Your SlideShare is downloading. ×
0
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

MCO 2011 - Slide 29 - R.A. Stahel - Mesothelioma

492

Published on

0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
492
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
0
Comments
0
Likes
2
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide
  • 1
  • Transcript

    • 1. Malignant Pleural Mesothelioma Rolf Stahel, MD University Hospital Zurich, Switzerland Ermatingen April 6.2011
    • 2. <ul><li>Pleural plaques </li></ul>Pleural plaques Asbestosis Pleural mesothelioma
    • 3. Epidemiology and tumorigenesis <ul><li>The incidence of mesothelioma in Europe will increase and peak between 2015 and 2020 </li></ul><ul><li>The median latency period from first exposure to clinical manifestation is over 40 years </li></ul><ul><li>Asbestos continues to be used in many countries outside North America and Europe without any laws on worker protection </li></ul><ul><li>Frequent inactivation of tumor suppressor genes include p16 INK4A /p14 ARF and neurofibromatosis type 2 (NF2) which encodes merlin </li></ul>
    • 4. Mesothelioma in Europe <ul><li>Peak incidence around 2020 </li></ul><ul><li>British mesothelioma register and male death rates for cancer of the pleura from 6 European countries </li></ul><ul><li>Statistical modeling taking intoaccount asbestos legislation and the long latency period </li></ul><ul><li>Peto, BJC 1999 </li></ul><ul><li>Peak leveling off between 2010 and 2015 </li></ul><ul><li>Perlucchi, BJC 2004; Hodgson BJC 2005 : </li></ul>
    • 5. Latency period in pleural mesothelioma after asbestos-exposure <ul><li>Data collected by the Italian mesothelioma registry in the period 1993-2000: median latency 44.6 years </li></ul>Marinaccio, EJC 2007
    • 6. Asbestos in the developing world
    • 7. Multistep carcinogenesis in pleural mesothelioma Mutsaers, 2004 <ul><li>Accumulation of asbestos fibers and chronic tissue injury </li></ul><ul><li>Persistent stimulation of tissue repair program (mesothelium stem cells) leading to: </li></ul><ul><ul><li>Epigenetic silencing or deletion of « caretaker » Ink4a locus (9p21) </li></ul></ul><ul><ul><li>Loss of « gatekeeper » NF2 function (22q12) </li></ul></ul><ul><li>Loss of contact-dependent growth inhibition and tumor progression </li></ul>
    • 8. <ul><li>In an experimental model, targeted inactivation of NF2 in mesothelial cells lining of the thoracic cavity rarely results in mesothelioma. However, concomitant loss of INK4a/ARF strongly accelerates mesothelioma development Jongsma, Cancer Cell 2008 </li></ul><ul><li>In tumors without NF2 truncation, NF2 activity is inhibited by phosphorylation, for example by increased expression of CPI-17 Thurneysen, Lung Cancer 2009 </li></ul><ul><li>CDKN2A and NF2 are dysregulated by miRNA in mesothelioma Guled, Genes Chrom Cancer 2009 </li></ul>Alterations of NF2 and ink4a/ARF are important for MPM development
    • 9. Alterations of NF2 in mesothelioma <ul><li>Mutations in NF2 have been described in 40% of mesothelioma Bianchi, PNAS 1995; Sekido, CR 1995; Deguen, IJC 1998 </li></ul><ul><li>In an experimental model, targeted inactivation of NF2 in mesothelial cells lining of the thoracic cavity rarely results in mesothelioma. However, concomitant loss of INK4a/ARF strongly accelerates mesothelioma development Jongsma, Cancer Cell 2008 </li></ul><ul><li>In tumors without NF2 truncation, NF2 activity is inhibited by phosphorylation, for example by increased expression of CPI-17 Thurneysen, Lung Cancer 2009 </li></ul>
    • 10. Soluble mesothelin-related peptide <ul><li>Mesothelin is a cell surface glycoprotein, expressed on normal mesothelial cells and &gt; 90% of mesotheliomas (binds to CA125) </li></ul><ul><li>Soluble mesothelin-related proteins in serum </li></ul><ul><li>Target for antibody therapy </li></ul>Robinson, Lancet 2003 Cristaudo, Clin Cancer Res 2007
    • 11. Soluble mesothelin-related peptide: Controls vs asbestos-exposed Stage Pass, ATS 2008 Disease monitoring, questionable value in earlydiagnosis No significant differences according to histology or stage Schneider, JTO 2008
    • 12. Systemic therapy <ul><li>Chemotherapy provides symptom relief </li></ul><ul><li>Based on a landmark study of Vogelzang et al., the combination of cisplatin and pemetrexed has become the preferred chemotherapy regimen </li></ul><ul><li>Most current studies examining neoadjuvant chemotherapy followed by extrapleural pneumonectomy include combined cisplatin and pemetrexed chemotherapy </li></ul><ul><li>Optimal second line chemotherapy is not defined, vinorelbine might be a good choice </li></ul><ul><li>Novel and targeting agents: so far no or very limited success </li></ul>
    • 13. MVP in Mesothelioma Provides Symptom Relief <ul><li>150 patients </li></ul><ul><li>RR 15% (95% CI 9%-21%) </li></ul><ul><li>Symptom improvement 69% </li></ul><ul><ul><li>Dyspnea 50% </li></ul></ul><ul><ul><li>Cough 62% </li></ul></ul><ul><ul><li>Pain 71% </li></ul></ul><ul><ul><li>Malaise 39% </li></ul></ul><ul><li>Median survival 7 months </li></ul><ul><li>1-year and 2-year survival: 31% and 11% </li></ul>Middleton, Ann Oncol 1998; Andreopoulou, Ann Oncol 2004
    • 14. Pemetrexed + Cisplatin vs Cisplatin: Tumor Response Rates and Survival Vogelzang , JCO 2003
    • 15. Pemetrexed and carboplatin in MPM <ul><li>Phase II 102 pts, RR 19%, MST 12.7 months Ceresoli, JCO 2006 </li></ul><ul><li>Phase II 76 pts, RR 25%, MST 14 months Castageneto, Ann Oncol 2008 </li></ul><ul><li>Elderly patients: No significant difference in toxicity and outcome Ceresoli, BJC 2008 </li></ul><ul><li>Pemetrexed with cisplatin or carboplatin in expanded access program: </li></ul>Manegold, JTO 2008 Reported responses: 28.3% for pem/cis and 21.7% for pem/carbo Time to progressive disease :
    • 16. Active symptom control with or without chemotherapy Muers, Lancent Oncol 2008
    • 17. Second line chemotherapy <ul><li>Agents identified in 1 st line: </li></ul><ul><li>Vinorelbine: </li></ul><ul><ul><li>single agent: RR 21% Steele, JCO 2000 </li></ul></ul><ul><ul><li>cisplatin/vinorelbine: RR 30% Sorensen, BJC 2008 </li></ul></ul><ul><li>Cisplatin/gemcitabine: RR 33% Nowak, BJC 2002 </li></ul><ul><li>Cisplatin/raltitrexed RR 24% Van Meerbeeck, JCO 2005 </li></ul><ul><li>Irinotecan/cisplatin/mitomycin C: RR 37% Fennell, Cancer 2007 </li></ul><ul><li>Vinflunine: RR 14% Talbot, JCO 2007 </li></ul>
    • 18. Second line chemotherapy <ul><li>Agents identified in 2 nd line: </li></ul><ul><li>Irinotecan/cisplatin/mitomycin C: RR 10% Fennell, Cancer 2007 </li></ul><ul><li>Pemetrexed vs BSC: RR 18%, better disease control rate (59% vs 19%), no survival benefit (imbalance in further therapy: 28% vs 51%) Jassem, JCO 2008 </li></ul><ul><li>Vinorelbine and gemcitabine: 30 pts, RR10%, median OS 10.6 months Zucali, Cancer, 2008 </li></ul><ul><li>Vinorelbine: 63 pts, RR 16%, median OS 9.6 months Stebbing, Lung Cancer 2009 </li></ul>
    • 19. Important questions on current treatment modalities <ul><li>Improvement of systemic therapy 1: </li></ul><ul><ul><li>Unlikely role of bevacizumab Zalcman, ASCO 2010, Kindler ASCO 2007 </li></ul></ul><ul><ul><li>Unlikely role of established TKIs </li></ul></ul><ul><ul><ul><li>Negative results with EGFR TKIs (gefitinib, erlotinib) and c-kit, PDGF TKI (imatinib) Govindan CR 2005; Garland, JCO 2007, Mathy, Lung Cancer 2005; Porta, Cancer Chemother Pharmacol 2007 </li></ul></ul></ul><ul><ul><ul><li>No consistant activity of VEGFR2 multitarged TKIs vatalanib, sorafenib, sunitinib Janan, ASCO 06; Jänne ESMO 06; Nowak ASCO 2010 </li></ul></ul></ul>Bevacizumab Placebo VEGF above median
    • 20. Important questions on current treatment modalities <ul><li>Improvement of systemic therapy 2: </li></ul><ul><ul><li>Histone deacetylase inhibitors: </li></ul></ul><ul><ul><ul><li>SAHA, phase I responses, phase III results pending Krug, Clin Lung Cancer 2006 </li></ul></ul></ul><ul><ul><ul><li>Belinostat: Inactive in phase II </li></ul></ul></ul><ul><ul><ul><li>Valproic acid: Preclinical activity demonstrated Vandermeers, CCR 2009 </li></ul></ul></ul>
    • 21. Important questions on current treatment modalities <ul><li>Improvement of systemic therapy 3: </li></ul><ul><ul><li>Antibodies to mesothelin </li></ul></ul><ul><ul><ul><li>MORAb-009: phase II combined with chemotherapy ongoing Hassan, CCR 2010 </li></ul></ul></ul><ul><ul><ul><li>Mesothelin-Immunotoxin SS1P Hassan, CCR 2007; Kreitman, CCR 2009 </li></ul></ul></ul><ul><ul><ul><li>Mouse Anti-C-ERC/mesothelin: NK mediated ADCC in xenograft Inami, Cancer Sci 2010 </li></ul></ul></ul><ul><ul><li>Antibody to IL13Rα2 Takenouchi, CCR 2011 </li></ul></ul><ul><ul><li>Novel human single chain antibody fragments (CD146) Lyer, CR 2011 </li></ul></ul>
    • 22. Important questions on current treatment modalities <ul><li>Improvement of systemic therapy 4: </li></ul><ul><ul><li>Bortezomib: preclinical data, clinical studies ongoing Gordon, Cancer Chemother Pharmacol 2008 </li></ul></ul><ul><ul><li>Tumor stroma targeting </li></ul></ul><ul><ul><ul><li>Thalidomid Baas, ASCO 2011 </li></ul></ul></ul><ul><ul><ul><li>NGR-hTNFα: TNF coupled to the peptide CNGRC, which is a ligand for CD13 expressed on tumor vasculature. Phase II with disease stabilization Gregorc, JCO 2010 </li></ul></ul></ul>
    • 23. Important questions on current treatment modalities <ul><li>Improvement of systemic therapy 5: </li></ul><ul><ul><li>“ Standard” chemotherapy </li></ul></ul><ul><ul><ul><li>In multimodality approach: Longer induction, postoperative chemotherapy? </li></ul></ul></ul><ul><ul><ul><li>Molecular selection? (ERCC1, TS, other) Righi, JCO 2010 </li></ul></ul></ul>
    • 24. Tymidylate synthase and ERCC1 in mesothelioma treated with pem/cis <ul><li>Retrospective analysis of TS and ERCC1 expression (RT PCR, immunohistochemistry: H-score) and outcome in 60 MPM patients treated with pemetrexed with (45 pts) or without (15 pts) platin </li></ul><ul><li>TS: Longer TTP and OAS with low expression </li></ul><ul><li>ERCC1: Longer survival with low expression (platin treated only) </li></ul>Righi, JCO 2010 TS (median H-score) ERCC1 (3 rd tertile gene expression)
    • 25. Surgery and multimodaltiy therapy <ul><li>The role of surgery continues to be a matter of debate </li></ul><ul><ul><li>Radical resectability? </li></ul></ul><ul><ul><li>Extrapleural pneumoectomy or pleurectomy and decortication? </li></ul></ul><ul><ul><li>Impact on survival? </li></ul></ul><ul><ul><li>Lack of prospective randomized data </li></ul></ul><ul><li>However: </li></ul><ul><ul><li>Longest median survival and long term survivors reported in series with multimodality therapy including EPP </li></ul></ul><ul><ul><li>Surgical mortality in experienced centers dropped to around 3% </li></ul></ul>
    • 26. Case report <ul><li>12/06 62 y/o woman is referred to thoracic surgery because of an apical tumor in the R lung </li></ul><ul><li>History of chronic pleural effusins since May 2005, thorascopic examination at this time not diagnostic CT: </li></ul>
    • 27. Case report <ul><li>1/06 Thoracoscopic wedge resection R upper lobe and resection of two pleural tumors: Histological diagnosis of epithelial mesothelioma (Calretinin, WT-1, CK 5/6 positive, CEA und TTF1 negativ) </li></ul><ul><li>Mulimodality therapy is discussed </li></ul><ul><li>2/06 Videomediastinoscopy: no lymph node involvement </li></ul>
    • 28. Multimodality therapy including extrapleural pneumonectomy (EPP) <ul><li>Boston: EPP with adjuvant chemotherapy and radiotherapy: </li></ul><ul><li>Retrospective series on 176/183 pts surviving EPP </li></ul><ul><li>MST 19 months, periop. mortality 3.8%, 35% local failure Sugarbaker JTCVS 1999; Baldini, ATS 1997 </li></ul><ul><li>Zürich/SAKK: Neoadjuvant chemotherapy and EPP (± radiotherapy): </li></ul><ul><li>Prospective phase II study on 61 pts </li></ul><ul><li>MST by intent to treat 19.8 months, operative mortality 2% </li></ul><ul><li>EPP 45 pts (74%), MST 23.8 months Weder and Stahel, Ann Oncol 2007 </li></ul>
    • 29. Neoadjuvant chemotherapy, EPP and radiotherapy in MPM Number of patients Survival (months) Author Stage Chemoth. EPP Radioth. ITT EPP Weder, JCO 2004 T1-3, N0-2 19 16 (84%) 13 (68%) 23 n/a Weder, AO 2007 T1-3, N0-2 61 45 (74%) 36 (59%) 19.8 23 Rea, LC 2007 T1-3, N0-2 21 17 (81%) 15 (71%) 25.5 27.5 Batirel, JTO 2008 T1-3, N0-2 20 16 (80%) 12 (60%) 17 19.6 Krug, JCO 2009 T1-3, N0-2 77 57 (74%) 44 (57%) 16.8 21.9 Van Schil, ERJ 2010 T1-3, N0-1 59 42 (73%) 38 (64%) 18.4 n/a 257 193 (75%) 158 (61%)
    • 30. Important questions on current treatment modalities <ul><li>EPP or no surgery? Inpossible to answer in context of a randomized study. MARS trial: 42% of 112 pts randomized, 16/24 assigned to EPP had surgery, 3/16 (18%) perioperative deaths Treasure, JTO 2009 </li></ul><ul><li>PORT to hemithorax after neoadjuvant chemo and EPP: SAKK 17/04 </li></ul>March 2011: - 122 pts entered - 39 pts randomized
    • 31. Adjuvant radiotherapy <ul><li>Radiotherapy after EPP: </li></ul><ul><li>88 pts, 13% local only failure vs 55% distal only failure, 61/88 EPP: MST 17 mo, Rusch, JTCVS 2001 </li></ul><ul><li>63/100 pts received IMRT, locoregional failure 13%, MST 14.2 months Rice, Ann Thor Surg 2007 </li></ul><ul><li>Importance of radiotherapy technique and dose patterns, in particular attention to V20 Allon, IJROBP 2007; Rice IJROBP 2007 </li></ul>
    • 32. Case report January 07 March 07 <ul><li>2-4/06 Three cycles of cisplatin and pemetrexed </li></ul>
    • 33. Case report <ul><li>5/07 Right extrapleural pneumonectomy, pericardial and diaphragmatic resection. Histology_ R0/1 resection, focal residual tumor, inflammation and fibrosis, all resected nodes negative </li></ul><ul><li>5/07 Surgical removal of hematoma </li></ul><ul><li>6/06 Patient refuses additional radiotherapy (and thus randomization) </li></ul><ul><li>10/09: Small nodule in dorsal thoracotomy scar, resection shows benign inflammation </li></ul><ul><li>2/11 Good performance status, no evidence of disease </li></ul>
    • 34. <ul><li>The incidence of mesothelioma in Europe will increase and peak between 2015 and 2020 </li></ul><ul><li>Inactivation of tumor suppressor genes include p16 INK4A /p14 ARF and neurofibromatosis type 2 (NF2) which encodes merlin are the major molecular characteristics </li></ul><ul><li>Pemetrexed combined with cisplatin has become the preferred first line chemotherapy for mesothelioma </li></ul><ul><li>Vinorelbine may be a good second line choice </li></ul><ul><li>Selected patients appear to benefit from a multimodality approach including neoadjuvant chemotherapy, extrapleural pneumonectomy, and potentially hemithoracic radiotherapy </li></ul><ul><li>So far limited success with novel and targeting agents </li></ul>Malignant Pleural Mesothelioma

    ×