department of Medicine I, Vienna, Austria. · Lung Cancer. · Pubmed #15261443 No free full text.

Abstract: This review summarises results of previously conducted clinical trials and subsequently presents data arising from all phase II-III studies on chemotherapy for malignant pleural mesothelioma (MPM) published since the last relevant overview. While response rates exceeding 30% have barely been achieved with established cytotoxic drugs in MPM therapy, novel chemotherapeutic agents and their combinations appear somewhat more promising. This applies especially to the antimetabolites, and in particular to pemetrexed which produced response rates of up to 45% in combination with platinum compounds. Raltitrexed combined with oxaliplatin has also been shown to be effective, and gemcitabine--applied as a single agent or in combination with cisplatin--as well as vinorelbine appear to improve quality of life in patients presenting with MPM. Data can now be more precisely analysed by increasingly implemented randomised studies, applying a standardised staging system, and distinguishing prognostic groups. While chemotherapy for MPM remains a challenging task, important steps have clearly been made in the past years to combat this aggressive disease. Publication of results from a phase III trial of pemetrexed with cisplatin in a peer reviewed journal may soon establish a standard of care.

Manegold C. · Thoraxklinik-Heidelberg GmbH, Germany. · Semin Oncol. · Pubmed #12917819 No free full text.

Abstract: Regimens with antimetabolites such as gemcitabine administered alone or in combination with cisplatin have shown promising phase II study data. Accordingly, antifolate agents are of considerable interest. Pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, IN), a folate-based inhibitor of thymidylate synthase., is currently under phase III investigation. The Evaluation of Mesothelioma in a Phase III Trail of Pemetrexed with Cisplatin (EMPHACIS) trial is the first phase III randomized study in mesothelioma with survival as the primary end point; it showed statistically significant superiority of the pemetrexed/cisplatin combination over cisplatin low-dose folic acid and vitamin B12 supplementation significantly reduced the toxicity observed with the use of pemetrexed/cisplatin will soon be recommended for malignant pleural mesothelioma as first-line standard chemotherapy.

Tomek S, Emri S, Krejcy K, Manegold C. · Department of Medicine I, Clinical Division of Oncology, University Hospital Vienna, Austria. · Br J Cancer. · Pubmed #12610498 links to  free full text

Abstract: This review summarises the results of previously conducted clinical trials, and subsequently presents data arising from all phase II-III studies on chemotherapy of malignant pleural mesothelioma (MPM) published since the last relevant overview. While response rates exceeding 30% have barely been achieved with established cytotoxic drugs in MPM therapy, novel chemotherapeutic agents and their combinations appear more promising. This applies especially to the antimetabolites, and in particular to pemetrexed that produced response rates of up to 45% in combination with platinum compounds. Raltitrexed combined with oxaliplatin has also been shown to be effective, and gemcitabine-applied as a single agent or in combination with cisplatin-as well as vinorelbine appear to improve the quality of life in patients presenting with MPM. Data can now be more precisely analysed by increasingly implemented randomised studies, applying a standardised staging system, and distinguishing prognostic groups. While chemotherapy for MPM remains a challenging task, important steps have clearly been made in the past years to combat this aggressive disease. The publication of pemetrexed with cisplatin phase III results in a peer-reviewed journal may soon establish a standard of care.

Tomek S, Manegold C. · Department of Medicine I, University Hospital Vienna, Austria. · Curr Opin Oncol. · Pubmed #12601280 No free full text.

Abstract: This paper covers the outcome of previously conducted clinical trials on chemotherapy for malignant pleural mesothelioma and presents data from recent phase II and phase III trials. In contrast to conventional cytotoxic drugs, which have barely produced response rates exceeding 30%, recently introduced chemotherapeutic agents and their combinations promise to be more effective. Especially pemetrexed has yielded response rates of up to 45% in combination with platinum compounds. Furthermore, raltitrexed-oxaliplatin has shown promising activity and gemcitabine was found to improve quality of life in patients with malignant pleural mesothelioma when applied as a single agent or in combination with cisplatin. Based on robust phase III study results, pemetrexed-cisplatin may soon be considered with chemotherapy for this aggressive disease.

Manegold C. · Thoraxklinik, Heidelberg, Germany. · Suppl Tumori. · Pubmed #12415805 No free full text.

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Manegold C, Aisner J. · Department of Medical Oncology/Internal Medicine, Thoraxklinik Heidelberg, gGmbH, Heidelberg, Germany. · Semin Oncol. · Pubmed #12023790 No free full text.

Abstract: The treatment of diffuse malignant pleural mesothelioma (MPM) is currently less than satisfactory. Survival statistics are best for the epithelial subtype and for tumors that can be completely removed by surgery. Radiotherapy provides no survival benefit and is used only to palliate symptoms or to prevent growth along needle tracks and incisions. The response to chemotherapeutic agents is poor, and to date there is no standard cytotoxic treatment. Antimetabolites may have some activity, and one trial of high-dose methotrexate has suggested a moderate response rate. There is also no evidence that any chemotherapy regimen given as a part of multimodality treatment, including radiotherapy and surgery, can improve survival. Recently, a renewed interest in MPM led to clinical trials with promising preliminary results for several agents alone or in combination, including gemcitabine, raltitrexed, vinorelbine, and pemetrexed. Pemetrexed, a folate-based inhibitor of thymidylate synthase and other enzymes, is currently under investigation in multiple malignancies. A phase I study of pemetrexed in combination with cisplatin showed a remarkable response rate of approximately 50% in patients with the epithelial subtype of MPM. This led to a large international study of the combination of pemetrexed plus cisplatin.

Carteni G, Manegold C, Garcia GM, Siena S, Zielinski CC, Amadori D, Liu Y, Blatter J, Visseren-Grul C, Stahel R. · Cardarelli Hospital, Medical Oncology, Via Cardarelli 9, 80100 Naples, Italy. · Lung Cancer. · Pubmed #19042053 No free full text.

Abstract: AIM: Peritoneal mesothelioma (PM) has rarely been studied. The Expanded Access Program (EAP) provided access to 109 patients with PM. METHODS: This was a nonrandomized, open-label study conducted in chemo-naïve or previously treated patients with PM not amenable to curative surgery. Patients received pemetrexed (PEM) 500 mg/m2 alone or with cisplatin (CIS) 75 mg/m2 or carboplatin (CARBO) AUC 5 every 21 days, supplemented with standard vitamin B(12), folate, and dexamethasone. RESULTS: Response rates (95% CI) for PEM, PEM/CIS, and PEM/CARBO were 12.5% (3.5, 29.0), 20.0% (7.7, 38.6), and 24.1% (10.3, 43.5), respectively. Median survival for PEM was 10.3 months. One-year survival rates for PEM/CIS and PEM were 57.4% (95% CI: 10.3, 100) and 41.5% (95% CI: 4.6, 78.4), respectively, and were not available for PEM/CARBO. Anemia was the most common serious adverse event (6.4%). Neutropenia (34.6%) was the most frequent CTC grade 3 or 4 toxicity reported. CONCLUDING STATEMENT: PEM with or without a platinum agent was both active and well tolerated in patients with peritoneal mesothelioma.

Santoro A, O'Brien ME, Stahel RA, Nackaerts K, Baas P, Karthaus M, Eberhardt W, Paz-Ares L, Sundstrom S, Liu Y, Ripoche V, Blatter J, Visseren-Grul CM, Manegold C. · Istituto Clinico Humanitas, Rozzano, Italy. · J Thorac Oncol. · Pubmed #18594322 No free full text.

Abstract: INTRODUCTION: Previously published results from a randomized phase III study of pemetrexed plus cisplatin in patients with malignant pleural mesothelioma (MPM) demonstrated a significant survival benefit and higher response rate compared with cisplatin. Although pemetrexed was under review by regulatory agencies, an International Expanded Access Program (EAP) provided more than 3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed in combination with cisplatin or carboplatin in 13 countries. This manuscript reports the safety and efficacy data from the nonrandomized open-label study in chemonaïve patients receiving pemetrexed plus platinum under the EAP. METHODS: Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed 500 mg/m in combination with either cisplatin 75 mg/m or carboplatin AUC 5, once every 21 days with standard premedication. Efficacy data were recorded at the end of study participation. RESULTS: A total of 1704 chemonaïve patients received pemetrexed plus cisplatin (n = 843) or pemetrexed plus carboplatin (n = 861) and were evaluated for safety. The efficacy evaluable population consisted of 745 patients in the pemetrexed plus cisplatin group and 752 patients in the pemetrexed plus carboplatin group for whom physician-reported tumor response was available. The pemetrexed plus cisplatin group demonstrated a response rate of 26.3% compared with 21.7% for the pemetrexed plus carboplatin group, with similar 1-year survival rates (63.1% versus 64.0%) and median time to progressive disease (7 months versus 6.9 months). The most common grade 3/4 hematologic toxicity was neutropenia in 23.9% of the pemetrexed plus cisplatin group and 36.1% of the pemetrexed plus carboplatin group. CONCLUSION: This large EAP confirmed the activity of pemetrexed plus cisplatin and pemetrexed plus carboplatin in chemonaïve patients with MPM, demonstrating clinically similar time to progressive disease and 1-year survival rates.

Jassem J, Ramlau R, Santoro A, Schuette W, Chemaissani A, Hong S, Blatter J, Adachi S, Hanauske A, Manegold C. · Radiotherapy and Oncology, Medical University of Gdansk, Debinki 7 St, Gdansk, Poland. · J Clin Oncol. · Pubmed #18375898 No free full text.

Abstract: PURPOSE: This multicenter, phase III study compared overall survival (OS) of second-line pemetrexed plus best supportive care (BSC) versus BSC alone in patients with advanced malignant pleural mesothelioma (MPM). Secondary end points included response rate, progression-free survival (PFS), time to tumor progression (TTP), time to treatment failure (TTF), and toxicity. PATIENTS AND METHODS: Patients with relapsed MPM after first-line chemotherapy were randomly assigned to receive pemetrexed 500 mg/m(2) plus BSC (P+BSC) every 21 days or BSC alone. RESULTS: The study enrolled 243 patients (123 on P+BSC arm and 120 on BSC arm). Median OS time was not significantly different between the arms (8.4 months for P+BSC and 9.7 months for BSC; P = .74). Cox regression modeling suggested a trending survival benefit for patients who responded to first-line therapy. Time-to-event measures significantly favored P+BSC (median PFS, TTP, and TTF). Partial response was achieved in 18.7% and 1.7% of patients in P+BSC and BSC arms, respectively (P < .0001), and a disease control rate (partial response plus stable disease) was achieved in 59.3% and 19.2% of patients in P+BSC and BSC arms, respectively (P < .0001). Use of postdiscontinuation chemotherapy was significantly greater among BSC patients compared with P+BSC patients (51.7% v 28.5%, respectively; P = .0002), with more BSC patients receiving pemetrexed (18.3% v 3.3%, respectively; P = .0001). Postdiscontinuation therapy was initiated earlier for BSC than P+BSC patients (median time to initiation, 4.3 v 15.7 months, respectively; log-rank P < .0001). Chemotherapy was well tolerated, with expected modest (4% to 7%) grade 3 and 4 hematologic toxicities. CONCLUSION: Second-line pemetrexed elicited significant tumor response and delayed disease progression compared with BSC alone in patients with advanced MPM. Improvement in OS was not seen in this study, possibly because of the significant imbalance in postdiscontinuation chemotherapy between the arms.

Bottomley A, Coens C, Efficace F, Gaafar R, Manegold C, Burgers S, Vincent M, Legrand C, van Meerbeeck JP, Anonymous00124. · EORTC Data Center, Quality of Life Unit, Avenue E. Mounier, 83, 1200 Brussels, Belgium. · J Clin Oncol. · Pubmed #18089874 No free full text.

Abstract: PURPOSE: Malignant pleural mesothelioma (MPM) is a rare disease. Unlike other advanced cancer types, little is known about patient-reported symptoms or health-related quality of life (HRQOL) and their possible prognostic value. This study reports an evaluation of the prognostic value of these factors using data gathered from a recent randomized controlled trial. PATIENTS AND METHODS: Patients were entered onto this trial if they had a histologically proven unresectable MPM, not pretreated with chemotherapy, WHO performance status < or = 2, and adequate hematologic, renal, and hepatic function. Patients were randomly assigned to receive cisplatin 80 mg/m2 intravenously on day 1, without or with preceding infusion of raltitrexed 3 mg/m2. HRQOL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30/Lung Cancer 13 tool. The Cox proportional hazards regression model was used for the univariate and multivariate analyses of survival, along with a bootstrap validation technique. Included were the EORTC prognostic index (PI) composed of stage of disease, histology type, time since diagnosis, and WBC, and, in addition, 10 selected key symptoms and HRQOL scales. RESULTS: Two hundred fifty patients were randomly assigned (80% male; median age, 58 years; WHO performance status 0, 1, 2 in 25%, 62%, and 13% of cases, respectively). Two hundred twenty-nine patients (91.6%) had a valid HRQOL assessment. The final multivariate model retained the PI, pain (P < .0001), and appetite loss (P = .0100) as independent prognostic indicators of survival. CONCLUSION: Results suggest that the PI, pain, and appetite loss may be independent prognostic factors in patients with advanced MPM.

Bottomley A, Gaafar R, Gaafa R, Manegold C, Burgers S, Coens C, Legrand C, Vincent M, Giaccone G, Van Meerbeeck J, Anonymous00009, Anonymous00010. · European Organisation for Research and Treatment of Cancer, EORTC Data Center, Brussels, Belgium. · J Clin Oncol. · Pubmed #16446322 No free full text.

Abstract: PURPOSE: For malignant pleural mesothelioma (MPM) patients with a poor prognosis, maintaining health-related quality of life (HRQOL) is important. This article compares the impact on HRQOL of first-line treatment with cisplatin versus raltitrexed and cisplatin. PATIENTS AND METHODS: Patients with histologically-proven unresectable MPM, not pretreated with chemotherapy were randomly assigned to receive cisplatin 80 mg/m2 intravenously on day 1, with or without preceding infusion of raltitrexed 3 mg/m2. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EORTC Lung Cancer Module (QLQ-LC13) tools. Assessments were conducted at baseline, immediately before every treatment cycle, at the end of treatment, and every six weeks for 12 months. RESULTS: Two hundred fifty patients were randomly assigned, 80% were male with a median age of 58 years, WHO performance status 0, 1, and 2, in 25%, 62%, and 13% of cases. The clinical results found raltitrexed and cisplatin to be superior to cisplatin with regard to overall survival (P = .048). The global HRQOL scale was comparable at baseline on both treatment arms (P = .848); at no point was any significant difference apparent on this end point. Both treatments led to an improvement, over time, in dyspnoea. This effect is an important clinically meaningful reduction from baseline in the cisplatin/raltitrexed arm. However, the majority of scales of the EORTC QLQ-C30 or LC13 showed stabilization of HRQOL with few clinically significant differences between the treatment arms. CONCLUSION: This study provides important information about the HRQOL of chemotherapy-treated MPM patients.

van Meerbeeck JP, Gaafar R, Manegold C, Van Klaveren RJ, Van Marck EA, Vincent M, Legrand C, Bottomley A, Debruyne C, Giaccone G, Anonymous00121, Anonymous00122. · Thoracic Oncology Unit, University Hospital -7K12IE, De Pintelaan 185, B 9000 Ghent, Belgium. · J Clin Oncol. · Pubmed #16192580 No free full text.

Abstract: PURPOSE: We conducted a phase III trial to determine whether first-line treatment with raltitrexed, a thymidine synthase inhibitor, and cisplatin results in superior outcome compared with cisplatin alone in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients with histologically proven advanced MPM, not pretreated with chemotherapy, WHO performance status (PS) 0 to 2, and adequate hematological, renal, and hepatic function were randomly assigned to receive cisplatin 80 mg/m2 IV on day 1, alone (arm A) or combined with raltitrexed 3 mg/m2 (arm B). In patients with measurable disease, response was monitored using the Response Evaluation Criteria in Solid Tumors criteria. Health related quality of life (HRQOL) was measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 and Lung Module (QLQ-LC13). RESULTS: Two hundred fifty patients were randomized: 80% male; median age, 58 years; and WHO PS, 0, 1, 2 in 25, 62, and 13% of cases, respectively. There were no toxic deaths. The main grade 3 or 4 toxicities observed were neutropenia and emesis, reported twice as often in the combination arm. Among 213 patients with measurable disease, response rate was 13.6% (arm A) versus 23.6% (arm B; P = .056). No difference in HRQOL was observed on any of the scales. Median overall and 1-year survival in arms A and B were 8.8 (95% CI, 7.8 to 10.8) v 11.4 months (95% CI, 10.1 to 15), respectively, and 40% v 46%, respectively (P = .048). CONCLUSION: A combination of raltitrexed and cisplatin improves overall survival compared with cisplatin alone. This study confirms that a combination of cisplatin and an antifolate is superior to cisplatin alone in patients with MPM, without harmful effect on HRQOL.

Manegold C, Symanowski J, Gatzemeier U, Reck M, von Pawel J, Kortsik C, Nackaerts K, Lianes P, Vogelzang NJ. · Heidelberg University Medical Center, Mannheim, Germany. · Ann Oncol. · Pubmed #15824080 links to  free full text

Abstract: BACKGROUND: A phase III trial in patients with malignant pleural mesothelioma demonstrated a survival advantage for pemetrexed plus cisplatin compared with single-agent cisplatin. Because post-study chemotherapy (PSC) may have influenced the outcome of the trial, we examined its use and association with survival. PATIENTS AND METHODS: Eighty-four patients from the pemetrexed plus cisplatin arm and 105 patients from the single-agent cisplatin arm received PSC. Kaplan-Meier survival estimates were compared by treatment groups, and by PSC and non-PSC subgroups. RESULTS: The percentage of patients receiving PSC was imbalanced between the treatment arms. Fewer pemetrexed plus cisplatin treated patients received PSC (37.2% versus 47.3%). A multiple regression analysis performed in this trial showed that PSC had a statistically significant correlation with prolonged survival (P <0.01), adjusting for baseline prognostic factors and treatment intervention. The adjusted hazard ratio for PSC over non-PSC subgroups was 0.56 (confidence interval 0.44-0.72). CONCLUSIONS: PSC in malignant pleural mesothelioma was significantly associated with prolonged survival. It is not known whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival tended to receive more PSC. The pemetrexed plus cisplatin treatment group had a statistically significant survival advantage even though fewer patients from that arm of the trial received PSC. The potentially beneficial role of PSC should be assessed in prospective trials.

Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. · University of Chicago, Cancer Research Center, 5841 South Maryland Ave, Chicago, IL 60637, USA. · J Clin Oncol. · Pubmed #12860938 No free full text.

Abstract: PURPOSE: Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. PATIENTS AND METHODS: Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. RESULTS: A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P =.020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P =.001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P <.0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. CONCLUSION: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

Scagliotti GV, Shin DM, Kindler HL, Vasconcelles MJ, Keppler U, Manegold C, Burris H, Gatzemeier U, Blatter J, Symanowski JT, Rusthoven JJ. · University of Turin, Department of Clinical and Biological Sciences, Azienda Ospedaliera S. Luigi, Regione Gonzole 10, 10043 Orbassano (Torino) Italy. · J Clin Oncol. · Pubmed #12697881 No free full text.

Abstract: PURPOSE: This phase II clinical study evaluated the efficacy of pemetrexed for the treatment of malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with a histologically proven diagnosis of MPM, chemotherapy-naive measurable lesions, and adequate organ function received pemetrexed (500 mg/m2) intravenously over 10 minutes every 3 weeks. After a protocol change, most patients also received folic acid and vitamin B12 supplementation to improve safety. RESULTS: A total of 64 patients were enrolled. Nine (14.1%) of the 64 patients had a partial response. The Kaplan-Meier estimate for median overall survival was 10.7 months. Forty-three patients received vitamin supplementation for all courses of therapy, and 21 patients did not. Seven of the nine responders were vitamin supplemented. The median overall survival was 13.0 months for supplemented patients and 8.0 months for nonsupplemented patients. Vitamin-supplemented patients completed more cycles of therapy than nonsupplemented patients (median, six v two cycles, respectively). Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. Fatigue and febrile neutropenia were the most commonly reported nonlaboratory events (grade 3, 6.3%; grade 4, 0.0% each). The incidence of these toxicities was generally lower in the supplemented patients. CONCLUSION: Single-agent pemetrexed for MPM resulted in a moderate response rate (14.1%) and median overall survival of 10.7 months. Patients supplemented with folic acid and vitamin B12 tolerated treatment better (less toxicity and more cycles of treatment) and had a 5-month greater median overall survival than nonsupplemented patients. These results indicate that patients with MPM could benefit from single-agent pemetrexed treatment combined with vitamin supplementation.

van Meerbeeck JP, Baas P, Debruyne C, Smit EF, van Klaveren RJ, Galdermans D, Lentz MA, Manegold C, Giaccone G, Anonymous00225. · Erasmus MC-Department of Pulmonology, PO Box 5201, NL-3008 AE, Rotterdam, The Netherlands. · Eur J Cancer. · Pubmed #11937311 No free full text.

Abstract: The aim of this study was to investigate the anti-tumour activity of temozolomide in patients with malignant pleural mesothelioma. 27 chemotherapy-naïve patients with histologically-proven malignant mesothelioma were treated with temozolomide 200 mg/m2/day, given orally on days 1-5 of each 28-day cycle. Therapy continued up to 10 cycles unless disease progression or excessive toxicity mandated discontinuation. Toxicity, symptom improvement and pain intensity were regularly assessed. With a median relative dose intensity of 97%, toxicity was moderate with grade 3 or more nausea, vomiting, thrombocytopenia, leucocytopenia, neutropenia, febrile leucocytopenia, arthralgia, infection and fever with infection occurring in 13, 13, 10, 3, 7 and 3% of patients for the remaining events, respectively. Overall, 1 objective response was observed (response rate 4%, 95% Confidence Interval (CI): 0.1-19). Median survival was 8.2 months. Symptom assessment showed no improvement and an increase of pain was observed during the study. Thus, oral temozolomide is an inactive agent in malignant mesothelioma.

van Meerbeeck JP, Baas P, Debruyne C, Groen HJ, Manegold C, Ardizzoni A, Gridelli C, van Marck EA, Lentz M, Giaccone G. · Department of Pulmonology, University Hospital, Rotterdam, The Netherlands. · Cancer. · Pubmed #10375105 links to  free full text

Abstract: BACKGROUND: Gemcitabine has shown activity in patients with less chemosensitive solid tumors. Phase II screening of novel drugs is an accepted method with which to investigate new therapies in malignant mesothelioma. The European Organization for Research and Treatment of Cancer-Lung Cancer Cooperative Group has performed several sequential Phase II trials of new agents for the treatment of mesothelioma over the last 10 years. METHODS: Twenty-seven chemotherapy-naive patients with histologically proven malignant mesothelioma were treated with gemcitabine as a 30-minute intravenous administration of 1250 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Therapy continued for up to ten cycles unless disease progression or excessive toxicity mandated discontinuation. RESULTS: With a median relative dose intensity of 96%, toxicity was mild and neutropenia of > or = Grade 3 (according to National Cancer Institute criteria) occurred in 30% of patients, without episodes of febrile neutropenia. One case of hemolytic-uremic syndrome, most likely related to gemcitabine use, was observed. Overall, 2 objective responses were observed (response rate of 7%; 95% confidence interval, 1-24%). The median survival was 8 months. CONCLUSIONS: At the prescribed dosage and schedule, single agent gemcitabine appears to have limited activity in chemotherapy-naive patients with malignant pleural mesothelioma.

Fischer JR, Ohnmacht U, Rieger N, Zemaitis M, Stoffregen C, Kostrzewa M, Buchholz E, Manegold C, Lahm H. · Department of Medical Oncology, Thoraxklinik Heidelberg gGmbH, Heidelberg, Germany. · Lung Cancer. · Pubmed #16893590 No free full text.

Abstract: Hypermethylation occurs frequently in neoplastic cells and affects tumorigenesis. Malignant mesothelioma is an aggressive cancer developing in the thoracic cavity and patients have a rather bad prognosis. Our goal was to determine epigenetic alterations of a series of genes and to analyse the potential correlation of such changes with overall survival. We have analysed the methylation status of the promoter region of nine genes in serum DNA of mesothelioma patients by a nested methylation-specific PCR. Modest methylation frequencies were detected for APC1A (14.3%), RASSF1A (19.5%) and DAPK (20.0%) while hypermethylation of E-cadherin (71.4%) and FHIT (78.0%) occurred at a high incidence. Intermediate values were seen for p16(INK4a) (28.2%), APC1B (32.5%), p14(ARF) (44.2%) and RARbeta (55.8%). The methylation status of none of the single genes significantly influenced prognosis. In contrast, combining RARbeta with either DAPK or RASSF1A showed a significantly shorter overall survival of those patients who had both genes methylated compared to those with only one or no epigenetic alteration (P=0.025 and 0.040, respectively). Similarly, the combination of all three genes revealed a worse prognosis for patients with double or triple methylations compared to the group which had only one or no gene methylated (P=0.028). Our results support the idea that the prognostic value of a combination of epigenetic alterations is superior to the impact of an individual gene alone on overall survival.

Manegold C. · Department of Oncology, Thoraxklinik, Heidelberg, Germany. · Clin Adv Hematol Oncol. · Pubmed #16163251 No free full text.

This publication has no abstract.

Manegold C, Stahel RA, Anonymous00178. · Thoraxklinik Amalienstr. 5, D-69126 Heidelberg, Germany. · Ann Oncol. · Pubmed #15888745 links to  free full text

This publication has no abstract.

van Klaveren RJ, Aerts JG, de Bruin H, Giaccone G, Manegold C, van Meerbeeck JP. · Department of Pulmonology, Erasmus University Medical Center, Rotterdam, Netherlands. · Lung Cancer. · Pubmed #14698538 No free full text.

Abstract: The newly introduced Response Evaluation Criteria in Solid Tumors (RECIST), which relies on a single largest dimension of tumor rather than on the product of perpendicular diameters World Health Organisation (WHO) is intended to simplify the assessment of tumor response. PURPOSE: Is to evaluate the performance and validity of the RECIST compared to the WHO criteria. DESIGN: Thirty-four consecutive patients with bidimensionally measurable malignant pleural mesothelioma (MPM) were evaluated prospectively. RESULTS: In 27% (9/34) a discrepancy was found between the WHO and RECIST response evaluation 9% (3/34) concerned best responses and 18% (6/34) objective confirmed responses. In 24% (8/34) disease progression was missed by RECIST. The percentage of patients in whom one or more discordance's between WHO and RECIST were detected was 47, 88% due to underscoring by RECIST. In a subgroup of 24 MPM patients with bidimensionally measurable pleural lesions only, the discrepancy rate was 29%, always due to underscoring by RECIST. However, when in the same subgroup the modified RECIST response evaluation was used the discrepancy rate was 21% and in all cases due to underscoring by WHO. CONCLUSION: For MPM bidimensional WHO response evaluation cannot automatically be replaced by RECIST because MPM has a non-spherical growth pattern. Our recommendation is to use the WHO criteria for bidimensional measurable lesions, RECIST for unidimensional measurable lesions and a modified RECIST response evaluation, in which the short axis perpendicular to the chest wall is used, for thickened pleural rind disease, according to the method used in the recently completed pemetrexed (Alimta) trial for MPM.

Münter MW, Nill S, Thilmann C, Hof H, Höss A, Häring P, Partridge M, Manegold C, Wannenmacher M, Debus J. · Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (dkfz), Heidelberg, Germany. · Strahlenther Onkol. · Pubmed #14509952 No free full text.

Abstract: BACKGROUND AND PURPOSE: Complex-shaped malignant pleural mesotheliomas (MPMs) with challenging volumes are extremely difficult to treat by conventional radiotherapy due to tolerance doses of the surrounding normal tissue. In a feasibility study, we evaluated if inversely planned stereotactic intensity-modulated radiation therapy (IMRT) could be applied in the treatment of MPM. PATIENTS AND METHODS: Eight patients with unresectable lesions were treated after failure of chemotherapy. All patients were positioned using noninvasive patient fixation techniques which can be attached to the applied extracranial stereotactic system. Due to craniocaudal extension of the tumor, it was necessary to develop a special software attached to the inverse planning program KonRad, which can connect two inverse treatment plans and consider the applied dose of the first treatment plan in the area of the matchline of the second treatment plan. RESULTS: Except for one patient, in whom radiotherapy was canceled due to abdominal metastasis, treatment could be completed in all patients and was well tolerated. Median survival after diagnosis was 20 months and after IMRT 6.5 months. Therefore, both the 1-year actuarial overall survival from the start of radiotherapy and the 2-year actuarial overall survival since diagnosis were 28%. IMRT did not result in clinically significant acute side effects. By using the described inverse planning software, over or underdosage in the region of the field matchline could be prevented. Pure treatment time ranged between 10 and 21 min. CONCLUSION: This study showed that IMRT is feasible in advanced unresectable MPM. The presented possibilities of stereotactic IMRT in the treatment of MPM will justify the evaluation of IMRT in early-stage pleural mesothelioma combined with chemotherapy in a study protocol, in order to improve the outcome of these patients. Furthermore, dose escalation should be possible by using IMRT.